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

ABSTRACT: 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.

ORGANISM(S): Mus musculus

PROVIDER: GSE278620 | GEO | 2024/10/02

REPOSITORIES: GEO

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Project description:Chronic psychosocial and metabolic stressors disrupt affective state and drive frequently co-morbid mood and cardio-metabolic disorders. However, central mechanisms underlying dysregulation of mood and metabolic homeostasis await definition. Behavioural and transcriptome-wide influences of chronic social and metabolic stresses were explored (testing for shared and unique mechanistic themes in male C57Bl/6 mice subjected to: chronic social stress (CSS) - social isolation for 7 wks + twice daily social confrontation in final 20 days; type 2 diabetes (T2D) - 75 mg.kg-1 streptozotocin/21 wk high-fat diet (43.2% kcal as fat); or control conditions. Frontal cortex (FC) was profiled via RNAseq (Illumina NovaSeq 6000 Sequencing System, 2x107 paired-end reads/sample). CSS induced anxiety-like behaviour together with anhedonia (reduced sucrose preference), in association with relative weight loss. T2D mice exhibited anxiety-like behaviour (reduced locomotion and thigmotaxis in open field) in association with modest (+20-30%) weight gain and hyperglycaemia, and 65-80% elevations in fasting insulin and insulin-resistance (HOMA-IR). The FC transcriptome was particularly sensitive to CSS, with 640 (316 down/324 up) differentially expressed genes (DEGs) from 15,097 detected (FDR<0.05, P<0.001). Gene-set enrichment analysis (GSEA) identified 222 Biological Processes and 25 Reactome Pathways sensitive to CSS. Most significant themes centred upon up-regulation of: growth/remodelling (axonogenesis, epithelial growth/morphogenesis, angiogenesis, cell junction, synapse and ECM organisation, brain/limb/heart/gland/eye development), Ras signalling and growth factor response genes; and down-regulation of: ATP metabolism, mitochondrial and RNA processing pathways. In contrast, the FC transcriptome was relatively insensitive to metabolic stress, however 107 DEGs (71 down/36 up) and 187 Biological Processes/5 Reactome Pathways were identified using less conservative criteria (FDR<0.10, un-corrected P<0.01). Despite little to no overlap in individual genes, GSEA indicates ~25% of pathway responses are shared, including organ development/morphogenesis (though not ATP metabolism/mitochondrial) processes. In summary, FC appears particularly responsive to social rather than metabolic stress, characterised by repression of mitochondrial metabolism together with adaptive induction of nerve growth/development. Shared anxiogenesis may involve disturbed neurogenesis/neuroplasticity, with depressive outcomes reflecting additional mitochondrial dysfunction.

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

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