Social Stress, Senescence, and Resilience: Biological Mechanisms Linking Chronic Stress to Accelerated Aging and Functional Decline

Chronic exposure to social and psychological stressors accelerates biological aging and reduces resilience, contributing to declines in physical and cognitive function. Mounting evidence suggests that persistent exposure to social stressors drives DNA damage accumulation, leading to cellular senescence. Different chronic stressors will cause DNA damage in a manner that is cell and tissue specific, ultimately resulting in the accumulation of different types of senescent cells (SNCs). Due to both the homeostatic and detrimental effects that SNCs can have, global versus selective SNC clearance can have varying impacts on overall health depending on the SNC subtype and the organ in which the SNCs have accumulated. Strategies like SNC clearance offer promising therapeutic approaches, but ultimately the biological mechanisms linking chronic social stress to accelerated aging and the role of SNCs in declining healthspan and lifespan remain poorly defined. This study aims to address that by employing chronic social stress models in females, chronic social instability (CSI), and chronic subordination stress (CSS) in males of the p16-3MR mouse line. These models of stress induced cellular senescence enable clearance of p16Ink4a-positive SNCs, through ganciclovir (GCV) binding to a 3MR cassette. Previous studies have shown how social stress in the male model of chronic stress (CSS) robustly induces DNA damage and senescent cell accumulation in the brain, notably hippocampus and cortex, but similar studies are needed in female mice to determine if the outcomes are similar. Chronic stress in females increases the amount of p16Ink4a-positive cells in the peripheral blood mononuclear cells (PBMCs), as well as leads to an increase in DNA damage in the brain as represented by COMET assay. CSI also induces hyperphagia, coupled with resistance to body weight gain and losses in fat-mass as compared to unstressed controls. Ongoing experiments will determine the sources of endogenous DNA damage in chronic social stress from brains in CSS and CSI animals, through novel DNA adductomics approaches. Our findings suggest that chronic social stress plays a causal role in reducing healthspan and accelerating aging, likely through the buildup of DNA damage and senescent cells. Further work is needed to clarify the mechanisms through which stress impairs physiological function, potentially in sex-specific ways, and to identify strategies to reverse these effects. This abstract was presented at the American Physiology Summit 2026 and is only available in HTML format. There is no downloadable file or PDF version. The Physiology editorial board was not involved in the peer review process.