Molecular Networks in Aging and Caloric Restriction in Rhesus Monkeys

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SUMMARY Age is the greatest risk factor for a host of chronic diseases, including cancer, diabetes, cardiovascular disease and neurodegeneration. The mechanistic basis for this shared risk and its continued increase as a function of age is not well understood. Caloric restriction (CR) without malnutrition has been proven to delay aging in diverse species, and in mammals it delays the onset of numerous age-related diseases, increasing healthspan. The Aging and CR in Rhesus Monkeys study at the Wisconsin National Primate Research Center established the efficacy of CR in improving health and survival: CR monkeys live longer, have lower incidence of age-related diseases, are more active, and maintain better glucoregulatory health. Molecular profiling studies suggest that CR induces a major reprogramming of metabolism, with changes in key cellular homeostatic pathways coordinated across transcriptional, proteomic, and post-translation modification regulatory mechanisms. Our limited studies to date have identified novel aspects in CR's mechanisms including lipid metabolism and signaling, and the role of RNA-based regulatory mechanisms including transcript processing and coordination of the CR response through microRNA. The proposed studies have potential to uncover further regulatory mechanisms engaged during aging and CR at the tissue specific level, derive interaction networks within and among tissues to define the molecular details of how CR works, and relate these data to whole animal physiology, health, morbidity, and survival. This unique cohort of monkeys presents an unprecedented opportunity to advance our understanding of aging biology. Although the intervention of CR may not be a reasonable choice for clinical application, the proposed unbiased high-resolution studies are certain to reveal new insights into how aging itself might be targeted clinically. There are three Specific Aims: Aim 1. Determine shared and tissue-specific mechanisms engaged by CR. Aim 2. Determine the life stage-resolved systemic response to CR. Aim 3. Integrate the physiological, systemic, and molecular responses to CR. Our study is designed to define the integrated response to CR within and among tissues and at the whole organism level in primates, and to determine how these CR-engaged mechanisms might coordinate to confer enhanced longevity. Rhesus monkeys are a highly translational model for human aging, in particular with regards to the timing of onset of age-related diseases and disorders and the dynamics of functional decline. Our cohort is derived from a unique study of effective implementation of CR, with physiological data and specimens in hand, along with substantial longitudinal clinical data, health records, and end of life pathology. Integrative analysis of high-density molecular profiles within and among tissues will present a new perspective in aging biology at the systems level, and by linking to clinical outcomes will deliver translational insights for human aging.