Patana TengPatana Teng--umnuay, M.D. Ph.D.umnuay, M.D. Ph.D.Phyathai 2 HospitalPhyathai 2 Hospital

From Science to Life Style ChangesFrom Science to Life Style Changes

AgingAging

• Aging is the accumulation of changes in the cells and tissues that increase the risk of death.

• The aging process produces aging changes at an exponentially increasing rate with advancing age.

• Anti-aging Medicine– The use of multidisciplinary techniques to prevent aging

process that leads to disabilities or death.

• Aesthetic Medicine– The use of medical techniques to enhance patient’s

satisfaction with his/her physical appearance.

• Regenerative Medicine– The process of creating living, functional tissues to repair or

replace tissue or organ function lost due to age, disease, damage, or congenital defects.

Percent of all individuals reporting the disease who are 65 years and older, USA, 1996

Cerebrovascular disease 68.9%Arthritis 45.6%Hearing impairment 43.7%Diabetes 41.7%Heart disease 41.3%Hypertension 40.8%Visual impairment 32.3%Asthma and emphysema 13.4%

Projected Global Deaths for Selected Causes 2002Projected Global Deaths for Selected Causes 2002--20302030

World Health Statistics 2007World Health Statistics 2007

Theories of AgingTheories of Aging

Telomere shorteningTelomere shortening

• Telomeres are sequences of nucleic acids extending from the ends of chromosomes.

• Every time the cell divides, telomeres are shortened, leading to cellular damage and death.

• Telomerase is an enzyme that can repair and replace telomeres, found only in germ cells and cancer cells.

Hormonal Hormonal Theory of Theory of

AgingAging

Geriatric medicine says

Anti-aging medicine says

Hormonal Imbalance in AgingHormonal Imbalance in Aging

INSUFFICIENCY• Melatonin• Growth hormone• Estrogen• Progesterone• Testosterone• DHEA• Pregnenolone• Thyroid hormone

EXCESS• Cortisol• Insulin

Impact of anabolic deficiency on survival rate in men with chronic heart failure

(Circulation 2006;114:1829)

Hormone Status Three-year Survival Rate

High levels of DHEA, testosterone, and IGF-1

83%

Deficiency in one hormone (DHEA, testosterone, or IGF-1)

74%

Deficiency in two hormones (DHEA, testosterone, or IGF-1)

55%

Deficiency in all three hormones (DHEA, testosterone, and IGF-1)

27%

Cross-linkage theory of Aging

• The formation of advanced glycosylation end products (AGEs) of mainly glucose-protein interactions, which form chemically cross-linked molecules

• Rate of formation of AGEs is proportional to the blood glucose level.

• AGEs have been identified in hemoglobin, β-2 microglobulin, β-amyloid protein, collagen, and lens crystalline.

• Deposition of AGEs results in protein dysfunction and inflammation

Approximate mean plasma glucose at different HbA1C levels(MPG change of 35 mg/dl or 2 mmol/l per 1% change in HbA1c)

Approximate MPGHbA1Cmmol/l mg/dl

4 3.5 655 5.5 1006 7.5 1357 9.5 1708 11.5 2059 13.5 24010 15.5 27511 17.5 31012 19.5 345

Rohlfing et al. 2002. Diabetes Care 25:275

Glycated HemoglobinGlycated HemoglobinNot just a risk factor for a diabetic!Not just a risk factor for a diabetic!

EPIC-Norfolk Study (Ann Intern Med 2004;141:413)

HbA1C concentrations predict mortality continuously across the whole population distribution in people with or without diabetes.

Prediabetic Patients Show Increased Prediabetic Patients Show Increased CVD Mortality RiskCVD Mortality Risk

(Circulation 2007, 10:1161)

• In an Australian cohort study, 10,428 adults were examined at baseline and followed for a median of about 5 years.

• All-cause mortality was higher among those with known diabetes, impaired fasting glucose, or impaired glucose tolerance than among those with normal glucose tolerance.

• Cardiovascular mortality was increased among those with diabetes or impaired fasting glucose.

To reduce AGEs formation, one must

obtain the lowest HbA1c possible without hypoglycemia

• Caloric restriction• Low glycemic index food• Exercise• Metformin• Acarbose, Voglibose• PPARγ activator• ACEI• Telmisartan

Caloric Restriction Caloric Restriction (CR)(CR)

Limiting dietary energy imiting dietary energy

intake to retard agingintake to retard aging

•• In human subjects, CR has been shown to lower cholesterol, In human subjects, CR has been shown to lower cholesterol, fasting glucose, and blood pressure. fasting glucose, and blood pressure.

•• Energy intake is minimized, but sufficient quantities of Energy intake is minimized, but sufficient quantities of vitamins, minerals, and other important nutrients must be eaten vitamins, minerals, and other important nutrients must be eaten (caloric restriction with optimal/adequate nutrition (CRAN)(caloric restriction with optimal/adequate nutrition (CRAN) diet)diet)..

•• Except for houseflies, animal species tested with CR so far, Except for houseflies, animal species tested with CR so far, including primates, rats, mice, drosophila, and C. elegans, haveincluding primates, rats, mice, drosophila, and C. elegans, haveshown lifespan extension. shown lifespan extension.

Glycemic Index of Foods

Classification GI Range ExamplesHigh GI 70 or more White rice, sticky rice, white

bread, potato, watermelon, ice cream doughnut, popcorn,

Medium GI 56-69 Sucrose, soda pop, carrot, bran rice, pineapple, noodle, orange

Low GI 55 or less Banana, mango, apple, strawberry, vegetable, yogurt, milk, fructose, chestnut

Lower GI Diet: Three FactorsLower GI Diet: Three Factors

1. Type1. Type2. Amount2. Amount3. Vegetables and protein lower GI3. Vegetables and protein lower GI

Severely obese subjects with a high prevalence of diabetes or the metabolic syndrome lost more weight during six months on a carbohydrate-restricted diet than on a calorie- and fat-restricted diet, with a relative improvement in insulin sensitivity and triglyceride levels, even after adjustment for the amount of weight lost. (N Engl J Med 2003; 348: 2074)

Replace Higher GI Foods Replace Higher GI Foods with Lower GI Foodswith Lower GI Foods

Free Radical Free Radical Theory of AgingTheory of Aging

• Aging is the accumulation of deleterious changes produced by free radical reactions, most initiated by the mitochondria.

• Life span is determined by the rate of such damage to the mitochondria.

• Excess nourishment, combined with sedentary lifestyle, results in sugar and fat accumulation within muscle, adipose tissue, and pancreatic cells, and leads to the generation of excess reactive oxygen species.

Generation of reactive oxygen species (ROS)(Johansen et al. Cardiovascular Diabetology, 2005)

How to Reduce Oxidative StressHow to Reduce Oxidative Stress•• Caloric RestrictionCaloric Restriction•• Losing WeightLosing Weight

DietDietExerciseExercise

•• Antioxidants Antioxidants Beta-caroteneAstaxanthinVitamin EVitamin CCo-enzyme Q10Alpha-lipoic acidN-acetyl cysteineGlutathioneSeleniumResveratrol

Clinical trials of antioxidantsStudy Intervention Results

Beta-carotene Increased risk of ischemic heart disease

ATBC

HOPE Vitamin E Negative

Vitamin E Increased risk of hemorrhagic stroke

CARET Beta-carotene and vitamin A

Increased risk of cardiovascular disease

Physicians’ Health Study

Beta-carotene No effect

Women’s Health Study

Beta-carotene No effect

The Alpha-Tocopherol Beta Carotene Cancer Prevention

Study Group(N Engl J Med 1994;330:1029-1035)

• No reduction in the incidence of lung cancer among male smokers after five to eight years of supplementation with α-tocopherol or β-carotene.

• Higher incidence of lung cancer among the men who received β-carotene

Alpha-tocopherol

Beta-carotene

ARE YOU TAKING THE WRONG ARE YOU TAKING THE WRONG FORM OF VITAMIN E?FORM OF VITAMIN E?

There are 8 forms of vitamin Eα, β, δ, γ tocopherolsα, β, δ, γ tocotrienols

It is gammaIt is gamma-- not alphanot alpha-- Tocopherol!Tocopherol!

•• Low dose alphaLow dose alpha--tocopherol improves and high dose alphatocopherol improves and high dose alpha--tocopherol worsens endothelial vasodilator function in tocopherol worsens endothelial vasodilator function in cholesterolcholesterol--fed rabbits (fed rabbits (J Clin InvestJ Clin Invest 1994; 93: 844).1994; 93: 844).

•• Alpha tocopherol (regular vitamin E) displaces critically Alpha tocopherol (regular vitamin E) displaces critically important gamma tocopherol in the cells (important gamma tocopherol in the cells (J Natl Cancer InstJ Natl Cancer Inst. . 2000; 92:1966). 2000; 92:1966).

•• While alpha tocopherol inhibits freeWhile alpha tocopherol inhibits free--radical production, gamma radical production, gamma tocopherol is required to trap and neutralize existing free tocopherol is required to trap and neutralize existing free radicals (radicals (Proc Natl Acad Sci USAProc Natl Acad Sci USA 1997; 94: 3217).1997; 94: 3217).

Clinical trials of antioxidants

Study Intervention Results

ALADIN Study

Alpha-lipoic acid Improved symptoms and signs of diabetic neuropathy

Lyon Diet heart Study

Mediterranean-type diet

Reduced coronary events

AREDS Vitamin C, E, zinc, and β-carotene

Delayed age-related macular degeneration and visual loss

Steno-2 Study

Intensive therapy plus vitamin C, E, folic acid, and chromium

Reduced cardiovascular and microvascular incidence by 50 percent

Selenium Prevent lung, prostate, and colorectal cancer

AcetylAcetyl--LL--carnitine carnitine (ALCAR) and lipoic (ALCAR) and lipoic

acid supplementation acid supplementation improves metabolic improves metabolic function in oldfunction in old ratsrats

(PNAS 2002;99:1870)(PNAS 2002;99:1870)

Coenzyme Q10 (Ubiquinone)

• Antioxidant, part of electron transport chain in mitochondria.

• Improves cardiac functions in cardiomyopathy, ischemic heart disease, post-chemotherapy, and sport medicine (proc Natl Acad Sci USA 82:4240-4244).

• Neuroprotective effects in parkinsonism and stroke (Arch neurol 59: 1541-1550)

• Precursor of coenzyme Q10, mevalonate, is inhibited by statins (J Clin Pharmacol 3: 226-229)

Inflammatory Theory of Aging

• Pathology of many age-related diseases showed immune cells and expression of inflammatory markers.

• Increased inflammatory markers (hsCRP, homocysteine, Interleukin-1, TNF-alpha) expression are associated with the severities of many chronic diseases including atherosclerosis, diabetes, cancer

• Anti-inflammatory medicine shows reduction in the incidence of cancer and severities of diabetes.

How to Reduce Inflammation•• Caloric RestrictionCaloric Restriction•• Losing Body FATLosing Body FAT

Low glycemic index foodLow glycemic index foodExerciseExercise

•• Antioxidants Antioxidants • Avoid animal fat• Fish oil• Medicine

Low dose aspirinLowering cholesterol levelACEI, ARB

Molecular structure of fatty acid

Bad Fat are saturated fat, trans fat, cholesterol

Good Fat are unsaturated fat

Trans fat increases the risk of Trans fat increases the risk of coronary heart diseasecoronary heart disease

•• Occur in small quantities in meat and Occur in small quantities in meat and dairy products. dairy products.

•• Industrially created by partial Industrially created by partial hydrogenation of plant.hydrogenation of plant.

•• The process developed in the early The process developed in the early 1900s and first commercialized as 1900s and first commercialized as Crisco in 1911.Crisco in 1911.

•• Considered to be more of a health risk Considered to be more of a health risk than saturated fat.than saturated fat.

Sources of Trans Fat in the U.S. Diet

Okie S. N Engl J Med 2007;356:2017-2021

Ascherio A et al. N Engl J Med 1999;340:1994-1998

Results of Randomized Studies of the Effects of a Diet High in Trans Fatty Acids (Circles) or Saturated Fatty Acids (Squares) on the Ratio of LDL Cholesterol to HDL Cholesterol

http://upload.wikimedia.org/wikipedia/en/8/87/Nyc-trans-poster.gif

Dietary sources of polyunsaturated fatty acidsDietary sources of polyunsaturated fatty acidsOmega-6 fatty acids Food sources

LA, linoleic acid18:2ω6

Vegetable oils (corn, soybean), animal meats

AA, arachidonic acid20:4ω6

Animal sources (meat, eggs)

Omega-3 fatty acids Food sources

ALA, alpha-linolenic acid18:3ω3

Flaxseed, canola oil, walnuts

EPA, eicosapentaenoic acid20:5ω3

Marine sources, fish oils

DHA, docosahexaenoic acid22:6ω3

Marine sources, fish oils, egg, dairy products

Metabolic conversion of Metabolic conversion of omegaomega--3 fatty acid3 fatty acid

• DHA, the prominent structural fatty acid in the gray mater of the brain and in the retina, is an essential nutrient to provide for optimal neuronal and visual function.

• Metabolic conversion of ALA to DHA/EPA is very limited in humans.

• Infants consuming breast milk via supplementation of the mothers with 200 mg DHA had significantly higher outcomes on the psychomotor development index at 30 months of age.

Effects of EPA on the production of eicosanoids and inflammatory cytokines

DHA/EPA: Reduction in triglyceride level

DHA/EPA and Stroke

• Increasing fish consumption up to 5 servings or more per week was associated with an approximate overall 31% reduction in stroke mortality (Stroke 2004; 35: 1538).

• Consumption of boiled or baked fish was associated with a lower risk of ischemic stroke while the intake of fried fish or fish sandwiches was associated with a higher risk (Arch. Intern. Med 2005; 165: 683).

Cardiac mortality in relation to different treatments(Studer et al. Arch Intern med 2005;165:725)

American Heart Association officially recommended one fatty fish meal per day (DHA/EPA of 900 mg/day) in patients with coronary disease and two fish servings/ week (250-300 mg/day of DHA/EPA) for healthy individual (Circulation 2000;102:2284).

Omega-3 Fatty Acid Supplement

Label Size DHA EPA

Omex-3 500 mg 125 mg 25 mg

Blackmore 1000 mg 120 mg 180 mg

MorEPA 1000 mg 70 mg 581 mg

MorDHA 800 mg 465 mg 64 mg

Three Mystery Oil and Health

• Olive Oil• Rice Bran Oil • Evening Primrose Oil

Antiaging medicine is NOT about one medicine.

It is about EVERYTHINGIt is about EVERYTHING

Pathway to WellnessPathway to Wellness•• NutritionNutrition•• ExerciseExercise•• Smoking cessationSmoking cessation•• Stress ReductionStress Reduction•• Vitamin SupplementsVitamin Supplements•• Hormonal SupplementsHormonal Supplements•• Risk Factors IdentificationRisk Factors Identification•• MedicineMedicine