Primary aging is the progressive deterioration in structure and function with advancing age that occurs independently of disease and lifestyle/environmental factors. Slowing of primary aging results in an increase in maximal life span. Caloric restriction (CR) slows primary aging in various short-lived organisms, such as guppies, flies, mice and rats. It is not known if CR slows primary aging in humans. Secondary aging is due to disease processes and harmful life-style/environmental factors. Protection against secondary aging results in rectangularization of the mortality curve without an extension of maximal life span. Available evidence suggests that CR protects against some aspects of secondary aging in primates. In contrast to CR, an exercise-induced, caloric deficit does not slow primary aging in rats, suggesting that the effect of CR on primary aging is mediated by decreased intake and metabolism of food rather than by decreased energy availability. In this context, the specific aims of Phase 1 of this study are: 1) To determine the feasibility of achieving prolonged 20% restriction of energy intake or prolonged 20% increase of energy expenditure by exercise, in overweight, 50-60 yr old women and men and refine the techniques needed to achieve adherence to the CR and exercise protocols. The efficaciousness of two approaches will be evaluated for CR (meal plans versus meal replacement) and for exercise (supervised versus independent exercise programs); and 2) To evaluate and compare the effects of 12 mo of the CR and exercise interventions on a number of potential markers of aging, on body composition and on risk factors for CAD and type 2 diabetes. In Phase 1, volunteers will be randomized to one of five groups: 2 CR groups, 2 exercise groups and one control group. There will be 16 participants per intervention group (i.e. 32 CR, 32 exercise) and 20 in the control, no intervention, group. We anticipate a drop out rate of approximately 25% based on previous experience. Our goal is to have at least 12 women and 12 men complete 1 yr of CR, and 12 women and 12 men complete 1 yr of exercise in Phase 1. The information obtained from the first 2 yrs, Phase 1, of this research, will be used in the planning and design of Phase 2. It should be possible to more accurately estimate the number of participants per group in Phase 2 based on our experience in Phase 1. In Phase 2, there will be 3 groups of healthy, overweight men and women aged 50-60 yr: CR, exercise and control. The CR and exercise protocols will be designed on the basis of our experience, and that of the other investigators, in Phase 1. In Phase 2, the duration of the CR and exercise interventions will be two years.

National Institute of Health (NIH)
National Institute on Aging (NIA)
Research Project--Cooperative Agreements (U01)
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Special Emphasis Panel (ZRG1-GRM (04))
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Romashkan, Sergei
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Washington University
Internal Medicine/Medicine
Schools of Medicine
Saint Louis
United States
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Das, Sai Krupa; Roberts, Susan B; Bhapkar, Manjushri V et al. (2017) Body-composition changes in the Comprehensive Assessment of Long-term Effects of Reducing Intake of Energy (CALERIE)-2 study: a 2-y randomized controlled trial of calorie restriction in nonobese humans. Am J Clin Nutr 105:913-927
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Meydani, Simin N; Das, Sai K; Pieper, Carl F et al. (2016) Long-term moderate calorie restriction inhibits inflammation without impairing cell-mediated immunity: a randomized controlled trial in non-obese humans. Aging (Albany NY) 8:1416-31
Romashkan, Sergei V; Das, Sai Krupa; Villareal, Dennis T et al. (2016) Safety of two-year caloric restriction in non-obese healthy individuals. Oncotarget 7:19124-33
Martin, Corby K; Bhapkar, Manju; Pittas, Anastassios G et al. (2016) Effect of Calorie Restriction on Mood, Quality of Life, Sleep, and Sexual Function in Healthy Nonobese Adults: The CALERIE 2 Randomized Clinical Trial. JAMA Intern Med 176:743-52
Fontana, Luigi; Villareal, Dennis T; Das, Sai K et al. (2016) Effects of 2-year calorie restriction on circulating levels of IGF-1, IGF-binding proteins and cortisol in nonobese men and women: a randomized clinical trial. Aging Cell 15:22-7
Villareal, Dennis T; Fontana, Luigi; Das, Sai Krupa et al. (2016) Effect of Two-Year Caloric Restriction on Bone Metabolism and Bone Mineral Density in Non-Obese Younger Adults: A Randomized Clinical Trial. J Bone Miner Res 31:40-51
Rochon, James; Bhapkar, Manjushri; Pieper, Carl F et al. (2016) Application of the Marginal Structural Model to Account for Suboptimal Adherence in a Randomized Controlled Trial. Contemp Clin Trials Commun 4:222-228
Sanghvi, Arjun; Redman, Leanne M; Martin, Corby K et al. (2015) Validation of an inexpensive and accurate mathematical method to measure long-term changes in free-living energy intake. Am J Clin Nutr 102:353-8

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