Chronic social stress induces p16-mediated senescent cell accumulation in mice

Life stress can shorten lifespan and increase risk for aging-related diseases, but the biology underlying this phenomenon remains unclear. Here we assessed the effect of chronic stress on cellular senescence-a hallmark of aging. Exposure to restraint stress, a psychological non-social stress model, increased p21^Cip1 exclusively in the brains of male, but not female mice, and in a p16^Ink4a-independent manner. Conversely, exposure to chronic subordination stress (only males were tested) increased key senescent cell markers in peripheral blood mononuclear cells, adipose tissue and brain, in a p16^Ink4a-dependent manner. p16^Ink4a-positive cells in the brain of chronic subordination stress-exposed mice were primarily hippocampal and cortical neurons with evidence of DNA damage that could be reduced by p16^Ink4a cell clearance. Clearance of p16^Ink4a-positive cells was not sufficient to ameliorate the adverse effects of social stress on measured metrics of healthspan. Overall, our findings indicate that social stress induces an organ-specific and p16^Ink4a-dependent accumulation of senescent cells, illuminating a fundamental way by which the social environment can contribute to aging.