Primate epigenetic and senescence biomarkers to advance aging science and anti-aging strategies. - PROJECT SUMMARY A crisis for global healthcare systems is looming with an expanding aged population encumbered by numerous age-related chronic diseases, driving interest and investment in therapies that improve healthspan. Strong evidence now suggests that the aging process and age-related diseases are not separate entities and have biological processes in common, including epigenetic changes and accumulation of senescent cells. A major challenge in aging research is the development of biomarkers that can track the biological age of an individual and discriminate, at an early stage, those on different health trajectories. As humans share much greater biological similarity with nonhuman primates (NHPs) than rodents, this project is committed to the development of epigenetic and senescent biomarkers based on NHP tissues, to allow aging biology and anti-aging studies to be conducted before translation to human subjects. An important property of an aging biomarker is that is derived from accessible tissues to allow minimally invasive sampling and longitudinal assessments; blood and skin are ideal sources and are the focus of the present studies. Age-related changes in methylation of DNA at discrete sets of dinucleotide CpG sites can be quantified and yield a biomarker tool (an epigenetic “clock”) that correlates strongly with chronological age. Such clocks have been used to identify differences in biological aging that skew individuals’ expected epigenetic age from that predicted by their chronological age. Accelerated epigenetic aging is associated with many age-related diseases, and remarkably, predicts all-cause mortality risk, independent from chronological age, lifestyle habits, and morbidity. Recent applications of epigenetic clocks in rodent studies confirm that experimental manipulations that extend life slow the rate of epigenetic aging, a discovery indicating that clocks satisfy the elusive criteria of a molecular biomarker of aging, though rodent aging differs significantly from human demanding more translationally relevant studies. In addition, aging in many tissues is accompanied by the accumulation of “senescent” cells that have exited the normal cell cycle, expressing a characteristic pattern of proteins that provide convenient quantifiable markers that serve as an index of aging in proliferative tissues. Skin comprises the largest organ in the body and detrimental skin changes, among the most visible signs of aging, can mirror and model the impact of aging on internal organs. Intriguingly, senescent cells secrete factors that induce senescence in other nearby or distant cells, likely contributing to organismal aging. This proposal will harness the expertise and resources of the “Clock Foundation” (founded by Dr. Horvath and Robert Brooke) and Virscio’s extensive nonhuman primate research resources to optimize and validate epigenetic and senescent biomarkers in blood and skin. This research will lay the foundation for Virscio to commercialize the ability to quantify induced changes in aging in a clinically relevant species, to test both therapeutic and adverse effects, which is urgently needed to enable efficacy and safety testing of novel rejuvenating therapies emerging from the growing number of industry and academic partners addressing critical healthspan extension strategies.
