Abstract
Senescent cells with replicative arrest can be generated during genotoxic, oxidative, and oncogenic stress. Long-term retention of senescent cells in the body, which is attributed to highly expressed BCL-family proteins, chronically damages tissues mainly through a senescence-associated secretory phenotype (SASP). It has been documented that accumulation of senescent cells contributes to chronic diseases and aging-related diseases. Despite the fact that no unique marker is available to identify senescent cells, increased p16INK4a expression has long been used as an in vitro and in vivo marker of senescent cells. We reviewed five existing p16INK4a reporter mouse models to detect, isolate, and deplete senescent cells. Senescent cells express high levels of anti-apoptotic and pro-apoptotic genes compared to normal cells. Thus, disrupting the balance between anti-apoptotic and pro-apoptotic gene expression, such as ABT-263 and ABT-737, can activate the apoptotic signaling pathway and remove senescent cells. Mitochondrial abnormalities in senescent cells were also discussed, for example mitochondrial DNA mutation accumulation, dysfunctional mitophagy, and mitochondrial unfolded protein response (mtUPR). The mitochondrial-targeted tamoxifen, MitoTam, can efficiently remove senescent cells due to its inhibition of respiratory complex I and low expression of adenine nucleotide translocase-2 (ANT2) in senescent cells. Therefore, senescent cells can be removed by various strategies, which delays chronic and aging-related diseases and enhances lifespan and healthy conditions in the body.
Highlights
In the 1960s, Hayflick documented that normal human fibroblasts could not eternally grow, with irreversible cell cycle arrest occurring at a certain point, which is known as replicative senescence (Hayflick and Moorhead, 1961; Hayflick, 1965)
Application of recombinant plateletderived growth factor AA (PDGF-AA) onto a wound area promotes its recovery by inducing myofibroblast differentiation (Demaria et al, 2014). These results indicate that cellular senescence has some beneficial roles during tissue repair by secreting senescence-associated secretory phenotype (SASP) factors
The frequencies of tandem-dimer Tomato (tdTom)+ cells were increased with serial passage in cultured mouse embryonic fibroblasts (MEFs) from p16tdTom/+ mice in vitro. They used a peritoneal inflammation mice model to demonstrate that tdTom+ macrophages exhibited some features of senescence in vivo, which are reduced proliferation, SA-β-gal positive staining, and increased mRNA expression of a subset of transcripts encoding factors involved in SASP, such as MMP12 and Cxcl12 (Liu et al, 2019). These results indicate that cells harboring activation of the p16INK4a promoter accumulate with aging and inflammation in vivo, and display characteristics of senescence
Summary
In the 1960s, Hayflick documented that normal human fibroblasts could not eternally grow, with irreversible cell cycle arrest occurring at a certain point, which is known as replicative senescence (Hayflick and Moorhead, 1961; Hayflick, 1965). Several different methods have to be used to properly define senescent cells This includes: flattened and enlarged morphology (Munoz-Espin and Serrano, 2014; Simay et al, 2018); SA-β-gal positive staining (Dimri et al, 1995; Kurz et al, 2000); increased p16INK4a expression (Krishnamurthy et al, 2004; Ressler et al, 2006; Liu et al, 2009); DNA damage (Sedelnikova et al, 2004; d’Adda di Fagagna, 2008; Hewitt et al, 2012); and SASP-related factors (Coppé et al, 2010; Tchkonia et al, 2013; Hernandez-Segura et al, 2018).
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