Dietary restriction (DR) is a major paradigm in gerontology because only DR strikingly retards the rate of aging in rodents. Whether DR retards aging in primates is unknown. This Program Project seeks to expand our group's adult-onset DR study (R01 AG7831-04) of rhesus monkeys. We hypothesize that DR influences aging processes in a primate species like it does in rodents and that this influence is reflected by an altered rate of change of certain measurable physiologic parameters of aging, and, eventually, by longevity. We, therefore, focus on two major and linked gerontologic topics which comprise the P01's two Specific Aims. The first is to contribute to the development of the rhesus monkeys as a model for the study of aging. The goal is to improve understanding of aging in this species and to develop more precise ways to monitor the aging rate using """"""""biomarkers of aging"""""""" evaluated longitudinally. We propose to study longitudinally three Cohorts of DR and Control rhesus monkeys. Cohort 1: the monkeys now under study (n=14/group, males). We will add Cohort 2: n=15/group, 8-14 yr old females to be followed as per Cohort 1, and Cohort 3: n=8/group, 8-14 yr old males also undergoing biopsy of liver, spleen and skeletal muscle to allow comparison of DR's influences in tissues well studied in rodents on DR. These Cohorts will be allow us to address the second aim which concerns determining the influence of DR on the rate of aging in a primate species. Our proposal is structurally simple but has highly interdependent components. The three projects depend entirely on the core and are linked by a common theme of energy metabolism and balance because the magnitude of DR's effects in rodents is related strongly to energy intake. We hypothesize that adjustments of energy and free radical metabolism are major mechanisms in DR's ability to retard aging in rodents and are involved in such actions in monkeys. Project 1 (""""""""The Mitochondrion: DNA Integrity and Enzyme Activities"""""""") assess the influence of DR and aging on mitochondrial function and DNA integrity (deletions, oxidized bases). Project 2 (""""""""Energy Balance and Insulin Sensitivity"""""""") examines the impact of aging and DR on energy metabolism and glucose utilization. Project 3 (""""""""IL-6 Dysregulation and Aging') investigate this cytokine because elevations with age may be causally involved in some major late-life diseases and physiologic changes. IL-6 may influence free radical metabolism. These three projects reflect an active effort to utilize the outstanding Primate Center to address a question at the heart of biogerontology.
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