Our approach also yielded the finding that senescent cells in tissues of aged mice are larger than nonsenescent cells. By utilizing technology that combines flow cytometry with high-content image analysis, we were able to quantify senescent cells in tumors, fibrotic tissues, and tissues of aged mice. The method combines a senescence-associated beta-galactosidase assay with staining of molecular markers for cellular senescence and of cellular identity. Here, we present a new way to precisely quantify and identify senescent cells in tissues on a single-cell basis. In vivo identification, quantification and characterization of senescent cells are challenging tasks that limit our understanding of the role of senescent cells in diseases and aging. Senescent cells are present in premalignant lesions and sites of tissue damage and accumulate in tissues with age. These findings define a novel pathway that regulates senescent cell viability and fibrosis. Notably, p21 knockout in mice eliminated liver senescent stellate cells and alleviated liver fibrosis and collagen production. NF-κB activation induced TNF-α secretion and JNK activation to mediate death of senescent cells in a caspase- and JNK-dependent manner. Upon p21 knockdown, senescent cells acquired multiple DNA lesions that activated ataxia telangiectasia mutated (ATM) and nuclear factor (NF)-κB kinase, leading to decreased cell survival. Here, we show that the CDK inhibitor p21 (CDKN1A) maintains the viability of DNA damage-induced senescent cells. A deeper understanding of the mechanisms regulating the viability of senescent cells is therefore required. However, accumulation of senescent cells in tissues during aging contributes to age-related pathologies. Our results implicate p53 in induction of club-cell senescence and correlate epithelial cell senescence of chronic airway inflammation and lung destruction.Ĭellular senescence is a permanent state of cell cycle arrest that protects the organism from tumorigenesis and regulates tissue integrity upon damage and during tissue remodeling. Furthermore, pharmacological elimination of senescent cells also protected wild-type mice from chronic LPS-induced bronchitis. Surprisingly, the club cell p53 knockout mice exhibited reduced airway senescence and bronchitis in response to chronic LPS exposure and were significantly protected from global lung destruction. To elucidate the function of airway epithelial p53 in such inflammation, we subjected genetically modified mice, whose bronchial epithelial club cells lack p53, to repetitive inhalations of lipopolysaccharide (LPS), an exposure that leads to severe chronic bronchitis and airway senescence in wild-type mice. Although p53 is known to limit inflammation during tumor development, its role in regulating chronic lung inflammation is less well understood. The tumor suppressor p53 limits tumorigenesis by inducing apoptosis, cell cycle arrest, and senescence. These data demonstrate that an aged, senescent immune system has a causal role in driving systemic ageing and therefore represents a key therapeutic target to extend healthy ageing. The treatment of Vav-iCre+/− Ercc1−/fl mice with rapamycin reduced markers of senescence in immune cells and improved immune function11,12. The transplantation of splenocytes from Vav-iCre+/− Ercc1−/fl or aged wild-type mice into young mice induced senescence in trans, whereas the transplantation of young immune cells attenuated senescence. Notably, non-lymphoid organs also showed increased senescence and damage, which suggests that senescent, aged immune cells can promote systemic ageing. We show that Vav-iCre+/− Ercc1−/fl mice were healthy into adulthood, then displayed premature onset of immunosenescence characterized by attrition and senescence of specific immune cell populations and impaired immune function, similar to changes that occur during ageing in wild-type mice8,9,10. To define the contribution of immune system ageing to organism ageing, here we selectively deleted Ercc1, which encodes a crucial DNA repair protein3,4, in mouse haematopoietic cells to increase the burden of endogenous DNA damage and thereby senescence5,6,7 in the immune system only. Ageing of the immune system, or immunosenescence, contributes to the morbidity and mortality of the elderly1,2.
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