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

Nat Aging. 2025 Jan;5(1):48-64. doi: 10.1038/s43587-024-00743-8. Epub 2024 Nov 11.

Abstract

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 p21Cip1 exclusively in the brains of male, but not female mice, and in a p16Ink4a-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 p16Ink4a-dependent manner. p16Ink4a-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 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 of senescent cells, illuminating a fundamental way by which the social environment can contribute to aging.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Biomarkers
  • Brain / metabolism
  • Cellular Senescence*
  • Cyclin-Dependent Kinase Inhibitor p16* / genetics
  • Cyclin-Dependent Kinase Inhibitor p16* / metabolism
  • DNA Damage
  • Female
  • Male
  • Mice
  • Mice, Transgenic
  • Neurons / metabolism
  • Sex Characteristics
  • Stress, Psychological* / genetics
  • Stress, Psychological* / metabolism

Substances

  • Cyclin-Dependent Kinase Inhibitor p16
  • Cdkn2a protein, mouse
  • Biomarkers