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Cellular senescence is a state of stable cell cycle arrest associated with macromolecular alterations and secretion of proinflammatory cytokines and molecules. From their initial discovery in the 1960s, senescent cells have been hypothesized as potential contributors to the age-associated loss of regenerative potential. Here, we discuss recent evidence that implicates cellular senescence as a central regulatory mechanism of the aging process. We provide a comprehensive overview of age-associated pathologies in which cellular senescence has been implicated. We describe mechanisms by which senescent cells drive aging and diseases, and we discuss updates on exploiting these mechanisms as therapeutic targets. Finally, we critically analyze the use of senotherapeutics and their translation to the clinic, highlighting limitations and suggesting ideas for future applications and developments.

Cells expressing high levels of the cyclin‐dependent kinase (CDK)4/6 inhibitor p16 (p16High) accumulate in aging tissues and promote multiple age‐related pathologies, including neurodegeneration. Here, we show that the number of p16High cells is significantly increased in the central nervous system (CNS) of 2‐year‐old mice. Bulk RNAseq indicated that genes expressed by p16High cells were associated with inflammation and phagocytosis. Single‐cell RNAseq of brain cells indicated p16High cells were primarily microglia, and their accumulation was confirmed in brains of aged humans. Interestingly, we identified two distinct subpopulations of p16High microglia in the mouse brain, with one being age‐associated and one present in young animals. Both p16High clusters significantly differed from previously described disease‐associated microglia and expressed only a partial senescence signature. Taken together, our study provides evidence for the existence of two p16‐expressing microglia populations, one accumulating with age and another already present in youth that could positively and negatively contribute to brain homeostasis, function, and disease., P16+ microglia increases in aging brains of mice and humans. P16+ cells are found in 597 different microglia populations, including two previously unknown clusters.

Multiple sclerosis (MS) is a chronic and often progressive, demyelinating disease of the central nervous system (CNS) white and gray matter and the single most common cause of disability in young adults. Age is one of the factors most strongly influencing the course of progression in MS. One of the hallmarks of aging is cellular senescence. The elimination of senescent cells with senolytics has very recently been shown to delay age-related dysfunction in animal models for other neurological diseases. In this review, the possible link between cellular senescence and the progression of MS is discussed, and the potential use of senolytics as a treatment for progressive MS is explored. Currently, there is no cure for MS and there are limited treatment options to slow the progression of MS. Current treatment is based on immunomodulatory approaches. Various cell types present in the CNS can become senescent and thus potentially contribute to MS disease progression. We propose that, after cellular senescence has indeed been shown to be directly implicated in disease progression, administration of senolytics should be tested as a potential therapeutic approach for the treatment of progressive MS.