Molecular Networks in Aging and Caloric Restriction in Rhesus Monkeys

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.

Grant Number: 5R01AG074503-05
NIH Institute/Center: NIH
Principal Investigator: Rozalyn Anderson