Nutrition and Fitness - Mental Health, Aging
229
description
Review and critique the latest scientific information on nutrition and fitness,taking into consideration genetic endowment, adaptation throughoutthe life cycle and the nutritional factors that contribute to fitness, specifically,the effect of the various dietary sources of energy on energy expenditure,exercise and performance.
Transcript of Nutrition and Fitness - Mental Health, Aging
Nutrition and Fitness: Mental Health, Aging,and the Implementation of a Healthy Diet and Physical Activity Lifestyle
AcknowledgementThe publication of these proceedings is made possible bya grant from the Stavros S. Niarchos Foundation
Series Editor
Artemis P. SimopoulosThe Center for Genetics, Nutrition and Health, Washington, D.C., USA
Advisory Board
Regina C. Casper USA Victor A.Rogozkin Russia
Cuiqing Chang China Leonard Storlien Sweden
Claudio Galli Italy Ricardo Uauy-Dagach Chile
Uri Goldbourt Israel Antonio Velázquez Mexico
C. Gopalan India Mark L.Wahlqvist Australia
Tomohito Hamazaki Japan Paul Walter Switzerland
Michel de Lorgeril France Bruce A.Watkins USA
World Review of Nutrition and DieteticsVol. 95
Basel · Freiburg · Paris · London · New York ·
Bangalore · Bangkok · Singapore · Tokyo · Sydney
Volume Editor
Artemis P. SimopoulosThe Center for Genetics, Nutrition and Health, Washington, D.C., USA
19 figures, 1 in color, and 26 tables, 2005
Nutrition and Fitness:Mental Health, Aging, andthe Implementation of aHealthy Diet and PhysicalActivity Lifestyle
5th International Conference on Nutrition and Fitness
Athens, June 9–12, 2004
Artemis P. SimopoulosThe Center for Genetics,
Nutrition and Health
Washington, D.C. (USA)
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Printed in Switzerland on acid-free paper by Reinhardt Druck, Basel
ISSN 0084–2230
ISBN 3–8055–7945–4
Library of Congress Cataloging-in-Publication Data
International Conference on Nutrition and Fitness (5th : 2004 : Athens,
Greece)
Nutrition and fitness : mental health, aging, and the implementation of a
healthy diet and physical activity lifestyle / volume editor, Artemis P.
Simopoulos.
p. ; cm. – (World review of nutrition and dietetics, ISSN 0084-2230
; v. 95)
Part 2 of the proceedings of the 5th International Conference on Nutrition
and Fitness, held in Athens, June 9-12, 2004.
Includes bibliographical references and index.
ISBN 3-8055-7945-4 (hard cover : alk. paper)
1. Nutrition–Congresses. 2. Mental health–Nutritional
aspects–Congresses. 3. Physical fitness–Congresses. 4. Nutritionally
induced diseases–Congresses.
[DNLM: 1. Nutrition–Congresses. 2. Aging–physiology–Congresses. 3.
Diet, Mediterranean–Congresses. 4. Health Behavior–Congresses. 5. Health
Promotion–Congresses. 6. Physical Fitness–Congresses. 7. Primary
Prevention–Congresses. QU 145 I60153nbc 2005] I. Title: Mental health,
aging, and the implementation of a healthy diet and physical activity
lifestyle. II. Simopoulos, Artemis P., 1933- III. Title. IV. Series.
QP141.A1W59 vol. 95
[QP141]
612.3 s–dc22
[612
2005013176
Additional proceedings from the conference are publishedin volume 94 of this series
Dedication
The proceedings of the conference are dedicated to the concept of positive
health as enunciated by the Hippocratic physicians (5th century BC).
Positive health requires a knowledge of man’s primary constitution (whichtoday we call genetics) and of the powers of various foods, both those natural tothem and those resulting from human skill (today’s processed food). But eatingalone is not enough for health. There must also be exercise, of which the effectsmust likewise be known. The combination of these two things makes regimen,when proper attention is given to the season of the year, the changes of thewinds, the age of the individual and the situation of his home. If there is anydeficiency in food or exercise the body will fall sick.
Olympian Ode 2004Lee Pinkerson
The Olympic games of Ancient Greece
even more than athletic feats
praise the spirit of life divine
handed down from God through our ancestral line
In body and soul, in heart and mind
the ways of goodness they refined
celebrated and known by all the Greek world
unified in this concept, there’s no place for war
Where the will to live burns bright
they try with all their might
awakening grace to join them and take flight
every four years at the great Olympic games
In the land of the wild olive branch
the walnut and the honey bee
embraced by a sea where the fish run free
is a diet that is high in omega-3
The goats eat their fill
of the plants on the hill
so even the cheese
has omega-3s
The ancients had the nourishment they’d need
to make them strong and make them smart
fill the air with song and excel in the arts
their world did dance in harmony
And the walls would melt away
when together they would play
where race and class no longer separate
every four years at the great Olympic games
A millennium has come again
the Olympics are back where they began
let’s remember all they truly are
More than a game, they’re a way of life
a torch to guide us past painful strife
for possessions will not take us very far
But the food we eat and the work we do
the way we treat each other and the planet too
will show how sweet we greet the daytime star
every four years at the great Olympic games
Lee Pinkerson wrote the lyrics and music for the Olympian song in
February 2004 in honor of the 2004 Olympic Summer Games in Athens, and for
the Fifth International Conference on Nutrition and Fitness. A CD recording of
her singing and guitar performance was given to the conference program par-
ticipants. She can be reached from her website at http://www.leepinkerson.com.
Olympian Ode 2004 VII
Commemorative 2004 Conference Medal
Medal commemorating the 5th International Conference on Nutrition and
Fitness. The medal is etched with the Olympic rings in honor of the 2004
Summer Olympic Games held in Athens, Greece.
Front Back
IX
Contents
XII Conference Organization
XIV Preface
XXV Declaration of Olympia on Nutrition and Fitness Ancient Olympia, Greece, May 28–29, 1996
Keynote Address
XXXIII Positive Health: Exploring Relevant ParametersFerris, A.E. (London)
Mental Health
1 Psychiatric Disorders, Mood and Cognitive Function: The Influence of Nutrients and Physical ActivityCasper, R.C. (Stanford, Calif.)
17 Nutrition and SchizophreniaPeet, M. (Sheffield)
Aging, Osteoporosis, and Physical Activity
29 Managing Obesity after Menopause: The Role of Physical ActivityDubnov, G.; Berry, E.M. (Jerusalem)
Contents X
35 Osteoporosis: A Complex Disorder of Aging with Multiple Genetic and Environmental DeterminantsFerrari, S.L. (Geneva)
52 Changes in Dietary Fatty Acids and Life Style as Major Factors for Rapidly Increasing Inflammatory Diseases and Elderly-Onset DiseasesOkuyama, H.; Ichikawa, Y.; Fujii, Y.; Ito, M.; Yamada, K. (Nagoya)
62 Physical Activity for Health: An OverviewWahlqvist, M.L. (Melbourne)
73 Physical Inactivity Is a DiseaseLees, S.J.; Booth, F.W. (Columbia, Mo.)
Defining the Components of a Healthy Diet and Physical Activity for Health
80 What Is So Special about the Diet of Greece? The Scientific EvidenceSimopoulos, A.P. (Washington, D.C.)
93 Balance of Omega–6/Omega–3 Essential Fatty Acids Is Important for Health. The Evidence from Gene Transfer StudiesKang, J.X. (Boston, Mass.)
103 Dietary Prevention of Coronary Heart Disease:The Lyon Diet Heart Study and Afterde Lorgeril, M.; Salen, P. (Grenoble)
115 The Nicotera Diet: The Reference Italian Mediterranean DietFidanza, F.; Alberti, A. (Rome); Fruttini, D. (Perugia)
122 Wine and Health: Evidence and MechanismsUrquiaga, I.; Leighton, F. (Santiago)
The Role of Government in Implementing a Healthy Diet and Physical Activity Lifestyle
140 Implications of Food Regulations for Novel Foods. Safety and LabelingLupien, J.R. (Amherst, Mass.)
151 A New Look at Intersectoral Partnerships Supporting a Healthy Diet andActive Lifestyle: The Centre of Excellence in Functional Foods, Australia,Combining Industry, Science and PracticeTapsell, L.C.; Patch, C.S.; Gillen, L.S. (Wollongong)
162 Why a Global Strategy on Diet, Physical Activity and Health?Waxman, A. (Geneva)
167 Nutrition and Fitness Policies in the United StatesLee, P.R. (Stanford, Calif.)
177 Author Index
178 Subject Index
Contents XI
XII
Conference Organization
Conference Chair
Artemis P. Simopoulos, MD (USA)
Conference Co-Chairs
George P. Chrousos, MD (USA/Greece)
Konstantinos N. Pavlou, DSc (Greece)
Executive Committee
Frank W. Booth, PhD (USA)
Peter Bourne, MD (USA/UK)
Regina C. Casper, MD (USA)
Cuiqing Chang, MD, PhD (China)
Nicholas T. Christakos, Esq (USA)
George P. Chrousos, MD (USA/Greece)
Raffaele De Caterina, MD, PhD (Italy)
Nikos Filaretos (Greece)
C. Gopalan, MD, PhD, DSc (India)
Sotiris Kitrilakis (Greece)
Demetre Labadarios, MD, PhD
(South Africa)
Alexander Leaf, MD (USA)
Philip R. Lee, MD (USA)
Federico Leighton, MD (Chile)
Harumi Okuyama, PhD (Japan)
José Ordovas, PhD (USA)
Costas Parisis, MD, PhD (Greece)
Konstantinos N. Pavlou, DSc (Greece)
Artemis P. Simopoulos, MD (USA)
Eliot Sorel, MD (USA)
Panos G. Stamatopoulos, MD (Greece)
Leonard Storlien, PhD (Sweden)
Bill Toomey (USA)
A. Stewart Truswell, MD, DSs
(Australia)
Mark L. Wahlqvist, MD, PhD
(Australia)
Clyde Williams, PhD (UK)
Local Committees in Greece
A. Organizing Committee
Chair: Panos G. Stamatopoulos
Co-chair: Leonidas N. Seitanidis
Secretaries: Evagelia Maglara
Kalliopi – Anna Poulia
Treasurer: Kostantinos N. Pavlou
Members: Elena Averoff
Antonia Georgiopoulou
Conference Organization XIII
Maria Hassapidou
Stavros Kavouras
Sotiris Kitrilakis
Saki Kypreou
Konstantinos Natsis
George P. Rontoyannis
Nikos Terzidis
Nikos Yiannakouris
B. Scientific Committee
Christos Aravanis
Eleni Avlonitou
Panos Behrakis
Athina Bei
Garifalia Emmanouil
Dimitrios Hassiotis
Nikos Katsilambros
Denis Kokkinos
Manousos Konstantoulakis
Maria Liparaki
Antonis Maillis
Pantelis Nikolaou
George P. Rontoyannis
Yiannis Steriotis
Pavlos Toutouzas
Alexandros Tsopanakis
Conference Organized by
The Center for Genetics, Nutrition
and Health
2001 S Street, N.W., Suite 530
Washington, DC 20009 (USA)
Tel. +1 202 462 5062
Fax +1 202 462 5241
E-Mail [email protected]
Major Sponsors
The Center for Genetics, Nutrition
and Health
Stavros S. Niarchos Foundation
Under the Patronage of
Food and Agriculture Organization of
the United Nations
International Union of Nutritional
Sciences
International Olympic Academy
Committee for Athens 2004 Olympics
Hellenic Ministry of Education
Hellenic Ministry of Sports
Conference Sponsors
AstraZeneca
Belovo
California Walnut Commission/Walnut
Marketing Board
Harokopio University
Hellenic American Union
Hellenic Football Federation
Mars, Inc.
Minami Nutrition/MorEPA/Barleans
National Dairy Council (USA)
Nutrilite Health Institute
World Cancer Research Fund
International/American Institute for
Cancer Research
Unilever
In Co-Operation with
Hellenic Association of Sports
Medicine
Hellenic Institute of Sports Research,
Athens
Hellenic Heart Foundation
National Institute on Alcohol Abuse
and Alcoholism, NIH, USA
Onassis Cardiosurgery Center, Athens
University of Thessaly
XIV
The Fifth International Conference on Nutrition and Fitness was held in
Athens, Greece, on June 9–12, 2004. This being the year when the Olympic
Games were returned to the country of their origin, the keynote address given
by Elizabeth Ferris, MD, a former Olympic medalist and Vice President of the
World Olympians Association, was entitled ‘Positive Health – Exploring
Relevant Parameters’.
The goals and objectives of the conference were to:
• Review and critique the latest scientific information on nutrition and fit-
ness, taking into consideration genetic endowment, adaptation throughout
the life cycle and the nutritional factors that contribute to fitness, specifi-
cally, the effect of the various dietary sources of energy on energy expendi-
ture, exercise and performance.
• Determine the relationship of nutrition and fitness to chronic diseases, par-
ticularly, the metabolic changes that occur with the type and amount of
physical activity for the prevention and management of cardiovascular dis-
ease, mental health, obesity, osteoporosis, diabetes and cancer.
• Consider the psychosocial and other determinants of physical activity
throughout the life cycle including intervention strategies, and emphasize
healthy lifestyles consistent with proper nutrition and fitness.
• Stimulate national governments and the private sector to coordinate and
thus maximize their efforts to develop programs that encourage proper
nutrition and participation in sports activities by all, throughout the life
cycle, to achieve their potential in fitness and thus increase the pool of
young athletes, from whom the elite athlete will be forthcoming.
Preface
Preface XV
• Develop strategies for the distribution and implementation worldwide of
the 1996 ‘Declaration of Olympia on Nutrition and Fitness’ for the New
Millennium, through the establishment of regional committees.
The conference consisted of 10 sessions of oral presentations and 2
poster sessions in which 110 abstracts were presented. Scientists from 46
countries participated representing the continents of Africa, Asia,
Australia/New Zealand, Europe, and North and South America. The proceed-
ings of the conference are presented in two volumes in this series. Volume 94
is entitled Nutrition and Fitness: Obesity, the Metabolic Syndrome,Cardiovascular Disease, and Cancer. Volume 95 is entitled Nutrition andFitness: Mental Health, Aging, and the Implementation of a Healthy Diet andPhysical Activity Lifestyle. Both volumes begin with the Dedication to the
concept of ‘Positive Health’, the 2004 Olympian Ode by Lee Pinkerson, the
Commemorative Medal, the Conference Organization, the Preface, the 1996
‘Declaration of Olympia on Nutrition and Fitness’ and the Keynote Address
entitled ‘Positive Health – Exploring Relevant Parameters’ by Elizabeth
Ferris, MD. The address sets the stage for the importance of physical activity
in health and the deleterious effects of inactivity. The Olympic spirit and the
Olympic games celebrate achievement and the individual. It is expected that
in the 21st Century scientific information will be developed that will deliver
individualized genotype-based health care. A conscious effort must be made
to develop in all dimensions the environment in which the human genome
finds its optimal expression. This, of course, represents a complete circle
returning and recognizing the Hippocratic concept of ‘positive health’ of
2500 years ago, based on the individual and in the 21st Century proving it
through molecular biology.
Volume 94 entitled Nutrition and Fitness: Obesity, the Metabolic Syndrome,Cardiovascular Disease, and Cancer presents the papers on obesity, syndrome
X, diabetes, cardiovascular disease, and cancer. The papers on obesity empha-
size the severe burden of obesity worldwide and the need to have a classifica-
tion system of obesity that relates to the specific population from whence the
data were obtained that relate obesity to morbidity and mortality. Kanazawa and
his coworkers in their paper ‘Criteria and Classification of Obesity in Japan and
Asia-Oceania Region’ presented by Shuji Inoue, clearly discuss the fact that
these populations are at risk for the development of chronic diseases at lower
body mass index (BMI) levels than Caucasians.
Cuiqing Chang, in her paper on ‘Exercise and Obesity in China’, discusses
the role of physical activity or exercise on the occurrence of obesity, specifi-
cally the function and effectiveness of exercise on weight reduction and a pre-
scription for weight loss. China has developed guidelines and recommendations
for the classification of obesity. Kafatos et al., in their paper on ‘Obesity in
Preface XVI
Childhood: The Greek Experience’, presents the Greek experience, a specific
program in which the teacher uses ‘customized’ classroom materials that
include a physical activity component and parental involvement. The program
is one of the few programs in Europe to have reported positive results in terms
of obesity and physical fitness in primary schools in Crete. Educational inter-
ventions in schools have great potential needed to tackle the urgent problems of
dietary and lifestyle choices contributing to the blight of childhood obesity and
its co-morbidities.
Aaron and coworkers, in their paper ‘Epidemiology of Physical Activity
from Adolescence to Young Adulthood’, provide a synthesis of the current
knowledge about the epidemiology of physical activity during the transition
from adolescence to young adulthood. The paper on ‘Adolescent Obesity and
Physical Activity’ by Hwalla's group describes the study carried out in
Lebanon. The results of this first national population-based study show that
adolescent obesity is largely caused by lack of physical activity, and the boys
fair worse than the girls. The authors recommend multi-component intervention
strategies at the societal and individual levels for weight control that include
health professionals, families, schools, businesses, and health care organiza-
tions, in order to increase programs and opportunities for physical activity.
Pavlovic and colleagues indicate in their paper titled ‘Nutrition and Physical
Activity of the Population in Serbia’ that for both children and adults, inade-
quate nutrition and physical activity are related to an increase in risk factors and
the need for health promotion programs. Drs. Andreoli and De Lorenzo, in their
paper on ‘Physical Activity and Body Composition’, emphasize the importance
of body composition to evaluate health status in nutritional terms both at the
population level and for the individual.
The etiology of the metabolic syndrome is not well understood. The
approach to its treatment includes lifestyle modification along with pharmaco-
logical therapy, as appropriate. Labadarios, in his paper ‘Syndrome X: Clinical
Aspects’ presents an overview of syndrome X and its relationship to obesity,
diabetes and cardiovascular disease.
Tataranni’s paper is on ‘Metabolic Syndrome: Is There a Pathophysiological
Common Denominator? Lessons Learned from the Pima Indians.’ In addition to
clinical physiologic and molecular studies, he carried out a factor analysis
designed to statistically test the hypothesis that insulinemia, body size, lipids and
blood pressure may result from a single etiologic abnormality. The study failed
to identify a single factor underlying the correlation structure of these variables.
As a result, Tatarani concluded that molecular and epidemiologic evidence from
the studies in Pima Indians suggests that the abnormalities constituting the meta-
bolic syndrome are the result of largely independent physiologic processes.
Therefore, clinical treatment and prevention strategies based on the ‘metabolic
syndrome’ hypothesis may prove suboptimal compared with treatment of the
individual components.
Storlien et al.’s paper on ‘Lifestyle-Gene-Drug Interactions in Relation to
the Metabolic Syndrome’ emphasizes the fact that obesity drives the metabolic
syndrome and the polygenic nature of disorders like obesity means that there
will be a need for many approaches that will include lifestyle changes along
with pharmaceutical support, greatly dependent upon understanding the indi-
vidual’s genetic make up. Common dietary components, such as fatty acids and
simple sugars, are potent gene regulators on many ‘pharmaceutical’ metabolic
syndrome targets. Novel drugs are almost certain to interact strongly with
dietary and other lifestyle variables. Storlien and coworkers refer to thiazo-
lidinediones, the only really new class of anti-diabetic therapy introduced in the
past few years, as a prime example. This class of drugs targets the nuclear hor-
mone receptor PPAR� and the relationship between weight gain and PPAR�2
polymorphism is highly dependent on the dietary polyunsaturated/saturated
(P/S) ratio. There are strong indications that modulating muscle metabolism
would be of enormous benefit in prevention and treatment of obesity. While
exercise training clearly moves muscle morphology and metabolism in a bene-
ficial direction, there is marked genetic heterogeneity in both compliance and
response to exercise training in the needy population, i.e. those with the meta-
bolic syndrome. Therefore, it is necessary to understand how drug/diet interac-
tions might act as a multiplier for the beneficial effects of exercise, thus
enhancing both the health benefits and the likelihood of compliance.
Donati and Iacoviello’s paper on ‘Coronary Heart Disease, Genetics,
Nutrition and Physical Activity’ discusses gene polymorphisms and their inter-
actions with diet and physical activity as they affect lipids, hemostatic and vas-
cular factors. Drs. De Caterina and Madonna in their paper ‘Role of Nutrients
and Physical Activity in Gene Expression’ review the subject of how the rapid
evolution of vascular and molecular biology in the last 20 years has completely
transformed our understanding of the development of coronary heart disease.
The authors discuss their studies on the role of omega–3 fatty acids in modulat-
ing the immune system and suppressing vascular cell adhesion molecules.
Physical activity protects or reduces the risk for the development of cardiovas-
cular disease by indirectly reducing a number of cardiovascular disease risk fac-
tors such as high blood pressure, hypercholesterolemia, obesity and diabetes,
and also promoting direct anti-atherogenic vascular responses through the
action of increased laminar shear on endothelial cells. Recent advances result-
ing from studies of vascular biology using molecular biology techniques are
revealing a previously unsuspected complexity of the vascular responses to
nutrients and physical activity, and are providing molecular explanations on
how healthy or unhealthy lifestyles interact with our genes, permitting or
Preface XVII
inhibiting the expression of the phenotype, even in the presence of unfavorable
genes. This has serious implications in providing solid scientific background
for preventive strategies that will focus on healthy nutrition, physical activity
and life habits. Rontoyannis’ paper ‘Physical Activity and Hypertension: An
Overview’ focuses on the benefits of exercise in the control of blood pressure.
Rontoyannis emphasizes that walking may be the best and safest aerobic physi-
cal activity. The underlying mechanisms responsible for an exercise-induced
reduction in blood pressure remain unclear. Possible mechanisms include the
lower cardiac output and peripheral vascular resistance at rest; and at any given
submaximal levels of work, the reduction in blood catecholamine levels and
plasma renin activity, the altered renal function leads to increased elimination
of sodium resulting in a reduction of blood volume; and the reduction in insulin
levels and insulin resistance, among others. The next paper by Leaf and col-
leagues, on ‘Omega–3 Fatty Acids and Ventricular Arrhythmias’ presents a
thorough review and new information on how omega–3 fatty acids decrease
ventricular arrhythmia and sudden death. Leaf showed that the effect of
omega–3 fatty acids is to stabilize electrically every contractile cell in the heart.
Recent data on the prevention of fatal ventricular arrhythmia in humans indi-
cate that cardiologists should prescribe 1 g of omega–3 fatty acids (EPA +
DHA) to their patients, who already had one episode of heart attack, in addition
to other medications.
The studies on the beneficial effects of the omega–3 fatty acids in both the
primary and secondary prevention of coronary heart disease demand the devel-
opment of methods to measure circulating fatty acids at the population level.
Only a few studies have reported data on the fatty acid composition of circulat-
ing lipids in confirmation of dietary intake. Marangoni’s group, in their paper
‘A Method for the Direct Evaluation of the Fatty Acid Status in a Drop of Blood
from a Fingertip in Humans: Application to Population Studies and
Correlations with Biological Parameters’ discuss their method to determine
fatty acids. The method has been validated, is rapid, less expensive than other
methods, does not require health personnel, is applicable to population groups,
and provides valuable information on the impact of dietary habits, lifestyles and
fatty acid supplementation on blood fatty acids.
There has been a lack of consistency in the data relating diet and cancer in
cohort studies, most likely due to the way in which dietary intake has been mea-
sured. All methods of dietary assessment are associated with measurement
error. This fact attenuates estimates of disease risk and reduces statistical power
so that a relation between diet and disease may be obscured. In her paper
‘Measurement Error in the Assessment of Interaction between Dietary and
Genetic Factors in Cohort Studies of Cancer,’ Bingham points out that the effect
of error on regression dilution and estimated sample size is compounded when
Preface XVIII
attempts are made to assess the interactions between dietary and genetic poly-
morphisms in assessing risk. Traditionally repeat results from the method used
in a cohort, usually a Food Frequency Questionnaire, are compared with those
from another assessed more accurate method. However, errors between meth-
ods may be correlated so that results from the reference method are not inde-
pendent of those derived from the test method, thus violating a critical requirement
of this procedure. Bingham therefore assessed dietary intake using both a food
frequency questionnaire and a detailed seven day diary of food and drink in
13,070 women. The hazard ratio for breast cancer for each quintile increase of
energy adjusted fat was strongly associated with saturated fat intake measured
using the food diary, but not with saturated fat using the food frequency ques-
tionnaire. These results support the view that measurement error might explain
the lack of relationship between fat and breast cancer risk in previous prospec-
tive studies using data obtained by Food Frequency Questionnaires. Muñoz
Rivera and coworkers in their paper ‘Cancer Frequency in Poor Rural
Communities Consuming a Very Limited Diet’ conclude that in Mexico, dietary
changes do not show a relationship with cancer, whereas they do in other
chronic diseases such as obesity and diabetes. This could be due to the age of
the indigenous population (the population is young) or to the level of physical
activity. In the next paper ‘Omega–6/Omega–3 Polyunsaturated Fatty Acids
Ratio and Breast Cancer,’ Bougnoux and colleagues clearly demonstrate the
importance of dietary components in the etiology and development of breast
cancer. In their studies, they found alpha-linolenic acid and docosahexaenoic
acid to be inversely related to the risk of breast cancer, where the trend was
opposite for linoleic acid, arachidonic acid, and for the omega–6/omega–3 long
chain fatty acids. The higher the omega–6/omega–3 ratio, the higher the esti-
mated relative risk of breast cancer. Similar results were obtained by Tavani
et al. In their paper ‘Fish, �–3 Polyunsaturated Fat Intake and Cancer at
Selected Sites’ they investigated the relation between fish consumption and
omega–3 polyunsaturated fatty acids, and the risk of selected neoplasms. Their
data show that consumption of even small amounts of fish decreases the risk of
several cancers, especially of the gastrointestinal tract. Physical activity is an
important component of healthy lifestyles. Willer, in his paper ‘Cancer Risk
Reduction by Physical Exercise’ reviews the evidence of the effect of physical
activity on cancer development and concludes that there is enough evidence to
recommend physical activity for life (long-term) for the prevention of certain
cancers.
Volume 95 is part 2 of the proceedings, Nutrition and Fitness: Mental
Health, Aging, and the Implementation of a Healthy Diet and Physical Activity
Lifestyle. Nutrition and physical activity influence mental health. Among the
fatty acids, the omega–6/omega–3 ratio and omega–3 fatty acids have been
Preface XIX
studied in patients with depression, schizophrenia, bipolar disorders, attention
deficit disorders and dementia. Casper in her paper on ‘Psychiatric Disorders,
Mood and Cognitive Function: The Influence of Nutrients and Physical
Activity’ reviews studies that have related variations in the amount of protein,
amino acids, carbohydrates, and polyunsaturated fatty acids to mood changes.
Efficacy data on omega–3 fatty acids used as adjunct or in monotherapy in
unipolar and bipolar depressive disorders are critically reviewed. Evidence now
exists that prenatal exposure to wartime famine may have had a bearing on the
development of psychomorbidity, in particular the schizophreniform disorders.
Casper also presents an evaluation of the literature that addresses the relation-
ship between regular physical activity in the form of exercise, in relation to
mood and cognitive function. Increasing evidence that psychiatric disorders are
not only multifactorial, but also multigenic diseases, suggests that genetic vari-
ation could emerge as an important variable mediating the effects between
nutrition and mental disorders.
Peet, in his paper ‘Nutrition and Schizophrenia’ presents a critical review
and evaluation of the literature on the role of dietary components on schizo-
phrenia. In addition to omega–3 fatty acid intervention studies, Peet reviews the
evidence that a low saturated fat and low sugar diet may be beneficial, but this
has not been tested in controlled clinical trials.
Dubnov and Berry in their paper ‘Managing Obesity after Menopause: The
Role of Physical Activity’ carried out a Medline and manual search for articles
on overweight and obesity following menopause, the risks and methods of treat-
ment emphasizing physical activity. Their results show that among postmeno-
pausal women, physical activity is a major mode of treatment and postmenopausal
women should engage in physical activity daily, because overweight and
obesity occurs in over 50% of that population.
Ferrari, in his paper ‘Osteoporosis: A Complex Disorder of Aging with
Multiple Genetic and Environmental Determinants’ reviews the genetic and
environmental factors influencing bone turnover and bone density, particularly
estrogen-deficient women and those with low calcium intake and genes associ-
ated with vertebral bone mass and size in adult men. The usefulness of the gene
variants or polymorphisms in predicting fracture risk and response to therapy
remains to be demonstrated.
Inflammation is now considered to be at the basis of many chronic dis-
eases and conditions including aging. Okuyama and coworkers, in their paper
‘Changes in Dietary Fatty Acids and Life Style as Major Factors for Rapidly
Increasing Inflammatory Diseases and Elderly-Onset Diseases’ indicate that
the major elderly-onset diseases in Japan are cancer, atherosclerosis related
diseases and pneumonia. Elevation of inflammatory tone is a likely major
cause for these diseases, which is brought about by excessive intake of linoleic
Preface XX
acid (LA, omega–6) and enhanced arachidonic acid (AA, omega–6) cascade.
Because omega–6 and omega–3 fatty acids and their metabolites (eicosanoids,
inflammatory mediators) are competitive at many steps of enzyme reactions
and receptors, not only the absolute amounts of omega–6 and omega–3 fatty
acids, but their balance, particularly the omega–6/omega–3 ratio, is an impor-
tant factor in regulating the inflammatory tone and related diseases. Changes
in life style, such as decreased physical activity and overnutrition in older
populations lead to unfavorable energy balance. Reduced frequency of skin
exposure to environmental changes (temperature, sweating conditions) is a
likely cause for enhanced skin and mucosal sensitivity to allergens in younger
populations. These environmental factors could be modified by changing the
life style, besides choosing foods to keep a good omega–6/omega–3 fatty acid
balance.
Despite the enormous interest in uncovering longevity genes in humans,
the results have been elusive. The effects of physical activity in delaying aging
are promising whereas the effects of caloric restriction in humans are now being
systematically investigated in three major studies funded by the National
Institutes of Health (Bethesda, Md., USA) at the Pennington Biomedical
Research Center in Baton Rouge, La., at Tufts University in Boston,
Massachusetts, and at Washington University in St. Louis, Mo., USA. Caloric
restriction (CR) is the only mechanism known to extend life span and retard
age-related chronic diseases. This has been proven repeatedly in a variety of
species including rats, mice, fish, flies, worms and yeast. CR reduces metabolic
rate and oxidative stress, improves insulin sensitivity and stress response, and
alters neuroendocrine and sympathetic nervous system function. Whether any,
or all of, these changes provide the mechanism for life-span extension effect is
presently unresolved. Furthermore, the effects of prolonged CR on biomarkers
of aging in nonobese humans are unknown. In experiments of nature, humans
have been subjected to periods of non-volitional partial starvation. However, in
almost all of these cases the diets have been of poor quality. The absence of
adequate information on the effects of good quality CR diets in non-obese
humans reflects the difficulties involved in conducting long-term studies in an
environment so conducive to overfeeding.
Diet and physical activity cannot be disassociated from each other, not
only because of energy need, but also because of the profile of food compo-
nents – macronutrients, micronutrients and phytonutrients – which allow, sus-
tain and optimize movement. In his paper ‘Physical Activity for Health: An
Overview’ Wahlqvist states that preventive physical activity can address the
burden of disease and longevity. Therapeutic physical activity can reduce the
problems of sarcopenia and frailty, or the growing burden of nutritional and
metabolic disease, and of senescence. We must seek a unifying strategy for
Preface XXI
health advancement and for optimal health that is sustainable. In order to
accomplish that, we must involve ourselves continuing as our own machines,
moving, thinking, socializing, and integrated with the natural world.
There is now enough evidence to consider physical inactivity a disease,
because epidemiologic studies provide robust evidence that physical inactivity
is strongly associated with an enhanced risk of premature chronic diseases and
death. Lees and Booth in their paper ‘Physical Inactivity Is a Disease’ provide a
concise review of the evidence of the importance of physical activity in the pre-
vention of many diseases that affect modern humans. There is now enough evi-
dence to define the components of a healthy diet as well as the components of
physical activity at the population level. At the same time, there are exciting
research data defining the type and frequency of genetic variation and how
genetic differences influence dietary response and how diet, nutrients and exer-
cise influence gene expression.
In her paper ‘What Is So Special about the Diet of Greece? The
Scientific Evidence,’ Simopoulos provides scientific evidence and empha-
sizes the importance to follow a diet consistent in composition to the diet
upon which humans evolved, and their genes were programmed to respond. In
this respect, traditional diets do not differ much or are similar in their compo-
sition relative to antioxidants, essential fatty acids and a balanced
omega–6/omega–3 ratio. The latter is very important because during evolu-
tion, the ratio was balanced 1:1 whereas this ratio is 16.8:1 in the diet of the
United States and 15:1 in the diet of Northern Europe, but 4:1 in Japan and
30:1 in India. What makes the diet of Crete different from the other
Mediterranean diets is the balanced omega–6/omega–3 ratio of 1–2/1. The
Greek diet, balanced in the essential fatty acids and high in antioxidants, is
the diet that is the closest to the diet on which humans evolved. In his paper
‘Balance of Omega–6/Omega–3 Essential Fatty Acids Is Important for
Health: The Evidence from Gene Transfer Studies’ Kang provides evidence at
the molecular level of the importance of the balanced omega–6/omega–3
ratio. Furthermore, de Lorgeril and Salen in their paper ‘Dietary Prevention
of Coronary Heart Disease: The Lyon Heart Study and After’ clearly show the
fact that a modified diet of Crete with a ratio of 4:1 of linoleic to alpha-
linolenic acid decreased mortality risk by 70%. Similar results have been
observed in studies in India showing that the lower the ratio, the lower the risk
for total mortality, coronary heart disease mortality, and sudden death.
Fidanza and coworkers in their paper ‘The Nicotera Diet: The Reference
Italian Mediterranean Diet’ describe the Nicotera Diet as a model for the
Italian population and present a food guide modeled after the Greek Column
Food Guide, but in the form of a Greco-Roman Temple rather than the
Preface XXII
Preface XXIII
Pyramid Food Guide developed by the US Department of Agriculture and the
US Department of Health and Human Services. Wine is an important compo-
nent in the diets among the Mediterranean countries as well as in South
America. Urquiaga and Leighton’s paper on ‘Wine and Health: Evidence and
Mechanisms’ is an excellent review of the status of research on wine.
Decreased cardiovascular disease and longevity are epidemiological parame-
ters associated with wine consumption. Recent evidence suggests that
longevity could also be the direct consequence of phenolics activating histone
deacetylation, a gene expression regulatory mechanism proposed to explain
the longevity associated with caloric restriction.
Over the last 15 years, new concepts have evolved about food’s functions.
Functional foods are thought to be foods that improve bodily functions, help
prevent various non-communicable diseases, or help in the cure of some condi-
tions. There has been a wide range of research into the beneficial effects of
foods and food ingredients, beyond essential nutritional requirements for
macronutrients and essential vitamins and minerals. Lupien’s paper on
‘Implications of Food Regulations for Novel Foods: Safety and Labeling’
includes a concise description of the regulatory schemes in the European com-
munity, the United States, Australia, New Zealand, Japan and China. The paper
provides examples of current functional food benefits and claims. The need for
adequate data is emphasized in order to substantiate claims and benefits to meet
current and possible future regulatory requirements.
Australia is one of the first countries to establish a Centre of Excellence in
Functional Foods. Tapsell and coworkers in their paper ‘A New Look at
Intersectoral Partnerships Supporting a Healthy Diet and Active Lifestyle: the
Centre of Excellence in Functional Foods, Australia. Combining Industry,
Science and Practice’ outline the basis for the scientific program at the Centre
of Excellence in Functional Foods, indicating how this may support the devel-
opment of healthy diets and healthy lifestyles. Research at the center takes the
form of strategic (government funded) and commercial (industry funded) pro-
jects.
The World Health Organization (WHO) has recognized the importance of
nutrition and physical activity. In May 2004, at the World Health Assembly,
member nations voted on WHO’s Global Strategy on Diet, Physical Activity
and Health that appears in the paper by Amalia Waxman. The ‘Nutrition and
Fitness Policies in the United States’ are discussed by Lee who reviews the pro-
grams and policies in the United States and the reasons for the difficulties in
their implementation. It will be necessary to develop a broad-based population
approach that includes improving accessibility of nutrition information, edu-
cation, and services; strengthening and sustaining broad-based community
Preface XXIV
programs and partnerships, and working with the nation’s public and private
elementary and secondary schools. Similarly, a population-based approach to
physical activity is needed.
These proceedings should be of interest to physicians, nutritionists, exer-
cise physiologists, geneticists, dietitians, food scientists and policy makers in
government, private industry and international organizations.
Artemis P. Simopoulos, MD
XXV
Background
The International Conferences on Nutrition and Fitness are held in Greece
every 4 years in the spring prior to the Olympic Games. Following each confer-
ence, a declaration is developed at a special meeting at the International Olympic
Academy to update advice on nutrition and fitness for all. The proceedings of the
conferences are published in the scientific literature listed on pages XXXI–XXXII.
The Third International Conference on Nutrition and Fitness was held at
the Olympic Athletic Center of Athens ‘Spyros Louis’, May 24–27, 1996, in
Athens, Greece. Four hundred and eighty participants from 31 countries
attended the conference. Following the conference, an international panel com-
posed of members of the conference Executive Committee, along with the ses-
sion chairs, met at the International Olympic Academy at Ancient Olympia to
develop the ‘Declaration of Olympia on Nutrition and Fitness’ for 1996.
This international panel agreed that on the occasion of the 100th anniversary
of the Olympic Games, it is important to reaffirm the concepts of positive health
postulated by Hippocrates and to reassess their relevance to the Olympic ideal and
the health of the world’s population. The concept of Positive Health, as enunciated
by Hippocrates, is based on the interaction of genetics, diet and physical activity.
Declaration of Olympia on Nutrition and Fitness
Ancient Olympia, Greece, May 28–29, 1996
‘Positive health requires a knowledge of man’s primary constitution (which today we call
genetics) and of the powers of various foods, both those natural to them and those resulting
from human skill (today’s processed food). But eating alone is not enough for health. There
must also be exercise, of which the effects must likewise be known. The combination of these
two things makes regimen, when proper attention is given to the season of the year, the
changes of the winds, the age of the individual and the situation of his home. If there is any
deficiency in food or exercise the body will fall sick’ (480 BC).
Among the Greeks, the concept of positive health was important and occu-
pied much of their thinking. Those who had the means and the leisure applied
themselves to maintaining positive health, which they often conceived esthetically,
and to this end put themselves into the hands of trainers who subjected them to a
regimen. Training for war and athletic competition was of course well known
among them. Health was an excellence in its own right, the physical counterpart
and condition of mental activation. The details of the regimen practiced for health
were an important part of Greek medicine. The Concept of Positive Health may be
represented by a triangle involving genetics, nutrition and physical activity that
influence the spiritual, mental and physical aspects of health (fig. 1).
Genetic Variation, Nutrition, Physical Activity, and Health
The interaction between genetic and environmental factors influences
human development and is the foundation for health and disease. Genetic fac-
tors define susceptibility to disease and environmental factors determine which
genetically susceptible individuals will be affected. Nutrition and physical
activity (exercise) are two of the most important environmental factors in main-
taining health and well being.
Each human being, in being unique, is exceptional in some way. Indivi-
duality is determined by genes, constitutional factors (age, sex, developmental
socio-economic status, occupation, education, time, geography, and climate).
Genetic variation is due to variants at a single locus, or polymorphisms, that
form the basis of human diversity, including the ability to handle environmental
challenges. How extensively variable the human species is depends on the
methods used for the determination of variability. At the DNA level, there is a
Declaration of Olympia on Nutrition and Fitness XXVI
Spiritual
MentalPhysical
Genetics
Nutrition Physicalactivity
Fig. 1. The interaction of genetics, nutrition and physical activity influences the spiri-
tual, mental and physical aspects of health.
great deal of variation, whereas at the level of protein diversity, there is much
less. In all animals, including humans and practically all other organisms exam-
ined, 30% of loci have polymorphic variants in the population. An average indi-
vidual is heterozygous at about 10% of the loci. Alleles that confer selective
advantage in the heterozygous state are likely to have increased in prevalence
because of positive selection acting on variants. Changes in the nutritional envi-
ronment and the type and degree of physical activity affect heritability of the
variant phenotypes that are dependent, to a lesser or greater degree, on these
environmental variables for their expression.
Genetic variation influences the response to diet. Nutrients and physical
activity influence gene expression. In many conditions, proper diet and exercise
have similar beneficial effects, and their effects may be additive. Because of
differences in gene frequency, dietary habits, and activity levels, universal
dietary and physical activity recommendations are not appropriate. Instead,
knowledge of specific genes and response to exercise and diet should guide
advice for health in the prevention and management of chronic diseases.
Diet
The purpose of diet is to supply energy and nutrients required for optimal
health. Energy intake must be balanced against physical activity. Over 800 mil-
lion humans are chronically energy deficient, but obesity is rampant in many
industrialized societies.
MacronutrientsFat is a concentrated energy source, but in affluent populations, excess fat
promotes chronic degenerative diseases. In such circumstances, total fat intake
should be reduced, mainly by decreases in saturated and trans fatty acids. In
energy-deficient populations, an increased fat intake may be necessary to
enhance energy availability and to insure absorption of fat soluble vitamins, but
such increases should avoid adding saturated fats where practicable. All popu-
lations need essential polyunsaturated fatty acids for mental and cardiovascular
health. An omega–6:omega–3 fatty acid ratio of 4:1 or less appears desirable.
Carbohydrate containing foods and soluble and insoluble fiber are needed
for energy intake and normal bodily function.
Protein intake should be adequate for normal growth and development
and in adults for maintenance of body structures.
MicronutrientsAdequate balanced micronutrient intake should be provided commensurate
with emerging understanding of their need. Since the most extensive nutritional
Declaration of Olympia on Nutrition and Fitness XXVII
influences throughout the world are related to inadequacies of micronutrients,
special attention should be directed to correcting these deficiencies: 2 thousand
million persons are anemic and 1 thousand million are at risk of iodine deficiency.
40 million children suffer vitamin A deficiency. Understanding of micronutrient
functions is currently increasing, and health workers should keep up-to-date with
this new knowledge regarding both deficiencies and optimal requirements, e.g. the
need for unitary ratios of calcium and magnesium in the diet. The variety of foods
in the diets helps to maintain adequate micronutrient intake. Most populations
would benefit from an increased intake of fruits and vegetables.
Physical Activity
A wealth of scientific reports points to the inescapable conclusion that
human fitness and health improve when sedentary individuals begin to exercise.
Although low physical activity levels most frequently occur in more industrial-
ized, affluent nations, this behavior is becoming increasingly common in devel-
oping countries as well. Because mechanization and industrialization have
reduced occupational physical activity levels, a need exists to supplement with
additional daily physical activities designed to improve health and fitness.
A wide variety of fitness parameters, including aerobic capacity, muscular
strength and endurance, coordination, flexibility and body composition
improve with increases in activity levels. Perhaps more importantly, indices of
human health also improve. Three of the most common chronic degenerative
diseases of westernized nations (hypertension, coronary heart disease, and non-
insulin-dependent diabetes mellitus) are increasingly being recognized as dis-
eases of insulin resistance. In all three cases, physical activity clearly has been
shown to reduce the severity, and outcome of these diseases. Physical activity
also has a well-known role in preventing and reducing obesity and also exerts a
beneficial influence upon insulin metabolism. Furthermore, increased levels of
physical activity positively impact virtually all chronic diseases, including, but
not limited to stroke, peripheral artery disease, coronary heart disease, chronic
obstructive pulmonary disease, osteoporosis, and some forms of cancer. For
previously sedentary individuals, even nontaxing physical activities such as
walking, gardening, bicycling, and swimming can elicit improved health, and
reduce all causes of morbidity and mortality. Table 1 lists the types of physical
activity. Sports training physical activities should include daily training pro-
grams in preparation for competition. Health-promoting physical activities aim
at promoting growth, improving body functions and protecting from illness.
Exercise prescription (regimen) as a means of treating or reversing various dis-
eases should be considered as an essential therapeutic component.
Declaration of Olympia on Nutrition and Fitness XXVIII
Education
Education about nutrition and physical activity needs to be adapted to each
country and to different populations and cultures. Education about the benefi-
cial physical and psychological effects of proper nutrition and physical activity
in health and disease needs to be directed at all age groups – children, adults,
and the elderly – since research has shown that awareness of the benefits of
physical activity is correlated with actual physical activity. Education needs to
address the detrimental effects of sedentary life-styles, undernutrition and mal-
nutrition, in particular for children. Education about opportunities to obtain
proper nutrition and to carry out physical activity is important in view of find-
ings that actual increases in elective physical activity depend on accessibility.
Education should reach people through various channels – the mass media,
print, television, and radio – at worksites, and in the community in order to reach
everybody in the population. Another means to achieve education would be
through role models in the family, schools, sports, and entertainment. Institutions
such as schools can set examples for proper nutrition and physical activity. The
food and sports foods industry needs to be cognizant of the scientific evidence
regarding optimal nutrition and physical activity levels. Another means of educa-
tion would be the labelling of the nutritional composition of all foods sold.
There is a particular need for education of health professionals and health
workers, nutrition and sport scientists, and educators.
Declaration of Olympia on Nutrition and Fitness XXIX
Table 1. Defining physical activity
1 Nonlabor daily physical activities
Feeding
Bodily functions (e.g. temperature regulation, heart rate, breathing rate)
All daily nonlabor minimum physical activities necessary for life maintenance
2 Labor physical activities
Industrial
Agriculture
Carpentry
Homecare, etc.
3 Leisure-recreational (exercise), low-to-moderate intensity of physical activities
Walking
Dancing
Hiking
Bowling
Cycling
Golf, etc.
Declaration
(1) Nutrition and physical activity interact in harmony and are the two
most important positive factors that contribute to metabolic fitness and health
interacting with the genetic endowment of the individual. Genes define oppor-
tunities for health and susceptibility to disease, while environmental factors
determine which susceptible individuals will develop illness. Therefore, indi-
vidual variation may need to be considered to achieve optimal health and to cor-
rect disorders associated with micronutrient deficiency, dietary imbalance and a
sedentary lifestyle.
(2) Every child and adult needs sufficient food and physical activity to
express their genetic potential for growth, development, and health. Insufficient
consumption of energy, protein, essential fatty acids, vitamins (particularly vit-
amins A, C, D, E and the B complex) and minerals (particularly calcium, iron,
iodine, potassium and zinc), and inadequate opportunities for physical activity
impair the attainment of overall health and musculoskeletal function.
(3) Balancing physical activity and good nutrition for fitness is best illus-
trated by the concept of energy intake and output. For sedentary populations,
physical activity must be increased; for populations engaging in intense occu-
pational and/or recreational physical activities, food consumption may need to
be increased to meet their energy needs.
(4) Nutrient intakes should match more closely human evolutionary her-
itage. The choice of foods should lead to a diverse diet high in fruits and veg-
etables and rich in essential nutrients, particularly protective antioxidants and
essential fatty acids.
(5) The current level of physical activity should match more closely our
genetic endowment. Reestablishment of regular physical activity into everyday
life on a daily basis is essential for physical, mental and spiritual well-being.
For all ages and both genders the physical activity should be appropriately vig-
orous and of sufficient duration, frequency, and intensity, using large muscle
groups rhythmically and repetitively. Special attention to adequate nutrition
should be given to competitive athletes.
(6) The attainment of metabolic fitness through energy balance, good
nutrition and physical activity reduces the risk of and forms the treatment
framework for many modern lifestyle diseases such as diabetes mellitus, hyper-
tension, osteoporosis, some cancers, obesity, and cardiovascular disorders.
Metabolic fitness maintains and improves musculoskeletal function, mobility,
and the activities of daily living into old age.
(7) Education regarding healthy nutrition and physical activity must begin
early and continue throughout life. Nutrition and physical activity must be inter-
woven into the curriculum of school age children and of educators, nutritionists
Declaration of Olympia on Nutrition and Fitness XXX
and other health professionals. Positive role models must be developed and
prompted by society and the media.
(8) Major personal behavioral changes supported by the family, the com-
munity, and societal resources are necessary to reject unhealthy lifestyles and to
embrace an active lifestyle and good nutrition.
(9) National governments and the private sector must coordinate their
efforts to encourage good nutrition and physical activity throughout the life
cycle and thus increase the pool of physically fit individuals who emulate the
Olympic ideal.
(10) The ancient Greeks (Hellenes) attained a high level of civilization
based on good nutrition, regular physical activity, and intellectual development.
They strove for excellence in mind and body. Modern men, women, and chil-
dren can emulate this Olympic ideal and become swifter, stronger and fitter
through regular physical activity and good nutrition.
Distribution of the Declaration
The declaration has been published worldwide in newsletters, magazines
and journals. It has been translated into the Olympic languages of Chinese,
French, Greek, Russian and Spanish. The ten points of the declaration have
been printed in these languages. The Executive Committee wishes to encourage
the translation and distribution of the declaration worldwide. The copyright is
held by the Executive Committee of the Conference.
The declaration was developed at Ancient Olympia, May 28–29,1996 by
the following persons:
Alexander Leaf, MD (Cochairman), William Clay, FAO, United Nations
USA Loren Cordain, PhD, USA
Peter G. Bourne, MD (Cochairman), S. Boyd Eaton, MD, USA
USA, UK Gilman Grave, MD, USA
Richard B. Birrer, MD Philip R. Lee, MD, USA
(Secretary), USA Konstantinos N. Pavlou, ScD, Greece
Regina Casper, MD, USA Catherine Siandwazi, Tanzania, UK
Ji Di Chen, MD, China Artemis P. Simopoulos, MD, USA
References
1 Simopoulos AP (ed): Proceedings of the First International Conference on Nutrition and Fitness.
Am J Clin Nutr 1989;49(suppl):909–1124.
2 Simopoulos AP, Pavlou KN (eds): Volume I. Nutrition and Fitness for Athletes. Proceedings of the
Second International Conference on Nutrition and Fitness. World Rev Nutr Diet. Basel, Karger,
1993, vol 71.
Declaration of Olympia on Nutrition and Fitness XXXI
3 Simopoulos AP (ed): Volume II. Nutrition and Fitness in Health and Disease. Proceedings of the
Second International Conference on Nutrition and Fitness. World Rev Nutr Diet. Basel, Karger,
1993, vol 72.
4 Simopoulos AP (ed): Volume I. Nutrition and Fitness: Evolutionary Aspects, Children, Health,
Policies and Programs. Proceedings of the Third International Conference on Nutrition and Fit
ness. World Rev Nutr Diet. Basel, Karger, 1997, vol 81.
5 Simopoulos AP, Pavlou KN (eds): Volume II. Nutrition and Fitness: Metabolic and Behavioral
Aspects in Health and Disease. Proceedings of the Third International Conference on Nutrition
and Fitness. World Rev Nutr Diet. Basel, Karger, 1997, vol 82.
6 Simopoulos AP, Pavlou KN (eds): Volume 1. Nutrition and Fitness: Diet, Genes, Physical Activity
and Health. World Rev Nutr Diet. Basel, Karger, 2001, vol 89.
7 Simopoulos AP, Pavlou KN (eds): Volume 2. Nutrition and Fitness: Metabolic Studies in Health
and Disease. World Rev Nutr Diet. Basel, Karger, 2001, vol 90.
Declaration of Olympia on Nutrition and Fitness XXXII
XXXIII
This year we are celebrating not only the Fifth International Conference on
Nutrition and Fitness with its strong connections with Greece but also the
return of the Olympic Games to the city where the modern Olympics was born
over a century ago in 1896. To me as an Olympian this conjunction of the
Conference with the Athens 2004 Olympics is of special importance and aug-
ments the honour of being invited to open the conference.
There is a saying, ‘Once an Olympian, always an Olympian’, – it was
coined because of the unique experience competing in the Olympic Games has
come to mean. There are 100,000 Olympians from over 200 countries around
the world. They form a unique resource, a valuable asset to sport and to the
Olympic Movement. It is by Olympians’ efforts and talents that the Olympic
Games come alive in the stadium, the pool and the sports arenas. Without them
there would be no Games. So it was in 1995, to recognise the contribution
Olympians make and provide opportunities for former athletes to continue to
play a part in the Olympic Movement, that, with the support of the International
Olympic Committee, the World Olympians Association was created of which
I am a co-founder and Vice President.
My involvement in sport influenced the choices I made as a doctor. As a
medical student at the Middlesex Hospital Medical School at London
University, I realised that I was more interested in health than disease and
my professional career has followed a path of seeking out ways in which we
can explore our capacities to create and maintain our own physical and
mental health.
Positive Health: Exploring RelevantParameters
Elizabeth Ferris
Department of Nutrition and Dietetics, King’s College London, London, UK
Keynote Address
My participation at this conference in a way brings together my several
identities – on the one hand as a former elite sportswoman and on the other as a
doctor interested in preventive medicine and holistic health, especially nutrition
and physical fitness.
The positive value to health of physical activity and nutrition is as old as
civilization itself. The case for good food as a means of enjoying a long and
healthy life is in no doubt. It was part and parcel of life for the ancient Greeks
and when Hippocrates said, ‘Let food be thy medicine and medicine be thy
food’, he was expressing something that instinctively people through the ages
have sensed must be true. Food is far more than simply a means of staying alive.
The song, ‘Food, glorious, food, there’s nothing quite like it’, from the musical,
‘Oliver’, based on Charles Dickens’ book, Oliver Twist, says it all.
The health benefits of physical exercise too have been widely proclaimed
over the centuries. The 18th century English poet, John Dryden, pre-empted
modern self-help devotees when he advised, ‘The wise for cure on exercise
depend; God never made his work for man to mend.’ So much for his faith in
the healing powers of doctors.
The ancient Greeks had a thorough knowledge of high-level physical train-
ing and knew that you can have too much of a good thing. We may think over-
training is a modern phenomenon considering the enormous pressures
professional athletes are under to perform well. But two and half millennia ago,
Hippocrates expressed his concern about its detrimental effects when he wrote:
‘Physical conditioning is at risk when exercise is at very high levels.’
Aristotle agreed. He warned of the dangers of exposing young children to
excessive training, pointing out that it undermined their powers of endurance
and scuppered young athletes’ ambitions of Olympic victory later on as adults1.
The ancient Greeks lived in a Mediterranean paradise awash with highly
nutritious green, yellow and red vegetables and fruit, nuts, olives, fish, and, of
course, wine. With the warm climate and their love of sport it is little wonder
that the concept of positive health through nutrition and physical fitness origi-
nated in Greece.
In my address today I’d like to explore the parameters of positive health,
starting with a little of the history of the Olympic Games to draw a connection
between the aspirations of the ancient Greeks and the aims of the creators of the
modern Olympics in 1896 that revived those aspirations and that, right up to the
present day, remain an important objective of the Olympic Movement. Using
Keynote Address XXXIV
1‘The disadvantages of excessive training in early years are amply proved by the list of
Olympic victors; not more than two or three of whom won a prize both as boys and as men. The
discipline to which they were subjected in childhood undermined their powers of endurance.’
[Aristotle, Politics, Book VIII]
this connection as a stepping stone, I will dip into recent scientific research that
provides evidence in support of Hippocrates’ analysis of positive health. I will
touch on public health issues surrounding the global pandemic of obesity and
its related serious health risks. Finally, looking to the future, I will suggest how
our growing knowledge of the human genome is likely to impact on how we
could maximize our potential for a healthy life.
More than fourteen hundred years after the last ancient Olympic Games
were held in the 4th century AD, the idea that physical activity was essential to
live a healthy life re-emerged, in particular in Victorian England on the playing
fields of boy’s public schools. The concept that to be sound of mind you needed
to take care of your physical health formed the basis for the physical education
movement that grew up in the 19th century2. But the movement did not focus
only on physical health. In tune with the ancient Greek approach, it embodied
moral, social and cultural principles as well. The physical education movement
provides a link between the ancient Greek cultural commitment to sport on the
one hand and the creation of the modern Olympic Games here in Athens in
1896 on the other.
Accepted wisdom has it that the modern Olympics was the brain-child of a
French aristocrat, Baron Pierre de Coubertin. But, as with so much in history,
the story was rather more complex and interesting. Before Coubertin was born,
a wealthy Greek called Zappas had made unsuccessful attempts to resurrect the
ancient Games in Greece. Meanwhile, in a tiny town in England called Much
Wenlock, an English country surgeon, Dr. William Penny Brookes, from 1850
onwards, organised annual Olympic-style sporting festivals. He called them the
Wenlock Olympian Games. Why would a rural doctor spend his time and effort,
and no doubt his own cash, in creating a re-enactment of the ancient Olympic
Games in a field in rural Shropshire – and who competed in them? Dr. Brookes
was a philanthropist who believed that everyone in the community, not only the
moneyed classes, was entitled to education and access to healthy leisure pur-
suits. He campaigned for physical education for children and petitioned
Parliament to make it compulsory in all elementary schools [1]. Like the ancient
Greeks, he believed that sporting participation produced moral and intellectual
benefits as well as contributing to physical health.
Dr. Brookes was also a Hellenist, a lover of all things from ancient Greece,
and he organised his Olympian Games as nearly as possible to the ancient
Olympics. The medals awarded to the winners bore the portrait of Nike, the
Greek Goddess of victory, with a quotation from Pindar, the classical poet of
the Olympic Games.
Keynote Address XXXV
2The concept of a sound mind in a healthy body, mens sana in corpore sano, originated
from the Roman satirist, Juvenal AD c.60–c.130.
Dr. Brookes’ Olympian Games had been in full swing for 40 years before
Pierre de Coubertin, who was a young educationalist on a mission for the French
government to research foreign systems of physical education, went to Much
Wenlock in 1890 to meet Dr. Brookes and see his Games in action. Coubertin
was deeply impressed and immediately recognised a kindred spirit in the country
doctor. The two men shared a passionate commitment to physical recreation, not
only for its health benefits but also for its moral and social value, values that
today characterise what is called Olympism. After his meeting with Brookes,
Coubertin wrote: ‘…if the Olympic Games that modern Greece has not yet been
able to revive still survive today, it is not due to a Greek but to Dr. W.P. Brookes.
It is he who inaugurated them 40 years ago and it is still he, now 82 years old but
still alert and vigorous, who continues to organise and inspire them’ [2, 3].
The two men shared a vision of recreating the Olympic Games in modern
times. As history reveals, Coubertin succeeded in this ambitious venture but
sadly Brookes did not live to see the dream become a reality; he died in 1895
aged 87 having given his blessing to Coubertin’s international vision.
The important thing to recognise is that for Brookes and Coubertin the
Olympic Games were a means by which universal physical education for all
could be attained. I maintain that this is just as true today as it was in 1896.
Notwithstanding the ways in which elite sport has changed of late, due in part to
professionalism and commercialism, and drug-taking, the Olympic Games have
the capacity to inspire young people at the grass roots level to participate in
sport and physical activities. I remember the overwhelming rush of young girls
wanting to practice gymnastics after Olga Korbut entranced the world with her
performance in Montreal in 1976. The power to awaken such interest on a
global scale is unique to the Olympic Games because of the extra dimension
that the Olympics possesses compared with other international sporting events
embodied in the philosophy of Olympism3. Their contribution to positive health
lies in the potential to encourage people, especially children, to become more
physically active4. And, there are added bonuses in being involved in sport that
I will come to a little later.
Keynote Address XXXVI
3The International Olympic Committee, in the Olympic Charter (in force as from 4 July
2003) under Fundamental Principles on p 9 defines Olympism as follows: ‘Olympism is a
philosophy of life, exalting and combining in a balanced whole the qualities of body, will and
mind. Blending sport with culture and education, Olympism seeks to create a way of life
based on the joy found in effort, the educational value of good example and respect for uni-
versal fundamental ethical principles.’4The story of the rise of women in the Olympic Games further illustrates my point. At the
first modern Olympics in 1896, there were no women because Baron De Coubertin thought the
Games should remain ‘the exaltation of male sport’. The traditional attitude was that women
I’d like to turn now to the immense contribution the scientific community
has made to the issue of positive health. Let’s fast forward to Britain in 1953,
the year when, as the nation watched the coronation of Queen Elizabeth II in
Westminster Abbey, news of the successful conquering of Mount Everest by the
British expedition lead by Sir Edmund Hilary was celebrated, and just a few
months later, arguably the most important sporting event of the 20th century
was held when Roger Bannister conquered the four-minute mile.
On the health front, Fleming’s discovery of penicillin and its development
as an antibiotic by Lord Florey, plus a mass vaccination programme saw the
gradual demise of infectious diseases as a principal cause of death. Fifty years
ago, medical concerns turned to focus on non-communicable diseases, in par-
ticular coronary heart disease (CHD), the major cause of premature death in the
world. Morris’ seminal study [4] showed that conductors on the famous London
red double-decker buses had significantly less coronary artery disease than the
drivers of the buses. The health benefits of being a conductor were attributed
not unreasonably to the fact that they were much more physically active than
sedentary drivers. Incidentally, anyone hoping to take up this healthy job in
future will be disappointed – these wonderful Red Routemasters, recognised
worldwide as icons of London, are being phased out in favour of buses with just
a driver whose only exercise is to press a button to open and close the doors
automatically. Alas, for us passengers, no more running and jumping on the
platform at the back of moving buses – a game Londoners love to play. An
opportunity for a little bit of exercise in the normal course of life itself will be
Keynote Address XXXVII
were biologically unsuited to taking part in sport and, anyway, it was a male domain – a view that
prevailed well into the 20th Century.
It didn’t take long for women to overturn the IOC’s entrenched view. Women golfers,
tennis players and sailors took part in the second Games in 1900 and women have partici-
pated in every Olympic Games since. Throughout the past 100 years, more and more women
have competed in the Olympics; in Athens 2004 the proportion of women to men will for the
first time approach parity. Of the 10,000 athletes women will make up approximately 41% and
will compete in all but boxing and baseball.
A positive by-product of more women athletes in the Olympics is the growth of women’s
sport around the world, especially in developing countries. The challenges women face in
many countries relating to religion, culture, education, poverty, and health take precedence
over concerns about sport. And yet, notwithstanding these social barriers and inequality,
women and girls are increasingly playing sport. There is still a long way to go but you have to
admit that progress is being made when you see that in Afghanistan, where until recently
women were hardly allowed to leave their homes, women are playing mixed table tennis
matches in public, and in Morocco, hundreds of women and girls turn up annually for a round-
the-houses run in Casablanca. From a public health point of view, perhaps the most important
fact is that physically active mothers are most likely to produce physically active children and
physically active children are most likely to maintain the habit into their adult years.
lost. No matter – perhaps we can make up for it by climbing the stairs in our
office buildings – if we can find them! This remark may sound flippant, but it is
relevant to my theme because it highlights the fact that opportunities for activ-
ity in our everyday lives, that we used to take for granted, are becoming less and
less common for reasons over which we have little or no control.
The benefits of an active lifestyle were further confirmed in the 1980s by
Paffenbarger and colleagues. Harvard alumni who took regular exercise, out-
putting 2,000 kcal or more per week, had a 39% lower risk of developing coro-
nary heart disease and of death from the disease than their less active
classmates [5]. We also now know, where a healthy heart is concerned, it is the
intensity of the exercise that matters [6].
Coronary heart disease is clearly a lifestyle disease with smoking and
physical inactivity top of the list of risk factors, and we know that exercise is
beneficial. What about the effects of diet? Recent research has revealed that a
nutritional substance – folic acid, one of the B vitamins – gives considerable
protection in heart disease by lowering homocysteine levels in the blood. In
addition, folate protects against a wide array of other serious diseases including
cancer, dementia and birth defects [7]. It has many diverse biological properties
expressed through a number of crucial gene pathways and has even been cited
as the panacea of the 21st century. The effect of folate research has been to open
up new avenues of intervention with vitamins and other nutrients in disease pre-
vention, and a new area of research has been identified – nutrigenomics, the
study of the links between nutrition and gene function. Nutrigenomics fits very
well with what Hippocrates knew instinctively when he spoke of the powerful
effects of various foods and physical exercise on man’s primary constitution.
In addition to the protective effect of exercise in coronary heart disease,
physical activity has been shown to be significant in other serious diseases that
are major causes of death in the modern world – diabetes, osteoporosis, obesity
related conditions and cancer5. The amount and type of exercise recommended
varies. In obesity, where weight loss is the goal, any increase in energy output is
desirable. The Chief Medical Officer in the UK just a few weeks ago, in an
Keynote Address XXXVIII
5An extraordinary story of bravery and endurance that raises important questions about
the relationship of exercise to cancer is that of Jane Tomlinson, a young British mother who,
in 2000, was diagnosed with terminal bone cancer and told she had just 6 months to live.
Since then, Jane has run three marathons, completed an ‘Iron Man’ event and recently cycled
2,500 miles from Rome to Yorkshire in the North of England where she lives. No-one knows
the role vigorous exercise has played in prolonging her life, or that of the professional
cycling phenomenon, Lance Armstrong, who had testicular cancer and went on after treat-
ment to win the Tour de France six times.
attempt to arouse the largely sedentary population to ‘get up and go’, produced
a report entitled, ‘Physical Activity and Health’ in which he recommended vac-
uuming and ironing as good examples of moderate exercise. Whilst this may
seem like too little too late, it is claimed that 30 min of moderate exercise
5 times a week is enough to prolong life.
We also know that exercise has positive effects on mood and feelings of men-
tal well-being. Fascinating research from the Salk Institute suggests that physical
activity has a positive effect on brain plasticity. There are stem cells in the adult
brain that produce new nerve cells in the dentate gyrus of the hippocampus, an
area associated with memory. Physical activity positively promotes this neurogen-
esis – in running mice at least [8]. For those of us who have those occasional
‘senior moments’, like when you find yourself in the cupboard under the stairs and
cannot for the life of you remember what you’ve gone there for, a little light run-
ning on the spot to stimulate a few new brain cells may help you to remember what
on earth you’re doing there – if you can remember the original piece of research! In
fact, this is a particularly productive line of research in support of physical activity
in the aged. We now have evidence that exercise combined with a diet rich in nutri-
ents, in particular folic acid, could help stave off symptoms of dementia and
Alzheimer’s disease in increasingly ageing populations.
The effects of nutrition on mental function and behaviour are equally inter-
esting. Young adult prisoners showed a remarkable reduction in antisocial
behaviour when their diets were supplemented with vitamins, minerals and
essential fatty acids [9]. Poor nutrition, on the other hand, has alarming effects.
Young schoolchildren who went without breakfast missed out in more ways
than one. Three hours into school, the children had powers of attention as poor
as an adult who had had a slug or two of whisky or a tranquiliser. And they did
equally badly when they had just a glucose drink. With cereal for breakfast,
however, they showed an enormous improvement [10].
With the scientific body of knowledge expanding, the case for physical
activity coupled with good food for a long and healthy life is made and is in no
doubt. And yet, hardly a day goes by without another report of the growing pan-
demic of obesity across the globe. Population surveys show that the world is
getting fatter and the incidence of Type 2 diabetes is increasing at an alarming
rate, in particular, and perhaps most disturbingly, in young children.
In our highly technologically developed modern world in which the need to
extend ourselves physically in the normal course of our lives is diminishing day
by day, our lifestyles have changed radically during the past 50 or more years. As
obesity levels rocket, it seems reasonable to blame the modern diet high in fat,
sugar and salt for the increases. This is hardly new: Plato was highly critical of
those who were a nuisance to their doctors because of leading an ‘idle life’ and
‘filling our bodies with gases and fluids like a stagnant pool’ [11].
Keynote Address XXXIX
Counter-intuitively, children it appears are actually eating less today, not
more, than they used to eat [12, 13]. Children are getting fatter because they are
much less active than they used to be and their energy intake in the food they eat
is greater than the energy they expend in physical activity. The reasons are
largely cultural: more car journeys with less walking, parental concerns about
security and safety that restrict where and when children can play, and, in par-
ticular, television watching and computer games are all cited as reasons for
inactivity in children across the globe [14], even in China where until recently
you would never see a fat person let alone an obese child [15]. Along with TV
watching goes snacking on high-density junk food and fizzy drinks that further
contribute to the greater energy intake/lesser energy output problem [16].
The emphasis, especially in the media, is predominantly on what children
eat because it’s obvious to see the outcome and it is easy to make value judge-
ments about children who are fatter than we think they ought to be. In fact, in
health terms, it is almost certainly better to be active, fit and a bit fat than lazy
and lean.
Perhaps the most alarming information to come to light concerning this
growing problem is in a report of the International Council of Sport Science
and Physical Education (ICSSPE) that states: ‘school physical education is in a
perilous position in all continental regions of the world’ [17]. PE has a low pri-
ority in school curricula, and is starved of funding, materials, time and teachers.
The future of PE looks bleak. Governments are giving out confusing mixed
messages. On the one hand, they are advising children to do more exercise
whilst on the other hand making it obvious that physical education is a
Cinderella subject on the school curriculum deserving few resources. It doesn’t
make any sense.
On a more personal level, good food and good eating initiatives are sprout-
ing as public interest in nutrition grows especially in developed countries. For
example, organic farming is expanding in Europe to counter the use of additives
and pesticides, alongside a popular anti-GM crops drive that has resulted in
Monsanto cancelling its GM crop production programme in Europe. Another
initiative is the slow food movement in Italy that has emerged as an antidote to
the fast food culture in an attempt to replace it with old values of sitting down to
meals with family and friends, and savouring good, wholesome nutritious food
and wine. Children too benefit from this style of eating. Children who eat meals
with their family consume more fruit and vegetables, fewer fizzy drinks and
less fat in food both at and away from home [18].
Again, the ancient Greeks got it right. According to a recently published
account of what Olympic winners eat in ancient Greece:
The main meal was dinner where the presence of family and friends and theconsumption of wine were important elements. Dinners were rather prolonged
Keynote Address XL
during which people were eating, drinking wine with water and discussing cur-rent issues. (The term ‘symposium’ means ‘drinking together with others’) [19].
In the commercial world, if one can believe the stock quotes, the leisure
industry is profiting from increasing membership of gym and fitness centres
although the percentage of people in the UK who regularly exercise hardly
reaches double figures, McDonald’s, under pressure from the media and the
public, is changing its image to provide more healthy salad and fruit options,
and the vitamin and supplement industry is booming as people self-administer
these products in an attempt to bolster their well-being.
In my early school days, I remember that the welcome mid-morning inter-
val between writing and arithmetic was called playtime, and play we did. I sug-
gest that, with respect to children at least, we need to put play back into physical
activity. Perhaps, we need to change the terms we use; ‘physical education’ is a
rather dry phrase, we could go back to using the word ‘recreation’ – it has a
more pleasurable ring about it.
Perhaps a clue to how to appeal to children can be found in what young-
sters like to do in their leisure time: they like to play computer games. Sony had
a brilliant idea when they called their equipment Play Station. To me the title is
an oxymoron. Sony used the word ‘play’ – which according to the Oxford
English Dictionary (OED) means to move about swiftly; to fly, to dart to and
fro; to frisk, to flit, to flutter, all words that exemplify what children do when
they play – juxtaposed with the word ‘station’ which, according to the OED,
means standing still, the opposite of motion. But the word ‘play’ is evocative
and enticing6. Why are computer games so beguiling to children? Is it because
they provide positive feedback, enjoyment, accomplishment, the possibility of
winning, and even applause for success – all the things an athlete gets, or hopes
to get, from sport?
But, not all children are good at sport and many are alienated from participat-
ing especially when the emphasis is on competition and performance. Even chil-
dren who show an aptitude for one sport, gymnastics say, may not show any talent
for another, a ball game, like soccer. I started my sporting life as a swimmer but I
became bored with the training. It didn’t suit my personality and if the opportunity
had not arisen to change to diving, a much more acrobatic sport, I am sure I would
have given up. I heard a similar story from an Olympic swimming champion. He
was hopeless at school sport – last in cross-country running, no eye-to-ball coordi-
nation. One day he fell through a plate glass window and severed a tendon in his
calf, couldn’t run and so, fortuitously, took up swimming, loved it and made it to
the very top winning 2 Olympic gold medals. The moral of his and my stories is
Keynote Address XLI
6Montaigne said 500 years ago, ‘It should be noted that children at play are not playing
about; their games should be seen as their most serious-minded activity.’
that if we had not had the good fortune each to find our own sporting niche neither
of us would have won our Olympic medals. Unless options are available to be tried
and tested by the individual, a child could be put off sport, and by association,
physical activity, for the rest of his or her life – and very possibly to the detriment
of their health.
The key question is how people can be enticed into changing their lifestyles
to incorporate physical activity and good nutrition into their normal everyday
lives. The World Health Organisation recently presented its global strategy to
improve public health through healthy eating and physical activity. Governments
are considering what public health initiatives they can provide to help solve the
problem. In 2004, a British Parliamentary Health Committee published a report
[20] in which it recommended 80 measures including a ban on the promotion of
sugary drinks and snacks in schools, curbs on advertising junk foods on televi-
sion in particular during children’s programmes, health warnings and clearer
labelling on foods, and new building developments to feature cycle paths, walk-
ways and playing fields. All good ideas – but will they work? And will they work
in time to defuse the ticking time bomb of poor health, shortened life spans and
premature death in the current generation of physically inactive children for
whom obesity and its concomitant problems are becoming the norm.
To date, the health argument has not exactly been able to inflame the pub-
lic’s imagination. The cosmetic argument only carries weight with those vain
enough to care. An alternative approach, it seems, is needed if public attitudes
are to change. A possible clue may be gleaned from a fascinating study of the
Pima Indians of Arizona [21]. Pima Indians suffer from high levels of obesity
and diabetes. The study tested the efficacy of lifestyle interventions. One group
of subjects, the Pima action group, had a mix of nutrition and physical activity
active interventions. The other group, the Pima pride group, received printed
leaflets about activity and nutrition but in addition they engaged in regular dis-
cussions on Pima culture and history. At the end of 12 months, the pride group
was showing much more favourable results than the action group in terms of
their health parameters – they had lost more weight and had more favourable
blood glucose and insulin levels. It seemed that by boosting their pride in their
Pima identity, almost as a side effect they were able to take more care of their
health compared with those in the action group who only focussed on changing
their diet and exercise. Did this effect have something to do with building up the
pride group’s self-esteem and respect for their Pima identity? I think so. It’s pos-
sible to link the concepts of respect and self-esteem with autonomy [22].
Researchers have found that control at work, or the lack of it, i.e. lack of auton-
omy, is associated with increased health risks [23, 24].
I have touched on some complex issues in an attempt to suggest that the
answers to the health problems we face do not lie in governments simply telling
Keynote Address XLII
people to eat less and walk more, good as that advice may be. Something has to
ignite a person’s interest and that is why I have come back full circle to sport.
Sport for me, before I reached the elite level, was a complete experience. It
provided me with a full social life, good friends who, 40 years later, I am still
in touch with, travel, teamwork, a sense of achievement and how to deal with
failure as well as success. The actual activity, the experience of diving, was com-
pletely personal. But it was the context in which I did it that provided the ground
in which I grew up and thrived. If, amongst the myriad of choices sport has
to offer, a person, in particular a child, can find something to illuminate
their curiosity and suit them mentally as well as physically, sport is an activity
that, in the broadest terms, can offer a rewarding lifestyle with healthy
by-products. Active children are more likely to become active adults, and physi-
cally fit and active adults have lower risks of heart disease, diabetes and cancer.
Turning now to the future, scientific studies and public health initiatives I‘ve
highlighted show that, when reaching for ways of dealing with chronic non-com-
municable diseases, advice on what lifestyle changes an individual can make has
tended to focus on just two variables – dietary habits and patterns of physical
activity (with smoking as well in the case of CHD). The underlying assumption
has been that these are possibly the most important or even the only parameters in
a person’s individual make-up relevant to health (and ill health). I suggest that this
is a very restricted view. My own view can be summarised as follows:
(1) Genetic factors play at least as important a role as exercise and diet.
Moreover, genetic constraints and regulation influence individual potential to
respond to exercise and dietary factors. For example, the Finnish Olympic
champion cross-country skier, Eero Maentryanta, was a medical mystery. He
had 15% more red blood cells than normal and some were convinced he was
blood doping although there was no evidence. The mystery was solved by
Lodish and colleagues at the MIT when they discovered that Maentryanta and
others in his family had a genetic mutation that accounted for the high levels of
red blood cells [25].
Another study showed that a single gene – dubbed the ‘performance gene’ –
may influence an athlete’s propensity to excel at either sprinting or long dis-
tance running. The gene, which encodes for an enzyme – angiotensin-converting
enzyme (ACE) –, researchers believe determines whether an individual grows
more ‘fast twitch’ or ‘slow twitch’ muscles fibres [26].
With respect to obesity, O’Rahilly’s group at Cambridge together with
other researchers have found a genetic connection between proneness to obesity
and PPARy genotype [27]. In simple terms, their work shows that some people
have a genetic propensity for obesity whilst others don’t. This corresponds to
our intuition. We’ve all said at some or other, ‘Lucky old so-and-so – he can eat
anything and stay thin’.
Keynote Address XLIII
We can say something similar regarding the connection between fitness
and health. Evidence is all around us of very fit people who succumb to illness
and die. Look at Jim Fixx, who started the jogging craze; a very fit man who
died suddenly and prematurely from a heart attack. At the other end of the
health spectrum is the Australian, Shane Gould, who at 15 years of age was a
multiple Olympic champion and the supreme swimmer in the world. This year,
30 years on, at age 47, she returned to swimming and qualified for the
Australian Olympic trials. She has to have an extraordinary genetic makeup.
These examples illustrate how an individual’s genotype may determine both
potential for protection from developing disease as well as the risk of developing
disease7. We know, for instance, that smokers vary in their risk of developing
lung cancer and coronary heart disease. It is possible that within a few years we
may be able to characterise people according to their genotype, and programmes
of dietary and exercise interventions could be tailor-made to the individual.
(2) Future research will eventually lead to an awareness of the importance
of other variables apart from diet and exercise. This in turn will eventually
expand our understanding, not only of the number of variables involved, but
also how these variables relate to one another.
In my ideal world, we would eventually end up with a detailed algorithm
that would specify all the variables involved and relate them to each other in a
quantifiable, indeed, mathematical, way. Statisticians are already grappling
with producing such a mathematical equation. How wonderful it would be if a
formula such as 2(A+1/2B+2/3C�D...n)/4 specified the exact relationship of
all the relevant variables in a unique equation for each individual, where, say, A
is exercise, B is diet, C is genotype, D is hitherto unknown variable and n is all
future relevant variables – along the lines that Hippocrates suggested, ‘the sea-
son of the year, the changes of the winds, the age of the individual and the situ-
ation of his home’ ...and any number more.
The human genome project has opened wide the potential for the kind of
outcomes I am suggesting. The future is exciting. We are very fortunate to have
leaders in these fields of research here at our meeting and I wish us to have a
wonderful and stimulating conference.
Thank you all for your attention.
Dr. Elizabeth Ferris, 2004
Keynote Address XLIV
7To see why diet and exercise cannot be the only variables that are relevant to health
see: Campos P: The Obesity Myth: Why America's Obsession with Weight Is Hazardous to
Your Health. New york, Gotham Books, 2004.
References
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(December 1890). WOS 2nd MB, p 182.
3 Mullins S: British Olympians: William Penny Brookes and the Wenlock Games. London, British
Olympic Association, 1986.
4 Morris JN, Heady JA, Raffle PAB, Roberts CG, Parks JW: Coronary heart disease and physical
activity at work. Lancet 1953;ii:1053–1057, 1111–1120.
5 Paffenbarger RS, Hyde RT, Wing AL, Steinmetz CH: A natural history of athleticism and cardio-
vascular health. JAMA 1984;252:491–495.
6 Tanasescu M, Leitzmann MF, Rimm EB, et al: Exercise type and intensity in relation to coronary
heart disease in men. JAMA 2002;288:1994–2000.
7 Lucock MD, Yates Z: A differential role for folate in developmental disorders, vascular disease
and other clinical conditions: The importance of folate status and genotype; in Massaro EJ (ed):
Folate and Human Development. Totawa, Humana Press, 2001, pp 263–298.
8 van Praag H, Christie BR, Sejnowski TJ, Gage FH: Running enhances neurogenesis, learning, and
long-term potentiation in mice. Proc Natl Acad Sci USA 1999;96:13427–13431.
9 Gesch CB, Hammond SM, Hampson SE, Eves A, Crowder MJ: Influence of supplementary vita-
mins, minerals and essential fatty acids on the antisocial behaviour of young adult prisoners. Brit.
J Psychiatry 2002;181:22–28.
10 Wesnes KA, Pincock C, Richardson D, Helm G, Hails S: Breakfast reduces declines in attention
and memory over the morning in schoolchildren. Appetite 2003;41:329–331.
11 Plato: The Republic. Part 111: Education, Book 111, Physical Education. London, Penguin Classics,
1987, p 109.
12 National Diet and Nutrition Survey: Young People aged 4–18 Years. London, Stationery Office,
2000.
13 Durnin JGVA: Physical activity levels – past and present; in Norgan N (ed): Physical Activity and
Health. Cambridge, Cambridge University Press, 1992, pp 20–27.
14 Dietz WH: The obesity epidemic in young children. BMJ 2001;322:313–314.
15 Cheng TO: Obesity in Chinese children. JRSM 2004;97:254.
16 Giammatei J, Blix G, Marshak HH, Wollitzer AO, Pettitt DJ: Television watching and soft drink
consumption. Arch Pediatr Adolesc Med 2003;157:882–886.
17 Hardman K, Marshall I: World-wide Survey of the State and Status of School Physical Education.
ICSSPE Report, 2002.
18 Gilman MW, Rifas-Shiman SL, Frazier AL, Rockett HRH, Camargo CA Jr, Field AE, et al: Family
dinner and diet quality among older children and adolescents. Arch Fam Med 2000;9:235–240.
19 Terkesidou L: The Golden Diet of the Ancient Olympic Winners. Athens, Kastaniotis Publishers,
2004.
20 House of Commons Health Committee: Obesity: Third Report of Session 2003–2004. Publication
Parliament UK.
21 Venkat Narayan KM, Hoskin M, Kozak D, Kriska AM, Hanson AM, Pettitt DJ, et al: Randomized
clinical trial of lifestyle interventions in Pima Indians: A pilot study. Diabet Med 1998;15:66F–72F.
22 Sennett R: Respect in a World of Inequality. New York, Norton, 2003.
23 Marmot MG, Bosma H, Hemingway H, Brunner E, Stansfield S: Contribution of job control and
other risk factors to social variations in coronary hear disease. Lancet 1997;350:235–240.
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ease within the Whitehall II study. J Epidemiol Commun Health 2003;57:147–153.
25 ‘Whitehead finds answer to old puzzle’ – article from MIT Tech Talk, May 17 1995. The work was
reported in Cell.
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26 Montgomery H: Renin-angiotensin systems and human performance. Genes in Sport Conference,
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nutrient interaction at the PPARy locus. Diabetes 2001;50:686–689.
Elizabeth Ferris, MBBS
Department of Nutrition and Dietetics
King’s College London, Franklin Wilkins Building
150 Stamford Street, London SE1 9NH (UK)
Tel +44 1367 860313, E-Mail [email protected]
Keynote Address XLVI
Simopoulos AP (ed): Nutrition and Fitness: Mental Health, Aging, and
the Implementation of a Healthy Diet and Physical Activity Lifestyle.
World Rev Nutr Diet. Basel, Karger, 2005, vol 95, pp 1–16
Psychiatric Disorders, Mood andCognitive Function: The Influence ofNutrients and Physical Activity
Regina C. Casper
Department of Psychiatry and Behavioral Sciences, Stanford University School of
Medicine, Stanford, Calif., USA
Human mental function is genetically based, yet modulated during develop-
ment and throughout life by environmental factors. Family and twin studies have
shown that hereditary factors play an important role in the incidence and clinical
expression of affective disorders and schizophrenia [1]. As a result, research has
increasingly focused on linking specific psychiatric disorders to specific genetic
markers. Hereditary studies, however, have revealed a significant environmental
influence on gene expression [1]. Psychological factors are important environ-
mental components which interact with genes or gene products to promote the
expression of a phenotype. For instance, Caspi et al. [2] reported that a polymor-
phism in the 5-HTT gene, in this case one or one or two copies of the short allele
of the 5-HT T promoter, increased an individual’s chance to react to stressful life
events with depressive symptoms, depressive disorder and suicidal behavior. The
heritability for psychiatric disorders [3] suggests that there is a significant envi-
ronmental component in the pathogenesis of psychiatric disorders. For nutrition
which powerfully impacts physical health and disease [4, 5], the mechanisms of
the gene-environment interaction are under investigation [6, 7].
In normal populations nutritional factors and physical activity have been
shown to have subtle effects on mood and cognitive ability [8]. Studies explor-
ing possible relationships between nutritional factors and the incidence and
course of psychiatric diseases are of recent origin.
This chapter will address four questions:
1. Assuming that psychiatric disorders have a genetic basis, is there a role
for environmental factors?
Mental Health
Casper 2
2. What are the beneficial effects of the essential �–3 polyunsaturated fatty
acids (�–3-PUFAS) on human development and what is the evidence that mal-
nutrition during prenatal life affects mental development?
3. In the second part findings from placebo controlled studies and uncon-
trolled trials will be reviewed with the question in mind: do the data support a
role for nutritional compounds, specifically the �–3-PUFAS, in altering the
prevalence or the occurrence of psychiatric symptoms?
4. Lastly, are there mental health benefits to physical exercise?
Psychiatric Disorders are the Products of Genetic Regulation and Environmental Influences
The genetic basis of human mental function and dysfunction is complex
and due to the interaction of multiple genes. Genes instruct the development of
the central nervous system (CNS), at the same time environmental factors
promote or in the case of hypoxia, infection or malnutrition may disrupt matu-
rational processes. For schizophrenia, even if 100% genes are shared as would
be the case for an individual with two schizophrenic parents, the risk of devel-
oping the condition is estimated to be no more than 46%, leaving a substantial
portion to environmental factors [1]. Furthermore the recent discovery of the
neuregulin gene which plays a central role in neural development and con-
tributes to schizophrenia in both Icelandic and Scottish populations suggests
the possibility of population based genetic variability [9]. An example of a
gene/nutritional environment interaction would be the APOE gene which has
been linked to schizophrenia in Chinese and seems to confer vulnerability dur-
ing times of malnutrition [6]. A hereditary component for affective disorders is
well documented [10]. Recently, the South Island Bipolar Study demonstrated
an increased prevalence of bipolar and depressive disorders in relatives of bipo-
lar patients [11], which, nevertheless, leaves �60% to environmental risk fac-
tors. Another example of a gene/environment interaction would be the variant
of the monoamineoxidase type A (MAOA) gene which has been linked to
aggressive, impulsive and even violent behaviors in monkeys and humans.
Maltreated children with a genotype conferring high levels of MAOA expres-
sion were less likely to develop antisocial problems [12, 13].
Early Development: Prenatal Growth and Diseases in Adult Life
Aside from genetic factors, the maternal environment influences fetal devel-
opmental milestones. In the late eighties, epidemiological studies began to point
Nutrients, Neurodevelopment and Psychiatric Disorder 3
to the conclusion that adults who had been born with normal, yet low birth weight
have an increased susceptibility to diseases in adult life. Barker’s [14] analyses of
birth and death certificates of people born in Hertfordshire, UK revealed that 2.3-
kg babies had double the rate of death from coronary heart disease, hypertension,
stroke and type II diabetes, compared to 4.5-kg babies. These observations which
were subsequently confirmed [15] generated the fetal origins hypothesis that pro-
poses that the fetus adapts to a limited supply of nutrients, and in doing so, per-
manently alters its physiology and metabolism. The new set point appears to
increase the risk of disease in later life. There is one report [16] which found a
relationship between low weight gain in infancy and suicide in adult life.
Observations that growth restriction during fetal life is associated with
increased adrenocortical and adrenomedullary activity [17] and a higher preva-
lence of autoantibodies to thyroid peroxidase (TPOAb) and thyroglobulin
(TgSAb) [18] are important in view of the presence of similar endocrine abnor-
malities in major depressive disorders. Remarkably, an excess of protein may
also modulate lifelong changes in the hypothalamic-pituitary-adrenal (HYPAC)
axis. Herrick et al. [19] described hypercortisolemia in 28- to 30-year-old sub-
jects whose mothers had been advised to consume 0.45 kg of red meat daily and
avoid carbohydrates during pregnancy, an intriguing finding given the popular-
ity of the Atkins diet. Another report [20] that described epigenetic metastabil-
ity following excess intake of folic acid, vitamin B12, choline, and betaine leading
to possible deleterious influences on the establishment of epigenetic gene regu-
lation in humans deserves further study in view of current recommendations for
large doses of folic acid in particular for patients taking antiepileptic drugs.
Epidemiological studies of psychiatric disorders [21] have linked severe
malnutrition during the first trimester to the risk of schizophrenia by analyzing
the incidence of schizophrenia in birth cohorts born between January-February
1944 and November–December 1946 in Holland during the German occupa-
tion. Those conceived during the height of the Dutch famine and exposed to
very low food rations during the first trimester (from February to April 1945)
had an excess of neural tube defects [22] and double the relative risk for schiz-
ophrenia [21]. Brain imaging studies [23] have shown decreased intracranial
volume and double the rate of brain abnormalities, in particular focal white
matter hyperintensities in a subset of these patients compared to controls born
during the Dutch hunger winter. As noted previously, Liu et al. [6] suggested
that the epsilon-4 genotype of the APOE gene may be associated with the risk
of malnutrition for schizophrenia. First trimester exposure to severe malnutri-
tion during the Dutch hunger winter has also been reported to double the risk of
schizoid personality disorders [24], schizophrenia spectrum disorders [25], and
antisocial personality disorder [26]. Malnutrition during the second trimester
appears to double the risk for affective disorders in adulthood [27].
Casper 4
Interaction between Nutrition, Growth and Development
Animal StudiesBourre et al. [28] have documented during cerebral development in
rodents a linear relationship between brain content of (�–3) acids and the (�–3)
content of the diet up to 200 mg of �-linolenic acid levels per 100 g food intake,
however DHA levels remained unaltered following ALA [28]. They observed
that a diet low in (�–3) acids affects learning in rodents. In rhesus monkeys,
Connor et al. [29] showed more fatty acid lability when �–3-deficient monkeys
were fed fish oil diets rich in DHA and other �–3 fatty acids. An earlier study
[30] described that rhesus monkeys long term deficient in �–3 fatty acids
displayed bouts of stereotyped behavior typical of monkeys raised in social
isolation compared to monkeys fed a matched control diet abundant in �–3
fatty acids.
Human StudiesFish oil supplements given from week 30 of the pregnancy extended the
pregnancy duration on average 4 days in Danish women compared to women
receiving olive oil supplements [31]. Low consumption of seafood has been
associated with premature delivery [32]. Cheruku et al. [33] found that higher
maternal DHA levels were associated with more mature infant sleep and wake
states in newborns. Maternal supplementation with cod liver oil (total 1.2 g
DHA �0.8 g EPA) versus corn oil (4.7 g linoleic acid (LA) and 0.09 g �-
linolenic acid (ALA) from week 18 of pregnancy until 3 months after delivery
increased children’s mental processing composite score significantly at 4 years
of age. Intelligence correlated with head circumference at birth, but not with
birth weight or gestational length [34]. Maternal supplementation with 2.8 g
ALA did not prevent decreases in maternal DHA and AA concentrations, yet
did increase EPA and DPA levels, with no difference in birth outcome [35].
Another study found similar visual, cognitive and language scores in breastfed
and DHA- and DHA�AA-enriched formula-fed children at 39 months [36]. In
a cross-sectional study phospholipid (DHA and AA) status at birth was not
associated with cognitive development at 4 years of age [37] or with cognitive
performance at 7 years [38].
Nutritional Factors in Affective Disorders
Studies on the effects of amino acids, protein and carbohydrates on
mood and the effects of caloric restriction on life span have been reviewed pre-
viously [8].
Nutrients, Neurodevelopment and Psychiatric Disorder 5
Polyunsaturated Fatty Acids (PUFAS) and Major DepressiveDisorders (MDD)
Phospholipids as components of membrane structure play a critical role in
signal transduction via receptor mediated phospholipid derived second mes-
sengers such as prostaglandins or arachidonic acid. A role for the eicasonoids
and immune activation in the pathophysiology of MDD [39, 40] is supported
by findings that antidepressants of several classes decrease the production of
pro-inflammatory cytokines such as interferon-gamma and tumor necrosis fac-
tor-�, and increase that of interleukin-10, an anti-inflammatory cytokine [41].
Significant decreases of plasma polyunsaturated �–3 fatty acids are inversely
associated with major depression [42], whereas increases in the �-6/�-3 plasma
ratio or red cell membrane phospholipids of patients with major depression
correlate directly with the severity of depression.
The comprehensive review by Hibbeln and Salem [43] makes it abun-
dantly clear that testing of the therapeutic efficacy of PUFAS has underdone
few double-blind trials, in fact most data derive from case reports, pilot studies,
open trials, cross-sectional analyses and unpublished communications.
Omega–3 Fatty Acids in Major Depressive Disorder (table 1)
Placebo-controlled studies typically have included treatment resistant or
partially improved patients who may not be representative and who are by defi-
nition difficult to treat.
Four placebo-controlled studies have randomly assigned patients on
antidepressant medication to receive �–3 fatty acids. Administration of 2 g EPA
daily reduced depressive symptoms by week 3 in a 4-week study of Nemets et
al. [44]. Peet and Horrobin [45] found that 1 g EPA daily, but not 2 or 4 g EPA
ameliorated depression scores in mostly female medicated patients by week 4
on the Hamilton rating scale (HRS) and the Montgomery Asberg depression
rating scale (MDRS) with the greatest improvement occurring at 12 weeks,
when patients rated themselves as improved on the BDI. Marangell et al.’s
6-week [46] study failed to show benefit from 2 g DHA daily on the MDRS,
even though the placebo group was more depressed at baseline. Su et al. [47]
gave EPA/DHA 2:1, a total of 6.6 g daily after a placebo washout in a 12-week
study and showed improvement in the HAMD score by 4 weeks with further
symptom reduction by 12 weeks. Cross-sectional analyses [48] found elderly
patients with MDD and with normal C-reactive protein levels to have lower �–3
plasma levels and higher �–6/�–3 ratios. A population-based study of all males,
50–69 years old residing in southwestern Finland [49] found no evidence
Casper 6
between fish consumption or overall �–3 dietary intake and depressed mood,
MDD or suicide.
Omega-3 Fatty Acids in Pregnancy and Postpartum Depressive Disorder
Hibbeln [50] analyzed prevalence rates for postpartum depressive disorder
(PPD) across countries and found an inverse relationship to seafood consump-
tion. Higher DHA, but not AA or EPA, breast milk concentrations predicted a
lower prevalence of PPD. Stronger evidence for a role of �–3 fatty acid defi-
ciencies in postnatal MDD comes from a study by De Vriese et al. [51] who
found lower �–3 PUFAS and lower �–3/�–6 ratio in plasma lipids of women
who developed postpartum depression compared to controls. Yet, a placebo-
controlled study supplementing breast-feeding women with 200 mg DHA daily
for 4 months postdelivery, even if it raised DHA lipid content, failed to influ-
ence measures of depression in a study by Llorente et al. [52]. This study was
not a valid test, since too few (15%) women with MDD were included. In a
small open label trial [53] which administered 2.96 g of fish oil (EPA/DHA
ratio 1.3) during the last 4 weeks of pregnancy, 4/7 women experienced post-
partum depression, not different from the relapse rate expected in untreated
Table 1. Placebo-controlled treatment studies of �–3 fatty acids
Author Type,dosage, duration Subjects, n Results
Major depressive disordersNemets et al. [44] Ethyl-EPA 2 g/day 4 weeks 20 ↓HRSD scores week 2
Peet and Horrobin [45], Ethyl-EPA 1,2 or 70 1 g/day ↓HRSD MADRS
4 g/day 12 weeks week 4
Marangell et al. [46] DHA 2 g/day 6 weeks 36 Response rates similar
�24–28% MADRS
Su et al. [47] EPA 4.4 g/day 28 ↓HSRD scores week 4 & 8
8 weeks � DHA 2.2 g/day
Breast-feeding women with postnatal depressive disorderLlorente et al. [52] DHA 200 mg/day 101 No difference; only 14%
of patients had MDD or
depressive symptoms
HRSD � Hamilton rating scale for depression; MADRS � Montgomery-Asberg depression rating
scale; MDD � major depressive disorder.
Nutrients, Neurodevelopment and Psychiatric Disorder 7
women. Considering the high rates of breast-feeding among current mothers
and the benefits from nursing, PPD merits further investigation in better
designed placebo controlled studies which ought to include an infant assess-
ment. Remarkably, infant monkeys fed a formula containing 1% DHA and 1%
AA displayed better visual orienting and motor skills by day 7 and day 14 than
breast-fed or standard formula-fed infant monkeys [54].
Omega–3 Fatty Acids in Bipolar Disorder (table 2)
Two studies have described either reduced erythrocyte membrane AA or
DHA content in bipolar disorder patients [55] or an increased prevalence of
bipolar I, bipolar II bipolar spectrum disorder in countries with less than 50 lb
seafood consumption per year [56]. These findings notwithstanding, only one
report found some benefit from �–3 fatty acids in bipolar disorders. Stoll et al.
[57] who compared time to relapse over 4 months in 14 bipolar patients who
received 6.2 g EPA�3.4 g DHA daily to that in 16 bipolar patients receiving
olive oil placebo found more patients in the PUFA supplemented group to
remain stable at 4 months than in the placebo group. Two studies by Keck et al.
[58] found no benefits from 6 g EPA added for 4 months to the medication
regime of bipolar patients.
Omega–3 Fatty Acids in Schizophrenia (table 3)
Schizophrenia is currently conceptualized as a neurodevelopmental disor-
der [1]. Among the nutritional deficiencies low vitamin D has been hypothe-
sized to underlie the relationships to excess of winter births, increased rates of
schizophrenia in urban versus rural settings and increased rates in dark-skinned
migrants to colder climates [59].
Table 2. Placebo-controlled treatment studies of �–3 fatty acids in bipolar disorders
Author Type, duration, dosage Subjects, n Results
Stoll et al. [57] 6.2 g EPA� 3.4 g DHA or 30 bipolar I and Longer time to
placebo; 4 months II, disorder relapse
Keck et al. [58] 6 g EPA/placebo 59 bipolar No difference
4 months depressed pts between groups
Keck et al. [58] 6 g EPA/placebo 62 bipolar rapid No difference
4 months cycling between groups
Casper 8
The rationale to use PUFAS in schizophrenia is based on Horrobin’s theory
[60] of abnormal lipid metabolism in schizophrenia and on findings that schiz-
ophrenic patients as opposed to normal controls and depressed patients display
a deficient flushing response to niacin subdermally suggesting reduced
membrane arachidonic acid levels and reduced production of prostaglandin D2
(PGD2) in schizophrenia. Noaghiul and Hibbeln [56] observed no relationship
between seafood consumption and lifetime prevalence rates of schizophrenia.
Arvindakshan et al. [61] a described lower than normal AA and DHA in drug
naïve unmedicated compared to medicated schizophrenia patients and controls
as well as modestly significant negative correlations between AA. An open
trial [62] found symptomatic improvement of negative symptoms in 20 schizo-
phrenia patients following 6 weeks of 10 g EPA/DHA- ratio 1.3. Another
uncontrolled study (180/120 mg EPA/DHA, as well as vitamins C and E) found
clinical improvement in 33 patients [63].
In four out of five placebo-controlled add-on trials to standard antipsychotic
medication EPA, but not DHA, reduced positive symptoms [64]. In a monotherapy
trial [64], 12 placebo-treated patients, but only 8/14 EPA treated patient required
antipsychotic medication after 3 months. Another analysis [65] in which 2 g EPA,
but not 1 or 4 g EPA were found to be better than placebo was based on 9 clozap-
ine-treated patients, only. The strongest evidence for consistent improvement from
Table 3. Polyunsaturated fatty acids in the treatment with schizophrenia: placebo-
controlled studies of medicated patients
Author Subjects, n Type, dosage, duration Outcome
Open-label trialsMellor et al. [62] 20 10 g EPA/DHA ratio: Improvement: AIMS
1.3; 6 weeks and PANSS
Arvindaksham 33 EPA 360 mg� DHA Sustained 4 months
et al. [63] 240 mg � improvement
vitamins C and E
Peet et al. [64] 14/12 2 g EPA/placebo ↓PANSS score
MonotherapyPeet et al. [64] 45 2 g EPA vs. 2 g EPA � DHA
DHA 3 months
Fenton et al. [67] 87 3 g EPA/placebo No difference
12 weeks
Peet and Horrobin [45] 115 1, 2, 4 g EPA/placebo, 2 g improvement in
12 weeks clozapine patients
Emsley et al. [66] 40 3 g EPA 12 weeks ↓PANSS score
↓dyskinesia
Nutrients, Neurodevelopment and Psychiatric Disorder 9
week 3 to 12 based on total PANSS scores and involuntary movement scores was
presented by Emsley et al. [66] who in contrast to Peet and Horrobin [65] found a
trend for patients on conventional antipsychotic drugs to fare better. Fenton et al.
[67] found no differences over the 12-week period between the placebo- and EPA-
treated group in an older chronically ill population.
Impulsivity and Irritability (table 5)
Although several uncontrolled studies [68–73] have reported reductions in
aggressive behavior or hostility scores after administration of DHA or EPA, no
firm conclusions can be drawn without more and better designed double blind
controlled studies. DHA supplements for 2 months in a placebo-controlled
study [72] did not improve concentration or the behavior of children with atten-
tion deficit disorder.
Mild Cognitive Impairment and Alzheimer’s Disease (table 5)
Epidemiological studies, summarized in table 4, suggest better cognitive
function with long-term use of vitamin C and vitamin E [74, 75]. A decreased
risk for Alzheimer’s disease (AD) and mild cognitive impairment (MCI) was
found in individuals who used both vitamin C and vitamin E [76, 77]. Plasma
Table 4. Studies examining the relationship between irritability, hostility and/or aggression and �–3
fatty acids
Authors, year Number of subjects Type, dosage Outcome/results
(age, years)
Hamazaki et al. [68] 22 vs.19 students DHA 1.6 g ↓aggressive behavior
3 months soybean oil stress-induced
Gesch et al. [69] 231 male offenders LA, ALA, DHA 26% reduction in
�18 years – 142 days 172, EPA 320 mg disciplinary action
Zanarini et al. [70] BPD 20/10 women; EPA 1 g mineral 1 g ↓aggression scores
8 weeks
Iribaren et al. [71] 3,581 youths DHA levels �1 SD ↓high hostility score
Hirayam et al. [72] ADHD 20/20 children DHA food 3.6 g/week ↑visual memory ↓errors
commission
Raine et al. [90] 83 children; 355 Enrichment ↓schizotypal, criminal
NC 3–5 years behavior
Casper 10
�–3 PUFA and phospholipid levels were found to be reduced in AD and other
dementias [78]. Four studies found a relationship between fish and PUFA
intake and the incidence of AD [79–81].
Physical Exercise and Emotional Health
Clinical and experimental evidence from studies in elite athletes and in
moderately depressed patient populations suggests that vigorous exercise
of 30 min or more of moderate intensity physical activity on most, preferably
all days, improves energy levels and reduces anxiety, tension and depressive
Table 5. Case studies and case control studies of nutritional factors in aging, dementia, and AD
Authors Number of subjects Type, dosage Outcome/results
(age, years)
Fletcher et al. [86] 1,214 (75–84) Ascorbate levels ↓mortality risk;
upper quintile HR 0.54
Otsuka [87] 64AD/80 NC AD disliked fish EPA at 900 mg
and green vegetable ↑cognitive function
Conquer et al. [88] AD/other dementias ↓�–3/�–6 ratios
versus NC phosphatidylcholine
Tabet et al. [89] 81 AD/81 NC Intake vitamins C, E, A ↓vitamins C and
E in severe AD
Morris et al. [79] 815 (65–94 ) Fish once/week ↓60% AD 3.9-year
follow-up
Grodstein et al. [74] 14,968 (70–79) Long-term vitamin C ↑cognitive
Nurses’ Health St. and E users status
Rinaldi et al. [75] 63 AD, 25 CI vs. 53 NC Vitamins E, C, A, etc. ↓antioxidant levels
↓oxidative enzyme
levels
Tully et al. [80] 148 AD/45 NC ↓EPA and DHA MMSE: 19.5 AD/
in AD vs. NC 28.9 NC
Zandi et al. [77] 200 AD/4,740 Vitamin C � �500 mg/day incidence of AD
�Vitamin E combined
Schaefer et al. [81] 899 Upper quartile DHA 180 mg ↓39% AD
DHA daily fish twice/week ↓47% dementia
9-year follow-up
MMSE � Mini mental status examination.
Nutrients, Neurodevelopment and Psychiatric Disorder 11
symptoms [82]. Table 6 lists the physiological and psychological mechanisms
which have been hypothesized to contribute to the improved wellbeing.
The benefits of daily physical exercise in healthy and depressed popula-
tions have been reviewed previously by Casper [82]. The lack of motivation and
interest, and the sense of leaden paralysis and lethargy in severe depressive dis-
orders reduce the possibility of exercise in these populations.
Antenatal Exercise and Birth Weight
Studies on the impact of exercise on birth outcome are of increasing impor-
tance considering that more young women now engage in strenuous exercise daily.
In a prospective controlled study [83] that compared pregnant women who exer-
cised �5 times per week with women who exercised 3 times or less per week, no
statistically significant difference in the mean birth weight of babies born was
found. However, the fact that at randomization 52% of women refused to be
assigned to the lower exercise group limits the generalizability. Another study
begun at 34 weeks of pregnancy [84] found a bimodal relationship with exercise;
women at the higher end, those who exercised � or � 5 times per week and
women at the lower end, those who exercised �or � 2 times per week were at
increased risk (odds ratios 4.61 and 2.64, respectively) to deliver babies with a low
birth weight. A much larger study using data from the National Maternal and
Table 6. Physical activity and mental health theories regarding physiological and
psychological changes
Physical activity induces physiological changesNeurotransmitters – noradrenalin, serotonin, dopamine- increase vigor and reduce
anxiety and tension
Increases steroid reserves which counteracts stress
Increases cerebral blood flow
Increases alpha rhythm and hemispheric synchronization
Lowers muscle action potential-reduces tension
Increases body temperature – sedative effects
Releases endorphins – analgesic properties
Physical activity induces psychological changesIncreases self-efficacy, self-esteem and self-sufficiency
Induces a meditative, relaxed state
Distracts from daily stress and anxiety
Repeatedly experiencing physical symptoms (sweating, hyperventilation, increased
heart rate) without an emotional disturbance helps desensitize
Individuals to the physiological correlates of anxiety
Casper 12
Infant Health Survey [85] found that women who failed to exercise and previously
active women who stopped physical activity during pregnancy were more likely to
have very low birth weight babies and low birth weight babies. No significant rela-
tionship between the duration of gestation and physical activity was observed.
Conclusion
Nutrients, specifically the �–3 fatty acids, but also vitamins, have a critical
role in the structural and functional development and operation of the central
nervous system (CNS). Placebo controlled studies in medicated patients suggest
that add-on treatment with eicosapentaenoic acid (EPA) in doses varying from 1
to 4 g daily may ameliorate symptoms of major depressive disorders and reduce
the abnormal movements and positive and negative symptoms in schizophrenia.
There is preliminary evidence from epidemiological studies that high plasma
levels of �–3 fatty acids combined with high intakes of antioxidants, such as
vitamins C and E protect against age related cognitive decline. Compared with
the well documented cardioprotective effects associated with �–3 fatty acid rich
diets, the antidepressant and antipsychotic effects of �–3 fatty acids seem to be
primarily associated with EPA and not to fit a dose-response curve. The data are
conflicting as to whether immune and inflammatory pathways mediate the asso-
ciation between �–3 fatty acid deficiencies and psychiatric symptoms. Lastly,
future need to clarify to what extent improved physical health, higher energy
levels, improved sleep and/or reduced abnormal movements may account for the
symptomatic improvements in MDD and schizophrenia.
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Regina C. Casper, MD
Department of Psychiatry and Behavioral Sciences
Stanford University School of Medicine
401 Quarry Road, Stanford, CA 94305–5723 (USA)
Tel. �1 650 725 2406, Fax �1 650 725 1353, E-Mail [email protected]
Simopoulos AP (ed): Nutrition and Fitness: Mental Health, Aging, and
the Implementation of a Healthy Diet and Physical Activity Lifestyle.
World Rev Nutr Diet. Basel, Karger, 2005, vol 95, pp 17–28
Nutrition and Schizophrenia
Malcolm Peet
Doncaster and South Humber NHS Trust, Sheffield, UK
Schizophrenia is a serious and disabling mental disorder which affects
almost one percent of the population worldwide. It is characterised by so-called
‘positive’ symptoms such as delusions (false beliefs) and hallucinations (such
as hearing voices), usually together with ‘negative’ symptoms such as lack of
drive and initiative, blunted emotions and lack of judgement. Current treatment
involves the use of antipsychotic medication and psychosocial interventions.
These treatments are palliative but not curative so that most people who suffer
from schizophrenia experience lasting disability, mainly due to the negative
symptoms.
It is generally accepted that the incidence of schizophrenia is broadly
similar throughout the world in all contemporary cultures [1, 2]. This has been
taken to imply that the genetic predisposition to schizophrenia appeared at a
very early stage of human evolution, and that this genetic makeup may even be
inherent to our humanity by promoting such attributes as language acquisition
and creativity [3, 4].
Whilst schizophrenia is of comparable incidence across modern cultures,
there are marked differences between countries in the long-term outcome of
schizophrenia. In particular, it is well established that the 2-year outcome of
schizophrenia is substantially better in developing countries such as India
and Nigeria, than in developed Western nations in Europe and North America
[1, 2, 5]. This distinction holds for a variety of outcome measures, including
both social functioning and clinical measures such as relapse rates. This must
mean either that the more developed medical services in the West are positively
damaging to the long-term outcome of schizophrenia, or alternatively that there
is some other powerful force affecting outcome, which is even stronger than all
the benefits of modern treatments. Not surprisingly, the latter explanation is
preferred by Western commentators, but the nature of that powerful positive
Peet 18
force in developing countries has not been identified. The usual explanation
revolves around theories of greater social cohesion, support and acceptance for
people with mental health problems in developing countries. However, there is
no substantial evidence to support this, and indeed direct personal observation
of the management of the mentally ill in developing countries would suggest
that this explanation is an example of Western mythology about the nature of
society in those countries.
The possible role of nutrition in determining the outcome of schizophrenia
has been largely neglected until recently. This neglect appears to stem from the
notion of a mind-body duality which somehow regards brain functioning as
being separate from the rest of the body. The concept that the brain is an organ
which evolved in the same biological environment as the rest of body, and
therefore that nutritional patterns which are good for the body as a whole will
also be good for the functioning of the brain, appears to be an alien concept to
most mental health researchers.
The rest of this article will explore evidence relating nutrition and schizo-
phrenia. Possible mechanisms by which nutrition may contribute to the neu-
ropathology of schizophrenia will be outlined.
Cross-National Ecological StudiesEcological studies have provided valuable insights into the aetiology of
many diseases with a nutritional component such as cancers and diseases of the
metabolic syndrome, but this approach has seldom been applied to the investi-
gation of mental health problems. The first such study was carried out more
than 15 years ago [6]. The researchers had noted that Scandinavian seamen who
consume a diet high in saturated fat, appeared to have a high prevalence of
schizophrenia [7]. In order to investigate this further, they used data on the
international variations in outcome of schizophrenia which had been collected
in a large World Health Organisation study [1]. It was this study that provided
the original basis for the well accepted better outcome of schizophrenia in
developing countries which is quoted in every standard psychiatric textbook.
They correlated schizophrenia outcome data with information on dietary intake
of fat from land animals and poultry (primarily saturated fat) relative to fat
intake from fish and vegetable sources (primarily polyunsaturated fat). They
found that more saturated fat and less polyunsaturated fat in the diet predicted a
worse outcome of schizophrenia, and that the ratio of saturated to polyunsatu-
rated fat predicted 99% of the variance in outcome. If this study had shown
such a strong relationship with a purely social variable such as a measure of
social cohesion, it would have been regarded as a landmark study. However,
because the relationship was with nutrition and this went against prevailing
thought, the study was almost totally ignored.
Nutrition and Schizophrenia 19
Based on this pioneering work we have conducted a further ecological
analysis [8].
We used schizophrenia outcome data from two studies: one was the WHO
study [1] used by Christensen and Christensen [6], and the other was a follow-up
study also sponsored by the WHO, which confirmed the earlier findings about
schizophrenia outcome using new patient cohorts [2]. We took nutritional data
from the Food and Agriculture Organisation website [9]. Instead of examining
dietary constituents, we examined the role of individual foodstuffs. The reason
for this was that nutritional intake of foodstuffs intercorrelate, so that diets which
are high in saturated fats are also high in sugar, for example. We found strikingly
similar predictors of poor two-year outcome of schizophrenia across both of the
schizophrenia outcome studies and whether social or clinical variables were
used as the primary outcome measure. On the straight correlations, high sugar
consumption was shown to relate to a poor schizophrenia outcome whichever
outcome measure was used. On several, but not all, measures dairy products
meat and eggs were found to be associated with the worse outcome of schizo-
phrenia and the consumption of pulses with a better outcome. The correlation
between outcome and sugar consumption is shown in figure 1. On multiple
regression analysis, consumption of sugar was the dominant predictor across all
social and clinical variables, although consumption of dairy products remained a
significant predictor for one clinical variable (hospitalisation rate).
0
10
20
30
40
50
60
100 200 300 400
Two-year total outcome for schizophrenia
Ref
ined
sug
ar c
onsu
mp
tion
(kg
per
cap
ita p
er y
ear)
India
Colombia
USSR
USA UKDenmark
Czechoslovakia
Nigeria
Fig. 1. Relationship between national sugar consumption and the 2-year outcome of
schizophrenia. Data for sugar consumption are taken from FAOSTAT and data for the relevant
year [9]. The 2-year total outcome data for schizophrenia take into account a range of social
and clinical variables and are derived from reference 1. A lower score indicates a better out-
come. This figure is based on the raw data published in [8].
Peet 20
Case-Control StudiesIt has been shown repeatedly that cell membrane levels of polyunsaturated
fatty acids, particularly docasahexaenoic acid DHA and arachidonic acid (AA),
are reduced in cell membranes of patients who suffer from schizophrenia
[10–13]. This has normally been measured in erythrocytes. Some of these
findings have been called into question on methodological grounds [14]. For
example, some studies did not control for the effects of smoking and storage
artefact. Nevertheless, such studies formed the basis for investigating nutrition
as a possible contributory factor to schizophrenia.
Mellor et al. [15] carried out a nutritional analysis of hospitalised schizo-
phrenic patients. She found a significant correlation between severity of symp-
toms and dietary intake of �–3 fatty acids. Those patients who had more �–3
fatty acids in their normal daily diet with no attempt at intervention, had less
severe schizophrenic symptoms.
Stokes and Peet [unpubl.] carried out a further nutritional study on a sepa-
rate group of schizophrenic patients in a rehabilitation unit. This examined
dietary intake of all nutrients with regard to their ability to predict severity of
schizophrenia symptoms. It was found that severity of symptoms correlated
with both polyunsaturated fatty acids (PUFA) and with sugar intake in the nor-
mal daily diet. The correlation with polyunsaturated fatty acids were in the
expected direction in that higher dietary intake of PUFA was associated with
less severe schizophrenic symptoms. However, the correlation with dietary
intake of sugar was, unexpectedly, in the opposite direction. Further analysis
showed that this was due to the confounding effect of background medication.
Patients taking the antipsychotic drug clozapine were consuming twice as much
sugar as those taking other antipsychotic drugs. Clozapine is an antipsychotic
drug with potentially life-threatening side effects (agranulocytosis), so it is
reserved for the treatment of patients who have not responded to other antipsy-
chotic agents. Therefore, it appears that treatment-resistant schizophrenic
patients taking clozapine have an exceptionally high consumption of sugar.
Whether this was present before prescription of clozapine and therefore may
have contributed to the treatment resistance, or whether it is a consequence of
taking clozapine, has yet to be determined. Work in this area is of particular cur-
rent interest because of concerns about the development of diabetes in patients
treated with some of the newer antipsychotic drugs, particularly clozapine [16].
The correlation between PUFA in the diet and severity of schizophrenic symp-
toms was found to be robust and independent of background medication.
Historical Association between Diet and SchizophreniaAt the beginning of the twentieth century it was widely believed that
indigenous populations who lived by hunter gathering and substance agriculture,
Nutrition and Schizophrenia 21
did not suffer from mental illness. This belief was based on overtly racist
concepts that the brains of these ‘primitive’ people were not sufficiently devel-
oped for them to experience the complex symptoms of mental illness. After the
Second World War concepts of this kind were no longer acceptable. It was
recognised that human beings all have the same capacity for brain functioning,
with the conclusion that the potential for mental illness is universal. This was
reinforced by the WHO studies showing that the incidence (but not the out-
come) of schizophrenia was similar across all contemporary cultures.
Unfortunately, this conceptual shift which was primarily driven by ideol-
ogy may have caused important epidemiological information to be overlooked.
There is a substantial body of evidence to suggest that schizophrenia as we
know it was relatively uncommon amongst indigenous populations and
increased when indigenous peoples came into contact with Western culture,
including the shift to a Western diet. This evidence has been summarised else-
where [17, 18]. By their very nature, these studies were conducted decades ago
and they can therefore be criticised because most of them do not conform to
modern methodological principles. That said, the number and variety of studies
all pointing to low rates of mental illness cannot be ignored.
There is also evidence that the prevalence of mental illness in Western
nations increased markedly during the Industrial Revolution [19]. At one time
there was vigorous debate as to whether this was due to a true increase in inci-
dence or a worse outcome [20, 21]. Whichever is true, the marked increase in
insanity (as it was then called) had to be accommodated by the rapid construc-
tion of asylums during this period of time. Sociologists have argued that the
reported increase in the rate of insanity was more apparent than real, and was
due to increased stigmatisation and lower tolerance of people who behaved
unusually, fuelled by the building of institutions to house them [22]. Whilst
there is some evidence that mental institutions were abused for the incarcera-
tion of people who behaved in a way that was perceived as socially deviant
rather than being mentally ill, this explanation cannot possibly account for the
massive need for increased provision for the insane which was driven by, rather
than being the driver for, the increased prevalence of mental illness in society.
At the same time as the mental health of the general population deteriorated,
their diet was undergoing enormous change. During this period, population
consumption of both saturated fat and sugar showed massive increases [23, 24].
There is a close association between reported cases of insanity and the con-
sumption of sugar by the general population for the period 1800 to 1914 [17]. If
this relationship is causal this would imply a fairly immediate harmful effect of
sugar on mental state, as there is no evident time-lag.
It therefore appears that indigenous people, who ate a diet with much less
saturated fat and sugar than ours, had lower levels of schizophrenia amongst
Peet 22
their population, and that there was a rise in the prevalence and perhaps
incidence of schizophrenia during the Industrial Revolution which correlates
with increased dietary intake of fat and sugar. This is consistent with the ecologi-
cal evidence suggesting that a high saturated fat, high sugar diet is associated
with a poor two-year outcome of schizophrenia.
Possible Mechanisms by which Diet Contributes to NeuropathologyThere is no doubt that genetic factors are important in the aetiology of
schizophrenia although putative genetic markers have proved difficult to repli-
cate. A polygenic inheritance is likely. The importance of the environmental
factors is demonstrated by the fact that concordance for schizophrenia in
monozygotic twins is only around 50% [25].
It is generally believed that schizophrenia is a disorder of neurodevelop-
ment. In a large birth cohort [26] it was found that those who became schizo-
phrenic later in life had delayed milestones of motor development, more speech
problems, lower educational test scores, solitary play preference, and less social
confidence as children. At age 15 both anxiety and lower IQ were independent
predictors of future schizophrenia.
Because many of these abnormalities in childhood of people who eventu-
ally become schizophrenic, are similar to those of children who are given feeds
deficient in DHA as babies and infants, there has been interest in the possible
relationship between diet in pregnancy and infancy and subsequent develop-
ment of schizophrenia. Susser et al. [27] examined the subsequent development
of schizophrenia in children of mothers exposed during early pregnancy to the
Dutch hunger winter of 1944/1945. Offspring of the mothers who were most
exposed to famine during the first trimester of pregnancy showed a double rela-
tive risk of schizophrenia. This nutritional deficiency was generalised, and
therefore any increased risk of schizophrenia cannot be attributed to any spe-
cific nutrient. However, the data do indicate that nutritional factors during preg-
nancy can be a determinant of future schizophrenia in the offspring. Several
studies have attempted to investigate the effect of breast-feeding on subsequent
development of schizophrenia. An initial study reporting an excess of formula
feeding relative to breast-feeding amongst people who subsequently developed
schizophrenia [28] was refuted by a large cohort study which found no differ-
ence in rates of schizophrenia between people who had been breast-fed as
infants and those who had received formula feeds [29]. More recent evidence
suggests that breast-feeding may have a more subtle influence on the presenta-
tion of schizophrenia. Avmore et al. [30] found that duration of breast-feeding
was positively correlated with the age at onset of illness suggesting that pro-
longed breast-feeding might delay the onset of schizophrenia.
Nutrition and Schizophrenia 23
There is a great deal of evidence that schizophrenia is associated with sig-
nificant neuropathology. Earlier studies have shown a well replicated increase
in the size of the cerebral ventricles which pre-dates the onset of overt schizo-
phrenic symptoms [31, 32]. There is continuing debate as to whether this abnor-
mality is static or progressive, possibly due to apoptosis of neurones [33]. More
recently, there is evidence that neuronal cytoarchitecture is abnormal in the
cerebral cortex of schizophrenic patients [34]. This has led to an interest in the
possible role of neurotrophins in the aetiology of schizophrenia.
Brain-derived neurotrophic factor (BDNF) is required to maintain den-
drites [35], and expression in BDNF in the prefrontal cortex shows a significant
increase during young adulthood at a time when the frontal cortex matures both
structurally and functionally [36]. Schizophrenia typically presents in young
adulthood. Lack of brain BDNF has been shown in mice to result in reduced
neuronal soma size and dendrite density in the prefrontal cortex [37]. This is
similar to the changes in neuronal architecture which have been reported in
brains from schizophrenia patients. BDNF is also a modulator of neurotrans-
mitters including gamma-amino butyric acid (GABA), which is regarded as
important in the pathogenesis of schizophrenia [38]. BDNF can also protect
neurones against apoptosis [39]. Recent molecular genetic studies have shown
an association between BDNF gene variants, schizophrenic illness, and the
response of schizophrenia to the anti-psychotic drug clozapine [40, 41].
A recent study showed reduced BDNF expression in the prefrontal cortex of
patients with schizophrenia [42].
In the light of all the evidence implicating BDNF in the pathogenesis of
schizophrenia, it is of considerable interest that BDNF levels in rat brain have
been shown to be significantly reduced by a diet which is high in saturated fat
and sugar [43]. The possible influence of other dietary constituents including
�–3 fatty acids has not yet been investigated. However, it is striking that the
same dietary components which appear to be detrimental to the outcome of
schizophrenia, also modulate a neurotrophin which is currently of great interest
in schizophrenia research. Evidence from dietary surveys of schizophrenia
patients suggests that their diet contains even more saturated fat and sugar than
the general population [44, 45].
Intervention StudiesThere is epidemiological evidence of an association between nutrition and
schizophrenia, and plausible biological mechanisms exist by which nutrition
could affect the onset and outcome of the schizophrenic process. However, the
only way to directly test the validity of a nutritional hypotheses is through inter-
vention studies. The feasibility of carrying out such studies depends upon the
time point at which nutritional factors come into play. We have seen evidence to
Peet 24
suggest that malnutrition in pregnancy increases the likelihood of schizophrenia
in offspring but breast-feeding may delay the onset of schizophrenia, and that
the neuropathology of schizophrenia is well established by the time overt symp-
toms become manifest. This implies that nutritional interventions for people who
have already developed schizophrenia may be of limited impact. Nevertheless,
there is evidence that nutritional approaches may be beneficial even after the
onset of the schizophrenic illness.
Most formal studies have focused upon treatment with omega-3 fatty
acids. This work was stimulated by initial findings, detailed earlier in this
article that schizophrenic patients have reduced cell membranes levels of
polyunsaturated fatty acids including DHA [10–13], and that dietary intake of
�–3 fatty acids appears to correlate with schizophrenic symptoms, such that
more �–3 fatty acids in the normal daily diet was associated with less severe
symptomatology [15]. This led to a pilot study of fish oil which was given in
addition to usual medical treatment to a group of schizophrenic patients who
were still symptomatic despite being on the most appropriate available antipsy-
chotic medication [15]. These patients showed significant reduction in schizo-
phrenic symptomatology after 6 weeks treatment with 10 g per day of
concentrated fish oil which contained around 2 g per day of DHA and 1.5 g of
EPA. They also showed a considerable reduction in the severity of a movement
disorder known as tardive dyskinesia. This is a neurological abnormality which
is found in up to 5% of patients with schizophrenia as part of the illness
process, but which increases in frequency after prolonged treatment with the
older antipsychotic drugs. There have now been five double-blind placebo con-
trolled trials of �–3 fatty acids in the treatment of schizophrenia. The first was
a pilot study comparing DHA with eicosapentaenoic acid (EPA) added to exist-
ing medication for 3 months [46]. The finding from this study was that EPA was
significantly more effective than placebo or DHA, and that DHA was no better
than placebo. A subsequent UK study comparing 1, 2 and 4 g of ethyl EPA as an
adjunct to current medication, found significant improvement in symptoms
when 2 g daily of ethyl EPA was added to the antipsychotic drug clozapine, but
no significant benefit in the whole patient group [47]. Three further studies
have produced contrasting results. An American study in which 3 g daily of
ethyl EPA was added to existing medication found no significant benefit [48].
A study carried out in South Africa found significant improvement for both
schizophrenic symptoms and tardive dyskinesia when 3 g daily of ethyl EPA
was given together with already prescribed antipsychotic drugs [49]. A recent
study from Australia in patients with first episode schizophrenia showed that
those treated with EPA required significantly lower dosages of antipsychotic
medication [50]. Several studies have also investigated EPA as a sole treatment
for schizophrenia. In one single case study, it was reported that EPA brought
Nutrition and Schizophrenia 25
about complete symptom remission accompanied by reversal of the pre-existing
cerebral ventricular enlargement [51]. A placebo-controlled study of EPA as a
sole treatment for schizophrenia was conducted in India [46]. The primary
efficacy measure was the number of patients who could be maintained without
the need to use antipsychotic drugs. All patients given placebo required
prescription of antipsychotic with the three months trial period whereas half of
the patients treated with EPA did not require antipsychotic medication, with no
detriment to their mental state: indeed, the EPA-treated patients had signifi-
cantly less schizophrenia symptoms than those who were treated with placebo
plus conventional antipsychotic drugs.
It is not clear why there is such variability in the results of studies of EPA
treatment of schizophrenia. It may be EPA is effective only for certain subtypes
of schizophrenia. Importantly, it seems likely that EPA given without reference
to the diet as a whole is not an effective strategy. If high levels of saturated fat
and sugar in the diet are important to the outcome of schizophrenia then this
would need to be addressed in any nutritional approach to the treatment of
schizophrenia. It is perhaps significant that the best results with EPA treatment
have come from the studies in India and South Africa, where consumption of
saturated fat and more particularly of sugar is less than in the UK and the USA
[9]. So for there have been no formal studies of a low saturated fat, low sugar
diet in the management of schizophrenia. However, some clinicians have
adopted this approach and have anecdotally reported success [52]. A period of
fasting often followed by a vegetarian diet was frequently used in the USSR to
treat mental disorders, and special units were set up for this purpose [53].
Fasting is known to increase brain levels of BDNF in animals [54]. More sig-
nificantly, some practitioners have urged approaches which involve reduced
consumption of saturated fat and sugar, for example by cutting out all processed
foods. This follows the principles of ‘orthomolecular’ psychiatry first put for-
ward by Pauling [55]. This was based on the philosophy that the body, and in
this case specifically the brain, functions at its best when in the biological envi-
ronment provided by the nutrition on which we evolved. This has been regarded
in the past as fringe medicine and even quackery, but it appears that modern sci-
ence is now offering support to such concepts.
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FS: A red blood cell membrane abnormality in a subgroup of schizophrenic patients: Evidence for
two diseases. Schizophr Res 1994;12:53–61.
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Ranjekar PK, Mahadik SP: Essential polyunsaturated fatty acid and lipid peroxide levels in never-
medicated and medicated schizophrenia patients. Biol Psychiatr 2003;53:56–64.
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reduced docasahexaenoic acid concentrations in erythrocyte membranes from schizophrenic
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phrenia or schizoaffective disorder. Biol Psychiatr 2003;53:431–441.
15 Mellor JE, Laugharne JDR, Peet M: Omaga–3 fatty acid supplementation in schizophrenic
patients. Hum Psychopharmacol 1996;11:39–46.
16 Ryan MC, Thakore JH: Physical consequences of schizophrenia and its treatment: the metabolic
syndrome. Life Sci 2002;71:239–257.
17 Peet M: Nutrition and schizophrenia: Epidemiological and clinical perspective. Nutr Health
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18 Torrey EF: Schizophrenia and Civilisation. New York, Jason Aronson, 1980.
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Prof. Malcolm Peet
Doncaster and South Humber NHS Trust
Swallownest Court
Aughton Road
Swallownest Sheffield, S26 4TH (UK)
Tel. �44 1114 2872570, Fax �44 1114 2879147, E-Mail [email protected]
Simopoulos AP (ed): Nutrition and Fitness: Mental Health, Aging, and
the Implementation of a Healthy Diet and Physical Activity Lifestyle.
World Rev Nutr Diet. Basel, Karger, 2005, vol 95, pp 29–34
Managing Obesity after Menopause:The Role of Physical Activity
Gal Dubnov, Elliot M. Berry
Department of Human Nutrition and Metabolism, Braun School of
Public Health, Faculty of Medicine, The Hebrew University-Hadassah
Medical School, Jerusalem, Israel
Obesity is an epidemic on a global scale [1], posing a major threat to human
health and well-being as well as consuming a large part of health care costs.
The health hazards associated with being overweight are numerous; including
increased all-cause and cardiovascular mortality, diabetes, hyperlipidemia, hyper-
tension, cancer and more. Post-menopausal women, deprived of the protective
effects of endogenous estrogen together with negative environmental factors,
have an increased tendency for gaining weight and its associated metabolic syn-
drome [2]. A major cause for the weight gain is lack of sufficient physical activity
(PA). Additionally, PA is paramount in managing obesity and combating weight
gain, including in the postmenopausal years [3–5].
Obesity: Prevalence, Causes and Consequences
Almost one fifth of US adults are obese, having a body mass index (BMI)
of over 30, and over 19 million American adult women are obese [6]. Almost
one half of the women in the western world are overweight, having a BMI of 25
or more [6, 7].
The causes of obesity are genetic and environmental. Yet the high and
growing prevalence of obesity is mainly due to environmental effects influenc-
ing a genetic susceptibility [8]. In some ways the development of obesity may
be considered as a ‘normal’ response to an ‘abnormal’ environment. Food and
energy intake are higher than actually needed, while the mechanized surround-
ings produce a low level of PA. This results in a natural net effect of weight gain
Aging, Osteoporosis and Physical Activity
Dubnov/Berry 30
throughout the years – both individually and globally. Menopause is associated
with weight gain [9], and lack of PA seems a major environmental contributor
[10]. This weight gain is accompanied by changes in body composition and fat
distribution toward a more android obesity [11], which is associated with the
metabolic syndrome [2]. This later results in increased mortality, reflected by a
closer association of mortality with the waist-hip ratio or waist circumference
(markers of android adiposity) than with BMI (a more general measure of
adiposity) [12, 13]. It should be noted that use of hormone replacement therapy
has been shown to decrease the shift from gynoid to android fat deposition after
menopause [11, 14]. Estrogen has therefore an effect on the site of obesity, and
its withdrawal after the menopause assists in bringing about the metabolic syn-
drome of overweight men.
Some medical complications of obesity are presented in table 1. A more
comprehensive list will include increased mortality, several forms of cancer,
coronary artery disease, diabetes mellitus, hypertension, stroke, heartburn, gall
bladder disease, kidney stones, osteoarthritis, low back pain, arthralgia, pseudo-
tumor cerebri, pulmonary emboli, obstructive sleep apnea, and depression.
Lifestyle Modifications for Intentional Weight Loss
Most obesity complications are reduced with intentional weight loss. The
most common methods of weight reduction are lifestyle modification, prescrip-
tion and non-prescription medications, and gastric surgery for subjects with
BMI over 38. Most importantly, whatever the method used for the initial weight
Table 1. The risk for some common disease conditions that are influenced
by weight gain, weight loss, and physical activity or physical fitness
Mortality Obesity Intentional Physical activity/
weight loss physical fitness
Overall ⇑ ⇓ ⇓Cardiovascular ⇑ ⇓ ⇓CAD events ⇑ ⇓ ⇓Metabolic syndrome ⇑ ⇓ ⇓Stroke ⇑ ⇓ ⇓Gallbladder disease ⇑ ⇓ ⇓Cancer ⇑ ⇓ ⇓
CAD � Coronary artery disease; HTN � hypertension. The metabolic syn-
drome includes type 2 diabetes mellitus, hypertension and hyperlipidemia.
Physical Activity and Postmenopausal Obesity 31
reduction, future lifestyle modification is crucial in order to maintain the newly
reduced weight; several methods exist to assist in adherence [15]. Guides for
the treatment of adult obesity are and proper food selection are available from
the National Institute of Health, the American Obesity Association and the US
Department of Agriculture [16–18].
Dieting only is not expected to maintain weight loss in the long term [19].
This is due to the concomitant reduction of muscle mass, which lowers the meta-
bolic rate and reduces energy expenditure. This leads to a lower caloric output
along the day. Therefore, current nutritional recommendations for weight loss are
simply adherence to the same guidelines that are established for all adults. Food
selection aimed for loss should allow a lower energy intake with a large enough
bulk of food, such as grains, fruits and vegetables. The weight reduction program
should include behavioral changes, as these carry a major role in the maintenance
of the newly reduced body weight [20].
Physical Activity in Postmenopausal Weight Loss
Among women aged 50–64, only half reported doing any regular PA, while
only about one quarter report high intensity exercise [21]. As discussed, insuffi-
cient PA is a major factor in postmenopausal weight gain. It is therefore an
important tool in weight loss and in the reversal of many obesity related co-
morbidities, as shown in table 1: good fitness and engaging in PA lower mortal-
ity rates [22, 23], lower the risk of fat and weight gain [24, 25], offer some
protection against the medical consequences of obesity and the metabolic syn-
drome [26, 27], lower the incidence of cancer [23, 28] and improve mood [29].
Exercise Prescription
It is recommended for every adult to engage in 30 min of moderate-intensity
PA on most, preferably all, days of the week [30–32]. In general, a brisk walk of
3.5 km a day is enough to exert most of the health benefits. The recommended
30 min may be accumulated through shorter bouts of activity along the day. In a
follow up after postmenopausal women who participated in a trial which
encouraged increasing walking distance, those originally assigned to the walk-
ing group were still walking more than the control group –10 years after trial
has ended [33]. Thus, lifestyle habits may be effectively changed even in this
age: you can teach an old dog new tricks.
In meta-analyses assessing weight loss programs, it has been shown that
exercise is more of importance in long term weight maintenance [19], while it
Dubnov/Berry 32
offered more fat loss, with less decrease in the energy-utilizing fat free mass
[34]. Further, a simple calculation shows that a person has to walk about
100 Km in order to expend the energy equivalent to 1 kg of adipose tissue.
The type of PA should include mainly aerobic exercises, such as walking,
jogging, swimming, cycling and aerobic dancing. Resistance training may be
added. The intensity can be as low as 40% of maximal heart rate (MHR � 220
minus the age in years) for beginners, corresponding to brisk walking. The fre-
quency of PA is 3–7 times a week, for at least 30 min, split into up to three bouts.
An important issue is that even if a person is unsuccessful at weight loss,
the health benefits of exercise alone may be similar to those achieved by weight
loss in modulating the metabolic syndrome [35–37]. A suitable summary of this
might be that ‘Fat and fit is better than lean and lazy’. Additionally, weight loss
by exercise preserves lean body mass [38], a very important factor in weight
loss maintenance.
Conclusion
Women in the postmenopausal years have an increased risk for weight gain
and its associated morbidities. This is mainly due to hormonal changes and an
increase in central adiposity, along with insufficient amount of PA. Increasing
the amount of PA is expected to attenuate most of the obesity-associated med-
ical situations. Its role in weight management and the prevention of weight gain
or regain along the years is fundamental. With the aid of proper nutrition, that is
rich in fruit, vegetables and grains, and limited in fat and salt, weight loss and
its maintenance is achievable. Behavioral changes aimed at supporting the
decreased food intake and increased engagement in physical activities is of
sound importance.
References
1 World Health Organization: Obesity: Preventing and Managing the Global Epidemic. Report of a
WHO Consultation on Obesity. Geneva, World Health Organization, 1998.
2 Carr MC: The emergence of the metabolic syndrome with menopause. J Clin Endocrinol Metabol
2003;88:2404–2411.
3 Dubnov G, Berry EM: Managing obesity following the menopause: The role of physical activity;
in Lebenthal E, Shapira N, (eds): Nutrition in the Female Life Cycle. Israel, ISAS International
Seminars, 2001, pp 105–126.
4 Dubnov G, Brzezinski A, Berry EM: Weight control and the management of obesity after
menopause: The role of physical activity. Maturitas 2003;44:89–101.
5 Astrup A: Physical activity and weight gain and fat distribution changes with menopause: Current
evidence and research issues. Med Sci Sports Exerc 1999;31(suppl 11):S564–567.
Physical Activity and Postmenopausal Obesity 33
6 Mokdad AH, Bowman BA, Ford ES, et al: The continuing epidemics of obesity and diabetes in the
United States. JAMA 2001;286:1195–200.
7 Beer- Borst S, Morabia A, Hercberg S, et al: Obesity and other health determinants across Europe:
The EURALIM project. J Epidemiol Community Health 2000;54:424–430.
8 Hill JO, Peters JC: Environmental contributions to the obesity epidemic. Science 1998;280:
1371–1374.
9 Wing R, Matthews K, Kuller L, et al: Weight gain at the time of menopause. Arch Intern Med
1990;151:97–103.
10 Samaras K, Kelly PJ, Chiano MN, et al: Genetic and environmental influences on total body and
central abdominal fat: The effect of physical activity in female twins. Ann Intern Med 1999;130:
873–882.
11 Reubinoff BE, Wurtman J, Rojanski L, et al: Effects of hormone replacement therapy on weight,
body composition, fat distribution, and food intake in early postmenopausal women: A prospec-
tive study. Fertil Steril 1995;64:963–8.
12 Kanaya AM, Vittinghoff E, Shlipak MG, Resnick HE, Visser M, Grady D, Barrett-Connor E:
Association of total and central obesity with mortality in postmenopausal women with coronary
heart disease. Am J Epidemiol 2003;158:1161–1170.
13 Folsom AR, Kushi LH, Anderson KE, et al: Associations of general and abdominal obesity with
multiple health outcomes in older women. Arch Intern Med 2000;160:2117–2128.
14 Arabi A, Garnero P, Porcher R, Pelissier C, Benhamou CL, Roux C: Changes in body composition
during post-menopausal hormone therapy: A 2 year prospective study. Hum Reprod 2003;18:
1747–1752.
15 Berry EM: Strategies to improve patient compliance in the management of obesity; in Oomura Y
(eds): Progress in Obesity Research. London, Libbey, 1990.
16 National Institutes of Health: The practical guide to identification, evaluation, and treatment of
overweight and obesity in adults. National Institutes of Health, 2000.
17 Shape Up America! and American Obesity Association: Guidance for treatment of adult obesity.
Shape Up America! and American Obesity Association, Bethesda, 1996. Also available at http://
www.shapeup.org, accessed 10.5.2002.
18 US Department of Agriculture: US Department of Health and Human Services, Dietary
Guidelines for Americans, ed 5. Washington, US Department of Agriculture, 2000.
19 Miller WC, Koceja DM, Hamilton EJ: A meta- analysis of the past 25 years of weight loss research
using diet, exercise or diet plus exercise intervention. Int J Obes Relat Metab Disord 1997;21:
941–947.
20 McGuire MT, Wing RR, Klem ML, et al: Behavioral strategies of individuals who have main-
tained long- term weight losses. Obes Res 1999;7:334–341.
21 McTiernan A, Stanford JL, Daling JR, et al: Prevalence and correlates of recreational physical
activity in women aged 50–64 years. Menopause 1998;5:95–101.
22 Blair SN, Kampert JB, Kohl HW, et al: Influences of cardiorespiratory fitness and other pre-
cursors on cardiovascular disease and all-cause mortality in men and women. JAMA 1996;276:
205–210.
23 Sherman SE, D’Agostino RB, Cobb JL, et al: Physical activity and mortality in women in the
Framingham Heart Study. Am Heart J 1994;128:879–884.
24 Kohrt WM, Obert KA, Holloszy JO: Exercise training improves fat distribution patterns in 60 to
70 year old men and women. J Gerontol 1992;47:M99–M105.
25 Williamson DF, Madans J, Anda RF, et al: Recreational physical activity and ten-year weight
change in a US national cohort. Int J Obes Relat Metab Disord 1993;17:279–286.
26 Blair SN, Brodney S: Effects of physical inactivity and obesity on morbidity and mortality:
Current evidence and research issues. Med Sci Sports Exerc 1999;31:s646–s662.
27 Wu FB, Stampfer MJ, Solomon C, et al: Physical activity and risk for cardiovascular events in dia-
betic women. Ann Intern Med 2001;134:96–105.
28 McTiernan A, Ulrich C, Slate S, et al: Physical activity and cancer etiology: associations and
mechanisms. Cancer Causes Control 1998;9:487–509.
29 Dubnov G, Berry EM: Physical activity and mood: The endocrine connection; in Warren MP,
Constantini NW (eds): Sports Endocrinology. Totowa, NJ, Humana Press, 2000, pp 421–431.
Dubnov/Berry 34
30 American College of Sports Medicine Position Stand on the recommended quantity and quality of
exercise for developing and maintaining cardiorespiratory and muscular fitness, and flexibility in
adults. Med Sci Sports Exerc 1998;30:975–991.
31 Pate RR, Pratt M, Blair SN, et al: Physical activity and public health – a recommendation from the
Centers for Disease Control and Prevention and the American College of Sports Medicine. JAMA
1995;273:402–407.
32 National Institutes of Health: Physical activity and cardiovascular health. NIH Consens Statement
1995;13:1–33.
33 Pereira MA, Kriska AM, Day RD, et al: A randomized walking trial of postmenopausal women.
Arch Intern Med 1998;158:1695–1701.
34 Ballor DL, Poehlman ET: Exercise training enhances fat- free mass preservation during diet-
induced weight loss: A meta-analytical finding. Int J Obes Relat Metab Disord 1994;18:35–40.
35 Farrell SW, Braun L, Barlow CE, Cheng YJ, Blair SN: The relation of body mass index, cardiores-
piratory fitness, and all-cause mortality in women. Obes Res 2002;10:417–23.
36 Blair SN, Kampert JB, Kohl HW 3rd, Barlow CE, Macera CA, Paffenbarger RS Jr, Gibbons LW:
Influences of cardiorespiratory fitness and other precursors on cardiovascular disease and all-
cause mortality in men and women. JAMA 1996;276:205–210.
37 Stevens J, Cai J, Evenson KR, Thomas R: Fitness and fatness as predictors of mortality from all
causes and from cardiovascular disease in men and women in the lipid research clinics study. Am
J Epidemiol 2002;156:832–841.
38 Karni Y, Kaplanski Y, Magazanik A, Berry EM: Energy deficit of 1,000 kcal/day (4,184 kJ)
through diet or exercise: which is better for men with obesity? Public Health Rev 2005;in press.
Elliot M. Berry, MD
Department of Human Nutrition and Metabolism
Faculty of Medicine, The Hebrew University-Hadassah Medical School
POB 12272, 91120 Jerusalem (Israel)
Tel. �972 2 675 8298, Fax �972 2 643 1105
E-Mail [email protected], [email protected]
Simopoulos AP (ed): Nutrition and Fitness: Mental Health, Aging, and
the Implementation of a Healthy Diet and Physical Activity Lifestyle.
World Rev Nutr Diet. Basel, Karger, 2005, vol 95, pp 35–51
Osteoporosis: A Complex Disorder ofAging with Multiple Genetic andEnvironmental Determinants
Serge L. Ferrari
Division of Bone Diseases, Department of Rehabilitation and Geriatrics, Geneva
University Hospital, Geneva, Switzerland
Determinants of Osteoporosis and Fracture Risk
Osteoporosis is a skeletal disorder characterized by compromised bone
strength predisposing to an increased risk of fracture [1]. This disease repre-
sents a major public health concern that will only increase in importance as life
expectancy increases and the population ages. Accordingly, osteoporosis has
been recognized as a ‘global problem’ by the World Health Organization
(WHO) [2]. Specifically, the lifetime risk of suffering an osteoporosis-related
fracture approaches 50% in women and 20% in men [3, 4].
Osteoporosis is diagnosed by dual-energy X-ray absorptiometry (DXA)
when bone mineral density (BMD, g/cm2) is below �2.5 SDs from the mean
bone density in young adults (i.e. ��2.5 T-score), so-called peak bone mass.
However, fracture risk increases continuously as BMD decreases [3], and at least
doubles for each SD decrease of BMD relative to peak [5, 6]. Osteoporosis
results from a failure to acquire optimal peak bone mass during growth [7],
and/or to maintain bone mass in later years. Women experience a more rapid
phase of bone loss after the menopause (0.5–2.0%/year), due mainly to estrogen
deficiency [8, 9], but bone loss continues in older persons [10, 11]. Osteoporosis
is less common in males than females [12] and men have a three times lower risk
of fractures compared to women because they reach higher peak bone mass,
which reflects a larger bone size rather than a greater bone mineral density
within bone [13]. Moreover, hypogonadism affects only about 30% of aging
males [14] and men have a shorter life expectancy compared to women.
Ferrari 36
In addition to bone density, osteoporosis is also determined by ‘bone quality’
traits, which represents the architecture of the skeleton, such as hip geometry,
femur cortical thickness and trabecular connectivity in the vertebrae, the proper-
ties of the bone material (collagen type 1 and mineral), and its turnover rate [15].
The latter can be evaluated indirectly by a series of serum and urine biochemical
markers that reflect bone formation (osteocalcin, bone specific alkaline phos-
phatase) and resorption (collagen degradation products, such as pyridinoline and
C-terminal cross-linking of type I collagen, CTx) [16]. These markers are com-
monly used to evaluate osteoporosis risk in addition to BMD [17, 18]. Although
BMD (by DXA), bone turnover markers and prevalent fractures, alone and in
combination, can predict fracture risk at least as well as cardiovascular risk fac-
tors can predict the risk of coronary heart disease, they remain relatively insensi-
tive to identify all individuals who will eventually have a fracture [6, 19, 20].
Multiple endogenous, environmental and life style factors concur to the
occurrence of osteoporosis and related fractures (table 1). In turn, intervention
trials using calcium supplements and/or dairy food products have proven bene-
ficial to improve bone mass gain in children, particularly those with a poor cal-
cium intake [21, 22]. Moreover, calcium, vitamin D and protein supplements all
improve bone mass and/or fracture risk in the elderly [23–26]. However, the
most important determinant of bone mass remains the genetic constitution.
Heritability of Bone Mass and Strength
Both women and men with a family history of osteoporosis have signifi-
cantly decreased BMD compared other subjects [27–30]. Twins and parents-
offspring studies have shown that heritability, i.e. the additive effects of genes,
Table 1. Risk factors for osteoporosis
Age
Low body weight (BMI �18)
Early menopause (�45 years)
Hypogonadism
Family history of osteoporosis/fracture
Low physical activity
Low calcium intake (�500 mg/day)
Smoking
Excessive alcohol intake
Medications (corticosteroids, anti-epileptic drugs, NSAIDS)
Chronic disease (malabsorption, RA, CRF, diabetes,
primary hyperparathyroidism, hyperthyroidism)
Osteoporosis 37
explains 60–80% of the population variance for peak bone mass, and the
influence of these genetic factors is expressed well before puberty [31, 32]. In
contrast, genetic contribution to the rate of bone turnover and bone loss after
menopause has been less precisely evaluated, and might actually be smaller
(40–60%) [33]. Fracture is a very complex phenotype, which, in addition to bone
quantity and quality-related factors (above), also depends on other endogenous
factors such as the propensity to fall [34], protective responses, soft tissue
padding, etc, and exogenous factors present in the living environment. The latter
factors likely explain why additive genetic factors appear to contribute only
about 30% to the population-based variance in the liability for fracture [35].
Genome Screens for Bone Mass in Humans
Genome-wide screening approaches search for loci flanked by DNA
microsatellite markers that co-segregate with the phenotype of interest in a pop-
ulation of related individuals. The pedigrees so far investigated are families
with a proband characterized by an extreme skeletal phenotype (high or low
bone mass [36–38]), as well as nuclear families and sibships from the popula-
tion at large [39, 40]. These studies have started to map a large number of QTLs
for BMD [41, 42] (fig. 1). In addition, QTLs for bone geometry and size at the
spine and femur [41, 43, 44], as well as for bone ultrasound properties [45],
have been identified. Although the actual number of genes contributing to bone
strength is currently unknown, dozens of genes with relatively small additive
effects and a few genes with rather large effects might be involved [46–50].
Fig. 1. Quantitative Trait Loci (QTLs) for bone mineral density (BMD) in Caucasians
were identified by genome-wide screening approaches in five separate studies (see text for
details). QTLs with suggestive or evidence of linkage are indicated (LOD scores 1.8–3.0 and
�3.0, respectively) and those identified in more than one study are shown in bold. Adapted
from Ferrari [147].
Ferrari 38
Population-Based Association Studies
Hundreds of association analyses have been reported with BMD, bone
turnover markers, and sometimes fracture, using polymorphic candidate genes
coding for bone structural molecules, hormones, growth factors and/or their
receptors implicated in bone and mineral metabolism, cytokines involved in
bone remodeling, etc. [42, 51]. Among them, association studies with the vita-
min D receptor (VDR), estrogen receptor-� (ESR1) and type I collagen A1
chain (Col1A1) have recently been meta-analyzed. The latter studies and those
involving interleukin-6 (IL-6) and the recently discovered LDL-receptor-related
protein 5 (LRP5) gene polymorphisms are summarized below. It is now clear
that genetic variants may influence bone mass at specific skeletal sites, such as
the vertebrae or hip, selectively affect males or females, young or old adults,
and estrogen-deficient or -replete females, and interact with environmental
factors, such as dietary calcium intake.
Vitamin D Receptor Gene (VDR) PolymorphismsThe vitamin D receptor (VDR) mediates the effects of calcitriol [1,25(OH)2
D3] on the intestinal absorption of calcium and phosphate and on bone mineral-
ization. The VDR gene, whose nine exons and multiple promoters span over
more than 80kb, carries multiple polymorphisms [52]. Morrison et al. [53] first
reported that VDR 3�-UTR Bsm1 alleles (B frequency, 0.4 and 0.1 among
Caucasians and Asians, respectively) were associated with BMD in adult women
and postmenopausal bone loss. A Fok1 variant in the VDR first start codon
(ATG), (f frequency, 0.4 among both Caucasians and Asians) was later reported
to be also associated with BMD in postmenopausal women [54]. Subsequently,
numerous population-based studies including hundreds to thousands of sub-
jects, mostly pre- and post-menopausal women, looked at the association
between VDR alleles, BMD and bone loss, with discordant results [55–67]. In
addition, several studies suggested that VDR alleles might be associated with
bone mass, bone and/or body size in children [62, 63, 68–72]. However, some
investigators failed to find such association [73, 74], and others noted a vanish-
ing influence of VDR genotypes on bone mass with advancing age [63, 75].
Two recent meta-analysis [76, 77] eventually support some significant associa-
tion of VDR polymorphisms with bone mass in women. In the first analysis,
Gong et al. found that 23 of 67 studies reported a significant association
between VDR genotypes and BMD at lumbar spine, whereas 22 of 51 studies
reported a significant association with femoral neck BMD. Despite an apparent
predominance of negative studies, the authors calculated that the number of
positive studies in pre- and post-menopausal women far exceeded the number
of false positive results expected under the null hypothesis (alpha � 5%) [76].
Osteoporosis 39
More recently, a meta-analysis of VDR association studies published between
1994 and 2001 found 13 eligible studies in post-menopausal women, leading to
an estimated 2.4% (p � 0.028) lower spine BMD in BB compared to Bb/bb (i.e.
a recessive effect of the B allele) [77]. Moreover, in 9 eligible cohort studies,
women with the BB and Bb genotypes had a significantly greater bone loss at
lumbar spine compared to bb (–0.43%/year, p � 0.011, i.e. a dominant effect of
the B allele). In contrast, this analysis did not confirm association in pre-
menopausal women nor at the femoral neck [77].
Epidemiological observations and prospective intervention studies suggest
an interaction between dietary calcium intake and VDR polymorphisms on their
association with bone mass in both children and aging subjects. In a cohort of
144 pre-pubertal girls receiving calcium supplements (850 mg/day) compared to
placebo [21], BMD gain in response to calcium was significantly increased at
several skeletal sites among BB and Bb, but not in bb girls [63]. In contrast, in
235 pre-pubertal boys, we failed to observe a significant effect of calcium sup-
plements, and either association or interaction with VDR genotypes [unpubl.
data]. Others found that VDR 3�-UTR genotypes were similarly distributed
among 105 rachitic children from Nigeria (calcium intake, 200 mg/d) and 94
healthy controls, whereas the Fok1 ff genotype was significantly under-repre-
sented among cases [78]. A significant interaction between VDR-3� genotypes
and calcium intake on BMD and BMD changes has also been observed in post-
menopausal women [65, 79–81]. For instance, a long-term follow-up (6.3 years)
study in elderly postmenopausal women (n � 193, mean age, 69 years) reported
that among those with low calcium intake (below 456 mg/day), VDR Taq1 TT
homozygotes (same as bb) had a significantly lower rate of bone loss at both the
femoral neck and lumbar spine compared to tt (same as BB). These differences
were no more detectable in those with the highest calcium intake [82]. Two large
cohort studies have examined the association between VDR genotypes and frac-
ture risk. In the Nurses Health Study (mean age 60 years), the BB genotype was
associated with a more than twofold increased risk of hip (but not forearm) frac-
ture compared with the bb genotype. Risk was greater for women who were
older, leaner, or less physically active or who had a calcium intake below
1078 mg/d (odds ratio, 4.3) [83]. In contrast, the Study of Osteoporotic Fractures
(SOF), including 9,704 community-dwelling women aged 65 years and older,
failed to demonstrate a difference in VDR alleles distribution among 530 cases
with a hip, vertebral or other fracture, and controls, both before and after stratifi-
cation for calcium intake and other variables [84].
In summary, under usual dietary calcium intakes, the VDR allele B could
be associated with a modest deficit of bone mass growth in infancy and with an
even more modest increase of bone loss after the menopause. However, it
remains uncertain whether VDR genotypes contribute significantly to fracture
Ferrari 40
risk in the elderly. Since it has been suggested that calcium supplementation
could be associated with a better bone mass response in carriers of the VDR
allele B [31, 85], this possibility needs to be investigated in prospective,
calcium-dosing trials stratifying the cohort by VDR genotypes.
Estrogen Receptors Gene (ESR1 and ESR2) PolymorphismsEstradiol plays a major role in the acquisition and maintenance of peak
bone mass in both females [86, 87] and males [8, 88, 89]. Genotypes identified
by PvuII and XbaI restriction enzymes in the first intron of the estrogen recep-
tor (ER) alpha gene (ESR1) were originally found to be significantly associated
with BMD in postmenopausal [90] and younger pre-menopausal [91] Asian
women. ESR1 gene polymorphisms, including PvuII, XbaI and a TA repeat
polymorphism in the promoter region, were subsequently analyzed in associa-
tion with bone mass, bone loss and/or fractures in Caucasian women, with
contrasting results [64, 92–100]. Interestingly, some authors reported an inter-
action between ESR1 polymorphisms and hormone replacement therapy (HRT)
[94, 101] as well as a gene-by-gene interaction between ESR1 and VDR
alleles [64, 92].
A meta-analysis of the association between ESR1 genotypes and BMD
including more than five thousand women from 22 eligible studies (n � 11 in
Caucasians and n � 11 in Asians), concluded that homozygotes for the XbaI
XX genotype have a modestly but significantly higher BMD (�1–2%) at lum-
bar spine or hip compared to xx [102]. No differences were found between
PvuII genotypes, but since the XbaI and PvuII sites are in strong linkage dis-equilibrium, this may explain why some authors found an association with P/p
alleles. In this meta-analysis, differences between genotypes tended to be up to
five time greater in pre- compared to post-menopausal women, suggesting that
ESR1genotypes might influence peak bone mass acquisition, although only
three studies were available before menopause. Most interestingly, differences
in fracture risk were disproportionately high compared to the small differences
of bone mass observed between genotypes (odds ratio, 0.66 [95% CI,
0.47–0.93] in XX vs. xx) [102], suggesting that ESR1genotypes might influ-
ence bone quality above and beyond BMD.
There is recent evidence that estrogen receptor-�, which is coded by a sep-
arate gene (ESR2), plays a distinct role in the regulation of bone mass [103].
Accordingly, associations were recently described between ESR2 CA repeat
polymorphisms and BMD in postmenopausal Japanese women [104], as well as
in men and women from the Framingham Osteoporosis Study [105]. It will
therefore be interesting to investigate potential interactions between ESR1 and
ESR2 alleles on bone mass.
Osteoporosis 41
Collagen 1�1 Chain Gene (Col1A1) Polymorphisms
Another widely investigated candidate gene for osteoporosis that carries a
functional polymorphism in its regulatory region is the collagen type 1�1 gene
(COL1A1). Collagen type 1 is a major structural molecule of the bone matrix
(and is also found in skin and tendons), where two collagen I�1 chains associ-
ate with one collagen 1�2 chain to form the triple helix of collagen. A G�Tpolymorphism in the binding site for the transcription factor Sp1 was described,
resulting in a rare s variant (frequency, 0.1–0.15 in Caucasians, ��0.1 in
Asians [106]). The s allele was first associated with lower lumbar spine BMD
and a higher prevalence of vertebral fractures in postmenopausal women [107].
A second large population-based study confirmed an allele-dosage effect of the
s allele on decreasing BMD, mostly in older subjects, as well as on increasing
the incidence of vertebral fractures during a 4-year observation period [108].
Most importantly, the COL1A1 s variant was recently shown to produce too
much collagen 1�1 molecules compared to the S allele in vitro, causing bone to
be less resistant to mechanical stress [109].
Despite this good evidence for functionality and association with bone
fragility, COL1A1 polymorphisms have also sometimes failed to show associa-
tion with BMD, bone loss, fractures, ultrasound properties of bone, or markers
of bone resorption [110–112]. In this case as well, a meta-analysis of published
data concluded to a modest effect of the s allele on BMD (equivalent to 0.1–0.2
SD decrease compared to S) but a more prominent association with fracture
risk (OR 1.5 and 1.9 in Ss and ss compared to SS genotypes, respectively)
[109]. Of note, another large meta-analysis looking at hundreds of genetic asso-
ciation studies across various complex disorders and polymorphic genes
confirmed a significant association of COL1A1 Sp1 alleles with fracture risk
(OR, 1.6) [113]. Taken together with the functional data mentioned above, these
results indeed suggest that COL1A1 Sp1 polymorphisms may affect some
‘bone quality’ component which is poorly reflected by BMD alone.
Interleukin-6 Gene Promoter PolymorphismsInterleukin-6 (IL-6) is a pleiotropic cytokine playing a central role in
the activation of osteoclasts, – the bone resorbing cell –, bone turnover, and
bone loss, particularly following estrogen deficiency [114, 115]. A common
–174G�C polymorphism (frequency of C, 0.4 among Caucasians) and, to a
lesser extent, a rare –572G�C polymorphism (frequency of C, 0.06 among
Caucasians) in the IL-6 gene promoter are associated with IL-6 activity in vitro
and in vivo [116, 117]. In turn, in 434 healthy white American postmenopausal
women (mean age, 72 years), bone resorption was significantly lower
among �174CC (and �572GG) compared to the other genotypes, and the age-
related decrease in BMD was more prominent among IL-6 �174 GG and GC
Ferrari 42
genotypes (�9 to �10% over 10 years) compared to CC (�5 to �6.1%)
[117, 118].
Several studies have identified the IL-6 gene locus (7p21) to be linked to
BMD in postmenopausal women [119, 120] and in families of osteoporotic
probands [121, 122], whereas no linkage was found in young, healthy sister pairs
[123]. These observations suggested that IL-6 genetic variation might specifi-
cally contribute to the population variance in bone mass in the elderly. However,
two studies reported an association of IL-6 polymorphisms with peak bone
mass, one in young adult males [124] and the other in pre-menopausal females
[125]. Moreover, the latter study failed to detect a lower rate of bone resorption
or bone loss associated with the �174CC genotype in 234 postmenopausal
women (mean age, 64 years). Subsequently, the interaction between IL-6
promoter polymorphisms and factors known to affect bone turnover, namely
years since menopause, estrogen status, dietary calcium and vitamin D intake,
physical activity, smoking, and alcohol, was examined in the Offspring Cohort
of the Framingham Heart Study [126]. This cohort comprises 1,574 unrelated
men and women (mean age 60 years) with cross-sectional bone mineral density
measurements at the hip. Consistent with the study of Garnero et al. [125], in
models that considered only the main effects of IL-6 polymorphisms, no signifi-
cant association with bone mineral density was observed in either women
(n � 819) or men (n � 755). In contrast, significant p values were found for an
interaction between IL-6 �174 genotypes and years since menopause, estrogen
status, dietary calcium and vitamin D intake in women. Thus, bone mineral den-
sity was significantly lower with genotype �174 GG compared to CC, and inter-
mediate with GC, past 15 years since menopause, in case of estrogen-deficiency
or insufficient calcium intake (�940 mg/day). In women with both estrogen-
deficiency and poor calcium intake, BMD differences at the hip between IL-6
�174 CC and GG were as high as 16.8%.
In summary, these data indicate that the influence of IL-6 gene variants on
bone mass may depend on gender, age, estrogen status and dietary calcium. It is
currently unknown whether IL-6 polymorphisms directly contribute to fracture
risk and it would be particularly interesting to investigate whether they could
modulate the skeletal response to selective estrogen receptor modulators
(SERMS) [127].
LDL-Receptor Related Protein 5 Gene (LRP5) Polymorphisms: A NovelGenetic Susceptibility Factor for Male OsteoporosisLRP5 is a member of the low-density lipoprotein (LDL) receptor-related fam-
ily coding for a transmembrane co-receptor for Wnt signaling [128]. Several lines
of evidence point to LRP5 as a candidate gene for osteoporosis. Loss-of-function
mutations in LRP5 are responsible for osteoporosis pseudoglioma (OPPG), an
Osteoporosis 43
autosomal-recessive disorder characterized by low bone mass, spontaneous
fractures and blindness [129], whereas LRP5 gain-of-function mutations result in
high bone mass and sclerosing bone dysplasias [130–132]. Moreover, mice with
targeted disruption of LRP5 have a deficit in bone formation and sustain fractures
[133]. Most importantly, a QTL for bone mineral density in the general population
was mapped at 11q12–13, the LRP5 locus (fig. 1) [134–136].
A population-based study of five LRP5 polymorphisms with allele fre-
quencies �2% found that a missense substitution in exon 9 (c.2047G�A,
p.V667M) and haplotypes based on exon 9 and exon 18 (c.4037 C�T,
p.A1330V) alleles were significantly associated with bone mass and projected
area of vertebrae at the lumbar spine in adult males, but not females, accounting
for up to 15% of the population variance for these traits in men [137].
Consistent with the presence of a QTL for stature at 11q12–13 [138] [139], the
exon 9 variant was also significantly associated with stature in both genders.
Moreover, 1-year changes in lumbar spine bone mass and size in pre-pubertal
boys were also significantly associated with these LRP5 variants [137], sug-
gesting that LRP5 polymorphisms could contribute to the risk of spine osteo-
porosis in men by influencing vertebral bone growth during childhood.
Accordingly, LRP5 polymorphisms were investigated in 80 European-Caucasian
men with idiopathic osteoporosis and 88 controls (mean age: 50.4 years, range
23–70). This rather uncommon form of osteoporosis affects middle-aged men
and is characterized by low peak bone mass and an increased incidence of ver-
tebral fractures in absence of secondary causes, and by a clear heritable component
[30, 140]. In keeping with the previous association study, exon 9 A and exon
18 T alleles were twice more common in cases than controls, and the odds for
idiopathic male osteoporosis and fractures among carriers of the 9A-18T haplo-
type were greater than 2 [unpubl. data].
Hence, LRP5 polymorphisms could be a first identified genetic factor for
gender-related differences in bone size and a specific susceptibility factor for
spine osteoporosis in men. Moreover, ongoing analyses of LRP5 polymor-
phisms in the Framingham Osteoporosis Study suggest an interaction with
physical activity in men, in that the favorable effects of physical activity on
BMD would be more prominent among carriers of the 18T allele.
Summary and Perspectives
Thirty years have elapsed since the first published evidence of a high heri-
tability for bone mineral density (BMD) in twins [141], and 10 years since vitamin
D receptor (VDR)-3�UTR alleles were the first described gene variants associated
with BMD in humans [53]. Meanwhile, genome-wide screens in humans (and
Ferrari 44
mice, although not discussed in this review [41]) have taught us where to look for
specific genes (fig. 1), and recent developments in molecular technology now
allow to identify these genes and their variants [142, 143]. Despite commonly
inconsistent results among different studies, population-based association analyses
are required to ultimately demonstrate the implication of gene variants to any com-
plex disease [144]. In doing so, we should be aware that the strength of the associ-
ation may depend on gender, age, ethnicity, and interactions with a number of life
style and environmental risk factors for osteoporosis (table 1). Most importantly,
we should start to directly evaluate whether candidate gene polymorphisms so far
identified in association studies could be translated into clinical practice, i.e. eval-
uate the positive and negative predictive values of gene markers with respect to
osteoporosis and fracture risk, and response to therapy, in the targeted population.
Guidelines for population screening as applied to genetic susceptibility to disease
have recently been published [145]. Rather than looking disdainfully at the
‘genetic revolution of medicine’ [146], we should do any efforts to bring this
increasing knowledge from the bench to the bedside.
Acknowledgements
I thank Prof. Jean-Philippe Bonjour, Prof. René Rizzoli, Dr. Thierry Chevalley and the
nurses, dietician and technical staff of the Division of Bone Diseases, Departments of
Geriatrics and Rehabilitation; Prof. Daniel Slosman and the technicians from the Division of
Nuclear Medicine, Department NEUCLID; Prof. Stylianos Antonarakis, Sam Deutsch and
Urmilla Chudhury, from the Department of Medical Genetics; Prof. Suzanne Suter and her
collaborators at the Department of Pediatrics, all at the Geneva University Hospital,
Switzerland; Prof. John Eisman (Sydney); Prof. Douglas Kiel, Dr. David Karasik and the
Framingham Osteoporosis Study investigators (Boston); Dr. Patrick Garnero (Lyon); Prof.
Steve Humphries and his collaborators (London), and Prof. Susan Greenspan and the DXA
technicians at BIDMC (Boston) for their contribution to this work.
I am indebted to all the volunteers who participated in our studies and to the Swiss
National Science Foundation (SNF), the Geneva University Hospital and the National
Institutes of Health (NIH, USA) for their financial support.
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Prof. Serge Ferrari
Service des Maladies Osseuses
HUG, 21, rue Micheli-du-Crest
CH–1211 Geneva 14 (Switzerland)
Tel./Fax �41 22 3829952/3829973, E-Mail [email protected]
Simopoulos AP (ed): Nutrition and Fitness: Mental Health, Aging, and
the Implementation of a Healthy Diet and Physical Activity Lifestyle.
World Rev Nutr Diet. Basel, Karger, 2005, vol 95, pp 52–61
Changes in Dietary Fatty Acids and Life Style as Major Factors for RapidlyIncreasing Inflammatory Diseases andElderly-Onset Diseases
Harumi Okuyama, Yuko Ichikawa, Yoichi Fujii, Masafumi Ito, Kazuyo Yamada
Department of Preventive Nutraceutical Sciences, Graduate School of
Pharmaceutical Sciences, Nagoya City University, and
Kinjo Gakuin University College of Pharmacy, Nagoya, Japan
After World War II (ended in 1945), the mortality from infectious dis-
eases decreased rapidly toward 1960 (fig. 1), and the Japanese are currently
enjoying the world’s longest life expectancy among the countries with rela-
tively large populations. However, the disease pattern has changed during this
period and the mortality from tuberculosis and pneumonia decreased toward
1970. Thereafter, the mortality from pneumonia, but not tuberculosis, began
to increase even when it was age-adjusted. This increase in pneumonia is
likely to be allergic in part, which is associated with increasing cancers of the
bronchi and lungs. Although the mortality from cardiovascular diseases
is currently much lower in Japan than in the USA (�1/4), it is increasing
steadily. Allergic hyper-reactivity is not directly associated with mortality,
but it is generally accepted that populations suffering from allergic hyper-
reactivity have increased several folds during the past 40 years in Japan.
Cancer is the leading cause of death after 1981, and the increase in cancers of
the US type (colorectum, pancreas, trachea, bronchus, lung, prostate and
esophagus) is prominent.
The major elderly-onset diseases in Japan are cancer, atherosclerosis-
related diseases and pneumonia. Elevation of inflammatory tone is a likely major
cause for these diseases, which is brought about by excessive intake of linoleic
acid (LA, �–6) and enhanced arachidonic acid (AA, �–6) cascade [1]. Because
Diet and Life Style in Inflammatory Diseases 53
�–6 and �–3 fatty acids and their metabolites (eicosanoids, inflammatory medi-
ators) are competitive at many steps of enzyme reactions and receptors, not only
the absolute amounts of �–6 and �–3 fatty acids, but their balance, particularly
the �–6/�–3 ratio, is an important factor in regulating the inflammatory tone
and related diseases [1, 2].
Changes in life style such as decreased physical activity and overnutrition
in older populations lead to unfavorable energy balance. Reduced frequency of
skin exposure to environmental changes (temperature, sweating conditions) is a
likely cause for enhanced skin and mucosal sensitivity to allergens in younger
populations. These environmental factors could be modified by changing the
life style, besides choosing foods to keep a good �–6/�–3 fatty acid balance.
Competition among Fatty Acids in Three Metabolic Series in Mammals
Fatty acids are classified into three series depending on their metabolism
in mammals: (1) saturated and monounsaturated fatty acid series; (2) �–6 series
(linoleic acid→arachidonic acid), and (3) �–3 series (�-linolenic acid → eico-
sapentaenoic acid, EPA→docosahexaenoic acid, DHA). In phospholipids,
Tuberculosis
Rat
e p
er 1
00,0
00
1950 1960 1970 1980 1990 2000 year
(1947–2002)
200
100
0
Pneumonia
Heart diseases
Malignant neoplasma
Cerebrovascular diseases
Diseases of liver
250
Changes inclassificationof diseasesadvised
Fig. 1. Annual mortality trends by leading causes of death in Japan (Vital statistics of
Japan, Statistics and Information Department, Ministry of Health, Labour and Welfare, Japan).
Okuyama/Ichikawa/Fujii/Ito/Yamada 54
saturated fatty acids are incorporated preferentially into the 1-position while
polyunsaturated fatty acids are confined to the 2-position, and these �–6 and
�–3 fatty acids compete with each other at the acyltransferase steps; saturated
and monounsaturated fatty acids are not effective as competitors in polyunsatu-
rated fatty acid incorporation. The �–6 and �–3 fatty acids at the 2-position of
membrane phospholipids are the major precursors and competitors of eicosanoid
synthesis. Therefore, the �–6/�–3 ratio of phospholipids is a good marker of
eicosanoid production and inflammatory tone [2].
Recently, unexpected observations were presented by Broughton et al. [3];
dietary animal fats enriched with saturated and monounsaturated fatty acids also
suppressed competitively the production of �–6 eicosanoids when �–6/�–3
ratios were high. Competition among dietary and de novo synthesized fatty acids
occurs not only at the steps of incorporation into various lipids but also at the
steps of mitochondrial and peroxysomal �-oxidation systems and possibly at the
step of excretion to skin/hair [4].
These observations are nutritionally important. Currently, nutritionists
tend to advice people to reduce the intake of animal fats first rather than reduc-
ing the intake of linoleic acid (�–6). If the intake of animal fats is reduced
without reducing �–6 fatty acids, eicosanoid tone would be elevated unless
the intake of �–3 fatty acids is increased. Because eicosanoids are not synthe-
sized from saturated and monounsaturated fatty acids, animal fats are relatively
safe for the diseases caused by over- and unbalanced productions of �–6
eicosanoids.
Regulation of Gene Expression by Fatty Acids
Various fatty acids have been shown to exert differential effects on gene
expression related to cholesterol and fatty acid metabolism, which is a major
topic in the current lipid nutrition research. Here is another world in which the
chain length and melting point of fatty acids play major role in the regulatory
mechanism.
Dietary long chain polyunsaturated fatty acids up-regulate �-oxidation
enzymes, uncoupling protein and anti-oxidative superoxide dismutase, regardless
of �–6 and �–3 series, while saturated and monounsaturated fatty acids, and
linoleic acid to a slightly lesser extent, up-regulate cholesterol synthesis. The
prenyl intermediates in cholesterol synthesis play divergent roles, one of which is
a role in cell proliferation through prenylation and activation of oncogene prod-
ucts. In this context, the intakes of saturated, monounsaturated and linoleic acids
should be restricted particularly in older people requiring to improve energy
balance.
Diet and Life Style in Inflammatory Diseases 55
Evidence Against Lipid Peroxide Theory of Aging
The original free radical theory of aging came out from comparing the
effect of dietary fish oil and several kinds of vegetable oils with different degree
of unsaturation in rats [5]. Error in a maze test increased along with increasing
the degree of unsaturation of dietary oils while those oils affected the longevity
little. Moreover, some inhibitors of free radical reactions prolonged the survival
of mice. These observations led to a hypothesis that feeding highly unsaturated
fatty acids such as fish oil for a long period leads to accumulation of lipid
peroxides in tissues, which, in turn, decompose to form free radicals and injure
tissues, thereby accelerating the aging process. In this hypothesis, the ‘free
radical injury’ is used synonymously with ‘lipid peroxide injury’ [6]. However,
the observed effect of free radical reaction inhibitors on longevity could be
interpreted in a different way because weight loss was observed by feeding such
inhibitors. These inhibitors are likely to have brought about energy restriction,
which is well known to prolong the survival of rodents.
In our studies, a simple maize test was not sufficient to estimate the learn-
ing ability of rodents accurately [7]. Using a more sophisticated test (operant-
type, brightness-discrimination learning test), we have shown that learning
behavior and memory retention are superior in the rats fed �–3 fatty acid-
enriched oil (�-linolenic acid-rich perilla seed oil and DHA-rich fish oil)
through 2 generations compared with linoleic acid (�–6)-rich oils (safflower
oil, soybean oil). [8, 9]. The effect of �–3 fatty acid-deficiency during preg-
nancy and lactation was reversed by feeding �–3 fatty acids after weaning but
not by feeding �–6 fatty acid [10] (fig. 2). Furthermore, impaired learning
behavior was reversed by DHA (�–3) only when the diet contained relatively
low concentrations of linoleic acid (�–6). These results indicate that taking �–3
fatty acids and restricting �–6 fatty acids are beneficial for the maintenance of
brain functions in aged rats [9].
Stroke-prone, spontaneously hypertensive (SHRSP) rats develop hyperten-
sion and die of stroke, particularly when salt solution was given as drinking
water. Using this animal model, dietary �-linolenic acid (perilla oil and
flaxseed oil) and DHA were shown to prolong the survival [11, 12]. Moreover,
DHA was effective in suppressing the stroke-related behavioral changes (loss
of circadian rhythm) [13].
Although tissues from fish oil-fed animals are enriched with EPA/DHA
and are more susceptible to auto-oxidation in vitro, no signs of elevated lipid
peroxide levels and denatured proteins are noted in vivo [14], but fresh tissues
tend to contain reduced amounts of lipid peroxides [15]. Oxygen pressure in
organs are much lower than in the atmosphere. Cells in tissues are under rela-
tively hypoxic conditions and chain reactions of lipid peroxidation would not
Okuyama/Ichikawa/Fujii/Ito/Yamada 56
occur when appropriate amounts of endogenous antioxidants (vitamins C and E,
glutathione) are present.
Free radicals produced in vivo attack polyunsaturated fatty acids and form
lipid peroxides, which decompose to form stable hydroxyl fatty acids by reac-
tion with reduced form of vitamin E, and the oxidized vitamin E is reduced
consuming vitamin C or glutathione, and the oxidized vitamin C and glu-
tathione are reduced using energy (NADPH). Thus in living cells, polyunsatu-
rated fatty acids and anti-oxidative vitamins serve as scavengers rather than
propagators of free radical reactions [16].
Hypoxia and Persistent Inflammation Induce Peroxidative Injury
Free radical injury is recognized as an early event under various pathologi-
cal conditions. However, elevated levels of free radicals are unlikely to be
Session (days) Session (days)
Res
pon
se/s
essi
on
Cor
rect
res
pon
se r
atio
(%)
YoungSaf
AgedSaf
AgedPer
YoungPer
AgedSaf
AgedSaf
500
400
300 300
200 200
100 100
0 10 20 30 0 10 20 30
100
90
80
70
60
50
40
30
0 10 20 30
***** *
***
***
*
Positive responses(diet pellets delivered)
Negative responses(no pellets delivered)
a b
Fig. 2. Brightness-discrimination learning behavior affected by dietary linoleic and
�-linolenic acids in aged rats [8]. Diet supplemented with high-linoleic safflower oil or high-
�-linolenic perilla oil was given to mothers (F0) and the learning test of male pups (F1) was
started at 19.7 months of age (80% of the mean survival time of the male F0 group fed the saf-
flower oil diet). a Diet pellet was delivered for the responses under bright light (positive
response) while no pellet was given for the responses under dim light (negative response), and
the test was performed once a day for 30 days. b Correct response ratio was calculated as 100�positive response/total responses. *p � 0.05; **p � 0.01 in Student’s t test. The difference
between the two groups was statisticallly significant in 2-way ANOVA (p � 0.05).
Diet and Life Style in Inflammatory Diseases 57
brought about by enrichment of membrane lipids with polyunsaturated �–3
fatty acids. Instead, we interpret that free radicals are produced and injure tis-
sues in vivo when cells are exposed to hypoxic conditions, where inflammatory
cells are recruited to clean the damaged cells, and eicosanoids serve as chemo-
attractants. When cells are enriched with arachidonic acid, �–6 inflammatory
mediators are produced in excess leading to persistent inflammation, and
inflammatory cells produce reactive oxygen species. Thus, ischemia and persis-
tent inflammation are the earlier events to increase free radicals. This inflam-
matory tone is regulated by �–6/�–3 balance of membrane lipids. Now, it has
been well established that ischemic conditions are induced by high �–6/�–3
ratios of dietary and tissue polyunsaturated fatty acids through eicosanoid
actions. The major risk factor for atherosclerosis was not dietary cholesterol or
hypercholesterolemia but high �–6/�–3 ratio of ingested foods as reviewed
elsewhere [17, 18].
Choice of Foods for the Prevention of Cancer
Cancer research used to focus on detecting environmental carcinogens
that initiate DNA damage and carcinogenesis. However, the involvement of
persistent inflammation in carcinogenesis has been widely observed. For
example, asbestos and glass beads administered to animals do not dissolve
easily, hence do not exhibit direct mutagenic activity. However, inflammatory
cells are mobilized to surround these substances and tumors are formed.
When inflammatory conditions persist, tumors are formed as noted in hepati-
tis virus infection, chronic hepatitis and hepatic cancer sequences. Subjects
suffering from ulcerative colitis develop colon cancer in several times higher
frequency. Helicobacter pylori is likely to develop stomach cancer through
persistent inflammation. Despite the reducing tendency of the impact of
smoking noted, lung cancer, particularly adenocarcinoma type, has been
increasing steadily along with the increasing incidence of pneumonia after
1970 in Japan.
Japanese intake of linoleic acid increased 2.5-fold from 1960 to 1975, and
the increase in meat intake was associated with a decrease in seafood intake
during this period. Consequently, the �–6/�–3 ratio of ingested fatty acids
increased significantly. Although the intake of animal fats also increased 2.5-
fold, the current intake of animal fats in Japan is roughly half that of average
Americans.
For the cancers of the US type, persistent inflammation caused by
enhanced linoleic acid and arachidonic acid cascade is interpreted to be a major
cause. This interpretation is supported by the following observations.
Okuyama/Ichikawa/Fujii/Ito/Yamada 58
(1) Oils with low �–6/�–3 ratios (perilla seed oil, flaxseed oil, fish oil)
suppress carcinogenesis compared with high linoleic acid oils.
(2) Inhibitors of arachidonic acid cascade suppress carcinogenesis, e.g.
steroidal and non-steroidal anti-inflammatory drugs, 5-lipoxygenase inhibitors.
(3) Knock-out of genes related to arachidonic acid cascade suppresses car-
cinogenesis, e.g. phospholipase A, cyclooxygenase-2, prostaglandin receptors
(EP2, EP4).
Despite the presence of many lines of evidence to support the interpreta-
tion that the enhanced linoleic acid cascade is a major risk factor for cancers of
the US type, epidemiological studies performed in the US do not necessarily
support this interpretation. The failure to reveal the causal relationship
between the linoleic acid intake and cancer mortality could be explained as
follows.
(1) In the populations without taking competitive amounts of seafood EPA
and DHA, membrane phospholipids are enriched with arachidonic acid even in
the group with low intake of linoleic acid.
(2) Serum EPA and DHA levels are good markers of seafood intake while
serum linoleic and �-linolenic acids are not [19]. High linoleic acid levels in
tissues are likely to reflect high seafood intake because EPA and DHA inhibit
the elongation and desaturation of linoleic acid to form long chain polyunsatu-
rated fatty acids.
(3) In the nested serum samples, preferential loss of long chain polyunsat-
urated fatty acids during storage leads to increased proportions of linoleic,
saturated and monounsaturated fatty acids.
Another process of fatty acids influencing carcinogenesis is through
prenyl intermediates in cholesterol synthesis. Saturated and monounsaturated
fatty acids, and linoleic acid to a slightly lesser extent, stimulate cholesterol
synthesis and are likely to up-regulate prenyl-intermediates and activate
oncogene products. Thus, various fatty acids appear to affect carcinogenesis
mainly through both the linoleic acid cascade and prenyl intermediate path-
way, and the relative importance of these two pathways is likely to differ
depending on the sites (tissues or cells) of carcinogenesis. At present, we
interpret that the impact of the linoleic acid cascade (persistent inflammation)
is greater than that of elevated prenyl intermediates for the promotion of can-
cers of the US type or that the impact of animal fats through prenyl interme-
diates is overcome by �–3 fatty acids, because their incidence was much
lower in the Greenland natives than in the Danes; both populations took large
amounts of saturated and monounsaturated fatty acids (�30 energy %) but
the former took much greater amounts of �–3 fatty acids and lesser amounts
of �–6 fatty acids.
Diet and Life Style in Inflammatory Diseases 59
Evaluation of Vegetable Oils by Their Fatty Acid Composition and Minor Anti-Nutritional Factors
Vegetable oils are nutritionally classified primarily by their fatty acids;
saturated fatty acid-rich oil (palm and coconut oils), oleic acid-rich oil (olive,
canola, high-oleic safflower and high-oleic sunflower oils), linoleic acid-rich
oil (high-linoleic safflower, corn, soybean, sesame, peanut and rice oils) and
�-linolenic acid-rich oil (perilla, flaxseed and chia oils). Obviously, high-linoleic
acid oil should be avoided in most of industrialized countries. The Japan
Society for Lipid Nutrition adopted a proposal that the direction of nutritional
recommendation should be changed so as to reduce the intake of linoleic acid
[20]. Saturated and monounsaturated fatty acids are not converted to inflamma-
tory lipid mediators and are relatively safe for the eicosanoid-related diseases.
However, the safety of these oils has not been established in animal experi-
ments; the intake of these oils in large quantities should be avoided because the
presence of minor anti-nutritional factors is suspected (canola, olive, corn, high-
oleic safflower, high-oleic sunflower, evening primrose, partially hydrogenated
soybean and partially-hydrogenated canola oils) [11, 12, 21]. �-Linolenic acid
is preferentially �-oxidized, excreted to skin and does not accumulate in tissues
in large amounts compared with saturated, monounsaturated and linoleic acids.
It is converted to EPA and DHA in part to suppress thrombotic and inflamma-
tory tendency. The demerits of �-linolenic acid-rich oils are their instability to
heat and easy inflammability under heating conditions although �-linolenic acid
is anti-inflammatory in the body. Use of electric frying pan is recommended for
�-linolenic acid-rich oils; those stabilized with vitamin E and C ester can be
used safely for baking meat, vegetable, egg and seafood at 200�C setting.
Conclusions – Recommended Choice of Foods and Fatty Acids for Healthy Aging
The so-called cholesterol hypothesis lost its bases, and those with high
cholesterol levels were found to exhibit lower cancer incidence and longer
survival among older people in the Western countries and among the general
population over 40 years old in Japan.
Nutritional values of foods of animal origin are evaluated by their content of
�–6 and �–3 fatty acids. Butter and meats from ruminants (cattle and sheep) con-
tain relatively small amounts of linoleic acid because ruminant bacteria convert
linoleic acid to saturated and monounsaturated fatty acids, hence these are rela-
tively safe. The �–6/�–3 balance of chicken and pork meats depends on that of
Okuyama/Ichikawa/Fujii/Ito/Yamada 60
their feed, and those with decreased �–6/�–3 ratios are recommended. Increased
intake of seafood is recommended for the prevention of cardiovascular diseases,
cancer and other inflammatory diseases. Currently, on the average the Japanese
ingest the largest amounts of seafood and associated endocrine disturbing sub-
stances (e.g. dioxin) among the industrialized countries. The beneficial effects of
seafood �–3 fatty acids have been well established but the relative impact of
dioxin on endocrine systems remains to be evaluated in our food environment.
Among vegetable oils, perilla oil and flaxseed oil with very low �–6/�–3 ratios
are recommended. Oleic acid is not converted to eicosanoids and is safe for the
diseases in the elderly, but all the high-oleic oils we have examined so far exhib-
ited anti-nutritional activity in animal experiments, hence the consumption of
large amounts of these oils listed above should be avoided even though the impact
of the anti-nutritional factor on human health is entirely unknown.
Acknowledgment
This work was supported in part by a Health and Labour Sciences Research Grant from
the Ministry of Health, Labour and Welfare Japan.
References
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Harumi Okuyama
Laboratory of Preventive Nutraceutical Sciences
Kinjo Gakuin University College of Pharmacy
Nagoya 463–8521 (Japan)
Tel. �81 52 798 0180, ext. 791, Fax �81 52 798 0754
E-Mail [email protected]
Simopoulos AP (ed): Nutrition and Fitness: Mental Health, Aging, and
the Implementation of a Healthy Diet and Physical Activity Lifestyle.
World Rev Nutr Diet. Basel, Karger, 2005, vol 95, pp 62–72
Physical Activity for Health:An Overview
Mark L. Wahlqvist
Asia Pacific Health and Nutrition Centre, Monash Asia Institute, Melbourne and
International Union of Nutritional Sciences, Melbourne, Australia
The Community Decline in Physical Activity
In general, the trend, with mechanization, computerization, passive leisure,
and urbanization, has been for people to reduce their levels of physical activity.
However, there are some notable national exceptions, in Finland and Canada,
which demonstrate that these trends can be countered [1]. Not only public health
strategies, but national leadership and infrastructural programmes are likely to
be required from an early age for the reversal of this downward trend in physical
activity and associated fitness. It is increasingly clear that, not to do so, invites a
major burden of chronic disease and disability and premature death [2, 3].
Until the late 19th and the 20th centuries, there were few examples of
regularized athletics and sports in society, with the notable exception of the
Greeks and Romans. This is because physique and performance needed recog-
nition and admiration and because settlement, organisation and facilities were
usually required, and so was relative wealth and the time to pursue such activity.
As a matter of fact, the physical requirements of work in servitude, employment
or in communities with subsistence agriculture were often so great as to view
time to oneself or one’s family as time for physical rest. Well into the 20th
century, it was a common belief that too much exercise would shorten one’s life.
Moreover, recent studies demonstrate that extensive sports and work patterns
(e.g. lumberjacks) can outstrip energy intakes in their energy requirements and
can lead to immune dysfunction [3]. A SWOT (strength, weaknesses, opportu-
nities and threats) analysis of the overall decline in physical activity takes this
issue of the health limits of physical activity into account (table 1).
Physical Activity for Health 63
The optima for physical activity, beyond that which is ‘self-paced’ (what
one does without thought – e.g. gesticulation whilst talking, restless movement
whilst awake or asleep), are probably much as shown in table 2.
In turn, physical activity goals and targets could be formulated as in tables
3 and 4.
For World Health Day in 2002, when the theme was ‘Move for Health’, the
degrees of health achievement through exercise were depicted graphically (fig. 2).
Table 1. Decline in physical activity SWOT analysis
Strengths Weaknesses
• Avoid tissue and system • Detrimental body composition
damage through excess • Decreased system reserve
(e.g. CV, respiratory, CNS)
Opportunities Threats• Replace physical activity at work • Eco-nutritional disease (END)
with physical activity as leisure (sport) or chronic non-communicable
• More time for education, diseases (CNCDs)
social networking
Table 2. Physical activity – optima
• Walking or other aerobic activities (6 days/week, 1–2 h/day)
• Strength training through multiple repetitions against
resistance (3–4 days/week)
• Integrated with goal
– Personal development
– Social development
Table 3. Physical activity – goals
• Include physical activity in workaday week and travel
(purposeful physical activity)
• Find enjoyable leisure-time physical activity (personal
and social fulfillment)
• Overcome seasonal, locality and situational barriers to
physical activity
• Improved sense of well-being
• Reduce burden of disease
Wahlqvist 64
The most obvious and impressive consequence of physical inactivity is
obesity, where prevalence is interesting worldwide, irrespective of the stage of
economic development and, often, in the face of protein malnutrition with
growth retardation and muscle wasting [4] (fig. 1). This constitutes the so-
called ‘Double Burden of Disease’ [5, 6].
Energy Throughput, Food Intake and Body Composition
Throughout much of the 20th century, energy intake remained largely
unchanged, even with economic development [7]. Yet the prevalence of obesitybegan to escalate and, whilst the quantity and quality of food intake have
become important issues, most of the obesity epidemic could probably have
Table 4. Physical activity – targets
• Walk most days irrespective of time of year, at least
20 min one way and 20 min return
• Be strong enough, through repetitive resistance
movement, to undertake ADL and sudden, unexpected but
reasonable demands for strength (e.g. carrying a load
upstairs, shoveling snow, moving a log)
• Keep active and strong with advancing years.
AustraliaNew ZealandPNG (urban)
JapanChina
EnglandGermany
NetherlandsCzech Republic
USACanadaBrazil
Saudi ArabiaUAE
Iran (south)
Prevalence of obesity (%)0 10 20 30 40 5001020304050
Men Women
Fig. 1. Global prevalence of obesity. BMI �30. UAE � United Arab Emirates;
PNG � Papua New Guinea.
Physical Activity for Health 65
been avoided if physical activity levels had remained adequate. One of the best
example of this is Japan, where people have continued to walk a lot, and obesity
(BMI �30) prevalences have remained as low as about 3%, compared to the
USA where they now exceed 20%.
Also, sub-groups in the population have not experienced the general trend
towards obesity, where they have been regular exercisers. For example, people
who walk, jog or run regularly are generally leaner, without the need to be pre-
occupied with food intake.
It is energy throughput at higher levels which is more important than
energy intake in determining the risk of positive energy balance (and, therefore,
overfatness). This is seen by reference to the studies of Peter Wood at Stanford
University, where he demonstrated that middle-aged runners actually eat more
and lose body weight (fat) [8]. If this phenomenon could be generalized across
the community, say by making walking, cycling and jogging more attractive,
substantial improvement in individual fitness and body composition would be
achieved.
People need to understand more clearly what weight represents – muscle and
bone mass to be optimized, fat stores to be appropriate and directed away from the
abdomen – and the nature of intra-daily and day-to-day fluctuations in body water
(and sodium). This means education about body composition and not pre-occupa-
tion with weight as the key health end-point in physical activity programmes.
Fig. 2. ‘Move for Health’: World Health Day 2002. Agita Mundo – Move for Health,
the slogan for World Health Day 2002, is a call to individuals, communities and countries to
associate action for health with the public health task of prevention. (‘Agita’ in Portuguese
means shake – Agita Mundo means shake the world.)
Wahlqvist 66
It is now appreciated that body composition and fat distribution are major
determinants of total and disease specific mortality [9–13].
There is increasing evidence that the energy density:
Energy density �Energy (cal or kJ)
Mass of food (g or kg)
is a determinant of energy balance [14, 15]. However, this will be less crit-
ical when one is physically active, since the errors in energy intake are more
likely to be corrected (through the set of appetite, and the energy cost of car-
riage of increased body mass).
Again, with greater levels of regular physical activity, food component(essential macro- and micro-nutrients; other biologically active and favourable
food components like phytonutrients) density is less critical.
Nutrient Density,
Mass of nutrient or phytonutrient or food
phytonutrient density �
component (e.g. Mg or �g)
or food component density Energy (e.g. 100 kJ)
The inactive, however, must be careful to have most of their food nutritious
as judged by their food component density.
The pathways to abdominal obesity, nevertheless, are several, although
physical activity is central (fig. 3).
Urbanisation
Psychological stressors
Pollutants Food supply
Maternal health and nutrition
Neuro-hormonal Energy balance
Growth and development
Pathological disorders
Intra-abdominal fat
Physical inactivity
Fig. 3. Pathways to abdominal obesity. From Wahlqvist [15].
Physical Activity for Health 67
Physical Activity for Life
Just as we have to realize with the long-term effects of maternal nutrition
and intra-uterine life on later life morbidity and mortality, so it is likely that we
will find the same for appropriate levels of maternal physical activity pre-
conception and during pregnancy, and lactation (table 5). However, more work
is required in this area, as there has been much debate about appropriate work
patterns and sporting engagement for pregnant women [16].
Nevertheless, we do know that physical activity affects gene expression[17], and plays a role in the expression of gestational diabetes, with its inter-
generational effects on insulin resistance [18].
Physical Activity,Well-Being and the Domains of Health
There is little doubt that regular physical activity is a key determinant of
well-being and mood [19], functional status [20] and perceived health status
[21] (fig. 4).
Preventive Physical Activity
The burden of disease in contemporary economically advanced societies is
located amongst the following health domains:
• Cardiovascular disease
• Metabolic disorders
e.g. obesity, diabetes
• Neoplasia
• Bone health
Table 5. Physical activity as a requisite for human species
• Conception and pregnancy
• Childhood, puberty and adolescence
• The reproductive years
• Later life
• Inter-‘life stage’ considerations
• Inter-generational considerations
Wahlqvist 68
• Immune function
• Cognitive function
• Mood
In Australia, the Burden of Disease and Injury is attributed to selected risk
factors as shown in figure 5.
Physical activity features highly in the contribution to Burden of Disease
[22, 23] and, therefore, in preventive programmes.
Inter alia, physical activity appears to be protective against disease by
• improving cardio-respiratory function
• improving lipid profiles, blood pressure, abdominal body fatness.
This can be seen in a number of studies of diabetes prevention [24], cancer
[25], and osteoporosis [26] (fig. 6).
Resistance or strength training is relevant for quality of sleep and
depression [27].
We can expect that regular physical activity will displace the onset of mor-
bidity towards the end of life [28], as well as prolong it [28, 29].
Disease-specific survivals are prolonged with regular physical activity, as
evidenced in the Harvard Alumni Study [30, 31] and in Finnish studies by
Pekkanen et al. [32].
Pre
vale
nce
of fa
iror
poo
r he
alth
sta
tus
%
Level of moderate or vigorous physical activity
50
45
40
35
30
25
20
15
10
5
018–44 45–64
Age (years)
65 or older
InactiveInsufficient level of physical activityRecommended level of physical activity
17.8
9.06.6*
37.1
16.612.2*
45.2
24.7
17.9*
Fig. 4. Prevalence of fair or poor health status by age and level of physical activity.
*Significant difference in likelihood of fair or poor health status across physical activity
groups after adjustment for age, race/ethnicity, gender, education, smoking status and BMI,
p � 0.001.
Physical Activity for Health 69
Therapeutic Physical Activity
The clear preventive health role of physical activity may well be translated
into therapeutics. To some extent, there is overlap between secondary and ter-
tiary prevention and therapeutics in any case.
Of great importance, with ageing populations is the reduction in the prob-
lems of:
• Sarcopenia and frailty
• The growing burden of nutritional and metabolic diseases
• Senescence
At least some cases of sarcopenia can be expected to be preventable and
reversible [33, 34].
Eco-Nutrition and Physical Activity
Healthy habitats and precincts, conducive to regular physical activity are
essential for community health. Not to have them is to encourage Eco-nutri-
tional Disease (END).
Favourable eco-nutritional precincts will:
• Link family life, leisure and work
Tobacco
What makes us sick
Proportion of total burden attributed toselected risk factors, Australia 1996
Physical inactivity
Hypertension
Alcohol
Overweight andobesity
Lack of fruit/veg
lllcit drugs
Occupation
Unsafe sex
%
0 2 4 6 8 10 12
FemaleMale
Fig. 5. ‘The Burden of Disease and
Injury in Australia’. Published by the
Australian Institute of Health and Welfare,
1999.
Wahlqvist 70
• Be safe and congenial for walking, climbing, cycling, playing, swimming,
skipping, dancing, skiing or gardening
• Provide contact with various plant and other animal species.
The term ‘chronic disease’ says nothing about the aetiology or pathogene-
sis. The logic of describing chronic disease as ‘eco-nutritional disease’ becomes
apparent when considering:
• The major importance of food, its variety and the requirement for biodiver-
sity on human health
• Movement, best achieved in safe, pleasurable and sustainable precincts
• The required ‘environmental buffer zones’ to minimize the risk of known
and emerging transmissible pathogens [35, 36].
Mouth andpharynx
Nasopharynx
Larynx
Oesophagus
Lung
Stomach
Pancreas
Gallbladder
Liver
Colon, rectum
Breast
Ovary
Endometrium
Cervix
Prostate
Thyroid
Kidney
Bladder
Vegetables
Fruits
Carotenoids in fo
od
Vitamin C
in fo
od
Minerals in fo
od
Cereals (grains)
Starches
NSP/fibre
Tea
Physical a
ctivity
Refrigeratio
n
KEYDecreases
riskconvinicing
Decreasesrisk
probable
Decreasesrisk
possible
Lodine
Colon only
Wholegrain
Selenium
Increasesrisk
convinicing
Increasesrisk
probable
Increasesrisk
possible
Fig. 6. Nutrition and physical activity in the prevention of cancer.
Source: World Cancer Research Fund/American Institute for Cancer Research, 1997.
Physical Activity for Health 71
Conclusion
We seek a unifying strategy for both health advancement and health opti-mization which is sustainable. This must involve us continuing as our own
machines, moving, thinking, socializing and integrated with the natural world.
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woman. J Sci Med Sport 2002;5:20–31.
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ulation of the human genome through physical activity. J Physiol 2002;543:399–411.
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Asia Pacific Health and Nutrition Centre, Monash Asia Institute
Floor Menzies Building, Monash University, Wellington Road
Clayton, Melbourne, Victoria 3800 (Australia)
E-Mail [email protected]
Simopoulos AP (ed): Nutrition and Fitness: Mental Health, Aging, and
the Implementation of a Healthy Diet and Physical Activity Lifestyle.
World Rev Nutr Diet. Basel, Karger, 2005, vol 95, pp 73–79
Physical Inactivity Is a Disease
Simon J. Leesa, Frank W. Bootha,b
Departments of aBiomedical Sciences, and bMedical Pharmacology and
Physiology, and Dalton Cardiovascular Center, University of Missouri-Columbia,
Columbia, Mo., USA
Physical inactivity annually produces 334,144 deaths in the United States
and �2 million deaths worldwide [1, 2]. Physical inactivity is one of the 10 lead-
ing global causes of death and disability [2]. In 1986, the expenditure in the US for
physical inactivity was USD 77 and USD 150 billion (expressed in 2,000 US dol-
lars) in direct and combined direct and indirect costs, respectively [3].
Epidemiological data indicate that physically inactive humans have an increased
prevalence of 25 chronic diseases (table 1). Indeed whereas the chronic diseases
are recognized as the medical factor for the deaths and economic costs, physical
inactivity is acknowledged by the Centers for Disease Control (CDC) as the actual
cause of the deaths [4]. Thus, it seems reasonable to suggest that physical inactiv-
ity is a medical problem of great impact. This review will use arguments presented
in debates as to whether obesity is a disease [5, 6] to provide a framework for the
claim that physical inactivity is a disease. The next sections will answer the ques-
tion as to whether physical inactivity fits the definition of ‘disease’.
Heshka and Allison [5] present some of the typical definitions of disease:
• ‘Condition of the body, or some part or organ of the body, in which its func-
tions are disturbed or deranged; a morbid physical condition; a departure
from the state of health, especially when caused by a structural change’ [7].
• ‘A condition in which bodily health is seriously attacked, deranged, or
impaired. Pathologically, disease is an alteration of state of the human
body…or of some of its organs or parts interrupting or disturbing the perfor-
mance of vital functions; any departure for the state of health presenting
marked symptoms…various forms of disease may be caused by parasites, fil-
terable viruses, and nutritional, environmental or inherent deficiencies.’ [8].
• ‘An interruption, cessation or disorder of body functions, systems or
organs.’ [9].
Lees/Booth 74
Table 1. Selected samples of alterations with physical inactivity
Tissue/physiological Dysfunction with physical inactivity
characteristic
Hippocampus Decreased neurogenesis, memory, and learning
Increased prevalence of dementia and Alzeheimer’s disease
Myocardial cells of heart Lower contractility, maximal stroke volume and maximal
cardiac output
Contributes to decreased aerobic fitness
Sympathetic nervous system Increased resting sympathetic drive, potentially leading to
increased blood pressure
Vascular endothelial cells in heart Less nitric oxide production and lower vasorelaxation in response
to vasodilators
Less protection from ischemia
Pro-inflammatory milieu in blood Increased blood C-reactive protein and tumor necrosis factor-�,
leading to greater prevalence of atherosclerosis
Plasma triglycerides Increased post-prandial hypertriglyceridemia
Increased prevalence
of coronary artery disease
Plasma glucose Increased post-prandial hyperglycemia and hyperinsulinemia
Increased prevalence of coronary artery disease and type 2
diabetes
Deep venous thrombosis Increased thrombi when sitting on long-distance airline flights;
‘Economy-class syndrome’, potentially producing a pulmonary
embolism
Pancreas Increased release of insulin due to insulin resistance
Blood HDL Decreased blood HDL
Increased prevalence of coronary artery
disease
Immunity Depressed immune response
Increased prevalence of breast, colon, and pancreatic cancers
Body fat Increased amount of body fat
Increase in all the co-morbidities related to obesity
Skeletal muscle, size Smaller mass of skeletal muscle
Premature sarcopenia and
physical frailty resulting in premature institutionalization
Skeletal muscle, insulin-mediated Increased resistance to insulin leading to pre-diabetes
glucose uptake Increased prevalence of type 2 diabetes
Work endurance Shorter durations of the ability to perform low level work loads
and a greater incidence of muscle fatigue-related work injuries
Bones Less calcification and strength
Increased prevalence of osteoporosis and broken hips
Aging Acceleration in many of the signs and symptoms associated with
aging, such as premature osteoporosis and physical frailty
Physical Inactivity Is a Disease 75
The characteristics of physical inactivity are presented in table 1, as docu-
mented in Chakravarthy and Booth [1]. Using the above definitions as a guide,
eight examples (brain, heart, peripheral nervous system, blood, immune cells,
adipose tissue, skeletal muscle, and bones) of ‘some part or organ of the body’
or ‘of some of its organs or parts’ are given with ten examples (decreased brain,
heart, lipid oxidation, carbohydrate oxidation, fibrinolysis, immune, muscle
strength, bone strength, aerobic fitness, and work endurance) ‘in which its func-
tions are disturbed or deranged’, ‘or of some of its organs or parts interrupting
or disturbing the performance of vital functions’, or ‘an interruption, cessation
or disorder of body functions, systems or organs’ and seven examples (increased
Alzheimer’s disease, coronary heart disease, type 2 diabetes, cancer, obesity,
physical frailty, and osteoporosis) of ‘a departure from the state of health’, or ‘a
condition in which bodily health is seriously attacked, deranged, or impaired’.
Thus, physical inactivity fits the presented definitions of disease.
Another rationale for categorizing physical inactivity as a disease is that
the level of voluntary physical activity can be manipulated by various chemical
changes. A well known example that implies a neurochemical drive for physical
inactivity is the spontaneous decrease in physical activity with aging in both
rats [10] and humans [11]. Morley et al. [11] state that decreased physical activ-
ity with aging appears to be the key factor involved in producing sarcopenia.
Thus, it is likely that a change in a biological drive could be responsible for
decreased physical activity with age, providing evidence for the supposition
that the putative neurochemical basis of a drive for physical activity becomes
deranged or impaired with aging. Other evidence for neurochemical changes
regulating voluntary physical activity follows.
Leptin plays a central role in regulating body weight. However, treatment
of obesity using recombinant leptin seems to be only effective in individuals
with a rare homozygous mutation in the gene for leptin or its receptor, or who
exhibit subnormal secretion of the hormone. In most cases, obese humans have
paradoxically elevated leptin levels, indicative of leptin resistance [12]. Thus,
leptin’s function is deranged or disturbed in most obese individuals and, accord-
ing to Bray [13] fits the definition for the neurochemical basis of disease.
Bray’s argument can be extended to positive feedback loops where physical
inactivity alters a molecule whose directional change is associated with a fur-
ther decrease in physical activity. Three examples are given: (1) Physical inac-
tivity begets obesity, which is associated with increased serum leptin and leptin
resistance, causing more physical inactivity. The data supporting the aforemen-
tioned positive feedback loop is that increased blood leptin results in greater
physical activity and energy expenditure in normal mice [14] and in increased
physical activity in parallel with a decrease in their obesity in the rare human
condition of leptin deficiency [15]. On the other hand, the majority of obese
Lees/Booth 76
individuals who have higher than normal blood leptin, are leptin resistant [16]
and have decreased voluntary physical activity [17]. (2) Aging is associated
with decreased physical activity, which lowers the chemical drive to maintain
muscle mass so that with smaller muscle mass even less physical activity is
undertaken, further lowering muscle mass [18]. (3) Training raises muscle
GLUT4 protein [19]. Mice engineered to overexpress GLUT4 in skeletal mus-
cle ran four times further in voluntary running wheels [20]. Thus physical activ-
ity enhances muscle GLUT4 and higher muscle GLUT4 levels are associated
with more voluntary running. These examples suggest potential positive chem-
ical feedbacks by which physical inactivity and activity creates molecular
changes associated with less and more, respectively, voluntary physical activity.
One advantage of classifying physical inactivity as a disease will be to
challenge the current logic of the majority of studies which employ exercise
training and designate the sedentary group as the control group. The proposed
revised logic of control group designation would have to emulate the following
question and answer. Does sedentary lifestyle ‘cause’ the onset of some chronic
diseases? Invariably, the research community would answer this question with a
‘yes’. However, most experiments from the research community are not designed
Preventative medicine
Sedentary lifestyle:
Disease group
Healthy control
Disease control
Treatment group
Clinical trial
Fig. 1. Schematic representation outlines the difference between clinical trial and
cause and effect research in preventative medicine. In the experimental design of an ‘exercise
physiology’ clinical trial, the sedentary disease group subjects are either prescribed an exer-
cise treatment or assigned to the continued physically inactive, disease control group. The
goal of such an experimental design is to delineate mechanisms of partial reversal of the dis-
ease symptoms by exercise. In order to effectively delineate the mechanisms underlying how
physical inactivity causes chronic disease, healthy active subjects must be designated as the
control. The latter approach is fundamental in preventative medicine.
Physical Inactivity Is a Disease 77
to prove this. The vast majority of experiments in exercise research that are
related to disease are set up to imitate a clinical trial (fig. 1). In this experimen-
tal design, the sedentary group is designated as the control and the exercise
group as the treatment. However, the clinical design logic breaks down when
extrapolated to a search for cause and effect. A sedentary lifestyle leads to
many chronic diseases, as described above, and is the actual cause, with poor
nutrition, of 16% of the deaths in the United States [4]. Therefore, the sedentary
group in the general population is analogous to the disease group of a clinical
trial and the subjects are currently randomly assigned to continued inactivity
(placebo) or given the ‘exercise’ treatment. These types of experiments are fine
when the goal of the experiment is to determine the effectiveness of exercise as
a treatment to restore the healthier condition, unfortunately, this experimental
design does not allow for the delineation of mechanisms related to diseases
caused by a sedentary lifestyle. It is clear that many mechanisms of physical
inactivity that produce maladaptations differ from the mechanisms of exercise
that reverse the pathological adaptations. Molecular proof for the aforemen-
tioned concept is that while skeletal muscle unloading and overload may share
some common regulatory units on the �-myosin heavy chain (�MyHC) pro-
moter, they have separate regulatory regions for unloading and overload, and
thus must have different transcriptional activations. For example, a 293-bp
promoter region of �MyHC responded to mechanical overload of the mouse
soleus muscle, whereas it was not sensitive to unloading [21], proving at the
molecular level that, in some cases, increases and decreases in exercise levels
do not use the same molecular mechanisms.
A further reason not to designate the sedentary group as the control group
is the misinterpretation by the general population and most of the scientific
community that a sedentary state is the normal physiological condition. By
extension, physical activity is misinterpreted as abnormal with the application
of physical activity being a ‘tool’ to cure rather than viewing physical activity as
the norm whose deficiency is the actual cause of chronic disease. As a result of
the designation of the sedentary group as the control group, the general popula-
tion and the much of the scientific community devalue physical inactivity
research. Further, exercise is considered an inconvenience rather than a required
physiological stimulus to maintain normal physiological function as dictated by
the acquired human genome.
A tenet of medicine is that understanding the molecular mechanisms of dis-
eases provides the scientific basis for therapy and prevention. Again, the only
way to truly decipher the mechanisms of disease prevention is to actually study
the process itself as it is evoked by decreased physical activity, poor diet, etc. It
is therefore anticipated that future research will investigate the molecular mech-
anisms of decreasing physical activity from its genetically selected higher level
Lees/Booth 78
to the sicker physically inactive population because physical inactivity, not activ-
ity, is the actual cause of genes to mis-express proteins, producing the metabolic
dysfunctions which, if continued long enough, result in overt clinical disease.
This is not a new concept. A statement in the Declaration of Olympia on
Nutrition and Fitness [22] that the current level of physical activity should match
more closely our genetic endowment introduced the concept that the true normal
condition in ‘exercise’ studies is the physically active, not the sedentary, group.
As long ago as the 5th century BC, Hippocratic physicians wrote that if there is
any deficiency in food or exercise, the body will fail [22]. This old advice holds
true today as inadequate opportunities for physical activity impair the attainment
of overall health [22] and produce many chronic health conditions.
Acknowledgment
The review was written while supported by NIH AR19393 (F.W.B.).
References
1 Chakravarthy MV, Booth FW: Exercise. Philadelphia, Elsevier, 2003.
2 World Health Organization: http://www.who.int/hpr/physactiv/sedentary.lifestyle1.shtml
3 Pratt M, Macera C, Wang G: Higher direct medical costs associated with physical inactivity.
Physician Sportsmed 2000;28:63–70.
4 Mokdad AH, Marks JS, Stroup DF, Gerberding JL: Actual causes of death in the United States,
2000. JAMA 2004;291:1238–1245.
5 Heshka S, Allison DB: Is obesity a disease? Int J Obes Relat Metab Disord 2001;25:1401–1404.
6 Kopelman PG, Finer N: Reply: Is obesity a disease? Int J Obes Relat Metab Disord 2001;25:
1405–1406.
7 Oxford English Dictionary. Oxford, Clarendon Press, 1989.
8 Webster’s Unabridged Dictionary, 2nd edition. New York, Random House, 1998.
9 Stedman’s Medical Dictionary, 27th edition. Philadelphia, Lippincott Williams Wilkins, 2000.
10 Brown M, Ross TP, Holloszy JO: Effects of ageing and exercise on soleus and extensor digitorum
longus muscles of female rats. Mech Ageing Dev 1992;63:69–77.
11 Morley JE, Baumgartner RN, Roubenoff R, Mayer J, Nair KS: Sarcopenia. J Lab Clin Med 2001;137:
231–243.
12 Zabeau L, Lavens D, Peelman F, Eyckerman S, Vandekerckhove J, Tavernier J: The ins and outs of
leptin receptor activation. FEBS Lett 2003;546:45–50.
13 Bray GA: Obesity is a chronic, relapsing neurochemical disease. Int J Obes Relat Metab Disord
2004;28:34–38.
14 Friedman JM, Halaas JL: Leptin and the regulation of body weight in mammals. Nature 1998;395:
763–770.
15 Licinio J, Caglayan S, Ozata M, Yildiz BO, De Miranda PB, O’Kirwan F, Whitby R, Liang L,
Cohen P, Bhasin S, Krauss RM, Veldhuis JD, Wagner AJ, DePaoli AM, McCann SM, Wong ML:
Phenotypic effects of leptin replacement on morbid obesity, diabetes mellitus, hypogonadism, and
behavior in leptin-deficient adults. Proc Natl Acad Sci USA 2004;[Epub ahead of print].
16 Flier JS: Obesity wars: Molecular progress confronts an expanding epidemic.Cell 2004;116:
337–350.
Physical Inactivity Is a Disease 79
17 Bernstein MS, Costanza MC, Morabia A: Association of physical activity intensity levels with
overweight and obesity in a population-based sample of adults. Prev Med 2004;38:94–104.
18 Fried LP, Walston J: Frailty and failure to thrive; in Hazzard WR, et al (eds): Principles of Geriatric
Medicine and Gerontology. New York, McGraw Hill, 2003, pp 1487–1492.
19 Daugaard JR, Nielsen JN, Kristiansen S, Andersen JL, Hargreaves M, Richter EA: Fiber type-
specific expression of GLUT4 in human skeletal muscle: Influence of exercise training. Diabetes
2000;49:1092–1095.
20 Tsao TS, Li J, Chang KS, Stenbit AE, Galuska D, Anderson JE, Zierath JR, McCarter RJ, Charron MJ:
Metabolic adaptations in skeletal muscle overexpressing GLUT4: Effects on muscle and physical
activity. FASEB J 2001;15:958–969.
21 McCarthy JJ, Vyas DR, Tsika GL, Tsika RW: Segregated regulatory elements direct beta-myosin
heavy chain expression in response to altered muscle activity. J Biol Chem 1999;274:14270–14279.
22 Simopoulos AP, Pavlou KN: Declaration of Olympia on nutrition and fitness. World Rev Nutr
Diet. Basel, Karger, 2001, vol 89, pp XVII–XXIV.
Frank W. Booth, PhD
Department of Biomedical Sciences, University of Missouri-Columbia
E102 Veterinary Medical Building, 1600 East Rollins Road
Columbia, MO 65211 (USA)
Tel. �1 573 882 6652, Fax �1 573 884 6890, E-Mail [email protected]
Simopoulos AP (ed): Nutrition and Fitness: Mental Health, Aging, and
the Implementation of a Healthy Diet and Physical Activity Lifestyle.
World Rev Nutr Diet. Basel, Karger, 2005, vol 95, pp 80–92
What Is So Special about the Diet ofGreece? The Scientific Evidence
Artemis P. Simopoulos
The Center for Genetics, Nutrition and Health, Washington, D.C., USA
The health of the individual and the population in general is the result of
interactions between genetics and a number of environmental factors. Nutrition
is an environmental factor of major importance [1–4]. Our genetic profile has
not changed significantly over the past 10,000 years, whereas major changes
have taken place in our food supply and in energy expenditure and physical
activity [5–18]. Today, industrialized societies are characterized by the follow-
ing: (1) an increase in energy intake and decrease in energy expenditure; (2) an
increase in saturated fat, omega-6 fatty acids and trans fatty acids and a
decrease in omega–3 fatty acid intake; (3) a decrease in complex carbohydrates
and fiber intake; (4) an increase in cereal grains and a decrease in fruit and veg-
etable intake, and (5) a decrease in protein, antioxidant and calcium intake
[5–18]. Furthermore, the ratio of omega–6 to omega–3 fatty acids is 16.74:1 in
the United States, whereas during evolution it was 2–1:1 (table 1; fig. 1).
Recent investigations of the dietary patterns and health status of the coun-
tries surrounding the Mediterranean basin clearly indicate major differences
among them in both dietary intake and health status. Therefore, the term
‘Mediterranean diet’ is a misnomer. There is not just one Mediterranean diet but
in fact many Mediterranean diets [19], which is not surprising because the coun-
tries along the Mediterranean basin have different religions, economic and cul-
tural traditions and diets. Diets are influenced by religious habits, that is, Muslims
do not eat pork or drink wine and other alcoholic drinks, whereas Greek Orthodox
populations usually do not eat meat on Wednesdays and Fridays, but drink wine.
Although Greece and the Mediterranean countries are usually considered as
areas of medium high death rates (14.0–18.0 per 1,000 inhabitants), death rates
on the island of Crete have been below this level continuously since before 1930
[cited in 20]. No other area in the Mediterranean basin has had as low a death
Defining the Components of a Healthy Diet and Physical Activity for Health
The Greek Diet: Scientific Evidence 81
rate as the island of Crete, according to data compiled by the United Nations in
their Demographic Yearbook for 1948. It was 11.3–13.7 pre-war and about 10.6
in 1946–1948 [20]. Cancer and heart disease caused almost three times as many
deaths proportionally in the US as in Crete [20]. The diet of Crete represents the
traditional diet of Greece prior to 1960. The Seven Countries Study was the first
to establish credible data on cardiovascular disease prevalence rates in contrast-
ing populations (United States, Finland, The Netherlands, Italy, former Yugoslavia,
Japan and Greece), with differences found on the order of 5- to 10-fold in coro-
nary heart disease [21]. In 1958 the field work started in Dalmatia in the former
Yugoslavia. From the inception of the research program an important focus was
on the diet and its possible relationship to the etiology of coronary heart disease.
Table 1. Omega–6:omega–3 ratios in various populations
Population ��6/��3 Reference
Paleolithic 0.79 [8]
Greece prior to 1960 1.00–2.00 [9]
Current Japan 4.00 [10]
Current India, rural 5–6.1 [11]
Current United Kingdom and northern Europe 15.00 [12]
Current United States 16.74 [9]
Current India, urban 38–50 [11]
30
20
40
10
0
�4 � 106 �10,000 1,800 1,900 2,000
10
30
100
600
% c
alor
ies
from
fat
Total fat
Saturated
�-3
�-6
Trans
Vitamin C
Vitamin E
mg/
day
Years
Hunter gatherer Agricultural Industrial
0
Fig. 1. Hypothetical scheme of fat, fatty acid (�–6, �–3, trans and total) intake (as per-
cent of calories from fat) and intake of vitamins E and C (mg/day). Data were extrapolated
from cross-sectional analyses of contemporary hunter-gatherer populations and from longi-
tudinal observations and their putative changes during the preceding 100 years [13].
Simopoulos 82
The 5-year follow-up found favorable all-cause death rates in Greece, Japan and
Italy compared with the other areas, as well as a lower incidence rate of coronary
heart disease [21]. The Seven Countries Study was designed to investigate rela-
tions between diet and cardiovascular diseases, primarily described in terms of
the fatty acid composition of the diet.
In a recent follow-up study on the relation of chronic diseases to 15-year all-
cause mortality risk from the Seven Countries Study, death rates from all causes
were very different among the seven countries, with high death rates in Croatia
and Finland and low rates in Greece (table 2) [22]. For coronary heart disease, the
excess risk of any deaths was greater than 60% in all areas except Greece where it
was 45.9%. Similarly, large risks were seen for other diseases from 47.8% in
Greece to 72.6% in Serbia. Peripheral arterial disease also carried a high risk of
death, ranging from 46.7% in Greece to 80.9% in Italy. The outcome for men with
prevalent stroke was 100% mortality in 15 years in the Netherlands and in Greece
and 57.1% in Japan. Men diagnosed with chronic obstructive pulmonary disease
(COPD) had a high risk of dying, 66.7% or more, except for Greece, 53.3% and
Italy, 47.6%. The main purpose of this analysis was to investigate the risk of dying
within 15 years related to the presence of specific chronic conditions as found in
population-based field studies in different countries.
Bioprotective Nutrients and Mechanisms in the Greek Diet
In order to precisely define the foods and their components in the diet of
Crete, we began a series of studies investigating the components of the traditional
Table 2. Men examined and followed up, and 15-year all-cause death rates
in the Seven Countries Study
Country Survey participation 15-year all-cause
n rate, % Death rate, % SE
Croatia 959 83.8 48.3 1.57
Finland 1,348 97.9 45.5 1.32
Serbia 1,281 92.1 40.0 1.34
Japan 867 98.7 39.2 1.57
The Netherlands 614 80.4 38.8 1.89
Italy 1,938 89.2 36.1 1.05
Greece 1,009 89.7 28.4 1.39
Modified from Menotti et al. [22].
The Greek Diet: Scientific Evidence 83
diet of Greece prior to 1960, which is represented by the diet of Crete in the
Seven Countries Study. Although the investigators of the Seven Countries
Study emphasized the low saturated fat intake and the high monounsaturated fat
intake from olive oil as the major factors responsible for the biological health
effects of the diet of Crete being associated with the lowest rate of coronary
heart disease and the longest life expectancy, there is good evidence that foods
rich in omega–3 fatty acids and antioxidants could account for the decreased
death rate of the people of Crete [23–27]. Omega–3 fatty acids have hypolipi-
demic, antithrombotic, anti-inflammatory, and antiarrhythmic properties, as
shown by a number of papers in these proceedings [28, 29] and influence gene
expression [29, 30] as well as being essential for normal growth and develop-
ment [5] and mental health [31]. Fruits and vegetables have been associated
with lower rates of heart disease [45].
Our own studies showed that the Cretans obtained �-linolenic acid (ALA)
by eating wild plants [32–36], snails, nuts [37], fruit (figs), and eggs [38, 39];
and eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) from fresh
fish and dry or canned sardines and herring, and from eggs [38, 39], game [40],
and snails. Meat from grazing animals contains omega–3 fatty acids whereas
meat from grain-fed animals does not [40]. Because sheep, swine, and goats
graze, they obtain omega–3 fatty acids from grass, moss, purslane (Portulacaoleracea) [32–34], and in general from the leaves and stems of green leafy veg-
etables. They also feed on dry fruits and nuts. In some areas the swine feed on
acorns. The livestock obtain a mixture of omega–6 and omega–3 fatty acids
from the foods they eat, and the same mixture is found in their meat and in the
milk and the cheese and all other dairy products made from the milk [18, 41].
This balance of omega–6:omega–3 fatty acids is lost in the Western diets (fig. 1)
[13, 42]. Because of agribusiness, the grain-fed animals have higher amounts of
omega–6 fatty acids in their meat unlike the animals in the wild. The vegetable
oils such as corn, sunflower, safflower, and cottonseed oil are all very rich in
omega–6 fatty acids and the margarines made from them contain trans fatty
acids that behave like saturated fats in terms of raising blood cholesterol [43].
Eggs from chickens eating wild greens, worms and insects produce eggs bal-
anced in omega–6 and omega–3 fatty acids whereas the US supermarket egg
has a ratio of about 20:1 [38, 39]. Recent studies in the serum cholesteryl esters
of the people in Crete showed a threefold increase of ALA versus the popula-
tion of Zutphen (table 3) [44]. Wine, fruits, vegetables, and olive oil provide
high amounts of vitamin C, vitamin E, lycopene, beta-carotene, polyphenols,
and other antioxidants [45–49]. The importance of a Cretan-type diet rich in
ALA, fish, fruits and vegetables has been demonstrated in the Diet and
Reinfarction Trial (DART) [50], the Lyon Heart Study [24–27], the studies by
Pella, Singh and coworkers [11, 51, 52], and the most recent Gruppo Italiano
Simopoulos 84
per lo Studio della Sopravivenza nell’Infarto miocardico (GISSI)-Prevenzione
trial [53].
The Omega–6:Omega–3 Ratio in the Greek Diet
Olive oil being high in monounsaturated fatty acids and low in saturated
and omega–6 fatty acids does not compete with the elongation and desaturation
of ALA nor with the incorporation of omega–3 fatty acids into the red cell
membrane phospholipids [5]. Furthermore, the omega–6:omega–3 ratio in the
Greek diet is between 2 and 1:1 which is very close to the dietary ratio of the
Paleolithic diet [8]. The beneficial effects of such a ratio and their importance
in normal growth and development [54–56] and in the prevention and manage-
ment of cardiovascular disease, hypertension, diabetes, arthritis, and possibly
cancer have been extensively reviewed [5, 57–63]. In the secondary prevention
of cardiovascular disease, a ratio of 4:1 was associated with a 70% decrease in
total mortality [24]. A ratio of 2.5:1 reduced rectal cell proliferation in patients
with colorectal cancer, whereas a ratio of 4:1 with the same amount of omega–3
polyunsaturated fatty acids (PUFA) had no effect [64–65]. The lower omega–6:
omega–3 ratio in women with breast cancer was associated with decreased risk
[66]. A ratio of 2–3:1 suppressed inflammation in patients with rheumatoid
arthritis [67], and a ratio of 5:1 had a beneficial effect on patients with asthma,
whereas a ratio of 10:1 had adverse consequences [68].
Table 3. Mean fatty acid composition of cholesteryl esters in serum of
92 elderly men from Crete and 97 elderly men from Zutphen
Fatty acid % methylesters p value
Crete Zutphen
16:0 11.1�1.0 11.9�1.3 �0.001
16:1 3.2�1.1 2.9�1.6 0.213
18:0 0.7�0.3 1.1�0.5 �0.001
18:1 31.0�2.7 21.4�3.9 �0.001
18:2��6 41.9�3.7 53.1�6.5 �0.001
18:3��3 0.9�0.5 0.3�0.4 �0.001
Ratio 18:2/18:1 1.37�0.20 2.60�0.75 �0.001
Results are expressed as mean % (by weight) methylesters � SD.
From Sandker et al. [44].
The Greek Diet: Scientific Evidence 85
Further support for the need to balance the omega–6/omega–3 fatty acid
ratio comes from the studies of Ge et al. [69] and Kang et al. [70]. The study by
Ge et al. [69] clearly shows the ability of both normal rat cardiomyocytes and
human breast cancer cells in culture to form all the omega–3s from omega–6
fatty acids when fed the cDNA encoding omega–3 fatty acid desaturase
obtained from the roundworm Caenorhabditis elegans. The omega–3 desat-
urase efficiently and quickly converted the omega–6 fatty acids that were fed to
the cardiomyocytes in culture to the corresponding omega–3 fatty acids. Thus,
omega–6 linoleic acid (LA) was converted to omega–3 ALA, and arachidonic
acid (AA) was converted to EPA, so that at equilibrium, the ratio of omega–6 to
omega–3 PUFA was close to 1/1 [70]. Further studies demonstrated that the
cancer cells expressing the omega–3 desaturase underwent apoptotic death
whereas the control cancer cells with a high omega–6/omega–3 ratio continued
to proliferate [69, 71]. Kang et al. [72] in their recent paper showed that trans-
genic mice expressing the C. elegans fat-1 gene encoding an omega–3 fatty
acid desaturase are capable of producing omega–3 from omega–6 fatty acids,
leading to enrichment of omega–3 fatty acids with reduced levels of omega–6
fatty acids in almost all organs and tissues, including muscles and milk, with no
need of dietary omega–3 fatty acid supply. This discovery provides a unique
tool and new opportunities for omega–3 research, and raises the potential of
production of fat-1 transgenic livestock as a new and ideal source of omega–3
fatty acids to meet the human nutritional needs. In the current volume, Dr. Kang
provides additional studies [73].
Summary of Characteristics of the Greek Diet
Because Greeks have a cultural dislike for animal fats, the saturated fat
intake of the Greek diet is lower than other Western diets [20]. The Greek diet
then is characterized by being moderate in fat, about 35%, low in saturated fat
(7–8%), high in monounsaturated fat, and balanced in the omega–6:omega–3
essential fatty acids. The antioxidant and phytoestrogen content, and other phy-
tochemicals is much higher than other diets of the people around the
Mediterranean basin because Greeks continue to eat wild greens which are rich
sources of ALA, vitamin C, vitamin E, glutathione and other phytochemicals
with antioxidant properties [32–36]. The beneficial effects of the various com-
pounds found in the vegetables and fruits eaten by Greeks have been shown to
have hypoglycemic, hypocholesterolemic, and antitumor properties in animal
experiments [45]. Even today the mortality from breast cancer is lower in
Greece than in the US, Japan and Europe [74]. Finally, the Lyon Heart Study
based on the modified diet of Crete described by de Lorgeril et al. [24] clearly
Simopoulos 86
showed cardioprotective and anticancer effects in a French population indicat-
ing that such a diet is not only palatable but can be adapted to other populations.
Furthermore, one could consider that the traditional diet of Greece even in its
present form is the diet that is closer than the diets of other developed countries,
to the diet on which humans evolved (fig. 1).
What appears to be so special about the Greek diet relative to the other
Mediterranean diets is the content of bioprotective nutrients, specifically:
(1) A more balanced intake of essential fatty acids from vegetable, animal
and marine sources, omega–6:omega–3 of about 2:1 instead of 15:1 in Europe
and 16.7:1 the US, respectively.
(2) Antioxidants: high amounts of vitamin C, vitamin E, �-carotene, glu-
tathione, phytoestrogens, and phytochemicals from green leafy vegetables; phe-
nolic compounds from wine and olive oil; high intakes of tomatoes, onions,
garlic and herbs, especially oregano, mint, rosemary, parsley and dill that con-
tain lycopene, allylthiosulfinates, salicylates, carotenoids, indoles, monoter-
penes, polyphenols, flavonoids, and other phytochemicals, used in cooking
vegetables, meat, and fish.
The Greek Way of Cooking
In addition to the differences in the food composition there are distinct dif-
ferences in the way Greeks use food ingredients. Traditionally, the Greeks start
with olive oil to sauté onions, garlic, parsley, mint, oregano, and either fresh
tomatoes, canned tomatoes, or tomato paste is used. This basic recipe contains
already 8 different foods that contribute a balance of fatty acids (from olive oil,
and additional omega–3 fatty acids and antioxidant vitamins from the green
leafy herbs and the tomatoes), potassium, calcium, magnesium, vitamin C, vita-
min E, vitamin A, and �-carotene. In other words, this basic recipe is an ‘antiox-
idant cocktail’ that is also balanced in omega–6 and omega–3 fatty acids. To this,
zucchini, potatoes, eggplant, meat, fish or beans may be added. This approach to
cooking has the advantage of using a variety of foods all at once that provide vit-
amins and minerals, is low in saturated fats and omega-6 fatty acids, and very
rich in monounsaturates, omega–3 fatty acids, antioxidants and fiber. Compare
this with a meal of potato, green beans and meat in which only 3 foods are eaten
or a New England Boiled Dinner of corned beef, potatoes, onions and cabbage.
Because honey and cinnamon are used in many of the sweets, the total
amount of sugar (sucrose, simple carbohydrates) is less than it would have been
otherwise. Another important feature is the use of the juice of grapes to make
cookies or puddings known as ‘must’ cookies. The recipe for ‘must’ cookies
was developed in classic times. Today we know that red wine or the juice from
The Greek Diet: Scientific Evidence 87
red grapes contains resveratrol that raises high-density lipoprotein (HDL) cho-
lesterol, lowers low-density lipoprotein (LDL) cholesterol, and decreases
platelet aggregation [75, 76].
Another important aspect of the Greek diet is that the recipes for fish or
meat (broiled or baked) always include olive oil, oregano, rosemary and lemon
juice added towards the end of cooking so that the olive oil does not oxidize.
Furthermore, the vitamin C (from the lemons) and vitamin E (from oregano and
rosemary) provide the two important antioxidant vitamins that may prevent the
oxidation of LDL and free radical formation. In animal studies and tissue cul-
tures it has been shown that it is the oxidized LDL that is deposited to form
atheromas that lead to coronary heart disease [77].
Egg lemon sauce is a frequently used sauce with either egg yolks or whole
eggs, olive oil and lemon juice (juice of one lemon per egg yolk). One can see
the wisdom of that sauce. Lemon juice provides vitamin C to prevent the oxida-
tion of LDL cholesterol from the egg yolk. This sauce is often served with
either fish, meat or over vegetables such as artichokes, asparagus, celery, broc-
coli, or cauliflower, all of which are high in fiber, which decreases serum cho-
lesterol levels and may also protect against colon cancer.
In summary, the Greek diet is low in saturated fat, is balanced in omega–6 and
omega–3 fatty acids, and is rich in antioxidant vitamins and minerals. Olive oil is
the most prominent oil in the Greek diet. The black olives are high in vitamin E.
Olives contain 2-(3,4-dehydroxyphenyl)ethanol, a phenolic compound which
inhibits arachidonate lipoxygenase activity, thus decreasing the formation of proin-
flammatory eicosanoids (leukotriene B4) [78]. The Greek diet is based on great
variety and moderation. About 14–20 different foods are consumed at a meal by
Greeks versus about 6–8 consumed by western Europeans and Americans.
Conclusions
Since World War II, the Mediterranean diet, as a model of a healthful diet,
has been the subject of many studies. It is now clear that there is not one
‘Mediterranean diet’. In fact, the only diet that is consistent with the Paleolithic
diet on which humans evolved is the traditional Greek diet as shown by the
surveys on the population of Crete and clinical intervention studies using a
modification of the diet of Crete [20, 24, 79]. What is then so special or what
are the characteristics of such a diet? First and foremost, the traditional Greek
diet has the following characteristics. The diet is:
1 Low in saturated fat, high in monounsaturated fat, balanced in omega–6
and omega–3 fatty acids that are present in every meal since both essential
fatty acids are found in vegetable, animal, and marine sources.
Simopoulos 88
2 High in fruits, vegetables, and legumes since Greeks continue to eat 0.5 kg
(1 lb) of fruit a day. In long-term (25 years) follow-up studies on cohorts of
the Seven Countries Study, high intake of fruit and fish were associated
with a lower risk of cardiovascular diseases.
3 Rich in antioxidants as a result of using several herbs in cooking legumes,
vegetables, meat and fish. The traditional Greek diet is very rich in many
antioxidant compounds from high fruit and vegetable intake and wine.
4 Moderate in the amounts of cereals in the form of bread, usually sourdough
bread which has a lower glycemic index than the quick breads used in other
Western countries.
The Lyon Heart Study based on a modified diet of Crete indicated that the
diet was responsible for a reduction in total death by 70% and that the tradi-
tional Greek diet can be adapted to other Western countries and cultures [24].
The most likely components that account for the difference in death rate from
cardiovascular disease in the Lyon Heart Study and in the Seven Countries
Study is the balance of omega–6 and omega–3 essential fatty acids being 4:1 or
less and the high amounts of compounds with antioxidant properties. Figure 2
illustrates the traditional Greek diet in the form of a Greek column which takes
into consideration genetic individuality, the principles of moderation, variety,
proportionality, and balancing energy intake with energy expenditure [80].
Greek columnfood guide
S
mea
t
legu
mes
pou
ltry
olive oil, lemon, vinegarolivesbreadcheeseyogurtfruits - fruit juicesnuts, garlic, onionsvegetables, herbs, spicespasta, ricewater, wine
fish
eggs
fish
pou
ltry
pas
ta
fish
legu
mes
legu
mes
legu
mes
legu
mes
legu
mes
M T W T F S
Genetics
Principles
ModerationVarietyProportionalityEnergy intake � Energy expenditure
Fig. 2. The Greek Column Food Guide. The guide is based on genetic individuality, the
principals of moderation, variety, proportionality, and energy intake � energy expenditure [80].
The Greek Diet: Scientific Evidence 89
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Artemis P. Simopoulos, MD
The Center for Genetics, Nutrition and Health
2001 S Street, N.W., Suite 530
Washington, DC 20009 (USA)
Tel. 1 202 462 5062, Fax 1 202 462 5241, E-Mail [email protected]
Simopoulos AP (ed): Nutrition and Fitness: Mental Health, Aging, and
the Implementation of a Healthy Diet and Physical Activity Lifestyle.
World Rev Nutr Diet. Basel, Karger, 2005, vol 95, pp 93–102
Balance of Omega–6/Omega–3 EssentialFatty Acids Is Important for HealthThe Evidence from Gene Transfer Studies
Jing X. Kang
Massachusetts General Hospital and Harvard Medical School, Boston, Mass., USA
The ratio of omega–6 to omega–3 essential fatty acids in today’s Western diets
is around 15–20:1, indicating that modern diets are deficient in omega-3 fatty acids
but too high in omega–6 fatty acids compared with the diet on which humans
evolved and their genetic patterns were established (omega–6/omega–3 � 1:1)
[1, 2]. This is the consequence of modern agriculture, agribusiness and aquaculture
with excessive production of vegetable oils, the emphasis on grain feeds, and
processed foods [1–3]. The lipid pattern of our diets renders our tissues very high in
omega–6 fatty acids. Since this change in dietary omega–6/omega–3 ratio occurred
within too short a time to affect genetic adaptation significantly, we do not have the
gene capable of converting omega–6 to omega–3 fatty acids. As a result, a high
omega–6/omega–3 ratio exists in our body tissues. The high omega–6/omega–3
ratio may contribute to the high prevalence of many modern diseases (heart disease,
cancer, etc.) [4], and appears to be a major problem of modern nutrition.
Although it is generally recognized that a lower ratio of omega–6/omega–3
fatty acids is more desirable in reducing the risk of many chronic diseases, the
optimal ratio has not been well defined. In order to examine the potential benefi-
cial effects of a balanced ratio of omega–6/omega–3 fatty acids (�1:1), we have
recently used a gene transfer approach to create such a ratio in mammalian cells
and studied its impact on cell function and physiology [5–6]. The fat-1 gene,
encoding the converting enzyme omega–3 fatty acid desaturase that catalyzes
conversion of omega–6 to omega–3 fatty acids, is found in the roundworm
Caenorhabditis elegans but missing in mammals [5]. We transferred the fat-1gene from C. elegans into cultured human cells and whole animals (mice) to ren-
der them capable of converting omega–6 to omega–3 fatty acids. The resulting
transgenic cells and mice can produce omega–3 from omega–6 fatty acids and
Kang 94
have a balanced omega–6/omega–3 ratio (�1:1) without the need of exogenous
omega–3 supplementation. Use of these cells and animals for study of omega–3
fatty acids can eliminate the potential confounding factors of diet or supplement.
Thus, the transgenic cells and mice can serve as a unique model for elucidating
the importance of the ratio of omega–6/omega–3 fatty acids. The data obtained so
far from these studies (in vitro and in vivo) are summarized as follows.
Cellular Studies
In order to introduce the fat-1 gene into mammalian cells efficiently, we
used a virus-mediated gene transfer strategy. We constructed a recombinant ade-
novirus (Ad.GFP.fat-1) carrying both the fat-1 gene and the green fluorescent
protein (GFP) gene and another adenovirus (Ad.GFP) carrying the GFP gene
alone (as control) and used them to infect various mammalian cells, including
heart cells, neurons, endothelial cells and human breast cancer cells [5, 7–9].
Following the virus-mediated gene transfer, cellular lipids were extracted
and fatty acid composition was analyzed by gas chromatography to determine if
the expression of the fat-1 gene in mammalian cells could change their lipid
profile. Our results showed that the fatty acid profiles were remarkably differ-
ent between cells expressing the fat-1 gene and control cells [5, 7–9]. In cells
expressing the fat-1 gene (omega–3 fatty acid desaturase), all types of omega–6
fatty acids were largely converted to corresponding omega–3 fatty acids,
namely, 18:2�–6 to 18:3�–3, 20:2�–6 to 20:3�–3, 20:3�–6 to 20:4�–3,
20:4�–6 to 20:5�–3, 22:4�–6 to 22:5�–3 and 22:5�–6 to 22:6�–3. As a result,
the contents of omega–3 fatty acids significantly increased whereas the levels
of omega–6 fatty acids decreased in the fat-1 transgenic cells, leading to a dra-
matic reduction of the omega–6/omega–3 ratio from 9–15:1 in the control cells
to about 1:1 (table 1). Similar effects were observed in all cell types that we
have tested [7–9]. We also measured the production of prostaglandin E2 (PGE2),
one of the major ecosanoids derived from 20:4�–6 (AA), in the fat-1 and con-
trol cells by using an enzyme immunoassay [5, 7–9]. We found that the amount
of prostaglandin E2 produced by the cells expressing the fat-1 gene was signifi-
cantly lower than that produced by the control cells (30–50% reduction) [5, 7,
8]. These results indicate that gene transfer of the omega–3 fatty acid desaturase
can effectively modify cellular fatty acid composition (the omega–6/omega–3
ratio) and the generation of eicosanoids.
Next, we determined if the gene transfer-induced change in the omega–6/
omega–3 ratio would provide the beneficial effects of omega–3 fatty acids as
observed with fatty acid supplementation. Our previous studies have demon-
strated an antiarrhythmic effect for omega–3 fatty acids when supplemented to
Omega–6/Omega–3 Ratio in the Gene Transfer Studies 95
cardiac myocytes [10]. To see whether the gene transfer can provide a similar
protective effect, neonatal rat cardiac myocytes expressing the fat-1 gene
were tested for their susceptibility to arrhythmias induced by arrhythmogenic
agents, such as high concentrations of extracellular calcium. As shown in
figure 1, when challenged with a high [Ca2�] (7.5 mM), the control cells promptly
exhibited arrhythmia characterized by spasmodic contractures and fibrillation,
whereas the cells expressing the fat-1 gene could sustain regular beating (resistant
to the arrhythmogenic stimulus), similar to the effect of omega–3 fatty acid sup-
plementation [10]. This suggests that gene transfer of the omega–3 desaturase
into heart cells can provide the antiarrhythmic effect of omega–3 fatty acids.
In human breast cancer cells (MCF-7), gene transfer of the omega–3 desat-
urase reduced both cellular omega–6/omega–3 fatty acid ratio from 12.0 to 0.8
and the level of PGE2 by about 40%, leading to an increase in apoptotic cell death
and a decrease in cell proliferation [7]. As shown in figure 2, a large number of
the cells expressing fat-1 gene underwent apoptosis, as indicated by morphological
Table 1. Polyunsaturated fatty acid composition of
total cellular lipids from the control heart cells and the trans-
genic cells expressing a C. elegans fat-1 cDNA
Mol% of total fatty acids Control fat-1
v–6 polyunsaturates18:2�–6 14.2a 9.2b
20:2�–6 1.2a 0.3b
20:3�–6 1.6a 0.4b
20:4�–6 15.2a 4.1b
22:4�–6 4.4a 1.0b
22:5�–6 0.2a 0.0b
Total 36.8a 15.0b
v–3 polyunsaturates18:3�–3 0.2b 3.6a
20:4�–3 0.0b 0.6a
20:5�–3 0.1b 6.1a
22:5�–3 1.2b 5.8a
22:6�–3 1.0a 1.3a
Total 2.5b 17.4a
�–6/�–3 ratio 14.7a 0.9b
Values are means of four measurements. Values for each
fatty acid with the same superscript letter do not differ sig-
nificantly (p � 0.01) between control and fat-1.
Kang 96
↑Ca2� (7.5 mM)
↑Ca2� (7.5 mM)
Ad.GFP.fat-1
Ad.GFP
Fig. 1. Effect of expression of the C. elegans �–3 fatty acid desaturase in cardiac
myocytes on their susceptibility to arrhythmia. Cultured (spontaneously beating) neonatal rat
cardiac myocytes infected with Ad.GFP (control) or Ad.GFP.fat-1 were challenged with
7.5 mM extracellular calcium. The control cells promptly exhibited arrhythmia (spasmodic
contractures and fibrillation), whereas the fat-1 cells could sustain regular beating.
Ad.GFP Ad.GFP.fat-1
Fig. 2. The gene transfer induces apoptosis of MCF-7 cells. MCF-7 cells were infected
with Ad.GFP (left; control) or Ad.GFP.fat-1 (right). Three days after infection, cell death was
examined using a fluorescence microscope. Upper panels: Infected cells were directly visu-
alized at 510 nm of blue light. Lower panels: Cells were stained with Hoechst dye for nuclei
and observed under 480 nm fluorescent light. The brighter looking spots are the nuclei of
apoptotic cells.
Omega–6/Omega–3 Ratio in the Gene Transfer Studies 97
changes (small size with round shape or fragmentation) and nuclear staining
(bright blue). Statistical analysis of apoptotic cell counts showed that 30–50% of
cells infected with Ad.GFP.fat-1 were apoptotic whereas only 10% dead cells
found in the control cells (infected with Ad.GFP). MTT analysis indicated that
proliferative activity of cells infected with Ad.GFP.fat-1 was significantly lower
than that of cells infected with Ad.GFP. Accordingly, the total number of viable
cells in the cells infected with Ad.GFP.fat-1 was about 30% less than that in the
control cells. In addition, DNA microarray assays showed that the gene transfer-
induced change in omega–6/omega–3 fatty acid ratio could result in a down-
regulation of a number of genes involved in cell proliferation, adhesion,
angiogenesis and invasion, and an up-regulation of apoptosis-inducing genes in
MDA-MB-231 cells [unpubl. data]. These results are consistent with the reported
anti-cancer effects of omega–3 fatty acid supplementation [11–13].
In primary culture of human umbilical vein endothelial cells (HUVEC),
expression of fat-1 significantly reduced omega–6/omega–3 fatty acid ratio
from about 9 to 1 [9]. This change in cellular omega–6/omega–3 ratio led to a
decrease in the surface expression of adhesion molecules (markers of inflam-
mation). The quantity of the adhesion molecules (as determined by immunoas-
say), E-Selectin, ICAM-1, and VCAM-1 was reduced by 42, 43, and 57%,
respectively, in response to cytokine exposure (TNF-� 5 U/ml, 4 h) [9]. We then
examined whether changes in the adhesion molecule profile were sufficient to
alter endothelial interactions with monocytes, the most prevalent white blood
cell type found in atherosclerotic lesions. Under laminar flow and a defined
shear stress of �2 dyn/cm2, fat-1 compared to control vector infected HUVEC
supported �50% less firm adhesion with almost no effect on the rolling inter-
actions of THP-1 cells [9]. These results indicate that expression of the fat-1gene in HUVEC inhibit cytokine induction of the endothelial inflammatory
response and firm adhesion of monocytes, suggesting that a balanced
omega–6/omega–3 fatty acid ratio may have an antiatherosclerotic effect.
We have also determined the effect of fat-1 expression on neuronal apopto-
sis. We found that the expression of the fat-1 gene, which could significantly
reduce the neuronal omega–6/omega–3 fatty acid ratio from 6 to 1.5 and
the production of prostaglandin E2 by 20%, resulted in protection from
growth factor-withdrawal-induced apoptotic cell death of rat cortical neurons
[8]. Following gene transfer, apoptosis was induced by 24 h of growth
factor withdrawal and detected by Hoechst staining. As shown in figure 3,
cortical cultures infected with the Ad.GFP.fat-1 underwent (�60%) less apo-
ptosis than those infected with Ad.GFP [8]. Accordingly, MTT analysis indi-
cated that the viability of Ad.GFP.fat-1 cells was significantly (�50%) higher
than that of cells infected with Ad.GFP. These observations confirm the protec-
tive effects of omega–3 fatty acid supplementation on neuron death [14, 15] and
Kang 98
highlight the importance of omega–6/omega–3 ratio in this neuropro-
tectve effect.
Animal Studies
To heterologously express the C. elegans omega–3 fatty acid desaturase in
mice, we modified the fat-1 gene encoding this protein by optimization of
codon usage for mammalian cells and coupled it to a chicken �-actin promoter.
We then microinjected the expression vector into fertilized eggs to produce
transgenic mouse lines. We have now successfully generated mice expressing
the fat-1 gene [6].
Both transgenic and wild-type mice are maintained at a diet high in
omega–6 fatty acids (mainly linoleic acid) with very little omega–3 fatty acids
Ad.GFP Ad.GFP.fat-1
Fig. 3. Photomicrographs showing the protective effect of the fat-1 gene on neuronal
apoptosis. Cells were infected with Ad-GFP (left panels, control) or Ad-GFP-fat-1 (right
panels). Cell death was examined after 24 hours of growth factor withdrawal using a fluores-
cent microscope. Bright-field (upper panels) and Hoescht staining (lower panels) images
showing appoptotic cells.
Omega–6/Omega–3 Ratio in the Gene Transfer Studies 99
(�0.1% of total fat supplied). Under this dietary regime, wild-type mice have
little or no omega–3 fatty acid in their tissues because the animals naturally
cannot produce omega–3 from omega–6 fatty acids, whereas the fat–1 trans-
genic mice have significant amounts of omega–3 fatty acids (derived from
omega–6 fatty acids) in their tissues [6]. Figure 4 shows the differential fatty
acid profiles of total lipids extracted from skeletal muscles of age and sex-
matched wild-type and transgenic mice. In the wild-type animals, the polyun-
saturated fatty acids found in the tissues are mainly (98%) the omega–6 linoleic
acid (LA, 18:2�–6) and arachidonic acid (AA, 20:4�–6) with trace (or unde-
tectable) amount of omega-3 fatty acids. In contrast, there are large amounts of
18:2
�–6
18:3
�–3
*
20:4
�–6 20
:5�
–3*
22:4
�–6
22:5
�–6
22:5
�–3
*
22:5
�–6
22:4
�–6
20:4
�–6
18:2
�–6
18:3
�–3
22:6
�–3
*22
:6�
–3
20 30 40 50 60
20 30 40 50 60
TM
WT
Column retention time (min)
Det
ecto
r si
gnal
Fig. 4. Partial gas chromatograph traces showing the polyunsaturated fatty acid pro-
files of total lipids extracted from skeletal muscles of a wild-type mouse (WT, upper panel)
and a fat-1 transgenic mouse (TM, lower panel). Both the wild-type and transgenic mice
were 8 weeks old female and fed with the same diet. Note, the levels of �–6 polyunsaturated
acids (18:2�–6, 20:4�–6, 22:4�–6 and 22:5�–6) are remarkably lower whereas �–3 fatty
acids (marked with *) are abundant in the transgenic muscle (lower panel) compared with the
wild-type muscle in which there is very little �–3 fatty acid (upper panel).
Kang 100
omega–3 polyunsaturated fatty acids, including linolenic acid (ALA, 18:3�–3),
eicosapentaenoic acid (EPA, 20:5�–3), docosapentaenoic acid (DPA, 22:5�–3)
and docosahexaenoic acid (DHA, 22:6�–3), in the tissues of transgenic mice.
Accordingly, the levels of the �–6 fatty acids LA and AA in the transgenic tis-
sues are significantly reduced, indicating a conversion of omega–6 to omega–3
fatty acids. The resulting ratio of omega–6 to omega–3 fatty acids in the tissues
of transgenic animals is close to 1. This omega–3 rich profile of lipid with a bal-
anced ratio of omega–6 to omega–3 and an even more balanced
AA/(EPA�DPA�DHA) can be observed in all of the organs/tissues, including
muscle and milk (table 2). Our data clearly show that the transgenic mice
expressing the fat-1 gene are capable of producing omega–3 fatty acids from
omega–6 fatty acids, resulting in enrichment of omega–3 fatty acids in their
organs/tissues without the need of dietary omega–3 supply, which is impossible
in wild-type mammals.
The transgenic mice appear to be normal and healthy. Availability of these
animals allows us to produce two different fatty acid profiles in experimental
animals by feeding them just a single diet. Therefore, this novel mouse model is
desirable for us to address the authentic biological effects of omega–3 fatty
Table 2. Comparison of the omega–6/omega–3 ratios and AA/(EPA�DPA�DHA) ratio in various organs and tissues between a wild-type mouse
(WT) and a fat-1 transgenic mouse (TG)
Omega–6/omega–3 AA/(EPA�DPA�DHA)
WT TG WT TG
Muscle 49.0 0.7 11.3 0.4
Milk 32.7 5.7 15.7 2.5
RBC 46.6 2.9 27.0 1.6
Heart 22.8 1.8 14.3 0.9
Brain 3.9 0.8 3.6 0.7
Liver 26.0 2.5 12.5 0.9
Kidney 16.5 1.7 11.9 1.2
Lung 32.3 2.2 19.8 1.2
Spleen 23.8 2.4 17.3 1.5
Both the wild-type and transgenic mice were 8-week-old females and fed
with the same diet.
The omega–6/omega–3 fatty acid ratio is (18:2�–6 � 20:4�–6 � 22:
4�–6 � 22:5�–6)/(18:3�–3 � 20:5�–3 � 22:5�–3 � 22:6�–3).
Omega–6/Omega–3 Ratio in the Gene Transfer Studies 101
acids and omega–6/omega–3 ratio in the body, without confounding factors of
diet. Most recently, we have just begun to examine the potential differences in
physiology and pathophysiology between the transgenic and wild-type mice,
and have obtained some exciting preliminary data. For example, when main-
tained on a high omega–6/omega–3 diet, the transgenic mice have a much lower
tumorigenicity of melanoma than wild-type animals; challenging lungs with
LPS or bleomycin produces less severity of pulmonary inflammation and fibro-
sis in the transgenic mice than wild-type animals; the fat-1 transgenic mice
have lower levels of blood triglyceride and appear to be less susceptible to ath-
erosclerosis. In addition, the wild-type mice behaviorally exhibit hyperactivity
whereas the fat-1 mice do not [unpublished data, these studies are underway].
Although more studies are needed, our observations in vivo obtained so far are
consistent with the in vitro data and support the notion that a balanced ratio of
omega–6/omega–3 fatty acids is more desirable in reducing the risk of many
diseases.
Conclusions
Our findings as presented here clearly indicate that gene transfer of the C.elegans omega–3 fatty acid desaturase to mammalian cells can dramatically bal-
ance cellular omega–6/omega–3 fatty acid ratio and provide beneficial effects of
omega–3 fatty acids, without the need for supplementation with exogenous
omega–3 fatty acids. Thus, our studies have demonstrated a novel and effective
approach to modifying fatty acid composition of mammalian cells. This genetic
approach in modifying omega–6/omega–3 ratio is helpful for studying the
importance of omega–6/omega–3 fatty acid ratio in a biological system. Indeed,
our data derived from these gene transfer studies clearly show that a low or bal-
anced omega–6/omega–3 fatty acid ratio exerts many beneficial effects either in
vitro or in vivo. These results support the notion that excessive amounts of
omega–6 fatty acids and a very high omega–6/omega–3 ratio promote the patho-
genesis of many modern diseases (heart disease, cancer, etc.), while balancing or
reducing the ratio of omega–6/omega–3 fatty acids may decrease the risk of
these diseases. I expect that our ongoing studies using fat-1 transgenic mice will
provide more meaningful and definite information in the near future.
In addition, our discovery in transgenic mice provides a new strategy for
producing omega–3 fatty acid-rich foodstuff (e.g. meat, milk and eggs) by gen-
erating large fat-1 transgenic animals/livestock (e.g. cow, pig, sheep and
chicken) with this technology. This genetic approach may be a cost-effective
and sustainable way of producing omega–3 essential fatty acids for the increas-
ing demand in the future.
Kang 102
Acknowledgements
The author would like to acknowledge the contributions of Jingdong Wang, Lin Wu and
Zhao B. Kang to this work and thank Dr. John Browse for generously providing the C. elegansfat-1 cDNA and Dr. Jun-ichi Miyazaki for providing the CAG promotor. The author is also
grateful to Ms. Natalie Landman for her technical assistance. This work was supported by
grants from the National Institutes of Health, the American Cancer Society and the American
Institute for Cancer Research.
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Jing X. Kang
Massachusetts General Hospital
149–13th Street, Room 4433
Charlestown, MA 02129 (USA)
Tel. �1 617 726 8509, Fax �1 617 726 6144, E-Mail [email protected]
Simopoulos AP (ed): Nutrition and Fitness: Mental Health, Aging, and
the Implementation of a Healthy Diet and Physical Activity Lifestyle.
World Rev Nutr Diet. Basel, Karger, 2005, vol 95, pp 103–114
Dietary Prevention of Coronary Heart Disease: The Lyon Diet HeartStudy and After
Michel de Lorgeril, Patricia Salen
Laboratoire Nutrition, Vieillissement et Maladies Cardiovasculaires (NVMCV),
UFR de Médecine et Pharmacie, Université Joseph Fourier, Grenoble, France
Sudden cardiac death (SCD) is usually defined as death from a cardiac
cause occurring within one hour from the onset of symptoms [1]. In many stud-
ies, however, investigators used quite different definitions with a time frame of
3 h or even 24 h in the old World Health Organization definition. The magnitude
of the problem is considerable as SCD is a very common, and often the first,
manifestation of coronary heart disease (CHD), and it accounts for about 50%
of cardiovascular mortality in developed countries [1]. In most cases, SCD
occurs without prodromal symptoms and out of hospital. As a matter of fact,
this mode of death is a major public health issue. Since up to 80% of SCD
patients had CHD [2], the epidemiology and potential preventive approaches of
SCD should, in theory, parallel those of CHD. In other words, any treatment
aimed at reducing CHD should reduce the incidence of SCD.
The hypothesis that eating fish may protect against SCD is derived from
the results of a secondary prevention trial, the Diet And Reinfarction Trial
(DART), which showed a significant reduction in total and cardiovascular
mortality (both by about 30%) in patients who had at least 2 servings of fatty
fish per week [3]. The authors suggested that the protective effect of fish might
be explained by a preventive action on ventricular fibrillation (VF), since no
benefit was observed on the incidence of nonfatal AMI. This hypothesis was
consistent with experimental evidence suggesting that �–3 polyunsaturated
fatty acids (PUFA), the dominant fatty acids in fish oil and fatty fish, have an
important effect on the occurrence of VF in the setting of myocardial ischemia
and reperfusion in various animal models, both in vivo and in vitro [4, 5]. In the
de Lorgeril/Salen 104
same studies, it was also apparent that saturated fatty acids are proarrhythmic as
compared to unsaturated fatty acids. Using an elegant in vivo model of SCD in
dogs, Billman and colleagues recently demonstrated a striking reduction of VF
after intravenous administration of pure �–3 PUFA, including both the long
chain fatty acids present in fish oil and �-linolenic acid, their parent �–3 PUFA
occurring in some vegetable oils [6]. These authors have found the mechanism
of this protection to result from the electrophysiological effects of free �–3
PUFA when these are simply partitioned into the phospholipids of the sar-
colemma without covalently bonding to any constituents of the cell membrane.
After dietary intake, these fatty acids are preferentially incorporated into mem-
brane phospholipids [7]. Nair and colleagues have also shown that a very
important pool of free (non-esterified) fatty acids exists in the normal
myocardium and that the amount of �–3 PUFA in this pool is increased by sup-
plementing the diet in �–3 PUFA [7]. This illustrates the potential of diet to
modify the structure and biochemical composition of cardiac cells. In case of
ischemia, phospholipases and lipases quickly release new fatty acids from
phospholipids, including �–3 fatty acids in higher amounts than the other fatty
acids [7], thus further increasing the pool of free �–3 fatty acids that can exert
an antiarrhythmic effect. It is important to remember that the lipoprotein lipase
is particularly active following the consumption of �–3 PUFA [8]. One hypoth-
esis is that the presence of the free form of the �–3 PUFA in the membrane of
every cardiac muscle cell renders the myocardium more resistant to arrhyth-
mias, probably by modulating the conduction of several membrane ion chan-
nels [9]. So far, it seems that the very potent inhibitory effects of �–3 PUFA on
the fast sodium current, INa [10, 11], and the L-type calcium current, ICaL
[12], are the major contributors to the antiarrhythmic actions of these fatty acids
in ischemia. Briefly, �–3 PUFA act by shifting the steady-state inactivation
potential to more negative values, as was also observed in other excitable tis-
sues such as neurons.
Another important aspect of the implication of �–3 PUFA in SCD is their
role in the metabolism of eicosanoids. In competition with �–6 PUFA, they are
the precursors to a broad array of structurally diverse and potent bioactive lipids
(including eicosanoids, prostaglandins and thromboxanes), which are thought
to play a role in the occurrence of VF during myocardial ischemia and reperfu-
sion [13, 14].
Other clinical data show suppression (by more than 70%) of ventricular
premature complexes in middle-aged patients with frequent ventricular
extrasystoles randomly assigned to take either fish oil or placebo [15]. Also,
survivors of AMI [16] and healthy men [17] receiving fish oil were shown to
improve their measurements of heart rate variability, suggesting other mecha-
nisms by which �–3 PUFA may be antiarrhythmic.
The Lyon Diet Heart Study 105
Support for the hypothesis of a clinically significant antiarrhythmic effect
of �–3 PUFA in the secondary prevention of CHD, as put forward in DART [3],
came from two randomized trials testing the effect of ethnic dietary patterns
(instead of that a single food or nutrient), i.e. a Mediterranean type of diet (con-
sistent with a modified diet of Crete) and an Asian vegetarian diet, in the sec-
ondary prevention of CHD [18, 19]. The two experimental diets included a high
intake of essential �-linolenic acid, the main vegetable �–3 PUFA. Whereas the
incidence of SCD was markedly reduced in both trials, the number of cases was
very small and the antiarrhythmic effect cannot be entirely attributed to �-
linolenic acid as these experimental diets were also high in other nutrients with
potential antiarrhythmic properties, including various antioxidants. These find-
ings were extended by the population-based case-control study conducted by
Siscovick and colleagues on the intake of �–3 PUFA among patients with pri-
mary cardiac arrest, compared to that of age- and sex-matched controls [20].
Their data indicated that the intake of about 5–6 g of �–3 PUFA per month (an
amount provided by consuming fatty fish once or twice a week) was associated
with a 50% reduction in the risk of cardiac arrest. In that study, the use of a bio-
marker, the red blood cell membrane level of �–3 PUFA, considerably
enhanced the validity of the findings, which also were consistent with the
results of many (but not all) cohort studies suggesting that consumption of one
to two servings of fish per week is associated with a marked reduction in CHD
mortality as compared to no fish intake [21, 22]. In most studies, however, the
SCD endpoint is not reported.
In a large prospective study (more than 20,000 participants with a follow-
up of 11 years), Albert et al examined the specific point that fish has antiar-
rhythmic properties and may prevent SCD [23]. They found that the risk of
SCD was 50% lower for men who consumed fish at least once a week than for
those who had fish less than once a month. Interestingly, the consumption of
fish was not related to non-sudden cardiac death suggesting that the main pro-
tective effect of fish (or �–3 PUFA) is related to an effect on arrhythmia. These
results are consistent with those of DART [3] but differ from those of the
Chicago Western Electric Study, in which there was a significant inverse asso-
ciation between fish consumption and non-sudden cardiac death, but not with
SCD [24]. Several methodological factors may explain the discrepancy between
the two studies, especially the way of classifying deaths in the Western Electric
Study [24]. This again illustrates the limitations of observational studies and the
obvious fact that only randomized trials can definitely provide a clear demon-
stration of causal relationships.
The GISSI-Prevenzione trial was aimed at helping in addressing the ques-
tion of the health benefits of foods rich in �–3 PUFA (and also in vitamin E)
and their pharmacological substitutes [25]. Patients (n � 11,324) surviving a
de Lorgeril/Salen 106
recent AMI (�3 months) and having received the prior advice to come back to
a Mediterranean type of diet (consistent with a modified diet of Crete) were
randomly assigned supplements of �–3 PUFA (0.85 g daily), vitamin E (300 mg
daily), both or none (control) for 3.5 years. The primary efficacy endpoint was
the combination of death and non-fatal AMI and stroke. Secondary analyses
included overall mortality, cardiovascular (CV) mortality and SCD. The exact
definition of SCD was not given in the paper. However, the clinical events were
validated by an ad-hoc committee of expert cardiologists [25], who presumably
used the current definition of SCD. Treatment with �–3 PUFA significantly
lowered the risk of the primary endpoint (the relative risk decreased by 15%).
Secondary analyses provided a clearer profile of the clinical effects of �–3
PUFA (table 1). Overall mortality was reduced by 20% and CV mortality by
30%. However, it was the effect on SCD (45% lower) that accounted for most of
the benefits seen in the primary combined endpoint and both overall and CV
mortality. There was no difference across the treatment groups for nonfatal CV
events, a result comparable to that of DART [3]. Thus, the results obtained in
this randomized trial are consistent with previous controlled trials [3, 18, 19],
large-scale observational studies [21–24] and experimental studies [4–7],
which together strongly support an effect of �–3 PUFA in relation with SCD.
An important point is that the protective effect of �–3 PUFA on SCD was
greater in the groups of patients who complied more strictly with the Mediterra-
nean diet (consistent with a modified diet of Crete). This suggests a positive
interaction between �–3 PUFA and some components of the Mediterranean
diet which is, by definition, not high in �–6 PUFA and low in saturated fats, but
rich in oleic acid, various antioxidants and fiber, and associated with a moder-
ate consumption of alcohol (see below for further comments).
Regarding the other dietary fatty acids, animal experiments have clearly
indicated that a diet rich in saturated fatty acids is associated with a high
Table 1. Clinical efficacy of (�–3) PUFA in the GISSI-
Prevenzione Trial [modified from 25]: see text for comments
Relative risk (95% CI)
Death, nonfatal AMI and stroke 0.85 (0.70–0.99)
Overall mortality 0.80 (0.67–0.94)
Cardiovascular mortality 0.70 (0.56–0.87)
Sudden cardiac death 0.55 (0.40–0.76)
Nonfatal cardiovascular events 0.96 (0.76–1.21)
Fatal and nonfatal stroke 1.30 (0.87–1.96)
The Lyon Diet Heart Study 107
incidence of ischemia- and reperfusion-induced ventricular arrhythmia,
whereas PUFA of either the �–6 or �–3 family reduce that risk [4–6]. Large
(but not all) epidemiological studies have shown consistent associations
between the intake of saturated fatty acids and CHD mortality [26]. However,
the SCD endpoint is usually not analyzed in these studies. In addition, a clear
demonstration of a causal relationship between dietary saturated fatty acids and
SCD would require the organization of a randomized trial, which is not ethi-
cally acceptable. Thus, besides the effect of saturated fatty acids on blood cho-
lesterol levels, the exact mechanism(s) by which saturated fats increase CHD
mortality remain unclear. If animal data, demonstrating a proarrhythmic effect
of saturated fatty acids, are confirmed in humans, the first thing to do in order
to prevent SCD in humans would be to drastically reduce the intake of saturated
fats. In fact, this has been done in randomized dietary trials and, as expected,
the rate of SCD decreased in the experimental groups [18, 19]. However, as
written above about the same trials [22, 23], the beneficial effect cannot be
entirely attributed to the reduction of saturated fats, because other potentially
antiarrhythmic dietary factors, including �–3 PUFA, were also modified in
these trials.
In contrast with �–3 PUFA, few data have been published so far in humans
regarding the effect of �–6 PUFA on the risk of SCD. Roberts et al have
reported that the percentage content of linoleic acid (the dominant �–6 PUFA
in the diet) in adipose tissue (an indicator of long-term dietary intake) was
inversely related to the risk of SCD, which was defined in that study as instan-
taneous death or death within 24 h of the onset of symptoms [27]. This is in line
with most animal data and may suggest that patients at risk of SCD may benefit
from increasing their dietary intake of �–6 PUFA, in particular linoleic acid, in
the same way as for �–3 PUFA. Let it be mentioned, however, that �–3 PUFA
were more effective on SCD than �–6 PUFA in most animal experiments [4–6].
In addition, diets high in �–6 PUFA increase the linoleic acid content of
lipoproteins and render them more susceptible to oxidation [28], which would
be an argument against such diets because lipoprotein oxidation is a major step
in the inflammatory process that renders atherosclerotic lesions unstable and
prone to rupture [29–31].
Erosion and rupture of atherosclerotic lesions were shown to trigger CHD
complications (see below, the section on plaque inflammation and rupture) and
myocardial ischemia and to considerably enhance the risk of SCD [32–35]. As
a matter of fact, in the secondary prevention of CHD, diets high in �–6 PUFA
failed to improve the overall prognosis of the patients [36]. Also, in the Dayton
study, a mixed primary and secondary prevention trial, in which the chief char-
acteristic of the experimental diet was the substitution of �–6 PUFA for satu-
rated fat, the number of SCD was apparently lower in the experimental group
de Lorgeril/Salen 108
than in the control group (18 vs. 27) but the number of deaths from other
causes, in particular cancers, was higher in the experimental group (85 vs. 71),
thus offsetting the potential protective effect of �–6 PUFA on SCD and result-
ing in no effect at all on mortality [37]. Such negative effects were not reported
with �–3 PUFA. Thus, despite the beneficial effect of �–6 PUFA on lipoprotein
levels, which could, in theory, reduce SCD in the long term by reducing the
development of atherosclerosis, it seems preferable not to increase the con-
sumption of �–6 PUFA beyond the amounts required to prevent deficiencies in
the essential �–6 fatty acid, linoleic acid (approximately 4–6% of the total
energy intake), which are found in the current average Western diet. As a sub-
stitute for saturated fat, the best choice is obviously to increase the intake of
vegetable monounsaturated fat (oleic acid) in accordance with the Mediterranean
diet pattern. If oleic acid has apparently no effect on the risk of SCD (at least by
comparison with �–3 and �–6 PUFA), its effects on blood lipoprotein levels are
similar to those of �–6 PUFA and it has the great advantage of protecting
lipoproteins against oxidation [38].
Thus, the best fatty acid combination to prevent SCD (and the other com-
plications of CHD) and, in other words, to cumulate antiarrhythmic, antioxidant
and hypolipidemic effects, would result from the adoption of a diet close to the
Mediterranean diet pattern (consistent with a modified diet of Crete) [38, 39].
Finally, Roberts et al. [40] reported no significant relationship between
trans isomers of oleic and linoleic acids in adipose tissue and the risk of SCD
whereas Lemaitre et al. [41] found that cell membrane trans isomers of linoleic
acid (but not of oleic acid) are associated with a large increase in the risk of pri-
mary cardiac arrest. As for the role of trans fatty acids on ventricular arrhyth-
mias, it has not been investigated in experimental models.
Thus, although specific human data on the effect of saturated fatty acids on
SCD are lacking, results of several trials suggest that it is important to reduce
their intake in the secondary prevention of CHD. Despite a possible beneficial
effect on the risk of SCD, increasing consumption of �–6 PUFA should not be
recommended in clinical practice for patients with established CHD. Diets
including low intakes in saturated fatty acid (as well as trans isomers of linoleic
acid) and �–6 PUFA (but enough to provide the essential linoleic acid) and high
intakes in �–3 PUFA and oleic acid (Mediterranean diet pattern consistent with
a modified diet of Crete) appear to be the best option to prevent both SCD and
nonfatal AMI recurrence [19, 38].
For several decades, the prevention of CHD (including the prevention of
ischemic recurrence after a prior AMI) has focused on the reduction of the tra-
ditional risk factors: smoking, HBP, hypercholesterolemia. Priority was given to
the prevention (or reversion) of vascular atherosclerotic stenosis. As discussed
above, it has become clear in secondary prevention that clinical efficiency
The Lyon Diet Heart Study 109
needs to primarily prevent the fatal complications of CHD such as SCD. This
does not mean, however, that we should not try slowing down the atheroscle-
rotic process, and in particular plaque inflammation and rupture. Indeed, it is
critical to prevent the occurrence of new episodes of myocardial ischemia
whose repetition in a recently injured heart can precipitate SCD or CHF.
Myocardial ischemia is usually the consequence of coronary occlusion caused
by plaque rupture and subsequent thrombotic obstruction of the artery. Recent
progress in the understanding of the cellular and biochemical pathogenesis of
atherosclerosis suggests that, in addition of the traditional risk factors of CHD,
there are other very important targets of therapy to prevent plaque inflammation
and rupture. In this regard, the most important question is: How and why does
plaque rupture occur?
Most investigators agree that atherosclerosis is a chronic low grade inflam-
mation disease [29]. Pro-inflammatory factors (free radicals produced by ciga-
rette smoking, hyperhomocysteinemia, diabetes, peroxidized lipids, hypertension,
elevated and modified blood lipids) contribute to injure the vascular endothe-
lium, which results in alterations of its antiatherosclerotic and antithrombotic
properties. This is thought to be a major step in the initiation and formation of
arterial fibrostenotic lesions [29]. From a clinical point of view, however, an
essential distinction should be made between unstable, lipid-rich and leukocyte-
rich lesions and stable, acellular fibrotic lesions poor in lipids, as the propensity
of these two types of lesion to rupture into the lumen of the artery, whatever the
degree of stenosis and lumen obstruction, is totally different.
In 1987, we proposed that inflammation and leukocytes play a role in the
onset of acute CHD events [42]. This has recently been confirmed [32–35]. It is
now accepted that one of the main mechanisms underlying the sudden onset of
acute CHD syndromes, including unstable angina, myocardial infarction and
SCD, is the erosion or rupture of an atherosclerotic lesion [32, 33], which trig-
gers thrombotic complications and considerably enhances the risk of malignant
ventricular arrhythmias [34, 35]. Leukocytes have been also implicated in the
occurrence of ventricular arrhythmias in clinical and experimental settings [43,
44], and they contribute to myocardial damage during both ischemia and reper-
fusion [45]. Clinical and pathological studies showed the importance of inflam-
matory cells and immune mediators in the occurrence of acute CHD events and
prospective epidemiological studies showed a strong and consistent association
between acute CHD and systemic inflammation markers [46]. A major question
is to know why there are macrophages and activated lymphocytes [29] in ather-
osclerotic lesions and how they get there. Issues such as local inflammation,
plaque rupture and attendant acute CHD complications follow.
Steinberg et al. [47] proposed in 1989 that oxidation of lipoproteins causes
accelerated atherogenesis. Elevated plasma levels of low-density lipoproteins
de Lorgeril/Salen 110
(LDL) are a major factor of CHD, and reduction of blood LDL levels (for
instance by drugs) results in less CHD. However, the mechanism(s) behind the
effect of high LDL levels is not fully understood. The concept that LDL oxida-
tion is a key characteristic of unstable lesions is supported by many reports
[29]. Two processes have been proposed. First, when LDL particles become
trapped in the artery wall, they undergo progressive oxidation and are internal-
ized by macrophages, leading to the formation of typical atherosclerotic foam
cells. Oxidized LDL is chemotactic for other immune and inflammatory cells
and up-regulates the expression of monocyte and endothelial cell genes involved
in the inflammatory reaction [29, 48]. The inflammatory response itself can
have a profound effect on LDL [29], creating a vicious circle of LDL oxidation,
inflammation and further LDL oxidation. Second, oxidized LDL circulates in
the plasma for a period sufficiently long to enter and accumulate in the arterial
intima, suggesting that the entry of oxidized lipoproteins within the intima may
be another mechanism of lesion inflammation, in particular in patients without
hyperlipidemia [30, 31, 48]. Elevated plasma levels of oxidized LDL are asso-
ciated with CHD, and the plasma level of malondialdehyde-modified LDL is
higher in patients with unstable CHD syndromes (usually associated with
plaque rupture) than in patients with clinically stable CHD [30]. In the acceler-
ated form of CHD typical of post-transplantation patients, higher levels of lipid
peroxidation [49–51] and of oxidized LDL [52] were found as compared to the
stable form of CHD in non-transplanted patients. Reactive oxygen metabolites
and oxidants influence thrombus formation [see 53 for review], and platelet
reactivity is significantly higher in transplanted patients than in non-transplanted
CHD patients [54].
The oxidized LDL theory is not inconsistent with the well-established
lipid-lowering treatment of CHD, as there is a positive correlation between
plasma levels of LDL and markers of lipid peroxidation [52, 55] and low
absolute LDL level results in reduced amounts of LDL available for oxidative
modification. LDL levels can be lowered by drugs or by reducing saturated fats
in the diet. Reduction of the oxidative susceptibility of LDL was reported when
replacing dietary fat with carbohydrates. Pharmacological/quantitative (lower-
ing of cholesterol) and nutritional/qualitative (high antioxidant intake)
approaches of the prevention of CHD are not mutually exclusive but additive
and complementary. An alternative way to reduce LDL concentrations is to
replace saturated fats with polyunsaturated fats in the diet. However, diets high
in polyunsaturated fatty acids increase the polyunsaturated fatty acid content of
LDL particles and render them more susceptible to oxidation (which would
argue against use of such diets. As a matter of fact, in the secondary prevention
of CHD, such diets failed to improve the prognosis of the patients [for a review,
see 36]. In that context, the traditional Mediterranean diet, with low saturated
The Lyon Diet Heart Study 111
fat and polyunsaturated fat intakes, appears to be the best option. Diets rich in
oleic acid increase the resistance of LDL to oxidation independent of the con-
tent in antioxidants [56, 57] and results in leukocyte inhibition [58]. Thus, oleic
acid-rich diets decrease the pro-inflammatory properties of oxidized LDL.
Constituents of olive oil other than oleic acid may also inhibit LDL oxidation
[59]. Various components of the Mediterranean diet may also affect LDL oxi-
dation. For instance, �-tocopherol or vitamin C, or a diet combining reduced
fat, low-fat dairy products and a high intake of fruits and vegetables were
shown to favorably affect either LDL oxidation itself or/and the cellular conse-
quences of LDL oxidation [60, 61].
Finally, significant correlation was found between certain dietary fatty
acids and the fatty acid composition of human atherosclerotic plaques [62, 63],
which suggests that dietary fatty acids are rapidly incorporated into the plaques.
This implies a direct influence of dietary fatty acids on plaque formation and
the process of plaque rupture. It is conceivable that fatty acids that stimulate
oxidation of LDL (�–6 fatty acids) induce plaque rupture whereas those that
inhibit LDL oxidation (oleic acid), inhibit leukocyte function (�–3 fatty acids)
[64] or prevent ‘endothelial activation’ and the expression of proinflammatory
proteins (oleic acid and �–3 fatty acids) [65, 66] contribute to pacify and stabi-
lize the dangerous lesions. In that regard, it is noteworthy that moderate alcohol
consumption, a well known cardioprotective factor, was recently shown to be
associated with low blood levels of systemic markers of inflammation [67],
suggesting a new protective mechanism to explain the inverse relationship
between alcohol and CHD rate. As both dietary �–3 fatty acids and moderate
alcohol consumption are major characteristics of the Mediterranean diet, it is
not surprising to observe that this diet was associated with lower rate of new
episodes of CHF in the Lyon Diet Heart Study.
Thus, any dietary pattern combining a high intake of natural antioxidants,
a low intake of saturated fatty acids, a high intake of oleic acid, a low intake of
omega-6 fatty acids and a high intake of omega–3 fatty acids would logically
produce a highly cardioprotective effect. This is consistent with what we know
about the Mediterranean diet pattern (consistent with a modified diet of Crete)
[38, 39] and with the results of the Lyon Diet Heart Study.
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39 Simopoulos AP, Sidossis LS: What is so special about the traditional diet of Greece. The scientific
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42 de Lorgeril M, Latour JG: Leukocytes, thrombosis and unstable angina. N Engl J Med
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43 de Lorgeril M, Basmadjian A, Lavallée M, et al: Influence of leukopenia on collateral flow, reper-
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44 Kuzuya T, Hoshida S, Suzuki K, et al: Polymorphonuclear leukocyte activity and ventricular
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45 Ernst E, Hammerschmidt DE, Bagge U, Matrai A, Dormandy JA: Leukocytes and the risk of
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46 Kruskal JB, Commerford PJ, Franks JJ, Kirsch RE: Fibrin and fibrinogen-related antigens in
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47 Steinberg D, Parthasarathy S, Carew TE, Khoo JC, Witztum JL: Beyond cholesterol: modifi-
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48 Hodis HN, Kramsch DM, Avogaro P, et al: Biochemical and cytotoxic characteristics of an in vivo
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49 Holvoet P, Stassen JM, Van Cleemput J, Collen D, Vanhaecke J: Correlation between oxidized low
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59 Visioli F, Bellomo G, Montedoro G, et al: Low density lipoprotein oxidation is inhibited in vitro
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Dr. M. de Lorgeril
Laboratoire Nutrition, Vieillissement et Maladies Cardiovasculaires (NVMCV)
UFR de Médecine et Pharmacie, Domaine de la Merci
La Tronche, Grenoble, FR–38706 (France)
Tel. �33 476 63 74 71, Fax �33 476 63 71 52, E-Mail [email protected]
Simopoulos AP (ed): Nutrition and Fitness: Mental Health, Aging, and
the Implementation of a Healthy Diet and Physical Activity Lifestyle.
World Rev Nutr Diet. Basel, Karger, 2005, vol 95, pp 115–121
The Nicotera Diet: The ReferenceItalian Mediterranean Diet
Flaminio Fidanzaa, Adalberta Albertia, Daniela Fruttinib
aHuman Nutrition Unit, University of Rome-Tor Vergata, Rome, and WBC Section,
CNR Research Center, Rome-Tor Vergata and bDepartment of Statistical Sciences,
University of Perugia, Perugia, Italy
Nicotera, a small town in the Calabria Region in Southern Italy, was the
third Italian rural area of the Seven Countries Study (SCS) examined in the fall
of 1957 as a pilot study. Because both due to shortage of funds and similarity
with the two rural areas of Greece, this study was not followed longitudinally.
Nicotera, selected for the quite high olive oil and legumes consumption, is
perched on a spot of the Poro Mountain overlooking the Tyrrhenian Sea about
60 km north of Reggio Calabria near the toe of Italy. The main farm products
were olives, grapes, figs, oranges, tomatoes, pulses, wheat, bergamot for the
perfume trade, and for local use, a little meat and poultry. In the hamlet of
Nicotera Marina few families were engaged in fishing. There was no manufac-
turing industry. The population was relatively poor in comparison to the two
rural areas of Italy in the SCS, but there was a migration of persons under the
age of 40. Besides the main center of Nicotera and the hamlet of Nicotera
Marina there were three more detached hamlets: Comerconi, Badia, and
Preitoni. The total population of the entire survey area was 9,043 inhabitants at
the time of the survey. About 80% of the people lived in the centers and went
out daily to work in their small fields often as far as several kilometers away.
Both men and women were engaged in moderate physical activity and only men
in some cases in rather heavy physical work. Because of its geography (altitude
0–641 m) and road conditions, transportation was mainly by mule. The preva-
lence of myocardial infarction in men aged 45–64 years was very low (4 cases
out of 598 examined in 1957), and hypertension, overweight and obesity were
uncommon. Similar findings were observed in the cohort of men from Corfu
(Greece) examined in 1960.
Fidanza/Alberti/Fruttini 116
The Dietary Habits of Subjects from Nicotera
The weighed record method for 7 days in three different seasons of 1960
was used for the dietary survey of the Nicotera families. Because this type of
dietary survey is time consuming and very expensive, this procedure was fol-
lowed in a sample of 32 families. From the roster of all men examined in 1957,
sixteen names were chosen at random. Then for each head of family so selected,
the family living closest to him was picked. In this way one dietitian could at the
same time carry out the survey on two families.
The procedure of the dietary survey with this method is fully described in
previous papers [1, 2]. Some difficulties occurred with the Nicotera family
dietary surveys. For the first survey in January one dietitian became ill and it
was impossible to find a replacement, so the total number of subjects had to be
reduced from 32 to 24. In the second survey in May–June, six of the families
refused to continue to cooperate, six substitute families were then statistically
selected from the roster. The final result was that 17 families were surveyed for
all three seasons, 11 families for two seasons and seven families for one season,
with a total of 35 families. Because of no significant seasonal difference in
energy nutrient, all the families were considered together [3].
The percentage distribution occupation of 35 Nicotera heads of families is
as follow: farmers 37, craftsmen 26, clerks 17, salesmen 11, construction work-
ers 6 and mule drivers 3.
Table 1 shows the three-season mean of food intake expressed in g/day of
328 components of 35 Nicotera families examined in 1960. Cereals were well
represented and also were vegetables, legumes and fish. Virgin olive oil was the
most common edible fat. Meat, eggs, cheese and milk were consumed spar-
ingly. Wine, mostly red wine, was used moderately by men.
Meal Patterns and Way of Cooking in Nicotera
We report here only the meal patterns of 35 Nicotera heads of families. For
the other components of the family the differences in food consumption at meal
was quantitative more than qualitative. Then, because of the differences in food
selection, the meal patterns of 35 heads of families examined in different sea-
sons, are subdivided in two homogeneous groups: one for craftsmen, clerks and
salesmen (n � 19) and one for farmers and construction workers (n � 16). The
prevalent foods consumed at each of three main meals are presented in a
decreasing order of three season mean frequency. Obviously, there are marked
differences related to home food production according to the season.
The Nicotera Diet 117
The craftsmen group meal pattern was the following. At breakfast, bread,
coffee, or more often roasted barley hot drink and milk were consumed. At
lunch, for the first course pasta with tomato sauce, soup with vegetables or
legumes and pasta, or vegetable soup were preferred. The second course was
composed of fish or meat and as side dishes cooked or green vegetables and
cured olives. Home-produced goat’s milk cheese or salami were consumed occa-
sionally. Homemade bread, garden fruit and homemade wine were consumed in
reasonable amounts. The dinner was composed of either olive oil or tomato
sauce pasta and sometimes vegetable soup. Fish or meat was followed by side
dishes as at lunch. Cheese was preferred to salami occasionally. The consump-
tion of bread, fruit and wine was similar to that at lunch.
The farmer group meal pattern was the following. At breakfast, coffee or
more often roasted barley hot drink with less bread and much less milk than the
other group was consumed. For lunch, the vegetables or legumes and pasta soup
was preferred to pasta with tomato sauce. As second course, fish was preferred
to meat; the selection of side dishes was similar to that of the craftsmen group.
Both cheese and salami were consumed occasionally. The consumption of
bread was similar to that of the craftsmen group, while the intakes of fruit and
wine were lower. At dinner, the vegetable or legume and pasta soup was always
Table 1. Mean daily intake of foods (g) of subjects from Nicotera (Italy) in 1960: mean
of three seasons
Age group, years Males Females
13–19 20–39 40–59 �60 13–19 20–39 40–59 �60
n 35 43 64 18 45 50 63 10
Cereals 531 519 455 444 319 351 346 241
Legumes 58 57 43 64 32 33 39 13
Potatoes 68 117 73 134 60 73 68 44
Vegetables 209 280 231 282 175 212 200 136
Fruit 75 96 104 77 79 98 60 96
Fish 26 37 44 35 20 30 22 43
Oils 37 48 40 50 28 34 32 26
Fats 3 5 3 5 2 5 3 1
Meat 36 62 50 30 25 37 24 35
Eggs 11 18 22 13 12 13 9 7
Cheese 13 20 17 36 9 15 9 16
Milk, ml 48 11 38 26 15 41 35 24
Sugar products 28 22 25 31 20 20 19 14
Wine, ml 93 291 288 234 35 45 59 31
Fidanza/Alberti/Fruttini 118
preferred to pasta with tomato sauce. Also, fish was preferred to meat as a sec-
ond course, and cooked vegetables as side dishes were preferred to raw ones.
Cured olives were regularly consumed while cheese was preferred to salami as
an occasional dish. For bread, fruit and wine, the consumption was similar to
that at lunch. Few people drank some milk in the evening. When farmers went
to their farms far away, they consumed as snacks bread with fruit or raw vegeta-
bles from their garden or farm.
The home preparation of some foods is interesting as is the way of cooking
of some dishes. Bread was made with high extraction flour from home-
produced wheat, milled using stone mills. The barley hot drink was prepared at
home from barley produced on the farm. It was roasted over charcoal in special
iron containers with continuous rotation until the barley became dark brown.
The roasted barley was grounded in a coffee-mill and then boiled in water and
passed through a strainer.
The majority of recipes were prepared using a great variety of ingredients
with important nutritional characteristics: various vegetables from the home
garden, cured olives, green leafy herbs, spices (oregano, parsley, basil, rose-
mary, red pepper). For example, the sauce for pasta was prepared with olive oil,
tomatoes, onions, garlic, basil, parsley, red pepper, wild herbs all from the
garden, and little meat or fish. For vegetable soup the variety of vegetables
was great so there was a high probability that the recipes included either many
different nutrients or an elevated concentration of certain nutrients. In the first
case, different nutritional properties of ingredients were combined. In the sec-
ond case, a synergy among the properties of the same nutrients was obtained.
The most common fish consumed was: stock fish (air-dried cod), dried
salted cod and blue fish. The fish recipes included olive oil, vegetables, parsley,
onion, garlic, cured olives, tomatoes, and red pepper. Regarding meat beef,
pork and kid, they were consumed in decreasing order using the same ingredi-
ents as in the fish recipes.
The Nicotera Diet as the Reference Italian Mediterranean Diet
To objectively assess how close a diet is to its Reference Mediterranean
Diet we have set up the Mediterranean Adequacy Index (MAI).The MAI is
simply obtained by dividing the sum of total energy percentage from those
food groups mostly consumed in a healthy Mediterranean Diet (bread, cereals,
legumes, potatoes, vegetables, fresh fruit, nuts, fish, wine, vegetable oils – espe-
cially virgin olive oil) by the sum of total energy percentage from those food
groups consumed less in a healthy Mediterranean Diet (milk, cheese, meat, eggs,
animal fat and margarines, sweet beverages, cakes/pies/cookies, sugar).
The Nicotera Diet 119
Each Mediterranean country should have its own Reference Mediterranean
Diet and accordingly for Italy we have proposed the diet of Nicotera subjects
examined in 1960 [4].
Table 2 shows the median values of MAI computed from energy percent-
age of food groups consumed by Nicotera subjects examined for three seasons
in 1960.The mean value of MAI can be, in general, higher because of non nor-
mal distribution of dietary data. Also different may be the mean values of MAI
computed from food groups values expressed as g/day or g/4.2 MJ because of
differences in energy density of some foods.
As an example, we report here the MAI values of diets consumed by the
two rural SCS Italian cohorts followed longitudinally from 1965 to 1991.In
Crevalcore (Northern Italy) the MAI value, computed from energy percentage
of food groups, changed from 2.9 in 1965 to 2.2 in 1991. The corresponding
values in Montegiorgio (Central Italy) were 5.6 and 3.9. In both areas, the MAI
values were lower than those of the Nicotera subject diet and deteriorated over
time, thus indicating a progressive abandoning of the traditional Mediterranean
diet particularly in Montegiorgio.
Recently, we have also computed the MAI of diets consumed by random
samples of men from 16 SCS cohorts examined around 1960. The MAI is
negatively correlated (R � �0.72) with 25-year death rate from coronary heart
disease [5].
The Healthy Italian Mediterranean Diet Temple Food Guide
On the occasion of the International Conference on European Mediterranean
Diets held in Rome at the Medical School at the University of Rome Tor Vergata
on January 20, 2003, we presented the Healthy Italian Mediterranean Diet Temple
Table 2. Median values of the Mediterranean Adequacy Index computed
from energy percentage of food groups consumed by Nicotera subjects exam-
ined for three seasons in 1960
Age class Males Females
n subjects MAI n subjects MAI
13–19 years 35 8.0 45 6.6
20–39 years 43 6.3 50 5.8
40–59 years 64 7.2 63 8.5
�60 years 18 6.9 10 6.5
Fidanza/Alberti/Fruttini 120
Food Guide (HIMDTFG), to clearly provide the message of the healthy
Mediterranean diet essence. The idea of the Temple came from the Simopoulos
paper on ‘The Mediterranean Food Guide’ [6].
The development of the Greek-Roman Temple was based on the Nicotera
diet of heads of families examined in 1960, which was set up as the Reference
Italian Mediterranean Diet for adults. In the three wide steps at the base of the
Temple there are written in upward order the following sentences: most healthy
lifestyle, energy intake � energy expenditure, virgin olive oil and wine. On the
big left lateral column it is written: brown bread, cereals and in smaller charac-
ters, potatoes. While on the big right column it is written: vegetables, fresh fruit
and in smaller characters, nuts. In the two smaller central columns the words
legumes and fish are written. All the above food groups are prevalently con-
sumed in a healthy Mediterranean diet. On the metopes in a progressive order,
the words of food groups less prevalently consumed in a healthy Mediterranean
diet (milk and dairy products, meats, eggs, fats, cakes, sugar) are written. On
the tympanum the word ‘Moderation’ which is a basic characteristic of a
healthy Mediterranean diet dominates. On the Temple, we preferred to indicate
food groups using words instead of misleading figures or drawings as in the
overly used and misleading Pyramid.
The HIMDFG, after appropriate modifications related to food availability,
life habits and cultural traditions can be adapted to other populations.
Conclusions
The Nicotera diet of heads of families is a well balanced diet. All nutrients
meet, in general, the national reference values. Very high are the intakes of
antioxidant vitamins and food components, and folate. The ratios of various
classes of fatty acids are more than satisfactory. The very low prevalence of
myocardial infarction, hypertension and obesity observed in Nicotera men can
be considered the biological answer to their diet; for this reason it was chosen as
the Reference Italian Mediterranean Diet. Consequently, the MAI of the
Nicotera diet can be considered an advisable value.
Then, as we have already said, the Nicotera diet is practically similar to the
diet of SCS cohort of men examined in Corfu (Greece) in 1960.The MAI value
of the Corfu diet computed from food groups expressed as g/day is 10.7. The
MAI of men examined in Nicotera computed in the same way is 8.2. In Corfu as
in Nicotera the prevalence of myocardial infarction in 1960 was low (3 cases
out of 529 men) as also hypertension, overweight and obesity. In Corfu the
coronary heart disease death rate per 1,000 in 25 years was in the same range of
cohorts from Japan, Crete, and Dalmatia, with the following MAI values:
The Nicotera Diet 121
4.4 (Crete cohort), 5.2 (Dalmatia cohort), 8.3 (Ushibuka-Japan cohort), 11.6
(Tanushimaru-Japan cohort).
However, the Mediterranean diets followed by the SCS cohorts and
retained healthy from epidemiological confirmation have not to be considered
as food suppliers only, but they should be set into the life style context of those
populations at that time.
In the above populations the sociocultural meanings related to foods have
changed considerably over the past generation. Accordingly, appropriate adap-
tations taking into account these new socioeconomic realities are needed.
References
1 Fidanza F, Fidanza-Alberti A, Ferro-Luzzi G, Proja M: Dietary surveys in connection with the
epidemiology of heart disease: Results in Italy. Voeding 1964;25:502–509.
2 Fidanza F, Fidanza-Alberti A: Rilevamento dei consumi alimentari di alcune famiglie in tre zone
agricole d’Italia. Quaderni Nutr 1971;31:139–188.
3 Fidanza F, Fidanza-Alberti A: Dietary surveys in connection with the epidemiology of heart dis-
ease: Reliability, sources of variation and other data from nine surveys in Italy. Voeding 1967;28:
244–252.
4 Alberti-Fidanza A, Fidanza F, Chiuchiù MP, Verducci G, Fruttini D: Dietary studies on two rural
Italian population groups of the Seven Countries Study. 3. Trend of food and nutrient intake from
1960 to 1991. Eur J Clin Nutr 1999;53:854–860.
5 Fidanza F, Alberti A, Lanti M, Menotti A: Mediterranean Adequacy Index: Correlation with
25-year mortality from coronary heart disease in the Seven Countries Study. Nutr Metab Cardiovas
2004;14:254–258.
6 Simopoulos AP: The Mediterranean Food Guide. Nutr Today 1995;30:54–61.
Prof. Flaminio Fidanza
Via S. Vetturino 4/B
I–06126 Perugia (Italy)
Tel. �39 075 31363, Fax �39 075 5839294
E-Mail [email protected]
Simopoulos AP (ed): Nutrition and Fitness: Mental Health, Aging, and
the Implementation of a Healthy Diet and Physical Activity Lifestyle.
World Rev Nutr Diet. Basel, Karger, 2005, vol 95, pp 122–139
Wine and Health: Evidence andMechanisms
Inés Urquiaga, Federico Leighton
Molecular Nutrition Laboratory, Faculty of Biological Sciences, Catholic University
of Chile, Santiago, Chile
Epidemiological observations provide us valuable insights in the role
played by the environment on human health. The observations lead to hypothe-
ses which necessarily have to be confronted in the laboratory. This sequence is
apparent in the development of our present ideas related to wine and health. The
epidemiological work is not finished and much remains to be evaluated experi-
mentally.
Epidemiological Evidence
Epidemiological studies show that moderate alcohol consumption, particu-
larly wine, is associated with decreased risk in all-cause mortality, especially
ischemic heart disease death as well as other chronic diseases, and a longer life
[1, 2]. The shape of the correlation is generally described as a J-shaped curve in
which moderate drinkers (two drinks per day) of any kind of alcohol have a
decreased risk of coronary heart disease relative to non-drinkers, whereas heavy
drinkers have an increased risk of infarction and stroke.
Moderate drinkers, male or female, show a 30–40% decrease in risk of
coronary heart disease mortality, and 10–20% decrease in mortality from all
causes. On cardiovascular disease a reduction which might reach 60% in mor-
bidity and mortality has been reported [3–8].
The studies and discussions held on the so called ‘French Paradox’ give
wine a special position. It is a characteristic component of the Mediterranean
diet and might account for the lower incidence of coronary heart disease among
Mediterranean populations [9–10]. Renaud and Ruf [10] show that the correlation
Wine and Health 123
among coronary deaths and various foods, in 21 countries, is stronger for wine
(�0.87, p � 0.001) than for other components like vegetables or vegetable fats;
at the same time they found a positive correlation with milk-fat products (0.66,
p � 0.001). Thus, wine would exert a more marked effect than that of fruits and
vegetables, also rich in antioxidants. The same general conclusions were
reached for alcohol, most particularly wine, in a study which involved countries
with similar economic development [11].
Gronbaek and collaborators in the Copenhagen City Heart Study on 6,051
men and 7,234 women, 30–79 years old, found that wine, but not beer or spirits,
was associated with a decrease in cardiovascular, cerebrovascular, and all
causes mortality [12]. In this study, 3 to 5 drinks per day led to reduction in car-
diovascular mortality by 47% in the wine drinkers, and also mortality by other
causes was 50% lower. This work is in contrast to others in which not only wine,
but also other alcoholic beverages are considered to be responsible for the ben-
eficial effects [13]. A more recent work by Renaud and collaborators on 34,014
middle-aged men from eastern France, 77% of them wine drinkers, led to the
conclusion that moderate consumers (2–5 glasses per day) have a 24–31%
reduction in all-cause mortality, attributed to cardiovascular disease and cancer
[6, 14]. The results also showed that the protective effect of a moderate intake of
wine on all-cause mortality is observed at all levels of blood pressure and serum
cholesterol.
The specificity of wine for lowering the risk of all-cause mortality and
cancer has been confirmed by Gronbaek and collaborators [15]. It was only in
wine drinkers that the all-cause mortality was lowered by more than 20% for an
intake of up to 3 drinks per day. They also found that it was only wine but not
spirits or beer that reduced cancer mortality by up to 20% (3 glasses of
wine/day). As for cancer, the subsequent question was to evaluate on what types
of cancer wine may have protective effects. Gronbaek and collaborators have
already shown that wine drinking does not increase the risk of upper digestive
tract cancer as compared to beer or spirits [16].
Moderate wine or alcohol consumption is also beneficial for conditions
associated with aging, and a better cognitive performance and lower risk of
dementia have been described [17, 18]. However, some studies showed a differ-
ence according to the type of alcohol. In the Canadian Study of Health and
Aging, the follow up of 4,088 persons for 5 years showed a 31% reduction in
the risk of developing dementia in alcohol drinkers compared to non drinkers
[19]. In addition, the risk was lower in wine drinkers (odds ratio (OD) 0.49;
95% confidence interval (CI) 0.28–0.88) than in beer or spirit drinkers (OR
0.84; 95% CI 0.51–1.41 and OR 0.78; 95% CI 0.52–1.19), respectively.
In another cohort study (the Copenhagen City Heart Study), the alcohol con-
sumption recorded in 1976 in a cohort initially designed to study cardiovascular
Urquiaga/Leighton 124
diseases has been linked to the risk of getting dementia in the period 1990–1994
[20]. Compared to non drinkers, the risk of developing dementia was signifi-
cantly lower among occasional wine drinkers (OR 0.43; 95% CI 0.23–0.82), in
weekly drinkers (OR 0.33; 95% CI 0.13–0.86), but nonsignificant in daily
drinkers (OR 0.57; 95% CI 0.15–2.11). However, an increased risk was
observed for beer (OR 2.28; 95% CI 1.13–4.60 in occasional drinkers, OR 2.15;
95% CI 0.98–4.78 in weekly drinkers and OR 1.73; 95% CI 0.75–3.99 in daily
drinkers) or for spirits (OR 0.81; 95% CI 0.42–1.57 in occasional drinkers, OR
1.65; 95% CI 0.74–3.69 in weekly drinkers and OR 1.12; 95% CI 0.43–2.92 in
daily drinkers).
In Bordeaux (France), a population-based prospective study found that
subjects drinking 3–4 standard glasses of wine per day (�250 and up to 500 ml),
categorized as moderate drinkers, the crude OR was 0.18 for the incidence of
dementia (p � 0.01) and 0.25 for Alzheimer’s disease (AD)(p � 0.03), as com-
pared with the non-drinkers. After adjusting for age, sex, education, occupation,
baseline cognitive performances and other possible confounders, the ORs were,
respectively, 0.19 (p � 0.01) and 0.28 (p � 0.05). In the 922 mild drinkers
(�1–2 glasses per day) there was a negative association only with AD, after
adjustment (OR 0.55; p � 0.05). The inverse relationship between moderate
wine drinking and incident dementia was explained neither by known predic-
tors of dementia nor by medical, psychological or sociofamilial factors [21–22].
A recent cohort of elderly persons from New York City included 980 com-
munity-dwelling individuals aged 65 and older without dementia at baseline
and with data on alcohol intake. The subjects were recruited between 1991 and
1996 and followed annually. After 4 years of follow-up, 260 individuals devel-
oped dementia (199 AD, 61 dementia associated with stroke). After adjusting
for age, sex, apolipoprotein E (APOE)-epsilon 4 status, education, and other
alcoholic beverages, only intake of up to three daily servings of wine was asso-
ciated with a lower risk of AD (OD 0.55; 95% CI 0.34–0.89). Intake of liquor,
beer, and total alcohol was not associated with a lower risk of AD. Stratified
analyses by the APOE-epsilon 4 allele revealed that the association between
wine consumption and lower risk of AD was confined to individuals without
the APOE-epsilon 4 allele [23].
Type II diabetes mellitus (NIDDM) is another condition that correlates
with aging and in which oxidative stress plays a pathogenic role. Moderate
alcohol consumers have a decreased risk of diabetes [24]. Moderate wine con-
sumption correlates with decreased risk of macular degeneration, an age-
related disorder [25].
Moderate wine drinkers appear to be at lower risk of becoming heavy and
excessive drinkers as well as developing alcoholic cirrhosis [26, 27]. This study
suggests that a person who prefers beer is more likely to become a heavy or an
Wine and Health 125
excessive drinker than a person who prefers wine. Among men, moderate
drinkers who included wine in their weekly alcohol intake had significantly
lower risks of becoming heavy or excessive drinkers as compared to those who
did not drink any wine. Women who included beer in their alcohol intake
showed increased risk of heavy and excessive drinking compared to non-beer
drinking women. Further they found that the risk of developing cirrhosis in
wine drinkers (more than 30% wine in their total alcohol intake) was less than
50% of the risk in non-wine drinkers for any given level of total alcohol intake,
while beer and spirits drinking did not modify the relation between total alcohol
intake and risk of developing cirrhosis.
Other studies have reported relations between beer drinking and high-risk
behaviors such as frequent heavy drinking and other alcohol-related problems,
while wine drinking seems to be considered ‘the beverage of moderation’
[28–30].
There is a large variety of other positive phenomena associated with
moderate wine consumption. Wine has been described as a healthy beverage
for centuries, a property mainly associated with its capacity of killing or stopping
the growth of microorganisms. This has been observed for many bacteria and
there is an interesting report on the capacity of wine to control oyster-borne
hepatitis A [31]. A particularly intriguing property of wine is that in contrast to
beer and hard liquor, it does not favor an increase in the waist-to-hip ratio, a para-
meter strongly associated with cardiovascular risk [32]. The risk of kidney stones
also decreases in moderate wine consumers, in studies that simultaneously show
that fruit juices, particularly grapefruit juice, increase the risk [33].
Wine
Alcohol
Phenolics
HDL
FibrinogenFactor VIIThrombosis
Platelet aggregation
LDL oxidation
Endothelial function (nitric oxide) eNOS
DNA damage
Plasma lipid peroxides
(nitric oxide) eNOS
(nitric oxide) eNOS
Fig. 1. Favorable changes in CV risk factors shown in moderate wine drinkers.
Urquiaga/Leighton 126
Deleterious Effects of Alcohol Consumption
When dealing with the negative effects of alcoholic beverage consumption
it is necessary to establish very clearly the levels of consumption that corre-
spond to a statement such as ‘alcohol consumption leads to cardiovascular
morbidity, to cirrhosis, to birth defects, to cancer, to hypertension, and to
migraine’. Indeed, the very concept of moderate consumption stems, among
others, from studies that identify the consumption levels associated with mini-
mal risk. There have been discussions on the meaning of the increased cardio-
vascular risk of non-drinkers, yet the meaning of the increased risk for heavy
drinkers is straight forward, but often forgotten by those who stress cirrhosis as
the consequence of excessive drinking. A positive correlation has been
observed for hemorrhagic stroke and drinking; however, this effect has to be
confronted with the higher frequency of obstructive events that do benefit from
moderate consumption [1].
There are a number of cancers that are referred to as alcohol-related;
cancers of the mouth, pharynx, larynx, esophagus, and sometimes stomach
and liver. They are associated with very heavy drinking, with alcohol abuse;
generally, they correlate with heavy smoking and heavy drinking, and do not
show increased frequency in light-to-moderate drinkers. Gronbaek and collabo-
rators in a population cohort study observed the association between alcohol
intake and cancer of the upper digestive tract [16]. Their conclusion was that a
moderate intake of wine probably does not increase the risk, whereas moderate
intake of beer or spirits increases the risk considerably. In an editorial commen-
tary, the possible role of nitrosamines is emphasized. For lung cancer, in three
prospective Danish studies, it was found that a high consumption of beer and
spirits is associated to an increased risk of lung cancer, whereas wine intake
apparently protects [34]. For mammary cancer no clear demonstration of alco-
hol beverages as a risk factor was found [35]. Yet, a significant correlation for
women drinking 3 or more glasses per day has been described [4] and in
Mediterranean populations, with a much lower breast cancer incidence than in
USA, a doubling in the frequency of women drinking two to three glasses per
day has been found [36]. The conclusion is that with the possible exception of
breast cancer, moderate drinkers are not at increased risk of any type of cancer
[37].
Wine should be considered as a healthy component of the diet in many cul-
tures. On the whole, with the evidence available, moderate wine consumption
should be considered as safe, with the sole exception of activities requiring a
maximum degree of alertness. Further research is required to examine the
hypothesis that genetically predisposed people might become addict to alcohol
through moderate consumption [38].
Wine and Health 127
Epidemiological Conclusions
Today the main concern for most epidemiologists is not the benefits, which
are not contested, but the potential negative consequences associated with mod-
erate drinking. Additionally, some epidemiologists reject a difference among
wine and other alcoholic beverages. The differences are attributed to lifestyle
differences among those who prefer one type of alcoholic beverage over another
thus making it exceedingly difficult to determine whether the differences in
apparent health effects are actually related to the beverage itself. Drinkers of
any type of wine have a lower mortality risk than do beer or liquor drinkers, yet
it remains unclear whether this reduced risk is due to nonalcoholic wine ingre-
dients, drinking patterns or associated traits [39].
Mechanisms
Biology of Wine Constituents: Effects of Alcohol and PolyphenolsAfter the epidemiologists recognized the potential beneficial role of wine,
the challenge was to find the biological basis of the phenomena. So far the
research has focused on alcohol and on phenolics as constituents of wine, and
on several biological targets, recognized as cardiovascular risk factors, that
would be modified in the alcohol consumers.
Alcohol
Alcohol intake modifies plasma lipids and hemostatics factors. The health
related biological effects observed in response to ethanol consumption are:
increased high density lipoprotein (HDL) cholesterol levels, decreased fibrino-
gen, increased plasminogen and tissue-type plasminogen activator (t-PA),
endothelial nitric oxide synthase (eNOS) stimulation, and a direct cardioprotec-
tive effect on the heart.
Lipid Factors
A high concentration of serum cholesterol is a major risk factor for
coronary heart disease (CHD). This risk is mediated through the major choles-
terol-carrying lipoprotein of serum, low-density lipoprotein (LDL). Addition-
ally, decreased HDL cholesterol levels constitute a central risk factor for
CHD [40].
Urquiaga/Leighton 128
At present there is consensus on the positive association between alcohol
intake and plasma HDL cholesterol level. From some studies it is estimated that
half of the beneficial effects of moderate alcohol intake are due to an increased
HDL cholesterol concentration. Rimm et al. [41] in a meta-analysis reported
that an experimental dose of 30 of ethanol a day increased HDL cholesterol by
3.99 g/dl (95% CI 3.25–4.73). There is also evidence that alcohol dehydroge-
nase genotype and alcohol metabolic rate do not modify the effects of alcohol
on plasma HDL concentration [42].
One of the main antiatherogenic functions of HDL is reverse cholesterol
transport. HDL removes unesterified, or ‘free’ cholesterol from peripheral tis-
sues, after which much of the cholesterol is esterified by the plasma enzyme
lecithin:cholesterol acyltransferase. Subsequently, HDL cholesterol is efficiently
delivered directly to the liver and steroidogenic tissues via a selective uptake
pathway [43]. Moderate alcohol intake increases serum HDL cholesterol level
and stimulates cellular cholesterol efflux [44]. Exercise also increases serum
HDL cholesterol level as improves reverse cholesterol transport [45].
Human serum paraoxonase, an esterase, is associated with HDL and has
been shown to reduce the susceptibility of LDL to lipid peroxidation [46]. As the
oxidative modification of LDL plays a central role in the initiation and accelera-
tion of atherosclerosis, increased serum levels of paraoxonase in HDL diminish
the atherogenic effect of LDL [47]. There is evidence that light drinking upregu-
lates, whereas heavy drinking downregulates paraoxonase activity and its
expression, irrespective of its genetic polymorphism in rats and humans [48].
The HDL receptor SR-BI (scavenger receptor class B type I) mediates the
selective uptake of plasma HDL cholesterol by the liver and steroidogenic tis-
sues. As a consequence, SR-BI can influence plasma HDL cholesterol levels,
HDL structure, biliary cholesterol concentrations, and the uptake, storage, and
utilization of cholesterol by steroid hormone-producing cells [49]. This recep-
tor also facilitates efficient transfer of vitamin E (�-tocopherol) from HDL to
cultured cells. In SR-BI-deficient mutant mice, relative to wild-type control
animals, there was a significant increase in plasma �-tocopherol levels. This
increase in plasma �-tocopherol was accompanied by a significant decrease
(65–80%) in the �-tocopherol concentrations in bile and several tissues includ-
ing ovary, testis, lung and brain but not in the liver, spleen, kidney or white fat.
These data show that SR-BI plays an important role in transferring �-tocopherol
from plasma lipoproteins to specific tissues. Defective tissue uptake of lipopro-
tein �-tocopherol in SR-BI-deficient mice may contribute to the reproductive
and cardiovascular pathologies exhibited by these animals [50]. Oxidative
stress regulates the expression of SR-BI receptor, oxidized LDL (oxLDL)
decreased SR-BI expression in a dose- and time-dependent manner and the
ability of oxLDL to decrease SR-BI expression was dependent on the degree of
Wine and Health 129
LDL oxidation. OxLDL decreased both [14C]cholesteryl oleate/HDL uptake
and efflux of [14C]cholesterol to HDL in a time-dependent manner [51].
Sex is another factor associated with decreased risk of developing cardiovas-
cular disease. Decreased risk is found in premenopausal women, together with
elevated HDL levels. HDL and estrogen stimulate eNOS and the production of
nitric oxide (NO) which has numerous protective effects in the vascular system,
including vasodilation, reduced leukocyte adhesion, and anti-inflammatory effects
[52]. HDL isolated from premenopausal women, or postmenopausal women
receiving estradiol replacement therapy, stimulated eNOS; whereas HDL isolated
from postmenopausal women or men had minimal activity. HDL-associated estra-
diol is capable of stimulating eNOS in an SR-BI-dependent manner [53] leading to
a new paradigm that involves eNOS, for the explanation of the cardiovascular
effects of HDL and estrogens.
Hemostasis Factors
The effects of alcohol on the coagulation and thrombolytic processes are
not sufficiently studied. In general, haemostatic factors in moderate alcohol
drinkers show a more thrombolytic profile. Consistent evidence has been pro-
vided linking moderate alcohol intake with lower fibrinogen levels. Rimm and
collaborators, in a meta-analysis, reported that 30 g of alcohol a day was associ-
ated with a 7.5-mg/dl decrease in fibrinogen concentration [41].
Numerous studies have investigated the effect of alcohol on platelet aggre-
gation. All tend to demonstrate that alcohol added in vitro leads to a significant
decrease of platelet aggregation induced by thrombin, collagen, epinephrine
and ADP [54]. Some human studies have shown that physiological concentra-
tions of ethanol inhibit platelet aggregation in humans as well as in animals in
response to several agonists, like collagen, thrombin, ADP and platelet-activat-
ing factor, in others this inhibition was not found [55–57]. Therefore, aggrega-
tion studies are not consistent, a finding attributed to the difference on assay
methods used in vitro or ex vivo to measure platelet aggregation [41].
A rebound phenomenon of hyperaggregability is observed after acute alco-
hol consumption but not after wine consumption. The apparent protection
afforded by wine has been replicated in animals with grape phenolics added to
alcohol. This rebound phenomenon could explain the ischemic strokes or sud-
den deaths known to occur after episodes of drunkenness [58].
Fibrinolysis is increased in alcohol drinkers. Rimm and collabo-
rators reported that 30 g of alcohol a day was associated with a 1.25-ng/dl
increase in t-PA antigen concentration, and a 1.47% increase in plasminogen
concentration [41].
Urquiaga/Leighton 130
Preincubation of human monocytes with low alcohol followed by incubation
in the absence of alcohol resulted in an increase in t-PA and urokinase-type
plasminogen activator (u-PA) expression [59]. And in mice, ethanol induces a
significative increase in clot lysis, increases expression for t-PA and u-PA and
decreases expression for PAI-1 (plasminogen activator inhibitor) [60].
We carried out an intervention study in humans to evaluate the effect of a
Mediterranean diet (MD), an Occidental diet (OD) and their supplementation
with red wine, on biochemical, physiological and clinical parameters related to
atherosclerosis and other chronic diseases. For 3 months, two groups of 21 male
volunteers each received either a MD or an OD; during the second month, red
wine was added isocalorically, 240 ml/day. At 0, 30, 60 and 90 days, clinical,
physiological and biochemical evaluations were made. We found that MD,
compared with OD, was associated with an improvement in hemostatic cardio-
vascular risk factors: lower plasma fibrinogen and factors VIIc and VIIIc,
higher levels of protein S and longer bleeding time. Red wine supplementation
of both diets resulted in further decrease in plasma fibrinogen and factor VIIc,
and in increases in PAI-1 and t-PA antigen. Red wine was also associated with
an increase in antithrombin III (ATIII) but only in individuals on MD. Overall,
these findings provide evidence that both MD and red wine have independent
but complementary benefits with regard to cardiovascular risk. They decrease
thrombosis [57, 61].
The antithrombotic effect of red wine is attributed in part to alcohol, but
mainly to wine phenols [62]. Alcohol and polyphenols are both involved, as dis-
cussed below.
Other Alcohol Effects
In rats, moderate alcohol consumption induced significant oxidative stress
in the heart which was then reflected into induction of the expression of several
cardioprotective oxidative stress-inducible proteins including heat-shock pro-
tein (HSP) 70. So alcohol by itself imparts cardioprotection by adapting the
heart to oxidative stress, with a reduction of myocardial ischemic reperfusion
injury, myocardial infarct size and cardiomyocyte apoptosis [63–64].
Polyphenols
Polyphenol BioavailabilityThe total amount of phenols found in a glass of red wine is on the order of
200 mg versus about 40 mg in a glass of white wine. Wine contains many
Wine and Health 131
phenolic substances, most of which originate in the grape berry. Wine phenolics
include the non-flavonoids: hydroxycinnamates, hydroxybenzoates and the stil-
benes; plus the flavonoids: flavan-3-ols, the flavonols, and the anthocyanins
[65]. These phenols are partly absorbed from the gastrointestinal tract in ani-
mals and humans, metabolized in the intestinal cells and in the liver and
excreted by the urine [66, 67]. Metabolites are glucuronide or sulfate conju-
gates and methylated conjugates [68]. While polymeric condensed tannins and
pigmented tannins constitute the majority of wine phenolics, their large size
precludes absorption so their health effects are likely restricted to the gut [69].
The health effects of dietary polyphenols might be explained by both intact
compounds and their metabolites formed either in the tissues or in the colon by
the microflora [70–73].
Polyphenol Effects
Polyphenols and their metabolites have many biological activities. They
present antioxidant, antithrombotic, anti-inflammatory and anticarcinogenic
properties. Their mechanism of action can be explained by a direct antioxidant
effect and by modification of some protein properties than produce changes in
enzymes activities (inhibition or activation) and gene expression. Some of these
effects are the following:
Antioxidant
Polyphenols are recognized as strong antioxidant and oxygen free radical
scavengers [74, 75]. Red wine and red wine phenols increase in vitro the resis-
tance of human LDL against oxidative modification [76]. Several studies report
an increased resistance to oxidative modification of human LDL after long-
term consumption of red wine and red wine polyphenols [77, 78]. In contrast,
other studies report that red wine and a phenolic extract from red wine do not
affect LDL oxidizability [79, 80]. In an acute ingestion study in humans, post-
prandial LDL obtained after a meal consumed with ethanol was more suscepti-
ble to metal-catalyzed oxidation than the homologous baseline LDL. On the
contrary, postprandial LDL obtained after a meal consumed with wine, was as
resistant as or more resistant to lipid peroxidation than fasting LDL [81]. Also
the experimental meal taken with wine provoked a significant increase in the total
plasma antioxidant capacity and in the plasma concentration of �-tocopherol and
SH groups. In another study, the supplementation of a meal with grape seed
Urquiaga/Leighton 132
extract reduced the postprandial oxidative stress by decreasing the oxidants and
increasing the antioxidant levels in plasma and, as a consequence, enhancing
the resistance to oxidative modification of LDL [82].
In our intervention study in humans described earlier, to evaluate the effect
of a MD, an OD and their supplementation with red wine, we found that the
total antioxidant reactivity (TAR) was significantly higher in volunteers on MD
compared to those on OD and wine intake increased TAR significantly in both
groups. The OD group showed higher levels of oxidative DNA damage, mea-
sured as 8-hydroxydeoxyguanosine (8-OHdG) levels in blood leukocyte DNA
and elevated protein damage markers, when compared with the MD group.
Wine intake significantly decreased 8-OHdG in both diets, particularly in the
OD, where the 8-OHdG levels decreased to values similar to those in the MD
plus wine group. Wine intake induced an increase in plasma and urinary
polyphenols. The results presented support the following conclusions: an OD
induces oxidative stress; a diet rich in fruits and vegetables enhances antioxi-
dant defenses; wine supplementation to an OD or a MD improved antioxidant
defenses in both groups and counteracted the oxidative damage produced by the
OD [83, 84].
Antithrombosis
In in vitro and ex vivo experiments, polyphenols enhance the generation of
NO, a platelet inhibitor and vasodilator [85, 86]. Some studies were also per-
formed to investigate the effect of wine polyphenols on experimental thrombo-
sis in rats. In these studies, NO was evaluated as a possible mediator of the
effects [87]. Supplementation for 10 days with red wine or alcohol-free red
wine, but not white wine or alcohol, induced a marked prolongation of bleeding
time (BT) (258 � 13 vs. 132 � 13 s in controls; p � 0.001) a decrease in
platelet adhesion to fibrillar collagen (11.6 � 1.0 vs. 32.2 � 1.3%; p � 0.01)
and a reduction in thrombus weight (1.45 � 0.33 vs. 3.27 � 0.39 mg; p � 0.01).
The effects of red wine were prevented by the NO inhibitor, L-NAME. In rats
with diet-induced hyperlipidemia, alcohol-free red wine supplementation for
one month reversed the prothrombotic effect of the diet, measured as delay in
the thrombotic occlusion of an artificial prosthesis inserted into the abdominal
aorta, without affecting the increased cholesterol and triglyceride levels [62].
Plasma antioxidant capacity measure as TRAP values, were significantly higher
in animals receiving alcohol-free wine. These studies provide evidence that red
wine modulates primary hemostasis and prevents experimental thrombosis in
rats, independent of its alcohol content, by a NO-mediated mechanism.
Wine and Health 133
Anti-Inflammation
Chemotaxis and accumulation of leukocytes in the arterial wall are consid-
ered to be critical events in the inflammation associated with atherosclerosis.
Flavonoids were reported to inhibit adhesion of immune cells to endothelial
cells. They downregulate gene expression of inflammatory mediators [88, 89].
Anticarcinogenesis
It has been reported that dehydrated-dealcoholized red wine (wine solids)
when consumed as part of a precisely defined complete diet, delays tumor onset
in transgenic mice that spontaneously develop externally visible tumors without
carcinogen pretreatment [90]. Particular phenol components of wine such as
resveratrol and quercetin have shown an inhibitory effect on carcinoma cell
proliferation [91, 92]. Other studies have shown that red wine contains phyto-
chemicals that inhibit aromatase activity in vitro and suppress aromatase-
mediated breast tumor formation in vivo [93, 94].
Some Protein Polyphenol Interactions
Polyphenols, especially flavonoids, have numerous effects caused by their
interaction with different proteins. Middleton and collaborators reviewed the
mammalian enzyme systems that are target of flavonoids [89]. Recent examples
of these are the inhibition of aromatase activity [94] and angiotensin-converting
enzyme (ACE) [95] and activation of sirtuin, an enzyme associated with
longevity [96].
Flavonoids and their in vivo metabolites may exert modulatory actions in cells
through actions at protein kinase and lipid kinase signalling pathways. They have
been reported to act on phosphoinositide 3-kinase (PI 3-kinase), Akt/protein kinase
B (Akt/PKB), tyrosine kinases, protein kinase C (PKC), and mitogen-activated
protein kinase (MAP kinase) signaling cascades. Inhibitory or stimulatory actions
at these pathways are likely to affect cellular function by altering the phosphory-
lation state of target molecules and by modulating gene expression [97].
Endothelial Function
Normal endothelium-dependent vasomotor function or endothelial func-
tion (EF) is a physiological response, mediated by NO, which appears to play a
key role in the prevention or reduction of the risk of atherosclerosis. Endothelial
Urquiaga/Leighton 134
dysfunction is associated with risk factors for coronary heart disease such as
hypercholesterolemia, hypertension, cigarette smoking, hyperhomocysteinemia
and diabetes mellitus. Red wine polyphenols activate tyrosine kinases, increase
cytosolic free calcium and stimulate a Ca2�-dependent release of NO in bovine
aortic endothelial cells [98].
Moderate red wine intake improves endothelial function evaluated as flow-
mediated dilation of the brachial artery [99]. Recalling our study on diets and
wine supplementation we showed that in the absence of wine, there is a reduc-
tion of endothelial function with OD when compared to the MD (p � 0.014).
This loss of endothelial function is not seen when both diets are supplemented
with wine (p � 0.001). These effects are attributed to oxidative stress associated
with an OD, and to the elevated plasma antioxidant capacity associated with
wine consumption and the MD. Wine polyphenols protect NO from oxidation.
Acute red wine consumption produces an increase in coronary flow-
velocity reserve in human volunteers. This finding suggests that some polyphe-
nols may have potent vasorelaxing effects on coronary microvessels during
hyperemia [100].
Red wine polyphenol extract enhances eNOS expression and increases NO
production in human umbilical vein endothelial cells (HUVECs) [101, 102].
Red wines strongly inhibit the synthesis of endothelin-1 (ET-1), a vasocon-
strictor peptide that decreases endothelial function. Wine polyphenols decreased
ET-1 release and transcription in bovine aortic endothelial cells [103]. ET-1
release induced by oxLDL is inhibited by quercetin [104].
Conclusion
The experimental results presented in this review do not support the fre-
quently held conclusion that ethanol is the main active component, independent
of antioxidants, when considering the biological consequences of moderate
alcoholic beverage consumption. Quite clearly, effects such as those shown for
hemostasis, or those to be expected when HDL levels increase, are related to
polyphenols or to an efficient antioxidant system, respectively, which wine could
provide. For example, if the new paradigm to explain the protective role of ele-
vated HDL levels requires the participation of eNOS, it is obvious that antioxi-
dants will be necessary to protect the NO generated, a well-known requirement
for NO-mediated effects. This consideration could also lead to the idea that
ethanol, consumed together with antioxidant-rich foods, would be biologically
safer than drinking alone. Equally, the different results obtained in epidemiologi-
cal studies that consider alcohol consumption could well be related to the dietary
habits of those populations, in particular the type, quantity and opportunity of
antioxidant-rich food consumption, as well as pro-oxidant food consumption.
Wine and Health 135
Acknowledgement
Work supported by PUC-PBMEC/2003.
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Federico Leighton, MD
Laboratorio de Nutrición Molecular, Departamento de Biología Celular y Molecular
Facultad de Ciencias Biológicas, Pontificia Universidad Católica de Chile
Alameda 340, Santiago (Chile)
Tel./Fax �56 2 222 2577, E-Mail [email protected]
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Implications of Food Regulations for Novel FoodsSafety and Labeling
John R. Lupien
Adjunct Professor of Food Science, University of Massachusetts,
Amherst, Mass., USA
Novel Foods,What Are They?
Novel or functional foods have been difficult to define in a legal sense. The
European Union has published regulations for novel foods, but the main thrust
of these rules is to control newer foods derived from present biotechnology
developments. Despite the difficulty of precise definitions, there appears to be a
common public understanding of the concept that many foods may contain ben-
eficial (or harmful) substances in addition to the common nutrients of digestible
carbohydrates, proteins, fats, ethanol, and essential vitamins and minerals. Both
from the public point of view, and as a result of science-based experimental test
systems, the concept of novel or functional foods or components is that such
foods or components can have a beneficial effect on bodily functions and struc-
tures. In some countries well-founded claims for such effects have been allowed,
while in other countries no claims have been permitted.
There is no current legal definition for ‘functional food’ in most countries
and foods of this type are regulated under existing food or related legislation in
countries where functional claims are made. In many countries regulations exist
for conventional foods, foods for special dietary use, dietary supplements, and
medical foods for use under the supervision of a physician for management of
specific diseases. In the European Union there are regulations for ‘novel foods’
which in some cases could also be considered as functional foods. Each of these
categories have regulations which govern which claims can be made, and either
specific rules or guidelines for the types of data which are needed to establish
The Role of Government in Implementing a Healthy Diet andPhysical Activity Lifestyle
Food Regulations for Novel Foods 141
the validity of any claims on the labels of foods, or in advertising. In most
countries there are also clear legislative provisions for drugs, and certain claims
for disease treatment can make a food product a drug in the legal sense and
lead to severe regulatory consequences, even if that was not intended by the
promoter making the claim for a food.
At the international level there has been discussion about functional foods,
novel foods, and labeling and claims for these types of foods and foods for spe-
cial dietary use. The FAO/WHO Codex Alimentarius Commission has adopted
a General Standard for the Labeling and Claims for Prepackaged Foods for
Special Dietary Use, and General Guidelines on Claims, Nutrition Labeling,
and Nutrition Claims, and all of these should be taken into consideration in
determining if a claim can be made, and the nature of the claim [26–28].
As discussed below, there are rules in the European Union, Australia and
New Zealand that cover novel foods and foods derived from recombinant DNA
techniques that are somewhat overlapping in the EU, while they are separate in
Australia and New Zealand. At the Codex international level foods derived
from biotechnology are being actively discussed, and a number of FAO/WHO
Expert Consultations have been held to better define basic concepts, examine
the quality and safety aspects of these foods, including possible problems of
allergenicity, and related topics. The FAO/WHO Expert Consultations have
endorsed the approach used in the USA of ‘substantial equivalence’ for foods
derived from biotechnology. This has meant up to now that if the nutritional and
other quality and safety aspects were substantially equivalent to similar foods
that were not produced using recombinant DNA techniques that specific label-
ing was not required. The Codex Committee on Food Labeling and the Codex
Task Force on Foods Derived from Biotechnology are actively discussing inter-
national aspects of labeling and a general standard for foods derived from
biotechnology, but no final recommendations have been made for adoption by
the 165 member country members that comprise the Codex Alimentarius
Commission.
Novel or Functional Food Claims
Foods are usually defined as articles for food and drink, while drugs are
usually defined as articles intended for use in the diagnosis, cure, treatment, or
prevention of disease. In the past there was no middle ground between foods
and drugs, and health-related claims were not permitted on foods. However,
developments in several countries and at the international level have tended to
take into account newer features of foods and how they are produced and
processed, research into the possible beneficial or protective effects of foods
Lupien 142
and their ingredients. Because of this, regulatory authorities and new legislation
in some countries have opened up the possibility of properly substantiated
health-related claims for foods and their ingredients.
This is an evolving area, in particular with the concept of ‘novel foods’ and
‘functional foods’, and it has been a difficult task to substantiate claims, and to
maintain a good and constantly stronger scientific database to support claims.
In the United States, one of the first claims on a food product was on an all bran
cereal product stating that increased intake of wheat fiber could reduce the risk
of colon cancer, and citing the US National Cancer Institute as the authority for
this claim. Subsequent nutritional and dietary research has not fully supported
this claim. Claims about increased intake of Vitamin A and cancer protection
have also been put in doubt due to a trial of smokers in Finland where results
showed that higher intakes of vitamin A actually increased the incidence of lung
cancer. Therefore, in making claims about the functionality of foods or their
ingredients, it is necessary to use caution, since a disproved or doubtful claim
can lead to regulatory problems or loss of market share for the product in ques-
tion, and other products of the same company.
Research into phytochemicals, probiotics and prebiotic substances that do
not have traditional nutritive value has shown a wide range of possible func-
tions for foods. Phytochemicals such as indoles, thiocyanates, sulfur containing
compounds, allium compounds, isoflavones and phenols have been shown to
have some possible beneficial or protective effects. Probiotics are microorgan-
isms such as lactobacilli and bifidobacteria, which can modify the bacterial
flora in the intestine and enhance certain immune functions, possible promote
absorption of certain essential minerals, and protect against some diseases of
the intestine and colon. Prebiotics are oligosaccharides, which may be instru-
mental in modifying the risks on intestinal disorders, osteoporosis, cancer and
heart disease. In each of these areas, considerable additional research is under-
way, and firmly establishing the beneficial effects of any of these substances
has been shown to be difficult. Table 1 includes a list of some examples of
foods or food ingredients that have shown possible benefits.
Other Product Classifications and Their Regulation
As mentioned above, in addition to foods sold as such, there are also foods
for special dietary use for the general public, novel foods, dietary supplements,
and medical foods, also called neutriceuticals. Each of these product classes has
a more specific definition than do ‘functional foods’, and the regulation of their
marketing is more structured in many countries.
Food Regulations for Novel Foods 143
Table 1. Examples of functional components* [taken from ref. 21]
Class/components Source* Potential benefit
CarotenoidsAlpha-carotene Carrots • Neutralizes free radicals which may cause
damage to cells
Beta-carotene Various fruits, vegetables • Neutralizes free radicals
Lutein green vegetables • Contributes to maintenance of
health vision
Lycopene Tomatoes and tomato • May reduce risk of prostate cancer
products (ketchup,
sauces, etc.)
Zeaxanthin Eggs, citrus, corn • Contributes to maintenance of health vision
Collagen hydrolysateCollagen hydrolysate Gelatin • May help improve some symptoms
associated with osteoarthritis
Dietary fiberInsoluble fiber Wheat bran • May reduce risk of breast and/or colon cancer
Beta-glucan** Oats • Resuces risk of cardiovascular disease (CVD)
Soluble fiber** Psyllium • Reduces risk of CVD
Whole grains** Cereal grains • Reduces risk of CVD
Fatty acidsOmega–3 fatty Tuna; fish and • May reduce risk of CVD and improve
acids – DHA/EPA marine oils mental, visual functions
Conjugated linoleic Cheese, meat products • May improve body composition, may
acid (CLA) decrease risk of certain cancers
FlavonoidsAnthocyanidins Fruits • Neutralizes free radicals, may reduce
risk of cancer
Catechins Tea • Neutralize free radicals, may reduce
risk of cancer
Flavanones Citrus • Neutralize free radicals, may reduce
risk of cancer
Flavones Fruits/vegetables • Neutralizes free radicals, may reduce
risk of cancer
Glucosinolates, Indoles, IsothiocyanatesSulphoraphane Cruciferous vegetables • Neutralizes free radicals, may reduce
(broccoli, kale), risk of cancer
horseradish
PhenolsCaffeic acid Ferulic acid Fruits, vegetables, citrus • Antioxidant-like activities, may reduce
risk of degenerative diseases;
heart disease, eye disease
Lupien 144
The Codex describes foods for special dietary uses as ‘foods which are spe-
cially processed or formulated to satisfy particular dietary requirements which
exist because of a particular physical or physiological condition and/or specific
diseases and disorders and which are presented as such. The composition of
these foodstuffs must differ significantly from the composition of ordinary foods
of comparable nature, if such ordinary foods exist’. While foods of this nature
are obviously intended to be ‘functional’, the specific nature of such products
Plant sterolsStanol ester Corn, soy, wheat, • Lowers blood cholesterol levels by
wood oils inhibiting cholesterol absorption
Prebiotic/probioticsFructo- Jerusalem artichokes, • May improve gastrointestinal health
oligosaccharides shallots, onion powder
(FOS)
Lactobacillus Yogurt, other dairy • May improve gastrointestinal health
SaponinsSaponins Soybeans, soy foods, soy • May lower LDL cholesterol; contains
protein-containing foods anti-cancer enzymes
Soy proteinSoy protein** Soybeans and • 25 g per day may reduce risk of
soy-based foods heart disease
PhytoestrogensIsoflavones – daidzein, Soybeans and • May reduce menopause symptoms,
genistein soy-based foods such as hot flashes
Lignans Flax, rye, vegetables • May protect against heart disease and
some cancers; lowers LDL cholesterol,
total cholesterol and triglycerides
Sulfides/thiolsDiallyl sulfide Onions, garlic, olives, • Lowers LDL cholesterol, maintains
leeks, scallions health immune system
Allyl methyl trisulfide, Cruciferous • Lowers LDL cholesterol, maintains
Dithiolthiones vegetables healthy immune system
TanninsProanthocyanidins Cranberries, cranberry • May improve urinary tract health
products, cocoa, chocolate • May reduce risk of CVD
*Examples are not an all-inclusive list.
**FDA-approved health claim established for component. December 1999.
Table 1 (continued)
Class/components Source* Potential benefit
Food Regulations for Novel Foods 145
and the restriction on their uses appear to clearly separate them from other types
of possible ‘novel foods’ or ‘functional foods’. The Codex description also
implies that newly discovered beneficial effects of traditional foods would not be
covered by the Codex description of foods for special dietary uses [26–28].
The European Union regulation on novel foods and novel food ingredients
(Regulation EC No. 258/97) applies to genetically modified products, foods
and food ingredients isolated from microorganisms, fungi, algae, and plants or
animals, except for foods and food ingredients obtained from plants or animals
by traditional propagating or breeding practices and having a history of safe
food use [4]. Food additives, flavorings, and extraction solvents are exempted
from the EU novel food regulation since they are regulated under other EU
rules. The EU novel foods regulations are mainly concerned with food safety,
are not specific about label claims, and have the thrust of having been prepared
to regulate foods and food ingredients derived from biotechnology. Many of the
novel foods regulated by EU rules have been developed to fit into the concept of
functional foods, and are regulated under the EU novel food regulation at pres-
ent. However, a lively level of discussion on the concept of functional foods is
also underway in Europe and elsewhere and could lead to additional regulation,
particularly with regard to health claims.
Dietary supplements such as vitamin and mineral capsules or tablets, and a
wide array of other products such as herbal remedies, and even foods that are
labeled as dietary supplements have become increasingly popular. In the United
States, there is specific legislation that exempts these products from many of
the restrictions for foods or drugs contained in the US Food, Drug and
Cosmetics Act [1]. Many of these dietary supplement products, and equivalent
products sold over the counter in pharmacies in Europe, and perhaps elsewhere,
have label claims that are considered by many food regulators as somewhat exu-
berant, and possibly false or misleading. In the USA, products of this type must
bear a label statement that these products have not been approved by the US
Food and Drug Administration (FDA) and that the product is not intended for
use as a drug [9–11].
Medical foods or neutriceuticals are specially formulated products
intended for use under the supervision of a physician for the specific dietary
management of a disease or condition. These foods meet distinctive nutritional
requirements that are based on recognized scientific principles and are estab-
lished by medical evaluation. As with foods for special dietary use, medical
foods are also intended to be functional and have a direct and beneficial influ-
ence on a specific medical condition. In the USA, medical foods do not require
pre-market clearance by FDA and there have been some concerns about the
quality and efficacy of some of the products that are being marketed as medical
foods [12–14].
Lupien 146
National Regulatory Systems and Requirements and International Considerations
Since ‘novel foods’ and ‘functional foods’ are not defined or set aside as a
specific class of product in most countries, they are regulated under existing
law as foods, novel foods, special dietary foods, medical foods, or as drugs,
depending on how they are marketed, and the claims that are made for the prod-
ucts in their labeling, or in advertising.
In the United States many products that are being sold as traditional foods
have label claims about their beneficial effects when consumed as a part of a
varied and balance diet. The 1990 Nutrition Labeling and Education Act
(NLEA) [2] required additional labeling about the nutritional content of foods
beyond that previously required or recommended under the Food, Drug and
Cosmetic Act. The NLEA also allowed for properly substantiated nutrition and
health claim on the labels of foods. With regard to health claims, FDA tended to
require that marketers of foods with health claims obtain prior approval of the
claim and present evidence of ‘significant scientific agreement’ among quali-
fied experts showing that any claims were justified. In practice, this process has
not been very effective, but FDA regulation of claims under NLEA was restric-
tive enough to lead to new legislation called the Dietary Supplement Health and
Education Act (DSHEA) [3, 15, 16, 18, 21].
The DSHEA further loosened control on products that are ingested and
allowed claims for pills, capsules, tablets, or even food-like products that were
labeled as dietary supplements and included a label statement declaring that the
products and claims were not approved by FDA, and that these products were
not intended for use as a drug. While no pre-marketing approval is required
from FDA, marketers of such products are required to notify of FDA of such
products and label claims, and to have evidence that any information provided
is truthful and not misleading.
The FDA can regulate materials that advertise foods and dietary supple-
ments if the advertising is used in association with the sale of a product and is
considered ‘labeling’, while other advertising is regulated by the US Federal
Trade Commission. In either case false or misleading claims are not allowed,
but the enforcement of these regulations has not been particularly vigorous and
products with questionable claims and possible safety problems continue to be
marketed in the USA [20, 22].
In the European Union countries foods are regulated under national food
laws, and under EU regulations. In general, the control of claims is more strict
that in the USA, but differences exist between various EU member countries
with regard to claims allowed under national law. These differences can lead to
EU wide marketing of products with hard to substantiate claims, since approval
Food Regulations for Novel Foods 147
of a product in one or two countries can lead to EU wide distribution of these
products under existing EU rules [5, 23].
As an example of European control of claims, local level Trading
Standards Officers in the UK have taken Nestle and other food marketers to
court over certain label claims. In June 2000, the Shropshire County Council
successfully sued Nestle for marketing a shredded wheat product with label
claims that eating this cereal would reduce the risk of coronary heart disease.
Nestle was fined GBP 7,500 for making an illegal medical claim, and also had
to pay GBP 13,600 costs involved in holding the court proceedings [6]. In the
UK, this court decision is considered as a test case, and will have significance
to all food marketers about making future claims unless they have adequate sci-
entific data to back up claims. In many cases it would appear necessary to liaise
with regulatory authorities prior to marketing products, but this had practical
difficulties when central government is not fully involved in regulating prod-
ucts, and at the same time allows local authorities to take legal action which has
nationwide or EU-wide significance [7, 8, 17].
In the EU novel food regulation, companies wishing to market a product
which is considered a novel food must present information to authorities in a
Member State where a product will first be marketed to demonstrate product
safety, and also present information on proposed labeling. Information pro-
vided should include product specifications, effects of production processes,
history of any organism used as a source of the novel food, anticipated intake or
extent of use, information of previous human exposure to the product, and
nutrition, toxicological and microbiological information. As noted above, the
main concern is the safety of the novel food, but some consideration of labeling
is also possible [4, 25, 28].
Food and related rules which govern claims for functional foods also are
in effect in Japan, other European countries, Australia and New Zealand, and
there are differences between procedures and products allowed in each of
these countries. Developing countries also have some legislation in place.
Marketers of functional food products in these markets must carefully assess
existing rules that apply because of the differences that exist in each of these
markets.
In Japan regulations for Foods for Special Health Uses (FOSHU) have been
in force for over two years. The Japanese rules require that a manufacturer or mar-
keter of a FOSHU product present a dossier to the Japanese government with per-
tinent information on the ingredients, processing, labeling, quality, safety, and
health effects of each FOSHU product. If the government authorities are satisfied
that the dossier supports quality and safety requirements, and substantiates the
health effects to be put on the label or used in advertising, approval of the FOSHU
product can be given. Over 200 FOSHU-approved products are currently on the
Lupien 148
market in Japan, and appear to be freely accepted by Japanese consumers. Similar
procedures are also in place in China.
In Australia and New Zealand, the Australia New Zealand Food Authority
(ANZFA) has published rules under Part 1.5 for Foods Requiring Pre-market
Clearance. Food Standard 1.5.1 covers Novel Foods, while Food Standard 1.5.2
covers Foods Produced using Gene Technology [29].
ANZFA Standard 1.5.1 describes non-traditional foods as foods with no
history of significant human consumption in Australia or New Zealand, and
‘novel foods’ as non-traditional foods with safety concerns. It requires pre-
market approval of novel foods on the basis of a dossier that includes information
on the composition of a product, on any undesirable substances that may be
present, on any known adverse effects from consumption of the product, on tra-
ditional preparation or cooking, and on patterns and levels of consumption.
ANZFA Standard 1.5.2 covers food produced using gene technology and
limits the technology to foods where recombinant DNA techniques have been
used. For such foods specific labeling in required which states that the food or
certain ingredients have been genetically modified. It can be seen from the
above paragraphs on current ANZFA rules that the concepts defined in the EU
rules on ‘novel foods’ have been divided into two separate ANZFA Standards,
with somewhat different procedures and results.
At the international level, the Codex Alimentarius Commission has not
held extensive discussions on functional foods. Work has been done on basic
labeling rules, on nutrition claims and nutrition labeling, and claims for foods
for special dietary use. In general these Codex standards and guidelines state
that packaged food should not be described or presented on any label or label-
ing in a manner that is false, misleading or deceptive or is likely to create an
erroneous impression regarding its character in any respect.
Supporting Data for Novel Food or Functional Food Claims andFuture Perspectives
Based on the discussion above, it is clear that marketers of foods which fit
the profile of novel foods or functional foods must be prepared to have in their
possession adequate scientific data to substantiate any claims that they wish to
make on products [24]. This will involve several steps in building an adequate
level of data, and must be done with the realization that data to establish the
safety and efficacy of foods and food ingredients is considerably more difficult
than is the case with food additives, pesticide residues, or chemical contaminants
which are used in or can occur in food production and processing. In previous
discussions on functional foods three sequential steps have been suggested:
Food Regulations for Novel Foods 149
1 Basic research and experimentation: identification and understanding of
the mechanisms of interaction between the food or ingredient and modifi-
cation of gene expression or cellular biochemical function in order to
demonstrate potential functional effects.
2 Development of models and methodologies including possible biomarkers
to demonstrate through studies on human nutrition possible functional
effects and the consequences thereof to justify specific functional or phys-
iological claims.
3 Design and carrying out of appropriate human nutrition studies, which
may have to be done on a large scale, to demonstrate functional effects and
benefits to health including reduction to disease where pertinent to justify
structure/function or health claims.
Consumer studies in the USA have shown that 95% of consumers believe
that certain foods can provide health promotion of disease prevention benefits
beyond basic nutritional benefits [19]. Consumers are willing to accept the con-
cept of functional foods and want to know more about them. It is likely that
consumers in Europe and other parts of the world have similar attitudes and
desires. Therefore, the future for novel foods or functional foods appears to be
very positive. However, marketers of novel or functional foods or ingredients
that can increase the functionality of foods must conduct careful and adequate
basic studies and human trials to justify the claims that may be made for func-
tional food products.
Given the differences in regulation of foods, special dietary foods, novel
foods, foods for special dietary use, and medical foods in different countries
and regions, potential marketers of these foods must be prepared to fully under-
stand the regulatory requirements which apply in each marketing area, and be
ready to meet these requirements both before marketing a product, and after a
product has been placed on the market through adequate post marketing sur-
veillance. The potential for novel or functional foods is great. Those meeting
the challenges of successful development of scientific data so that products can
be marketed should meet with great success.
References
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4 Regulation (EC) no 258/97 of the European Parliament and of the Council of 27 January 1997
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pp 1–7.
Lupien 150
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Publishing Group, 1999.
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Lippincott/Williams & Wilkins, 1999.
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Philadelphia, Lippincott/Williams & Wilkins, 1999.
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Group, 2000.
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John R. Lupien
Adjunct Professor of Food Science
University of Massachusetts
Amherst, MA 01003 (USA)
Fax �1 508 888 6779, E-Mail [email protected]
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A New Look at IntersectoralPartnerships Supporting a Healthy Diet and Active Lifestyle:The Centre of Excellence in FunctionalFoods, Australia, Combining Industry,Science and Practice
Linda C. Tapsell, Craig S. Patch, Lynda S. Gillen
Smart Foods Centre, University of Wollongong, Wollongong, Australia
Reviews on healthy lifestyles normally begin with a picture of health prob-
lems, with nutrition and/or food positioned along the way as an element of con-
cern. This review starts with food, and with reference to the Centre of
Excellence in Functional Foods, argues that to establish effective health pro-
moting partnerships we must be prepared to genuinely address competing
imperatives and find a space for co-operative activity.
Food can be described from so many perspectives. It is part of our social,
economic and population health fabric. In Australia, food has special signifi-
cance in all these domains. The food industry employs 17% of the total manu-
facturing workforce and Australia’s food exports account for around 22% of
overseas trade [1]. The National Food Industry Strategy, an initiative of the
Department of Agriculture, Fisheries and Forestry, underpins the significance
of food to Australia’s economic health, with business, innovation and environ-
mental platforms. The National Centre of Excellence in Functional Foods
(NCEFF) was funded through the innovation platform to provide leadership for
functional foods in Australia, with an emphasis on integrating science and busi-
ness interests.
Food is also referred to in Australia’s research priorities, with the develop-
ment of new health-promoting foods, a part of the Preventive Healthcare priority
goal [2]. The food supply is noted as a key ‘settings strategy’ in the framework for
Tapsell/Patch/Gillen 152
the national obesity prevention strategy, Healthy Weight 2008 [3]. In this section,
outcomes sought include increased choices and local availability of lower energy
density and healthy foods and drinks, increased proportions of manufactured
foods and meals with reduced energy density and increased proportions of meals
with reduced portion size, including meals consumed outside the home. Thus,
the scene is set for intersectoral activity that can use any number of starting
points or organising principles to make it happen. The path, however, must navi-
gate through a number of ambiguities underpinning the need for an effective
knowledge management strategy. These issues will now be explored, positioning
the National Centre of Excellence in Functional Foods within the analysis.
Functional Food:An Intersectoral View
One of the essential attributes in developing effective intersectoral partner-
ships is adequate communication. There are many different ways in which
information on food is communicated and positioned. The concept of func-
tional foods, for example, may well have different meaning or weight depend-
ing on the context in which it is being discussed. From the Centre of Excellence
perspective, these were seen as the nutrition (science), marketing, and regula-
tory perspectives.
Nutrition PerspectiveThere is no universal definition of functional foods, but there is a common
reference to foods that provide benefits beyond basic nutrition [4]. This implies
an understanding of foods and food components and the link between their con-
sumption and specific health outcomes. The identification of whole dietary pat-
terns and their potential relationship to improved health outcomes [5], however,
would also fit this way of thinking. The concept of functional foods has a num-
ber of origins, but there are clear links with advances in nutrition science and in
particular food science and technology. A recent edition of the journal of the
Australian Institute of Food Science and Technology provides information
(under the heading of functional foods) on pecan nuts, lutein-enriched eggs, cit-
rus fruits, anti-oxidants obtained from grapes and apples, and alternative sweet-
eners [6]. These represent different categories in which the functional food
concept may be examined, in particular whole foods and bioactive components
of foods. The American Dietetic Association position statement on Functional
Foods [7] lists foods and components in terms of potential health benefits and
associated scientific evidence, displaying the disparity that often lies between
the food category and the science to support its position. There is a wide range
of studies that can address certain health outcomes, but the amount and type of
A New Look at Intersectoral Partnerships 153
research required to justify a health claim is open to debate. This then creates
another perspective for functional foods, that of regulation.
Regulatory PerspectiveAround the globe, the way in which information on food can be legally
presented to consumers is an interesting line of investigation in its own right.
There are clear differences in the American, European and Japanese frame-
works, but also there are efforts to gain some synergy [8], bearing in mind the
implications for regional and world trade.
Australia has a long-standing history of food regulation, including food
standards legislation that dates back into the early part of the last century. In the
last decade, Australia and New Zealand formed a joint Food Standards Code,
which currently includes a description of health claims (Standard 1.1A.2), but
prohibits them on food. The only authorised health claim is the link between
folate and a reduced risk of neural tube defects [9].
Standard 1.1A2 describes heath claims as those that relate to
• intrinsic weight-reducing properties
• a therapeutic or prophylactic action or equivalent
• the word ‘health’ or equivalents with the name of the food
• any expression or implication of advice of a medical nature
• the name or reference to a disease or physiological condition.
In December 2003, a policy guideline on health claims was announced by
the Australia New Zealand Food Regulation Ministerial Council [10] to guide
the development of a system of health claims. The policy includes 26 broad
principles and refers to criteria for general and high level claims. General level
claims will require the industry to provide evidence on request for conditions
that do not refer to serious diseases. High level claims, referring to serious dis-
eases, will require pre-approval by Food Standards Australia New Zealand
(FSANZ). The development of a model for substantiation will underpin the sys-
tem for approval of health claims. This will necessitate effective problem solv-
ing between the scientific and regulatory sectors, bearing in mind that the
output from this exercise concerns communication between the food industry
and consumers, and this brings us to the market place.
Market PerspectiveThe literature on functional foods in the marketing domain is widespread,
and takes many forms. Like the nutrition and regulatory sectors, the term has a
defined space in this context, where it appears relatively unconstrained to
describe market trends. Data in this literature refer to sales and consumer sur-
veys. Functional foods are constructed as responding to a consumer demand for
more ‘hands on’ responsibility for their own health, resulting in substantial
Tapsell/Patch/Gillen 154
growth in sales of this food category, particularly in the US, Japan and Europe
[11]. The language describing functional foods is in contrast to that of the nutri-
tion and regulatory contexts (table 1).
The nutrition perspective refers to foods and food components, while the
regulatory descriptors identify broad domains of action or implications of
actions, including reference to a role of giving medical advice. The marketing
language has an appearance of confabulation, a less formal approach, drawing
on any number of concepts and disciplines. Here, the language used in refer-
ence to functional foods alone can be seen to display the disparity between
groups and the challenges facing intersectoral partnerships in which food has a
primary position. There are many other examples, and indeed there are sectors
other than the three mentioned here, which all add to the complexity of the task.
Understanding the differences between groups, and developing frameworks that
enable genuine sharing of the central issues, however, warrants consideration.
Intersectoral Partnerships in Food
If there is one issue in the world today that is linking food with a vast range
of intersectoral components it is obesity. While the issue is identified and
Table 1. Terms used to describe functional foods in the Nutrition, Regulatory and
Marketing context
Nutrition1 Regulatory2 Marketing3
Low fat foods Slimming food, with intrinsic Broader nutrient and specialty
weight reducing properties ingredient fortification
Foods containing sugar Therapeutic or Condition-specific
alcohol in place of sugar prophylactic action marketing
Oatmeal/oat bran/whole ‘Health’ in the name Lifestyle enhancers
oat products
Milk-low fat Medical advice Sports market crossover
Vegetables and fruit Referent to a disease or Kid’s health
physiological conditions
Cereal with added Gender, age and ethnic
folic acid positioning
1First 5 foods listed in table 1 of ADA position statement on functional foods. 2Descriptors used in Standard 1.1A2 of the Australia and New Zealand Food Standards Code.3First 5 categories of functional foods listed by Sloan [11].
A New Look at Intersectoral Partnerships 155
prioritised by the health sector, the need for intersectoral approaches to address-
ing the problem is well recognised [12].
In Australia, over 60% of the adult population (25 years and over) are over-
weight and 20% obese. The rate of childhood obesity is one of the worst on record,
resulting from a decline in physical activity and rise in energy intake [13]. The sit-
uation is causing concern, not least because there have been obesity prevention
strategies in place for some time and they seem to have had little impact [14].
In New South Wales a school canteen policy has been put in place through
an intersectoral partnership between Health and Education which outlines a
number of resolutions including a statement that foods regarded as ‘extras’ in the
Australian Guide to Healthy Eating can only be sold on two occasions per term
[15]. A recent study of food consumption patterns of Australian children 5–15
years of age found on average 37% of energy was consumed at school. Fourteen
percent of the children purchased food from the canteen, but overall, energy
dense foods and beverages were over-represented in foods consumed at school
whether brought from home or purchased at school [16]. The authors recom-
mended that biscuits, snack bars, and cordials/drinks brought from home, and
fast food, packaged snacks and confectionery bought at the canteen be replaced
by fruit and water. This simple solution lies in stark contrast to the information
provided on consumer food purchasing trends in the marketing literature [11]. It
seems that if we could combine this latter knowledge with the nutrition con-
cerns, a more innovative solution may be developed that addresses the need for
less energy-dense foods and which will be adopted by children and their parents.
This leads to the issue of the technological know-how to produce new prod-
ucts. A recent review of research trends indicates the extent of this knowledge
and the capacity it brings to improve the food supply [17]. This knowledge base
is substantially greater than many areas referred to in the traditional domains of
nutrition and health, drawing on aspects of the chemical, physical and structural
analyses of foods to links between biology and engineering [17]. Technological
advances from this domain are closely aligned to new product development and
lie behind the emergence of the functional food market. It will be important for
those working in the nutrition and health field to appreciate this sector if new
solutions to well-described problems such as obesity are to be found.
The missing element in the discussion is of course the consumer. While the
marketing literature would suggest that consumers are adopting functional foods,
their sustained acceptance of this range is a complex matter, and one that has
implications for all forms of food and nutrition communications. One review of
this area suggests that risk perceptions and concerns relating to technology, scien-
tific innovation and personal health issues should form the basis of these commu-
nications [18]. A study of Finnish consumers found that functional foods were not
seen as a separate category, but rather as a secondary category within a food
Tapsell/Patch/Gillen 156
group, with reasons for selecting these foods varying depending on that category
[19]. In this respect, the strategies developed for influencing consumers’ food
intake would seem to benefit from a deeper understanding of this psychology.
In summary, obesity is well recognised as a serious health problem requiring
an intersectoral approach. Food is implicated in the problem by virtue of its con-
tribution to energy intake. The food and nutrition sector itself, however, has many
parts, but if the capacity of this sector is to be maximally enhanced in helping to
solve the problem, then developing frameworks to enable full participation needs
to be on the agenda. There are limitations, for example in comparing tobacco con-
trol to food control, when unlike tobacco, food is an essential part of life [20]. It is
likely, however, that we need some paradigm shifts in our relationships with food,
where the strategic uptake of nutrition knowledge becomes an imperative in food
product development, marketing and distribution addresses the question of
energy delivered to the target population, and consumers become much more
conscious of their management of energy intake and energy expenditure.
The National Centre of Excellence in Functional Foods, Australia
The Australian National Centre of Excellence in Functional Foods (NCEFF)
was established in July 2003 to support the Australian food industry in the
development of a functional foods market. The Centre itself is based on inter-
sectoral collaboration, a joint venture between the Commonwealth Scientific
and Industrial Organisation (CSIRO) – Division of Health Sciences and
Nutrition, the Department of Primary Industries, Victoria, Food Science
Australia and the Australian Research Council Key Centre for Smart Foods at
the University of Wollongong. The task of the Centre is to provide leadership in
the functional food area, bringing together science, technology, industry and
related stakeholders. The collaboration between the four partner organisations
creates additionality by combining capacities in food technology, nutrition and
consumer sciences (from basic sciences through to human trials), and disci-
plines in public health, food regulation, marketing and innovation management.
The Centre has two main streams of operation, a generic stream funded by
the National Food Industry Strategy and the four partner organisations, and a
separate industry-funded stream. The generic stream funds independent pre-
competitive research and activities, while the industry-specific stream works
closer to the market on projects sponsored by industry. This enables the genera-
tion of new knowledge available to all and a framework for building concepts
for a functional food market generally.
Projects are organised under clusters of substantiation research and devel-
opment (nutrition perspective), regulation, and market intelligence/innovation
A New Look at Intersectoral Partnerships 157
management. Thus, research undertaken is considered in the light of the types
of nutrition communications that might lead from the research, as well as the
likely market for any emerging products. In keeping with the direction
Australian legislation is taking on health claims, a whole of diet approach lies at
the centre of the research strategy. The first stage of the strategic (generic)
research program focuses on the impact of types and amounts of macronutri-
ents and of anti-oxidants on energy balance, energy expenditure and oxidative
capacity. This set of studies, currently underway, will produce knowledge that is
relevant to new food formulations that support optimal metabolic responses
under various conditions, including physical activity. In marketing terms this
would relate to foods for healthy aging, weight control, healthy lifestyle and
child and adolescent health. Projects in the regulatory and market intelligence
clusters relates to the strategic research program, identifying business opportu-
nities, keeping up with developments in the regulatory environment, and facili-
tating communication between stakeholders on nutrition related issues.
As the Centre develops new linkages will be formed with other research
providers and organisations as part of the consolidation of effort. The functional
foods platform is aimed toward improved nutrition and carries with it a view to
a healthy lifestyle. The achievement of this aim, however, has many dimensions,
but starting with food, it is possible to see how these dimensions can be system-
atically and productively linked. To finish, the example that follows is based on
research conducted at the Smart Foods Centre prior to the formation of NCEFF.
It demonstrates how whole foods can have a functional label, why dietary
methodology is relevant in substantiating effects and what consumers think of
the consequences of the area under research.
A Case Study of Functional Food Research:Walnuts in the Dietary Management of Type 2 Diabetes mellitus
The role of dietary fat in insulin resistance has been well researched at a
number of levels [21]. However, while there is strong evidence implicating
dietary saturated fat (SFA) in the development of type 2 diabetes mellitus
(T2DM) [22], the potentially protective role of dietary polyunsaturated fats
(PUFA), first observed many years ago, appears to have been forgotten, and is
relatively under-researched in diabetes management [22]. There are a number
of ways in which PUFA may protect against insulin resistance and T2DM, but
one interesting mechanism is the effect on body fatness. In animal model stud-
ies Huang and colleagues have demonstrated the effect of type of fat on obesity
via an impact on body fatness and various measures of hormonal systems regu-
lating food intake and energy balance (leptin, Arc receptor, NPY and
Tapsell/Patch/Gillen 158
AgRPmRNA expression). In obesity prone mice, a high SFA diet induces
obesity without hyperphagia, but the effect could be reversed by changing the SFA
for PUFA (notably – n�3) with a much less effective response by changing to a
low-fat diet [23, 24]. A higher PUFA diet (and with attention to the type of
PUFA) resulted in a lower energy intake and a low food efficiency ratio (weight
gain/intake) [25], something that could be assessed in human studies.
Nutrition principles for the management of type 2 diabetes mellitus are
based on a systematic review of the scientific evidence [22]. The nature of this
evidence relates to the effects of macronutrients on metabolic control and other
health variables. In particular, the evidence in support of the inclusion of
polyunsaturated fats is quite strong [26], such that foods that deliver these fatty
acids could be seen as having a functional role in the diet. This functionality
could be defined in terms of delivering the essential fatty acids, or through the
impact of these fatty acids (or foods) on health indicators such as body fat. If
this were the case, it would also be helpful to know if patients were able to con-
sume these foods regularly and whether they perceived the foods to have a func-
tional role. Because walnuts have a unique composition providing high amounts
of n�6 and n�3 fatty acids, their functionality in this regard was of interest.
In this study, 55 adult men and women with type 2 diabetes mellitus were
randomly allocated to three dietary advice strategies (low fat, LF, LF inclusive
of PUFA-rich foods, LFP, and LFP with the inclusion of 30 g walnut supplied).
Dietary intakes were assessed by validated diet history interview at baseline, 3
and 6 months and nutrient intake analysis was done using Foodworks (v.3.01,
Xyris, Brisbane). There was no significant difference in nutrient intakes
between groups at baseline, but after 6 months the walnut group was the only
group to achieve all dietary targets (table 2).
This study demonstrated the significance of including 30 g walnuts per day
in the diet [27] to deliver the required amounts of essential fatty acids [see 28].
In this sense the walnuts provided a functional role in meeting target intakes of
nutrients that stands to be limiting if high fat foods are excluded from the diet.
In this study walnuts could be seen as n�3 enriched functional foods. To gain
insights into consumer perceptions here and with another group of patients in a
similar trial (n � 126) [29], we applied a questionnaire derived from focus group
interviews to elucidate the three determinants of intention to consume these
foods in the Theory of Planned Behaviour [30] attitude, normative and control
factors. Using regression analysis we were able to show that the TPB provided a
significant explanation of intention (R2 � 0.54, p � 0.01) and was able to predict
intention 55% of the time. Attitude was a significant determinant of intention
whereas subjective normative beliefs and control beliefs were not related.
Overall the odds of intending to use n�3 enriched functional foods doubled for
each one-unit increase in attitude score. There were significant correlations
A New Look at Intersectoral Partnerships 159
between age (r � 0.21, p � 0.05) and income (r � �0.19, p � 0.05) with inten-
tion; however, these were not determinants of intention. With attitude having the
greatest influence on intentions, immediate prospects for modifying behaviour
come through a change in attitude. Thus, if functional foods are to be adopted by
consumers, then their attitudes towards functional foods warrants attention. This
has implications for the communication of science, another important string to
the bow of intersectoral collaboration.
The above case study outlines how animal model research can inform food
based research with humans, and how this in turn may provide evidence of the
functionality of specific foods in the diet. On top of this, consumer research
provides information on how nutrition knowledge needs to be communicated
and the potential acceptance of related products in the marketplace. These are
some of the aspects of the research program of the National Centre of Excellence
in Functional Foods.
Conclusions
Where food is seen as the starting point for developing healthier lifestyles,
a number of stakeholders may be identified, and clearly the food industry is a
major one. The concept of functional foods unites health, industry and regula-
tory groups in a move towards providing healthy food products, but effective
communication of this concept and of approaches to its development is central
to its successful adoption by consumers. The National Centre of Excellence in
Table 2. Dietary intakes by group after 6 months intervention
Dietary variable Goal LF LF-P Walnut p value1
(n � 20) (n � 19) (n � 16)
Energy, kcal 2,145.95�431.8 1,977.76�500.14 2,006.59�376.19 NS
Saturated fat, %E �10a 10.16 � 4.07 7.72 � 2.29 6.88 � 1.56 0.004
Polyunsaturated �10a 5.77 � 1.84 9.39 � 2.75 11.67�1.84 �0.001
fat, %E
�-Linolenic acid, g 2.22b 1.4 � 0.71 1.69 � 1.44 3.35 � 1.90 �0.001
EPA�DHA, g 0.65b 0.36 � 0.19 1.19 � 1.12 0.81 � 0.55 0.003
aRecommended by American Diabetes Association.bRecommended by ISSFAL based on 2,000 cal intake.1One-way analysis of variance for differences between groups.
Tapsell/Patch/Gillen 160
Functional Foods, Australia, has taken all these aspects on board in developing
an infrastructure to support this process.
Acknowledgements
The Smart Foods Centre is supported by the Australian Research Council. The
California Walnut Commission funded the intervention study referred to in the manuscript.
Other researchers acknowledged in this study were Dr. Marijka Batterham, Dr. Alice Owen,
Ms Marian Bare and Ms Meredith Kennedy.
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A New Look at Intersectoral Partnerships 161
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Prof. Linda C. Tapsell,
National Centre of Excellence in Functional Foods
Northfields Avenue, University of Wollongong
Wollongong, NSW 2522 (Australia)
Tel. �61 2 4221 3152, Fax �61 2 4221 4844, E-Mail [email protected]
Simopoulos AP (ed): Nutrition and Fitness: Mental Health, Aging, and
the Implementation of a Healthy Diet and Physical Activity Lifestyle.
World Rev Nutr Diet. Basel, Karger, 2005, vol 95, pp 162–166
Why a Global Strategy on Diet,Physical Activity and Health?
Amalia Waxman
World Health Organization, Geneva, Switzerland
The Growing Burden of Noncommunicable Diseases
In January of 2004, the World Health Organization’s (WHO) Executive
Board agreed to forward the WHO Global Strategy on Diet, Physical Activity
and Health to its World Health Assembly, after allowing countries an extended
period, until 29 February, for comments. The strategy was endorsed by the
WHO member states at the 56th World Health Assembly in May 2004. The
strategy is an important global public health initiative, which was prompted by
Member States’ concern at the explosion in noncommunicable diseases (NCDs),
for which unhealthy diet and physical inactivity are, together with tobacco use,
among the key risk factors.
Noncommunicable diseases are increasing at alarming rates globally. The
burden of NCDs in developing countries already outweighs that of communica-
ble diseases, both in high- and low-income countries. In 2002, NCDs accounted
for 60% of total mortality worldwide and 46% of the global burden of disease
[1]. Low- and middle-income countries account for the increase in burden of
disease from NCDs. One example comes from China. In China’s rural areas –
and that’s still more than 800 million people – NCDs account for more than
80% of deaths; communicable diseases, less than 3% [2, 3]. Only in Africa do
deaths from communicable diseases outweigh those from noncommunicable
diseases. For example, in South-East Asia 5,730,000 deaths were attributed in
2002 to communicable diseases and 7,423,000 to noncommunicable diseases.
In the Eastern Mediterranean 1,746,000 deaths were attributed to communica-
ble diseases and 2,030,000 to noncommunicable diseases and, in this region, the
Western Pacific, 9,000,000 deaths were attributed to NCDs with 1,701,000 to
communicable diseases [1].
Global Strategy on Diet, Physical Activity and Health 163
This disease burden is expected to increase to 60% by the year 2020.
Countries have not yet been able to successfully defeat the burden of infectious
diseases and they are already faced with a double burden of noncommunicable
diseases. Heart diseases, stroke, cancer and mental disorders are expected to be
the largest contributors. Of the estimated 57 million deaths which occur each
year, 33.4 million are attributed to NCDs. Of these, 16.7 million are attributed
to cardiovascular diseases (CVDs), especially ischemic heart disease and cere-
brovascular diseases. Twice as many die from CVDs in developing countries
than in developed countries.
Obesity is now also a global epidemic [4]. There are globally more than
1 billion overweight people and at least 300 million of them are clinically
obese. Close to 800 million people are suffering from malnutrition, a slow
decline over the past decade.
In some Pacific Island states as much as 70% of women and about 60% of
men in urban areas are obese (BMI �30).
The number of people with type two diabetes is expected to increase three-
fold by 2020, and most of this growth is projected to occur in Asia.
The Causes of Noncommunicable Diseases
Noncommunicable diseases are increasing for several key reasons. Throu-
ghout the world, birth rates are declining, life expectancy is increasing and
populations are aging. One consequence of this change in world demographics is
increased rates of chronic diseases. These demographic changes can be
explained by significant improvements in both medical science, technology, and
successful public health and other development efforts over the last 100 years.
The world population exposure to the modifiable risk factors for cardio-
vascular diseases, cancer, diabetes and other NCDs is also increasing at a very
rapid pace. Lifestyle and consumption patterns are key determinants of such
diseases and include changes in diets, physical activity and tobacco use. These
risk factors are indicators of future health status [4]. Five of the top 10 global
disease burden risk factors identified by the World Health Report 2002 – high
blood pressure, high cholesterol, low intake of fruit and vegetables, high body
mass index and physical inactivity – independently, and often in combination,
are the major causes of these diseases. Food is clearly a major factor in all this.
This report reflects the impact of risk factors over the last decade or so. But cur-
rent risk levels predict major increases in chronic diseases.
The increased prevalence of modifiable risk factors is closely linked
to economic development. Urbanization is key to understanding lifestyle
changes [5]. Rapid growth of urban centers results, in most parts of the world,
Waxman 164
in deficiencies in housing, infrastructure, and basic services. This trend is
accompanied by influences of global trade, industrialization and expansion of
food markets. Populations are exposed to increased availability and aggressive
promotion of processed cheap food – generally high in fat, sugar and salt – but
reduced access and affordability of fruits and vegetables. An increase of 82% of
caloric sweetener has been recorded due to higher income levels and urbaniza-
tion. In addition, lifestyles become sedentary with a rapid shift from energy-
expenditure-intensive to automated occupations, changes in transportation and
the increased use of motorized vehicles [6, 7]. All lead to a decrease in energy
expenditure.
Need for a New Approach
This is, therefore, a global epidemic and requires a global response.
Countries need to act now to ensure that developing countries do not experience
the high peak in NCD prevalence that has occurred in the developed world.
The evidence for the disease burden is strong. The science behind the role
of the two risk factors, diet and physical activity, in the etiology of NCDs is
robust, and experience from countries taught us that we know enough to act and
change the current trends.
Upon request by its Member States, WHO has over the past 2 years devel-
oped the Global Strategy on Diet, Physical Activity and Health. Consistent with
an approach in which countries participated from the outset, six regional con-
sultations with Member States were completed between March and June 2003.
These involved more than 80 countries in formal meetings. The strategy also
reflects the expertise and advice of several United Nations organizations, in
particular the Food and Agriculture Organization (FAO). WHO has also
received significant input from representatives of civil society and nongovern-
mental organizations, and from the private sector, in particular the food and
non-alcoholic drinks industry, as well as sport manufacturing organizations.
WHO has been supported in this process by a reference group of prominent
experts from all over the world, representing several fields and disciplines. This
group provided scientific and policy input and advice for the development of
the strategy throughout the process.
The strategy builds upon the vast evidence, best practices and experience
in countries in tackling and preventing NCDs. It also draws on the experience
and knowledge of health, nutrition and physical activity experts from a wide
range of disciplines and countries, both developed and developing. One of the
strategy’s most important conclusions is that reducing the burden of NCDs
requires a multi-sectoral, multi-stakeholder approach.
Global Strategy on Diet, Physical Activity and Health 165
The strategy is not prescriptive but, like a toolbox, provides WHO Member
States with a comprehensive range of policy options from which to choose.
Many countries are already developing their own national strategies.
What are the policy options the strategy is recommending? The strategy
suggests recommendations for action by all stakeholders: WHO, Member
States, NGOs, the private sector and UN agencies. Key principles are set to
guide the development of strategies to address unhealthy diets and physical
inactivity: best available scientific evidence, comprehensiveness, multisectoral
and multidisciplinary approaches, a life course perspective, addressing poverty,
gender and culture sensitivities, and the accountability of all stakeholders to
achieving success. The strategy sees governments assuming a steering role in
changing the environment to support their populations and individuals improve
their lifestyle. It stresses the importance of building on existing structures and
national mechanisms rather then creating new ones. It suggests that national
effective legislation and appropriate infrastructure are critical for introducing
effective policies. The main policy recommendations of the strategy are: for
countries to develop national dietary and physical activity guidelines, provide
accurate and balanced information to consumers, in particular with regard to
nutrition labelling, nutrition and health claims, addressing issues related to mar-
keting of foods, especially to children. The strategy recommends that countries
review and evaluate their food and agriculture policies to be consistent with
healthy diet. In particular, it suggests that countries provide incentives to pro-
mote a healthy diet. Price policies are important as prices determine food
choices, especially among the poor. Food programmes need to take note of the
growing burden of NCDs and their risk factors, and agriculture polices can have
a great effect on national diets. The strategy advocates for policies to change
social norms to increase physical activity and incorporate it into daily life.
Many public policies such as transport and urban planning play a huge role in
levels of physical activity. Further, the strategy reiterates the importance of pro-
viding clear messages about the benefits and amounts of physical activity levels
needed to reduce risks for NCDs. School policies and supportive school envi-
ronments for healthy diet and physical activity are also recommended.
The strategy pays much attention to the role of health services and health
professionals in primary prevention and urges that diet and physical activity
recommendations and follow up are built into health services. The document
also elaborates on the role of surveillance and the importance of continued
research and evaluation at a national, as well as a global, level to monitoring
progress and trends.
For the private sector the strategy highlights the importance of improving
the nutrition profiles of products, to reduce salt, fat (and type of fat) and sugar.
It also advocates for a review of current marketing practices.
Waxman 166
Civil society has a major role to play. The strategy acknowledges its role
and describes how NGOs can assist governments in disseminating information,
influencing consumers, promoting availability of healthy foods and advocating
and supporting health promoting programmes.
Finally the strategy appreciates the important role of the United Nations
and other intergovernmental organizations in assisting WHO and its Member
States in addressing issues which are crucial for implementing the strategy but
which are often outside the health sector, such as: economic analysis, develop-
ment programmes, agriculture policies.
National action can be effective – it has provided much of our evidence
base for effective interventions. But independent action is not enough in an
increasingly globalized and interdependent world. The WHO’s goals to advance
public health worldwide – and perhaps as importantly, to set new public health
priorities – can only be met through decisive and coherent action by countries,
sustained political commitment, and broader, multi-level involvement with all
relevant stakeholders worldwide.
References
1 WHO: Shaping the Future. The World Health Report, 2003.
2 Ruitai S: The challenge of epidemiology transition in China. Chin Prev Med 2001.
3 Ruitai S: Epidemiology transition in China. East meets West for 21st Century, Sino-America
Medical Conference, Boston, 2001.
4 WHO: Obesity: Preventing and managing the global epidemic. Report of a WHO consultation.
WHO Technical Report Series, 2000, No 894.
5 Popkin BM:. Urbanization, Lifestyle Changes and the Nutrition Transition. World Dev 1999;27:
1905–1916.
6 Prentice AM, Jebb SA: Obesity in Britain: Gluttony or Sloth. BMJ 1995;311:437–439.
7 Bell AC, Ge K, Popkin B: The road to obesity or the path for prevention: Motorized transportation
and obesity in China. Obes Res 2002;10:277–283.
Ms. Amalia Waxman, Project Manager
Global Strategy on Diet, Physical Activity and Health, Office of the Assistant Director-General
Noncommunicable Diseases and Mental Health, World Health Organization
Avenue Appia 20
CH-1211 Geneva 27 (Switzerland)
Tel. �41 22 791 3353, E-Mail [email protected]
Simopoulos AP (ed): Nutrition and Fitness: Mental Health, Aging, and
the Implementation of a Healthy Diet and Physical Activity Lifestyle.
World Rev Nutr Diet. Basel, Karger, 2005, vol 95, pp 167–176
Nutrition and Fitness Policies in theUnited States
Philip R. Lee
School of Humanities and Sciences, Stanford University, Stanford, Calif., USA
Nutrition and fitness policies in the United States must be considered a
failure from a public health perspective. Obesity in the United States has been
increasing steadily over the past several decades, particularly in the past decade.
It is now considered to be an epidemic. Reports from the US Department of
Health and Human Services [1–4], RAND [5–7] and a growing number of
scholars attest to this fact [8–11]. In fact, eight million children ages 6–19 years
are overweight, a number that has tripled in the past 20 years. Moreover, obesity
can play a major role in the disability, particularly among adults from 30 to 70
years of age. It is now linked to higher health care costs than cigarette smoking
or problem drinking.
The picture with respect to physical activity and fitness is hardly any bet-
ter. According to the Healthy People 2000 review in 1999, only 15% of adults
aged 18 years and older engaged in 30 min of moderate physical activity 5 days
per week, down from 22% in 1985 [12].
The costs in terms of the health of the population are enormous. It has been
estimated that the poor diets of Americans, their sedentary lifestyle and their
excess alcohol consumption contributes to about 400,000 of the 2,000,000 or so
annual deaths in the United States. This amount is the same as the toll from cig-
arette smoking [11, p 7].
How did this happen? How did the United States become an overweight,
sedentary, unfit population?
In order to provide some perspective on these developments and what is
described as the ‘obesity epidemic’ in the United States, I will review the evo-
lution of public policies related to nutrition, fitness, physical activity, and the
health of the population, particularly during the past 40 years. In this review, I
will draw on various federal government documents, including those of the
Lee 168
Department of Health and Human Services (DHHS), prior to 1980, the
Department of Health, Education and Welfare (DHEW), the Department of
Agriculture (USDA), and the US Congress; on my service as Assistant
Secretary for Health and Scientific Affairs in DHEW during the Johnson
Administration (1965–1969) and the Assistant Secretary for Health in DHHS
during the first Clinton Administration (1993–1997); scholarly work with col-
leagues at UCSF, as well as contributions by the Institute of Medicine and
Professor Marion Nestle of New York University. After my historical review, I
will examine some of the forces that have influenced and continue to influence
the public policy process, particularly at the federal level. Commercial interests
have had a far greater influence on nutrition policies than the public interest
[11]. Federal policies on physical fitness during the past 40 years have had little
effect. Finally, I will discuss some recent policy developments that may affect
current trends. Throughout I will stress the tensions between a population
health perspective and a focus on individual behavior or lifestyle.
Historical Perspective
Physical Fitness and Physical ActivityPhysical fitness was of little interest to federal policymakers, except those
in the armed forces until President Eisenhower created the President’s Council
on Youth Fitness and Sports by Executive Order in 1956 after the President
learned that American children were less fit than European children. Over the
decades, Presidents have expanded the Council’s mandate to include all
Americans and changed its name to the President’s Council on Physical Fitness
and Sports.
Over the years, the President’s Council devoted relatively little attention to
health-related fitness activities for the whole population and concentrated pri-
marily on working with private industry, insurance companies, and schools.
President Clinton transferred the support for the Council to DHHS to achieve
greater integration with the work of the Office of Disease Prevention and
Health Promotion in the Office of the Assistant Secretary for Health. President
Bush has continued the emphasis on linking the Council’s activities to health
promotion efforts at the national, state, and local level [13].
It was not until the 1970s, particularly after the publication in 1974 of the
report A New Perspective on the Health of Canadians [14] that health behaviors,
such as eat habits and physical activity, began to attract the attention of policy-
makers. A great deal of attention was paid to health promotion, particularly the
behavior of the individual, as an important factor in health. Many of America’s
health problems were labeled ‘behavioral’ or ‘lifestyle’ problems. The bad habits
Nutrition and Fitness Policies in the US 169
were said to contribute to the growing burden of chronic illness, increasing
demand for health care and contributing to the rising costs of health care.
This point of view was expressed succinctly in 1977 by the late Dr. John
Knowles, who was then President of the Rockefeller Foundation in an essay
entitled, ‘The Responsibility of the Individual’: ‘Prevention of disease means
forsaking the bad habits which many people enjoy – overeating, too much
drinking, taking pills, staying up at night, engaging in promiscuous sex, driving
too fast, and smoking cigarettes’ [15].
Beginning in the 1960s, population-based studies in Alameda County,
California demonstrated the importance of seven health-related behaviors (e.g.
maintaining normal body weight, engaging in regular physical activity) in increas-
ing life expectancy among those who maintained these behaviors compared to
those who did not engage in at least four of these healthy behaviors [16–18].
While legislation enacted in the mid-1970s included an emphasis on health
promotion and disease prevention, the legislation had little impact on health
promotion and disease prevention policies at the state or local levels [19, 20].
In 1978, the DHEW Task Force on Disease Prevention and Health Promotion
identified strategy targets in 12 categories of health-related goals (e.g. chronic
disease, communicable disease). In the goal, ‘Enhance General Physical and
Emotional Well Being,’ three key variables were stressed: nutrition, unwanted
fertility/family planning, and exercise. The potential role of employee health
programs and school physical education programs in promoting exercise
were noted. The Task Force stated a theme that was to be repeated over the years:
‘A strong national commitment to disease prevention and health promotion is
needed to ensure that Americans will be a truly healthy population’ [21].
Twenty-five years and eight Secretaries of DHEW and DHHS later, the
Secretary of DHHS, Tommy Thompson, convened a national health summit in
2003 ‘to call on Americans to take the steps that will lead to a healthier nation’
[22]. The 25 years between these two clear statements has seen more words than
effective action.
In the late 1970s, there were a number of important developments in the
DHEW, under the leadership of Dr. Julius Richmond, the Assistant Secretary for
Health/Surgeon General. He began to shift the focus of federal health policy from
health services and financing medical care to health promotion and disease pre-
vention. He also initiated what has become known as the Healthy People process.
Healthy People 2000: National Health Promotion and Disease Prevention
Objectives, released in 1990, listed Physical Activity and Fitness as the first pri-
ority and nutrition as second [23]. At the Healthy People 2000 Review in
1998–1999, the percentage of overweight adults (age 20–74 years) had risen
from 26% in 1976–1980 to 35% in 1994; the figures for black females had risen
from 44 to 52%, for Hispanic females from 33% in 1990 to 35% in 1995 and for
Lee 170
low-income females aged 20–74 from 37% in 1976–1980 to 47% in 1991.
Vigorous physical activity for children and adolescents (age 10–17 years) was
stable at 64 percent. However, only 27% of students in grades 9–12 were
engaged daily in physical education at school; for adults (18 years and older),
the figure was only 16% engaged in vigorous physical activity [12].
The importance of health-related behavior, or lifestyle, was stressed by
McGinnis and Foege in their famous paper, ‘Actual Causes of Death in the
United States,’ published in 1993. In this paper, the method of calculating
the cause of death differed sharply from the usual listing of the most
common causes of death, headed by diseases of the heart (29.5%), all cancers
(22.9%), and stroke (6.9%). The actual causes of death identified by
McGinnis and Foege [24] are headed by tobacco (19%) and poor diet/lack of
exercise (14%).
The 1996 Surgeon General’s Report on Physical Activity and Health
reflected a major change in thinking about physical activity at the federal level
[25]. The focus shifted from an emphasis on intensive, regular aerobic physical
exercise to a wide range of health enhancing physical activities. The report
noted low levels of physical activity among the majority of adults including
25% who are not active at all. The population reporting no leisure time physical
activity was higher among women, African Americans and Hispanics, among
older adults and among the less affluent.
Healthy People 2010, released in January 2000, represented a significant
shift from past Healthy People publications in the goal to ‘eliminate health dis-
parities’ and its greater consideration of the relationship of education and
household income to health status. This broader perspective was evident in the
breadth of actions needed to achieve equity: ‘Healthy People 2010 recognizes
that communities, states, and national organizations will need to take a multi-
disciplinary approach to achieving health equity – an approach that involves
improving health, education, housing, labor, justice, transportation, agriculture
and the environment, as well as data collection itself’ [26].
Physical activity is now considered a leading health indicator and, as I
noted at the outset of this paper, the picture is not a good one. During recent
decades overweight prevalence has increased significantly and levels of light to
moderate physical activity and vigorous activity have changed little.
It is important to note that the barriers most adults face when trying to
increase physical activity are lack of time, lack of access to convenient facilities
and lack of a safe environment in which to be active. For example, many sub-
urbs lack sidewalks and in many inner city areas the sidewalks are not safe for
the elderly walking alone or for children walking to school.
We do not seem to have made much progress since 1979 when Dr.
Richmond issued his first health objectives for the nation.
Nutrition and Fitness Policies in the US 171
Nutrition PolicyA sound nutrition policy is fundamental to any effort to improve our
nation’s health. From its foundation in 1862, the US Department of Agriculture
(USDA) had two functions: (1) to assure a reliable and adequate food supply,
and (2) to provide information to the public on ‘subjects connected to agricul-
ture in the most general way,’ which has been interpreted as giving dietary
advice [11, p 33].
In 1917, the USDA issued its first set of dietary recommendations in a 14-
page pamphlet, How to Select Food. While establishing precedents with respect
to food groups and dietary advice, permitting all foods to be recommended, it
ignored the analysis of the USDAs first director of research, W.O. Atwater,
related to the harm done to our health by the excessive consumption of sugar
and large quantities of fat meats.
The establishment of the Food and Nutrition Board, National Research
Council, National Academy of Sciences in 1941 and the enactment of the
School Lunch Program by Congress in 1946 were early developments in nutri-
tion policy. In the mid-1960s, there were two modest expansions of nutrition
policies: the Food Stamp Program in 1965 and the Child Nutrition Act of 1966.
The Child Nutrition Act established the School Breakfast Program. In addition,
President Johnson outlined the Food for Freedom Program, also called the ‘war
on hunger’.
The DHEW began nutrition surveys after the report, Hunger USA [27], by
the Citizen’s Board of Inquiry, revealed serious problems of malnutrition
among the poor. Based on the survey results, a number of food assistance pro-
grams were expanded in the 1970s – including the Food Stamp Program, the
School Lunch Program, and the Child Nutrition Program. In addition, a nutri-
tion program for the elderly was launched. Most of these programs were admin-
istered by the USDA, but the nutrition program for the elderly was administered
by the Administration on Aging/DHHS. The period from the turn of the century
to the 1960s has been described by Professor Marion Nestle as ‘Eat More –
Preventing Dietary Deficiencies 1890 to 1960s’ [11].
The Senate Select Committee on Nutrition and Human Needs, chaired by
Senator McGovern, became a key player in the development of federal policies
for food assistance for the poor in the late 1960s and early 1970s. By the mid-
1970s, the Select Committee began to address broader nutrition policies [28].
While domestic issues initially attracted the Select Committee’s attention,
it was the grain shortage in the Soviet Union and the inflation produced by the
Arab oil embargo in the early 1970s that led Congress to take broader measures
to ensure adequate food supply that have continued to this day: (1) income sup-
port for farmers to assure adequate food production, and (2) expansion of the
Food Stamp Program in order to protect the poor from food price inflation.
Lee 172
Regulation of food labeling was stepped up by the Food and Drug
Administration (FDA), and Congress gave added nutrition responsibilities to
the USDA to be shared with DHEW, including dietary advice to the public, in
the Food and Agriculture Act of 1977 [11].
Although many areas of agriculture policy that are germane to the consid-
eration of this conference remain controversial, I will focus on dietary recom-
mendations and nutrition policy – an area of continuing conflict.
Just as the advances in research related to exercise and other determinants
of health began to shift health policies in the DHEW toward health promotion
and disease prevention, nutrition policymakers began to pay attention to the
research that elucidated the relationship between diet and chronic illness, par-
ticularly coronary heart disease. In 1977, the Senate Select Committee on
Nutrition and Human Needs issued its report, Dietary Goals for the United
States [29], which generated a great deal of controversy because of its recom-
mendations to eat less fat, cholesterol, saturated fat, sugar, and calories. The
Dietary Goals represented a fundamental shift in federal dietary advice from
‘eat more’ to ‘eat less’ [11]. The controversy and intense pressure by the food
industry interest groups led the Select Committee to modify its recommenda-
tions regarding salt, cholesterol and meat consumption.
The shift in policies from eat more to eat less was also reflected in the
DHEW Task Force Report on Disease Prevention and Health Promotion [21]
and in the Surgeon General’s Report Healthy People [30] in 1979. The Task
Force recommended, ‘total fat intake, especially animal fats, refined carbohy-
drates, and salt should be reduced as part of a prudent diet’ [21].
The Dietary Guidelines for Americans were first issued jointly by the
USDA and DHHS in February 1980 as the consensus about the relationship of
diet to a variety of chronic diseases grew. In the mid-1980s, the National Heart,
Lung, and Blood Institute/National Institutes of Health launched a major
nationwide campaign to lower blood cholesterol across the entire population.
The campaign included specific advice regarding the intake of fat, especially
saturated fat. In 1988, after years in preparation, the DHHS issued the Surgeon
General’s Report on Nutrition and Health [31]. The report described the magni-
tude of the problem as follows: ‘As the diseases of nutritional deficiency have
diminished, they have been replaced by diseases of dietary excess and imbal-
ance – problems that now rank among the leading causes of illness and death in
the United States, touch the lives of most Americans, and generate substantial
health care costs’ [31].
While providing support for the Dietary Guidelines for Americans, the
Surgeon General’s Report on Nutrition and Health gave special emphasis to the
importance of obesity as a public health problem and on the need to reduce
the intake of total fats, especially saturated fats [31].
Nutrition and Fitness Policies in the US 173
In the section on Implications for Public Health Policy, the report noted:
‘Americans, in general, would benefit from a lifestyle that includes more phys-
ical activity and a diet containing fewer calories’ [31].
The Policy ProcessWhy, when the research related to diet and exercise was so consistent, was
it so difficult during the past 25 years to reach agreement on dietary advice and
to implement programs that dealt more effectively with the increasingly obese
population? In part, the answer is politics and the policy process.
During this period, food companies exerted significant influence on
dietary guidelines and nutrition policy. They effectively lobbied Congress and
members of the executive branch as well as co-opted nutrition experts as allies.
The practice of the food companies and the response of government are not
unique, but reflect the public policy process more broadly. Professor John
Kingdon has been a longtime student of Congress and how an issue becomes a
priority for policymakers and is enacted into law. Some policies, such as Food
Stamps and agricultural subsidies, were initiated when there was agreement on
the problem, when policy options had been developed and when the political
stream was aligned with the problem and the policy streams. This has been
described by Kingdon as a ‘window of opportunity’ [32].
Other analysts have focused on the reasons why certain policies are so
resistant to change. According to Paul Sabatier and Hank Jenkins-Smith, long-
term policy change depends on the competition among two or more ‘advocacy
coalitions’ whose members monitor and actively try to influence specific policy
issues. In their view, most policy change is the product of shifts in large-scale
social, economic, or political conditions. However, even with a major shift
in political power or other external circumstances, it is often difficult for
government to respond to even serious problems because an effective response
would violate the core values of an advocacy coalition. Altering dietary advice
to advise people to eat less red meat would not only violate the core values of
some about the proper role of government, it would also have a negative eco-
nomic impact on all those who raise, slaughter, process, and market beef.
In the absence of changes in broader, contextual conditions, Sabatier and
Jenkins-Smith observe that policy can still change if partisan positions are
modified through a process of ‘policy learning.’ Policy learning is a fairly sub-
tle and gradual process. The members of an advocacy coalition almost never
change their deep-core values and beliefs, which dictate their basic orientation
to an issue and the role of government. They may, however, change their ‘near-
core’ policy-oriented beliefs and a variety of ‘secondary’ beliefs when new
information successfully challenges their claims about the nature of a problem
Lee 174
or the effectiveness of a solution. Given a new understanding of the problem
and potential remedies, current policies may become indefensible and a coali-
tion may accept new methods of governmental intervention [33].
Professor Nestle astutely summarized the issue when she wrote: ‘Diet is a
political issue. Because dietary advice affects food sales, and because compa-
nies demand a favorable regulatory environment for their products, dietary
practices raise political issues that cut to the heart of democratic institutions’
[11, p 28].
The struggle in terms of policy and politics is over the way the government
balances corporate interests and the public interest. To date, the balance has
favored the corporate interests. However, we have seen in the case of cigarette
smoking and the tobacco companies that a combination of grass roots organiza-
tions and legal challenges can dramatically change the landscape. The process
is, however, more complex. Twenty-three years ago, Thomas and coworkers
wrote: ‘The health prospects of Americans during the last two decades of the
twentieth century will depend on the quality of decisions made by federal, state,
and local governments, by business and industry, by community organizations,
by voluntary and professional health associations, by health professionals
themselves, and by families and individuals acting on their own behalf. In short,
if the health of Americans is to improve, both individual and collective actions
will be necessary’ [34, p 146].
The record of the past 23 years has not been a good one in achieving
national health objectives related to physical activity and nutrition. Will the next
20 years be any different?
Will the growing efforts to stimulate action at the grassroots with respect
to obesity, overweight, and physical activity now be successful when they have
had so little impact in the past? The evidence about physical activity and diet in
relation to health status, chronic disease and disability is growing. Efforts by
the Surgeon General of the US Public Health Service in collaboration with non-
profit and professional organizations and several major foundations have initi-
ated national efforts to increase physical activity among adults. Some of these
efforts seem to be bearing fruit. Time will tell whether a broad-based movement
can be initiated and sustained.
The New York Times has reported changes in the landscape of food politics
in a recent article, ‘Lawyers Shift Focus From Big Tobacco to Big Food’ [35].
To date, lawyers have settled five cases out of court, three with major food com-
panies, one with McDonalds, and one with the New York City school system. In
tobacco suits, the lawyers became successful when they focused on deceptive
marketing rather than personal injury. This appears to be the focus in the current
food cases.
Nutrition and Fitness Policies in the US 175
Conclusion
The United States faces an epidemic of obesity with grave consequences
for the health of the population and the costs of health care. During the past
century, and particularly during the past 40 years in the United States, health
and nutrition policies have not been effective in improving the diets of
Americans or increasing their levels of physical activity. It is suggested that the
struggle with tobacco companies and the recent declines in cigarette smoking
may have lessons for diet and physical activity. In the meantime, do as we say,
not as we do.
References
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Philip R. Lee
Program in Human Biology
Bldg. 80, Inner Quad, Stanford University
Stanford, CA 94305–2160
Tel. �1 650 725 7531, Fax �1 650 725 5451, E-Mail [email protected]
177
Alberti, A. 115
Berry, E.M. 29
Booth, F.W. 73
Casper, R.C. 1
Dubnov, G. 29
Ferrari, S.L. 35
Ferris, A.E. XXXIII
Fidanza, F. 115
Fruttini, D. 115
Fujii, Y. 52
Gillen, L.S. 151
Ichikawa, Y. 52
Ito, M. 52
Kang, J.X. 93
Lee, P.R. 167
Lees, S.J. 73
Leighton, F. 122
Lorgeril, M. de 103
Lupien, J.R. 140
Okuyama, H. 52
Patch, C.S. 151
Peet, M. 17
Salen, P. 103
Simopoulos, A.P. XIV, 80
Tapsell, L.C. 151
Urquiaga, I. 122
Wahlqvist, M.L. 62
Waxman, A. 162
Yamada, K. 52
Author Index
178
Subject Index
Aggression
monoamine oxidase polymorphisms in
type A gene 2
omega–3 fatty acid treatment trials 9
Alzheimer disease
benefits of moderate alcohol
consumption 124
cognitive function effects of nutrients 9,
10
Apolipoprotein E, gene polymorphisms and
schizophrenia 2, 3
Atherosclerosis
dietary fatty acids and plaque
composition 111
epidemiological benefits of moderate
alcohol consumption 122–125
inflammation role 109
oxidized low-density lipoproteins
109–111
prevention 108, 109
risk factors 163, 164
Australia
food industry 151
intersectoral partnerships in food
154–156
National Centre of Excellence in
Functional Foods
diabetes type 2 case study of walnuts
157–159
market perspective 153, 154
nutrition perspective 152, 153
organizations and partnerships 156, 157
prospects 159, 160
regulatory perspective 153
novel food regulation 148
obesity rates 155
Bipolar disorder, omega–3 fatty acid
treatment trials 7
Bone mineral density, see Osteoporosis
Brain-derived neurotrophic factor (BDNF),
schizophrenia neuropathology 23
Cancer
alcohol
benefits of moderate alcohol
consumption 123, 133
deleterious effects 126
fat-1 omega–3 fatty acid desaturase gene
transfer effects in breast cancer cell
line 95, 97
mortality trends 52, 53
omega–3 fatty acids in prevention 57,
58
Cardiomyocytes, fat-1 omega–3 fatty
acid desaturase gene transfer effects 94,
95
Collagen 1�1, osteoporosis gene
polymorphisms 41
Cooking
Greek diet 86, 87
Nicotera diet 118
Coronary heart disease, seeAtherosclerosis
Declaration of Olympia on Nutrition and
Fitness XXV–XXXI
Depression, omega–3 fatty acid studies
clinical trials of treatment 5, 6, 12
deficiency in patients 5
postpartum depression treatment 6, 7
Diabetes type 2
benefits of moderate alcohol
consumption 124
National Centre of Excellence in
Functional Foods case study of
walnuts 157–159
Diet and Reinfarction Trial (DART),
omega–3 fatty acid protection 103, 105
Dietary Guidelines for Americans,
establishment 172
Disease
definition 73
physical inactivity as disease 73–78
Docosahexaenoic acid, see Omega–3 fatty
acids
Eicosapentaenoic acid, see Omega–3 fatty
acids
Energy density, calculation 66
Estrogen, cardioprotective mechanisms
129
Estrogen receptor, osteoporosis gene
polymorphisms 40
European Union, novel food regulation
144–147
Exercise, see Physical activity
fat-1, omega–3 fatty acid desaturase gene
transfer studies
cultured cell studies
breast cancer cell line 95, 97
cardiomyocytes 94, 95
fatty acid composition effects 94, 95
human umbilical vein endothelial cells
97
neuronal apoptosis 97, 98
rationale 93, 94
transgenic mice
diet study prospects 100, 101
fatty acid profile 99, 100
production 98
Free radical theory of aging, overview 55,
56
Functional food, see National Centre of
Excellence in Functional Foods; Novel
food
Global Strategy on Diet, Physical Activity,
and Health, implementation 164–166
GLUT4, physical activity effects on muscle
levels 76
Greek diet
bioprotective nutrients compared with
other Mediterranean diets 86
characteristics 87, 88
Crete death rates 80, 81
fatty acid composition and protective
effects 82–85
food preparation considerations 86, 87
Lyon Heart Study 88, 111
Healthy Italian Mediterranean Diet Temple
Food Guide (HIMDTFG), development
119, 120
Healthy People 2000, overview 169, 170
Healthy People 2010, overview 170
High-density lipoprotein (HDL), wine
induction 127–129
HIMDTFG, see Healthy Italian
Mediterranean Diet Temple Food Guide
Human umbilical vein endothelial cell
(HUVEC), fat-1 omega–3 fatty acid
desaturase gene transfer effects 97
Interleukin-6, osteoporosis gene
polymorphisms 41, 42
Intrauterine growth retardation
antenatal exercise effects on birth weight
11, 12
health risks later in life 3
Japan
dietary fatty acids and disease 52–54
novel food regulation 147, 148
Leptin, derangements in physical inactivity
75, 76
�-Linolenic acid, cooking effects 59
Subject Index 179
LRP5, osteoporosis gene polymorphisms
42, 43
Lyon Heart Study, cardioprotective effect of
Crete diet 88, 111
Mediterranean Adequacy Index (MAI),
comparison of Mediterranean diets
118–121
Mediterranean diet, see Greek diet;
Nicotera diet
Menopause, physical activity and exercise
prescription in postmenopausal weight
loss 31, 32
Monoamine oxidase (MAO),
polymorphisms in type A gene and
aggression 2
National Centre of Excellence in Functional
Foods (NCEFF), see Australia
Neurons, fat-1 omega–3 fatty acid
desaturase gene transfer effects on
apoptosis 97, 98
Neutriceuticals, European Union regulation
144, 145
Nicotera diet
dietary habits 116, 117
food preparation 118
Healthy Italian Mediterranean Diet
Temple Food Guide development 119,
120
meal patterns 116–118
Mediterranean Adequacy Index for
comparison with other Mediterranean
diets 118–121
overview of lifestyle 115
Nitric oxide (NO), polyphenol induction
133, 134
Noncommunicable diseases
causes 163, 164
global burden 162, 163
global strategy for prevention 164–166
Novel food, see also Australia
claims 141, 142, 148, 149
definition 140, 141, 146
examples and potential benefits 143,
144
prospects for study 148, 149
regulation
European Union 144–147
Japan 147, 148
United States 146
Nutrient density, calculation 66
Obesity
Australia 155
complications 30
energy throughput vs intake importance
64, 65
etiology 29, 30
lifestyle modification for weight loss 30,
31
pathways to abdominal obesity 66
physical activity and exercise
prescription in postmenopausal weight
loss 31, 32
prevalence 29, 64, 163
United States 167, 175
Olive oil, composition and health benefits
87
Olympics, history and positive health
parameters XXXIII–XXXVI
Omega–3 fatty acids
aggression treatment trials 9
Alzheimer disease cognitive function
effects 9, 10
anti-inflammatory activity 56, 57
benefits in aging 59, 60
bipolar disorder treatment trials 7
cancer prevention studies 57, 58
depression studies
clinical trials of treatment 5, 6, 12
deficiency in patients 5
postpartum depression treatment 6,
7
desaturase gene, see fat-1gene expression regulation 54
metabolic competition with other fatty
acids 53, 54
prenatal deficiency and cognitive
development disorders 4, 55
schizophrenia treatment trials 7–9, 12,
24, 25
sudden cardiac death protection
103–108
Subject Index 180
Omega–6 fatty acids
gene expression regulation 54
inflammation promotion and
peroxidative injury 56, 57
metabolic competition with other fatty
acids 53, 54
sudden cardiac death studies 107, 108
Omega–6/omega–3 fatty acid ratio
fat-1 omega–3 fatty acid desaturase gene
transfer studies
cultured cell studies
breast cancer cell line 95, 97
cardiomyocytes 94, 95
fatty acid composition effects 94, 95
human umbilical vein endothelial
cells 97
neuronal apoptosis 97, 98
rationale 93, 94
transgenic mice
diet study prospects 100, 101
fatty acid profile 99, 100
production 98
geographic differences 80, 81
Greek diet 84, 85
trends 80
Western diet 93
Osteoporosis
bone mineral density
genome screening for quantitative trait
loci 37
measurement 35, 36
epidemiology 35, 36
fracture risk 35
gene polymorphisms
collagen 1�1 41
estrogen receptor 40
interleukin-6 promoter 41, 42
LRP5 42, 43
screening guidelines 44
vitamin D receptor 38–40
heritability of bone mass and strength
36, 37, 43
Physical activity
antenatal exercise effects on birth weight
11, 12
decline 62
eco-nutritional disease prevention 69, 70
emotional health benefits 10, 11
exercise prescription in postmenopausal
weight loss 31, 32
goals 63, 64
inactivity as disease 73–78
optima 63
overview of benefits, XXXVII–XL, 67
preventive medicine 67, 68
public policy in United States 168–170
therapeutic physical activity 69
Platelet aggregation, inhibition by wine
129
Polyphenols
anti-inflammatory activity 133
anticarcinogenesis activity 1333
antioxidant activity 131, 132
antithrombotic activity 132
bioavailability in wine 130, 131
nitric oxide induction 133, 134
protein interactions 133
President’s Council on Physical Fitness and
Sports, historical perspective 168
Schizophrenia
apolipoprotein E gene polymorphisms 2,
3
clinical features 17
intrauterine growth retardation as risk
factor 3
nutrition interactions
case-control studies 20
cross-national ecological studies 18,
19
historical studies of diet 20–22
intervention studies 23–25
neuropathology 22, 23
omega–3 fatty acid treatment trials 7–9,
12, 24, 25
outcomes in developing vs developed
countries 17, 18
Seven Countries Study, cardiovascular
disease rates 81, 82
Sudden cardiac death (SCD)
epidemiology 102
omega–3 fatty acid protection 103–108
omega–6 fatty acid studies 107, 108
Subject Index 181
Tissue plasminogen activator (t-PA), wine
effects 129, 130
United States
economic impact of poor lifestyle 167
novel food regulation 146
obesity rates 167, 175
public policy and trends
nutrition 170–173
physical fitness and physical activity
168–170
policy process 173, 174
Urokinase plasminogen activator (u-PA),
wine effects 130
Vegetable oils, cooking effects 59
Vitamin C, Alzheimer disease cognitive
function effects 9, 10
Vitamin D receptor (VDR), osteoporosis
gene polymorphisms 38–40
Vitamin E, Alzheimer disease cognitive
function effects 9, 10
Wine
cardioprotective mechanisms
fibrinolytic activity 129
heat shock protein induction 130
high-density lipoprotein induction
127–129
platelet aggregation inhibition 129
polyphenols
anti-inflammatory activity 133
antioxidant activity 131, 132
antithrombotic activity 132
bioavailability 130, 131
nitric oxide induction 133, 134
protein interactions 133
cirrhosis risks compared with other
alcoholic beverages 124, 125
deleterious effects of alcohol
consumption 126
epidemiological benefits of moderate
alcohol consumption 122–125
French paradox 122
World Health Organization (WHO), Global
Strategy on Diet, Physical Activity, and
Health 164–166
Subject Index 182
