Caloric Restriction and Longevity Lisa Cui Tin Wing

Caloric Restriction and Longevity Lisa Cui, Tin Wing (Faneu) Liu, Ayumi Tsurushita November 8, 2011

Outline Introduction Mouse studies of caloric restriction Human studies of caloric restriction Cautions of caloric restriction Conclusion

Introduction Caloric restriction (CR)– generally defined as 2040 % of ad libitum consumption with adequate nutrients First study on mice was done in the 1930 s by Mc. Cay et al Showed an increase in mean and maximal lifespan Other proposed benefits: Decreased CVD risk, later onset of chronic disease, decreased oxidative damage

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

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 defenses Oxidative 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

Rodent Study by Sohal et al. Study Design 59 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, O 2 and H 2 O 2 production in the brain, heart, and kidney.

Rodent Study by Sohal et al. Results: CR rats exhibited a 43% extension in average life span Mitochondrial oxidants production increases with age = biomarkers of aging Protein Oxidative Damage is associated with aging process CR lessens the damage

Rodents Study by Masoro et al. Effect of CR on Age-associated Diseases Male ad lib. Rats and CR rats (60% intake) Common problem with increasing age in male mice: Chronic Nephropathy Ad lib. –fed rats had more kidney lesions DR rats were much older at the time of death than the ad. lib-rats Decrease the contribution of pituitary adenoma to death

Rodents Studies by Masoro et al. § The reduction of dietary energy intake but NOT a specific dietary component is responsible for the antiageing action of CR.

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

Human Studies Pub. Med Biosphere 2 CALERIE studies Epidemiological Study of population in Okinawa

Biosphere 2 Completely closed, selfsustaining 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

Biosphere 2 Study design: Diet: low-calorie (1750– 2100 kcal/d) vegetables, fruits, nuts, grains, and legumes, with small amounts of dairy, eggs, and meat 12% calories from protein, 11% from fat, and 77% from complex carbohydrates daily vitamin and multivitamin supplements. Blood samples were drawn from the eight crew members to monitor biological markers.

Biosphere 2 Results: 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

Biosphere 2 Strength of the study: Length (2 years) Subjects were human Calorie closely monitored, and caloric restriction maintained Weakness of the study: Small sample size No control group Other confounding variables such as the daily physical exercise

CALERIE Study 1 Effect 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)

CALERIE Study Result: reduced weight, fat mass, fasting serum insulin levels, and core body temperature in caloric restriction groups calorie restriction results in a decline in DNA damage No strong evidence for reduced oxidative damage

CALERIE Study Calorie 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

Result: improves CHD risk profile loss of 10% of body weight. reduced triacylglycerol reduced LDL-C favorable changes in blood pressure

CALERIE study Improvements 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/m 2 ) 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

Result: improves glucose tolerance Insulin sensitivity

Summary of Human Studies reduced weight, fat mass, fasting serum insulin levels, and core body temperature in caloric restriction groups calorie restriction results in a decline in DNA damage No strong evidence for reduced oxidative damage improves CHD risk profile (TG, LDL-C, BP) loss of 10% of body weight. improves glucose tolerance Insulin sensitivity

Epidemiological study of the Okinawa population Life expectancy 86. 0 years for Okinawan women 77. 6 years for Okinawan men Caloric restriction due to traditional 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 1960 s

Epidemiological study of the Okinawa population Low incidence of CHD Lymphoma, 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

Cautions Regarding Calorie Restriction Bone Loss and Bone Fracture Decreased Aerobic Capacity Changes in immune function Menopause and low estrogen cause bone loss…but usually it’s much slower and less severe

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

Reduction in Bone Mineral Density Washington 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

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 VO 2 max, whereas a similar 1 -yr energy deficit induced by exercise completely preserves thigh muscle mass and strength and improves VO 2 max.

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

Conclusion There 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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