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Exploratory Studies of Caloric Restriction in Non-Obese Persons Primary Sponsor: National Institute on Aging Deadline: 1/12/2001; 4/25/2001 KEYWORDS (RFA-AG-01-001) Complete Title: EXPLORATORY STUDIES OF SUSTAINED CALORIC RESTRICTION IN NON-OBESE PERSONS: PHYSIOLOGIC EFFECTS AND COMPARISONS/INTERACTIONS WITH PHYSICAL ACTIVITY National Institute on Aging Letter of Intent Receipt Date: January 12, 2001 Application Receipt Date: April 25, 2001 PURPOSE The National Institute on Aging (NIA) invites applications for cooperative agreements (U01s) for exploratory controlled human intervention studies on the effects of caloric restriction (CR) interventions on physiology, body composition, and risk factors for age-related pathologies in non-obese persons. Applications are also invited for studies of similarities, differences and/or potential interactions between the effects of CR and of physical activity (PA) on these outcomes. Studies in young adults and/or middle-aged persons up to age 60 may be proposed. Subject populations of interest are overweight persons (Body Mass Index of 25.0-29.9), other individuals at high risk for becoming overweight or obese, and formerly obese persons at risk for recurrence of obesity. Proposals for studies of interventions in persons currently obese will be considered non- responsive to this Request for Applications (RFA). The use of reliable techniques for tracking caloric intake and expenditure (especially doubly-labeled water techniques), and level of physical activity are considered essential features of these exploratory studies. The results from these studies will be valuable in guiding the design of possible subsequent studies or clinical trials to determine the long-term effects of CR and PA on the development of age-related pathologies. HEALTHY PEOPLE 2010 The Public Health Service (PHS) is committed to achieving the health promotion and disease prevention objectives of "Healthy People 2010," a PHS-led national activity for setting priority areas. This Request for Applications (RFA), "Sustained Caloric Restriction in Non-Obese Persons: Physiologic Effects and Comparisons/Interactions with Physical Activity", is related to one or more of the priority areas. Potential applicants may obtain a copy of "Healthy People 2010" at www.health.gov/healthypeople/. ELIGIBILITY REQUIREMENTS Applications may be submitted by domestic and foreign for-profit and non-profit organizations, public and private, such as universities, colleges, hospitals, laboratories, units of state and local governments, and eligible agencies of the Federal government. Racial/ethnic minority individuals, women, and persons with disabilities are encouraged to apply as principal investigators. MECHANISM OF SUPPORT This RFA will use the cooperative agreement (U01) mechanism. The cooperative agreement is an assistance mechanism in which substantial involvement of the NIA with the recipient is anticipated during the performance of the planned activity. The nature of the NIA's involvement is described under Terms and Conditions of Award. Responsibility for the planning, direction, and execution of the proposed project will be solely that of the applicant/awardee. The total project period for an application submitted in response to the present RFA may not exceed seven years. The anticipated award date is September, 2001. This RFA is a one-time solicitation. Future unsolicited competing continuation applications will compete with all investigator-initiated applications and be reviewed according to the customary peer review procedures. Applicants from institutions that have a General Clinical Research Center (GCRC) funded by the NIH National Center for Research Resources may wish to identify the GCRC as a resource for conducting the proposed research. If so, a letter of agreement from either the GCRC program director or principal investigator should be included with the application. FUNDS AVAILABLE For the initial year of funding, the amount of funds available to support projects submitted in response to this RFA is approximately $2,500,000, plus funds for the purchase of doubly labeled water (see "Research Goals and Scope" section). Total funding for the second year of awards will be at approximately the same level. Depending on the requirements for Phase 2 of funded projects (see "Special Requirements" section), a larger amount may be available for years 3-7 of the project period. It is anticipated that 2-4 awards will be made. However, awards will be contingent upon availability of funds and the receipt of a sufficient number of applications of outstanding scientific and technical merit. The number and size of awards made, may vary given the potential variation in the nature and scope of the research projects submitted in response to this RFA. RESEARCH OBJECTIVES Background Numerous studies in laboratory animals have shown that chronic caloric restriction (CR), i.e., limiting caloric intake below ad libitum levels, extends maximum and average life span by as much as 40% and delays age-related pathologies correspondingly. CR increases life span whether initiated in early adult life or middle age, but its effects diminish with increasing age of onset of CR. The amount of life span extension increases with the degree of caloric restriction (up to approximately 40% restriction; substantial effects have occurred with 20% restriction. Among the aging changes slowed by these regimens are declines in glucose tolerance and insulin sensitivity, and increases in body weight. (These regimens do not produce sustained weight loss: After transient weight loss, weight either remains stable or increases more slowly than in controls.) Chronic CR in nonhuman primates has been found to produce parallel physiologic changes to those seen in rodents. Studies of its effects on nonhuman primate life span have not been completed. An important question is whether these effects on life span and development of age-related pathologies can be explained by CR's effects on weight, body composition, or physical activity. CR prevents most or all of the weight gain and increase in fat mass over adult life in laboratory rodents, and increases spontaneous physical activity. Though the issue is not fully resolved, experimental animal data indicate that these factors may not fully explain CR's effect on longevity and age- related pathologies. Much of the evidence supporting this inference comes from studies of effects of chronic exercise in experimental animals. In studies in which chronic exercise affected body weight and body fat comparably to CR, it had significantly less effect on mean life span. In particular, though both interventions increased mean life span in the animals studied, only CR consistently increased maximum life span. These findings have raised the possibility that either CR may have some beneficial effect on aging processes, not mediated by body weight, that exercise may lack, or that exercise may have some adverse effect that counteracts some of the benefits it may share with CR. The implications of these findings regarding effects of voluntary CR on life span and development of age-related diseases in humans are unknown. There are essentially no data from epidemiologic studies on the relationship of caloric intake or voluntary caloric restraint over the life span to these outcomes. Human weight-loss intervention studies (primarily in obese or overweight persons) have included regimens for sustained reduction of caloric intake, but the duration of interventions has been at most only a few years. In most of these studies, the interventions have combined CR with other interventions such as physical activity. In addition, caloric intake of individuals in these studies (as well as in epidemiologic studies) cannot be estimated well because of limitations in the accuracy of self-reported data on food intake. As a result of these factors, a clear determination of the effects of sustained caloric restriction per se on life span, development of age-related pathologies, or on risk factors for these pathologies, is not possible from existing data. Hence, it is also not possible to draw firm conclusions from existing data about similarities, differences, or interactions between sustained CR and PA in their effects on these outcomes in humans. In March 1999, the NIA and NIDDK (National Institute on Diabetes Digestive Diseases and Kidney) co-sponsored the Caloric Restriction Clinical Implications Advisory Group. The Advisory Group reviewed data and made recommendations for epidemiologic, experimental therapeutic, mechanistic, and human intervention studies relating to the relationships of caloric intake, energy balance, and weight gain over the lifespan with longevity and morbidity. The proceedings from this Advisory Group meeting will be published in the Journals of Gerontology: Series A Biological and Medical Sciences, with an anticipated publication date in late 2000. Notice of publication will be posted on the NIA Website at www.nih.gov/nia/news/. The Advisory Group recommended studies of human CR interventions in non-obese persons lasting for at least two years, to determine effects on a variety of physiologic and psychological factors and disease risk factors. The Advisory Group noted that an effective initial target range for weight reduction in CR interventions in non-obese persons could be tentatively set at 15-20% of initial body weight, and also noted that several caloric restriction studies at different levels of dietary restriction will be needed to assess the potential benefits and disadvantages of CR in human populations. The Advisory Group also recommended studies comparing effects of chronic exercise with those of CR, and interactions between the effects of exercise and CR. This Request for Applications solicits projects that will address these topics. INQUIRIES Inquiries concerning this RFA are encouraged. The opportunity to clarify any issues or questions from potential applicants is welcome. Direct inquiries regarding programmatic issues to: Chhanda Dutta, Ph.D. Director, Musculoskeletal Research and Nutrition, Metabolism and Gastroenterology Research Geriatrics Program National Institute on Aging 7201 Wisconsin Avenue, Suite 3E-327 MSC 9205 Bethesda, MD 20892-9205 Telephone: (301) 435-3048 FAX: (301) 402-1784 Email: cd23z@nih.gov Direct inquiries regarding fiscal matters to: Ms. Cynthia Riddick Grants and Contracts Management Office National Institute on Aging Gateway Building, Suite 2N212 7201 Wisconsin Avenue, MSC 9205 Bethesda, MD 20892-9205 Telephone: (301) 496-1472 FAX: (301) 402-3672 Email: riddickc@exmur.nia.nih.gov