Quantifying the genomic consequences of chronic social stress for accelerated aging

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PROJECT SUMMARY People that experience chronic exposure to unresolved social stress, including that induced by low socioeconomic status or social isolation, exhibit increased risk of immune dysregulation, major diseases of aging, and mortality itself. These observations have led to the hypothesis that social stress accelerates the process of aging by altering some of same biological pathways that are also changed with age. Support for this idea has come from a small number of well-characterized markers of inflammation and cellular senescence (e.g., IL-6 levels, CRP levels, and shortened leukocyte telomeres). However, we know much less about how changes in gene regulation link experienced social stress to biological aging, in part because identifying the causal effects of social stress on gene regulation remains a major challenge. Recent work in nonhuman primate animal models has helped overcome this challenge by showing a direct causal relationship between chronic social stress and gene expression in immune cells. The goal of the proposed research is to build on these models to address three outstanding questions about the relationship between social stress and aging. First, does chronic, social subordination-induced social stress cause accelerated aging in immune gene expression patterns, such that low status animals exhibit expression patterns typical of older individuals? Second, is the relationship between the gene regulatory signature of social stress and the gene regulatory signature of aging exacerbated by environmental challenge with aging-relevant environmental stimuli? Third, does social stress induce increased cell-to-cell variance in gene expression levels, either at baseline or in an immune challenged state, consistent with recently reported increased variance during aging? To address these questions, the proposed study will take advantage of a powerful model for studying the causal effects of social status: experimental manipulation of dominance rank in adult female rhesus macaques, where earlier introduction into newly formed social groups predicts higher social status. It will draw on both cross- sectional and longitudinal samples from 50 animals in 10 social groups, allowing us to ask whether the alleviation of social stress also alters gene expression signatures of aging. Together, the proposed analysis will provide valuable insight into whether, when, and to what degree social stress recapitulates, and potentially accelerates, aging at the gene regulatory level. Notably, rhesus macaques are not only excellent translational models for human social stress, but also the most intensively studied primate model for environmental effects on human aging. The results of this project will therefore have direct translational value for understanding the risks that chronic social stress pose to healthy aging, including environmental factors that exacerbate or ameliorate these risks.