Single cell analysis of senescent cells of old p16-FDR mice (lung)
Ontology highlight
ABSTRACT: We report the analysis of single cell based sequencing to understand the cellular and molecular heterogeneity of senescent cell populations in vivo in multiple organ types. The findings will help characterise the roles different cell types play during the aging process.
Project description:We report the analysis of single cell based sequencing to understand the cellular and molecular heterogeneity of senescent cell populations in vivo in multiple organ types. The findings will help characterise the roles different cell types play during the aging process.
Project description:We report the analysis of single cell based sequencing to understand the cellular and molecular heterogeneity of senescent cell populations in vivo in multiple organ types. The findings will help characterise the roles different cell types play during the aging process.
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.
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.
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.
Project description:We report the analysis of RNA sequencing aimed at understanding the effects induced by AU-15330 (SMARCA4 PROTAC)-mediated degradation of SMARCA4 in P53-deficient senescent ID8 ovarian tumour cells. Specifically, we focus on exploring the repercussions of inhibiting SMARCA4, a constituent of the SWI/SNF complex subunit, on the SASP and immune activity within cisplatin-treated senescent cancer cells. The findings will help characterise the role of SMARCA4 inhibition on senescence surveillance by Natural Killer cells.
Project description:We report the analysis of RNA sequencing aimed at understanding the effects induced by the knockdown of various target genes on senescent cells. These genes were initially identified through a genetic screening process designed to locate regulators responsible for upregulating SASP. Specifically, we focus on exploring the repercussions of SMARCA4 knockdown, a constituent of the SWI/SNF complex subunit, on the SASP and immune responses within senescent cells. The findings will help characterise the role of SMARCA4 inhibition on senescence surveillance by Natural Killer cells.