Development and comparison of multi-tissue and liver-specific epigenetic clock models to measure variation in biological aging in the rhesus macaque.

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PROJECT SUMMARY While life expectancy in the United States has risen dramatically over the past several decades, the number of years spent free of major disease and disability (healthspan) has remained relatively unchanged. This is a major public health concern. Health disparities among same-aged individuals reflect variation in the pace of age-related deterioration and decline (biological aging) that is not captured by a fixed metric like chronological age. Chronological age is a relatively strong but highly limited predictor of disease and mortality risk because, unlike biological age, it cannot account for environmentally-driven variation in the pace of aging. Recently developed epigenetic clock models in humans and mice predict chronological age with very high accuracy and are able to identify individuals who deviate from the expected pace of aging. This ability to quantify biological age and determine under which conditions biological age exceeds chronological age (age acceleration) can help deconstruct the complex, multifaceted nature of the aging process. However, it remains difficult to determine how specific environmental factors impact the progression of aging in humans due to inherent lack of control over the highly variable environment. Coupled with the controlled environments in which macaque research colonies are maintained, their close evolutionary relationship to humans makes macaques an ideal biomedical model for addressing gaps in our understanding of biological aging. Studies in both model and non-model organisms suggest that dysregulation of metabolic processes is a central theme in the aging process. Hence, here we propose the development of an epigenetic clock specific for liver in rhesus macaques that will enable us to investigate the relationship between environmental factors (e.g., diet), biological aging, and age-related diseases. The proposed research will develop a liver-specific epigenetic clock model for rhesus macaques (Sub-Aim 1A) and characterize age-related differential methylation and gene expression in the liver (Sub-Aim 1B). In addition, we will leverage these data and comparable datasets that we have collected from brain (hippocampus) and blood to generate a multi-tissue clock for rhesus macaques. Because nutrition is one of the most powerful environmental determinants of health over the long lifespan typical of humans and other primate species, we will test the plasticity of our clocks using studies of long-term calorie restriction and Western-style (obesogenic) diet to determine whether such dietary modifications engender a detectable change in the pace of biological aging (Sub-Aim 2A).To complement this approach, we will also use patterns of differential methylation and gene expression between the two extreme diets and controls to identify which metabolic pathways are disrupted by these interventions (Sub-Aim 2B). The long- term goal of this research is to provide a biomedical research tool that enables more rigorous assessment of the efficacy of therapeutic interventions that aim to slow, or even reverse, the aging process.