Caloric Restriction and Longevity
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Transcript of Caloric Restriction and Longevity
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Caloric Restriction and LongevityLisa Cui, Tin Wing (Faneu) Liu, Ayumi Tsurushita November 8, 2011
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OutlineIntroduction
Mouse studies of caloric restriction
Human studies of caloric restriction
Cautions of caloric restriction
Conclusion
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IntroductionCaloric restriction (CR)– generally defined as 20-40 % of ad libitum consumption with adequate nutrients
First study on mice was done in the 1930s by McCay et al
Showed an increase in mean and maximal lifespan
Other proposed benefits:Decreased CVD risk, later onset of chronic disease, decreased oxidative damage
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Hypothesis of the Mechanism of CR
Decreased energy expenditure
Decreased body weight
Decreased oxidative stress/free radicals
Hormesis - low levels of stress have positive, potentially life- extending effects
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Rodents Study by Sohal et al.
Oxidative Damage during aging and in response to food restriction in the mouse
Oxidative Damage:Inherent inadequacy of antioxidant defensesOxidative stress: imbalance between oxidant fluxes and antioxidant defenses
Aim: to test the relevance and validity of oxidative stress hypothesis of aging in life span extension by CR
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Rodent Study by Sohal et al.
Study Design59 mice aged 9, 16 or 23 months
Ad libitum (AL) fed mice and CR (40% lower in calories) fed mice
Obtaining data of reduced protein oxidation, O2- and H2O2 production in the brain, heart, and kidney.
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Rodent Study by Sohal et al.
Results:CR rats exhibited a 43% extension in average life spanMitochondrial oxidants production increases with age = biomarkers of agingProtein Oxidative Damage is associated with aging processCR lessens the damage
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Rodents Study by Masoro et al.
Effect of CR on Age-associated DiseasesMale ad lib. Rats and CR rats (60% intake)Common problem with increasing age in male mice: Chronic NephropathyAd lib. –fed rats had more kidney lesions DR rats were much older at the time of death than the ad. lib-ratsDecrease the contribution of pituitary adenoma to death
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Rodents Studies by Masoro et al. The reduction of dietary energy intake but NOT a
specific dietary component is responsible for the anti-ageing action of CR.
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Summary of results of rodent studies
Increase in mean and maximal lifespan
Decrease in oxidative damage
Later onset of kidney disease
Photo Credit rats image by Olga Barbakadze from Fotolia.com
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Human StudiesPubMed
Biosphere 2
CALERIE studies
Epidemiological Study of population in Okinawa
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Biosphere 2Completely closed, self-sustaining ecological system
Subjects: Four women and four men from the ages 27 to 42 years, and one aged 67 years
Biosphere 2 in Oracle, Arizona
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Biosphere 2Study design:
Diet: low-calorie (1750–2100 kcal/d) vegetables, fruits, nuts, grains, and legumes, with small amounts of dairy, eggs, and meat12% calories from protein, 11% from fat, and 77% from complex carbohydratesdaily vitamin and multivitamin supplements.
Blood samples were drawn from the eight crew members to monitor biological markers.
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Biosphere 2Results:
Decrease in BMI of the men decreased by 19%, and the BMI of the women by 13%. Decrease in fasting blood sugar decreased by 21%Decrease in fasting insulin by 42%Decrease in cholesterol by 30%.Decline in LDL:HDL rati
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Biosphere 2Strength of the study:
Length (2 years)Subjects were humanCalorie closely monitored, and caloric restriction maintained
Weakness of the study:Small sample sizeNo control group Other confounding variables such as the daily physical exercise
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CALERIE Study 1Effect of 6-Month Calorie Restriction on Biomarkers of Longevity, Metabolic Adaptation, and Oxidative Stress in Overweight Individuals
6 months of calorie restriction
Randomized controlled trial of healthy, sedentary men and women (N=48)
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CALERIE StudyResult:
reduced weight, fat mass, fasting serum insulin levels, and core body temperature in caloric restriction groupscalorie restriction results in a decline in DNA damageNo strong evidence for reduced oxidative damage
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CALERIE StudyCalorie restriction or exercise: effects on coronaryheart disease risk factors. A randomized, controlledtrial
Length: 1-yr
Randomized, controlled trial in middle- aged lean and overweight men and women
Group 1: 20% increase in energy expenditure alone
Group 2: 20% decrease in energy intake alone on metabolic risk factor
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Result:improves CHD risk profile loss of 10% of body weight.reduced triacylglycerolreduced LDL-Cfavorable changes in blood pressure
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CALERIE studyImprovements in glucose tolerance and insulin action induced by increasing energy expenditure or decreasing energy intake: a randomized controlled trial
Sedentary men and women aged 50 – 60 y with a body mass index (kg/m2 ) of 23.5–29.9 were randomly assigned to 1 of 2 weight- loss interventions [12 mo of exercise training (EX group; n = 18) or calorie restriction (CR group; n =18)] or to a healthy lifestyle (HL) control group (n =10).
decrease calorie intake by 16% during the first 3 mo and by 20% during the remaining 9 mo.
improves glucose tolerance and insulin action
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Result:improves glucose toleranceInsulin sensitivity
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Summary of Human Studies
reduced weight, fat mass, fasting serum insulin levels, and core body temperature in caloric restriction groupscalorie restriction results in a decline in DNA damageNo strong evidence for reduced oxidative damageimproves CHD risk profile (TG, LDL-C, BP)loss of 10% of body weight.improves glucose toleranceInsulin sensitivity
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Epidemiological study of the Okinawa population
Life expectancy86.0 years for Okinawan women77.6 years for Okinawan men
Caloric restriction due totraditional Okinawa diet is low in calories but nutritionally dense a result of periodic crop failures and marginal food supply that occurred post WWII until the 1960s
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Epidemiological study of the Okinawa population
Low incidence ofCHDLymphoma, prostate cancer, breast cancer, and colon cancer are remarkably low in age-matched Okinawans versus other Japanese and Americans
life-long low BMI
extended mean and maximum life span
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Cautions Regarding Calorie Restriction
Bone Loss and Bone Fracture
Decreased Aerobic Capacity
Changes in immune function
Menopause and low estrogen can cause bone loss…but usually it’s much slower and less severe
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CR Induces Bone Loss and Bone Fracture?
Pennington Comprehensive Assessment of Long-Term Effects of Reducing Intake of Energy (CALERIE) Research Team
Subject: young, overweight individuals
Duration: 6 month
Result: 2 of the 3 biomarkers for longevity—fasting insulin concentrations and core body temperature—were reduced with CR
Possible mechanism: significant reductions in fasting concentrations triiodothyronine and leptin
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Reduction in Bone Mineral DensityWashington CALERIE Study
Subject: middle-aged, non-obese adults aged 50 through 60
Duration: 12 months
Results: reduction in bone mineral density (BMD) (approximately 1.5% overall) at the lumbar spine, total hip, femoral neck, and intertrochater was correlated to weight loss in the CR group
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Decreased Aerobic Capacity
Washington University School of Medicine CALERIE
Subject: Healthy 50 to 60 year old nonobese men and women
Duration: 12 months of CR
Results: significant reductions in absolute thigh muscle mass, knee flexor strength, and VO2 max, whereas a similar 1-yr energy deficit induced by exercise completely preserves thigh muscle mass and strength and improves VO2 max.
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Don’t Like Bone Loss and Decreased Aerobic Capacity?
Changes in bone mass and/or turnover are less pronounced when the same energy deficit is achieved by combining CR with structured aerobic exercise
Aerobic classes (step dancing)
Treadmills
Exercise bicycles
Ski machines
Air gliders
Jogging
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ConclusionThere are both benefits and cautions to prolonged caloric restriction
CR may be improved if combined with exercise
Long term studies are necessary to assess relationship between caloric restriction and aging
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ReferenceHeilbronn, L. K., de Jonge, L., Frisard, M. I., DeLany, J. P., Larson-Meyer, D. E., Rood, J., et al. (2006). Effect of 6-month calorie restriction on biomarkers of longevity, metabolic adaptation, and oxidative stress in overweight individuals: A randomized controlled trial. JAMA : The Journal of the American Medical Association, 295(13), 1539-1548.
Lefevre, M., Redman, L. M., Heilbronn, L. K., Smith, J. V., Martin, C. K., Rood, J. C., et al. (2009). Caloric restriction alone and with exercise improves CVD risk in healthy non-obese individuals. Atherosclerosis, 203(1), 206-213.
Masoro, E. J. (1995). McCay's hypothesis: Undernutrition and longevity. The Proceedings of the Nutrition Society, 54(3), 657-664.
Sohal, R. S.; Ku, H. H.; Agarwal, S.; Forster, M. J.; Lal, H. Oxidative damage, mitochondrial oxidant generation and anti- oxidant defense during aging and in response to food restriction in the mouse. Mech. Ageing Dev. 74:121-133; 1994.
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ReferenceTrepanowski, J. F., Canale, R. E., Marshall, K. E., Kabir, M. M., & Bloomer, R. J. (2011). Impact of caloric and dietary restriction regimens on markers of health and longevity in humans and animals: A summary of available findings. Nutrition Journal, 10, 107.
Villareal, D. T., Fontana, L., Weiss, E. P., Racette, S. B., Steger-May, K., Schechtman, K. B., et al. (2006). Bone mineral density response to caloric restriction-induced weight loss or exercise-induced weight loss: A randomized controlled trial. Archives of Internal Medicine, 166(22), 2502-2510.
Walford, R. L., Mock, D., Verdery, R., & MacCallum, T. (2002). Calorie restriction in biosphere 2: Alterations in physiologic, hematologic, hormonal, and biochemical parameters in humans restricted for a 2-year period. The Journals of Gerontology.Series A, Biological Sciences and Medical Sciences, 57(6), B211-24.
Weiss, E. P., Racette, S. B., Villareal, D. T., Fontana, L., Steger-May, K., Schechtman, K. B., et al. (2007). Lower extremity muscle size and strength and aerobic capacity decrease with caloric restriction but not with exercise-induced weight loss. Journal of Applied Physiology (Bethesda, Md.: 1985), 102(2), 634-640.
Willcox, B. J., Willcox, D. C., Todoriki, H., Fujiyoshi, A., Yano, K., He, Q., et al. (2007). Caloric restriction, the traditional okinawan diet, and healthy aging: The diet of the world's longest-lived people and its potential impact on morbidity and life span. Annals of the New York Academy of Sciences, 1114, 434-455.