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. 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 p21Cip1 exclusively in the brains of male, but not female mice, and in a p16Ink4a-independent manner. Conversely, exposure to chronic subordination stress (CSS; males only were tested) increased key senescent cell (SNC) markers in peripheral blood mononuclear cells, adipose tissue and brain, in a p16Ink4a-dependent manner. p16Ink4a-positive cells in the brain of CSS-exposed mice were primarily hippocampal and cortical neurons with evidence of DNA damage that could be reduced by p16Ink4a cell clearance. Clearance of p16Ink4a-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 p16Ink4a-dependent accumulation SNCs, illuminating a fundamental way by which the social environment can contribute to aging. Overall design: Brain sections from 4 control (ctrl), and 6 chronic social stress (CSS) exposed mice were prepared using the Nanostring GeoMx Digital Spatial Profiling with the mouse Whole Transcriptome Atlas. Matching areas of interest (AOIs) were selected from each sample in areas CA1 and CA3 of the hippocampus, the somatosensory cortex (SS), motor cortex (MC) and choroid plexus (CP).