Chronic social stress induces p16-mediated senescent cell accumulation in mice
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PROVIDER: PRJNA1168108 | ENA |
REPOSITORIES: ENA
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Project description: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.
2024-10-02 | GSE278620 | GEO
Project description:The accumulation of senescent cells promotes aging, but a molecular mechanism that senescent cells use to evade immune clearance and accumulate remains to be elucidated. Here, we report that p16-positive senescent cells upregulate the immune checkpoint protein programmed death-ligand 1 (PD-L1) to accumulate in aging and chronic inflammation. p16-mediated inhibition of CDK4/6 promotes PD-L1 stability in senescent cells via the downregulation of ubiquitin-dependent degradation. p16 expression in infiltrating macrophages induces an immunosuppressive environment that can contribute to an increased burden of senescent cells. Treatment with immunostimulatory anti-PD-L1 antibody enhances the cytotoxic T cell activity and leads to the elimination of p16, PD-L1-positive cells. Our study uncovers a molecular mechanism of p16-dependent regulation of PD-L1 protein stability in senescent cells and reveals the potential of PD-L1 as a target for treating senescence-mediated age-associated diseases.
2024-02-14 | GSE225286 | GEO
Project description:The accumulation of senescent cells promotes aging, but a molecular mechanism that senescent cells use to evade immune clearance and accumulate remains to be elucidated. Here, we report that p16-positive senescent cells upregulate the immune checkpoint protein programmed death-ligand 1 (PD-L1) to accumulate in aging and chronic inflammation. p16-mediated inhibition of CDK4/6 promotes PD-L1 stability in senescent cells via the downregulation of ubiquitin-dependent degradation. p16 expression in infiltrating macrophages induces an immunosuppressive environment that can contribute to an increased burden of senescent cells. Treatment with immunostimulatory anti-PD-L1 antibody enhances the cytotoxic T cell activity and leads to the elimination of p16, PD-L1-positive cells. Our study uncovers a molecular mechanism of p16-dependent regulation of PD-L1 protein stability in senescent cells and reveals the potential of PD-L1 as a target for treating senescence-mediated age-associated diseases.
2024-02-14 | GSE225285 | GEO
Project description:Transcriptional profiling of p16-induced senescent human diploid fibroblasts compared with proliferating cells. TIG-3 ER-p16 cells (primary normal human diploid fibroblasts expressing a 4-hydroxytamoxifen(4-OHT) regulatable form of human p16) were cultured for 7 days with or without 4-OHT. Total RNA was isolated using TRIzol reagent and were analyzed using the hum
2014-04-10 | E-GEOD-49863 | biostudies-arrayexpress
Project description:Senescent cells are in a state of permanent cell cycle arrest, which is mediated by the Cyclin Dependent Kinase (CDK)4/6 inhibitor p16. During ageing, p16-expressing (P16pos) cells accumulate in tissues and promote multiple age-related pathologies, including neurodegenerative diseases. We evaluated the accumulation and the phenotype of senescent cells in the aged brain with a transgenic reporter mouse (p16-3MR), which allows for isolation of P16poscells. First, we showed that the number of P16pos cells is significantly increased in old brains. Second, using bulk RNAseq, we demonstrated that P16pos cells express high levels of inflammatory and lysosomal genes. Third, using single-cell RNAseq, we identified P16pos brain cells as being primarily microglia. Interestingly, the transcriptional profile of P16pos microglia cells is distinct from cell type signatures associated with senescence or defined microglia populations. Taken together, our study provides evidence for the accumulation of a novel P16pos microglia population in the aging brain, which could result in loss of tissue homeostasis and contribute to brain dysfunction.
2021-10-14 | GSE151459 | GEO
Project description:Transcriptional profiling of p16-induced senescent human diploid fibroblasts compared with proliferating cells.
2014-04-10 | GSE49863 | GEO
Project description:Senescence is a cellular state linked to aging and age-onset disease across many mammalian species. Acutely, senescent cells promote wound healing and prevent tumor formation; but they are also pro-inflammatory, thus chronically exacerbate tissue decline. While senescent cells are active targets for anti-aging therapy, why these cells form in vivo, how they affect tissue aging, and the impact of their elimination remain unclear. Here we identify naturally-occurring senescent glia in aged Drosophila brains and decipher their origin and influence. Using AP1 activity to screen for senescence, we determine that senescent glia can appear in response to neuronal mitochondrial dysfunction. In turn, senescent glia promote lipid accumulation in non-senescent glia; similar effects are seen in senescent human fibroblasts in culture. Targeting AP1 activity in senescent glia mitigates senescence biomarkers, extends fly life and health span, and prevents lipid accumulation. However, these benefits come at the cost of increased oxidative damage in the brain, and neuronal mitochondrial function remains poor. Altogether, our results map the trajectory of naturally-occurring senescent glia in vivo and indicate that these cells link key aging phenomena: mitochondrial dysfunction and lipid accumulation.
2024-05-24 | GSE263928 | GEO
Project description:p16-dependent upregulation of PD-L1 impairs immunosurveillance of senescent cells
| PRJNA934895 | ENA
Project description:Senescence is a cellular state linked to aging and age-onset disease across many mammalian species. Acutely, senescent cells promote wound healing and prevent tumor formation; but they are also pro-inflammatory, thus chronically exacerbate tissue decline. While senescent cells are active targets for anti-aging therapy, why these cells form in vivo, how they affect tissue aging, and the impact of their elimination remain unclear. Here we identify naturally-occurring senescent glia in aged Drosophila brains and decipher their origin and influence. Using AP1 activity to screen for senescence, we determine that senescent glia can appear in response to neuronal mitochondrial dysfunction. In turn, senescent glia promote lipid accumulation in non-senescent glia; similar effects are seen in senescent human fibroblasts in culture. Targeting AP1 activity in senescent glia mitigates senescence biomarkers, extends fly life and health span, and prevents lipid accumulation. However, these benefits come at the cost of increased oxidative damage in the brain, and neuronal mitochondrial function remains poor. Altogether, our results map the trajectory of naturally-occurring senescent glia in vivo and indicate that these cells link key aging phenomena: mitochondrial dysfunction and lipid accumulation.
2024-05-24 | GSE263929 | GEO
Project description:The goal of this study is to identify the senescent cells expressing high level of p16Ink4a (p16Ink4a Hi) in GBMs and characterize their action on the tumor microenvironment at an early timepoint. We introduced the p16-3MR transgene in the GBM mouse model to selectively delete p16Ink4a Hi senescent cells upon ganciclovir (GCV) injection. We compared p16-3MR+GCV to WT+GCV control GBMs that were harvested 7 days after the last GCV injection.
2022-12-15 | GSE198439 | GEO