Linking social stress, senescence and aging

Chronic stress is a risk factor for several aging-related diseases and has been associated with accelerated aging. However, the underlying mechanisms are still unclear. A new study showing that social stress accelerates senescence in mice provides new clues on how stress during life might impact aging.

Cellular senescence is a fundamental aging process during which cells cease division and undergo several phenotypic changes. Several aging-related diseases, including those associated with chronic stress, have been linked to the accumulation of senescent cells, suggesting potential connections. To test the hypothesis that chronic stressors might induce cellular senescence, the researchers measured key senescence markers in male mice after exposing them to two different 4-week chronic stress paradigms: a psychosocial chronic subordination stress (CSS) model, in which mice are exposed daily to an aggressive, dominant mouse; and a psychological chronic restraint stress (CRS) model in which mice are restrained in conical tubes for 3h per day. The results show that CSS and CRS differentially increased the expression of senescence markers p16^Ink4a and p21^Cip1, two cyclin-dependent kinase inhibitors involved in cell cycle arrest. While CRS increased p21^Cip1 in the brain of mice and had no effect on p16^Ink4a expression, CSS caused an increase in p16^Ink4a expression in the brain and other organs, which was associated with an increase in the expression of p21^Cip1 and other senescence markers. p16^Ink4a-positive cells in the brains of CSS-exposed mice were primarily hippocampal and cortical neurons showing signs of DNA damage.

Altogether, this study shows that social and non-social stressors have different effects on mouse biology, with social stress having a more pronounced impact by inducing a p16^Ink4a-dependent accumulation of senescent cells in different organs. By revealing that chronic social stress induces cellular senescence, an established hallmark of aging, these findings could help protect against the adverse effects of life stress on the aging process.

Original reference: Lyons, C.E. et al. Nat. Aging https://doi.org/10.1038/s43587-024-00743-8 (2024)