A Senescence-Centric View of Aging: Implications for Longevity and Disease

There is increasing evidence of the detrimental role of senescent cells in aging. Clearance of senescent cells has been shown to improve age-associated pathologies in animal models, leading to promising new clinical trials. Different mechanisms of senescent cells can be exploited pharmacologically to develop new therapeutic targets. 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. 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. diseases whose incidence increases with aging, most of them sharing an inflammatory pathogenesis and correlating with increased levels of cell senescence. molecular and cellular damage accumulation over time leading to a progressive decline in physical and mental capacity, and to an increased risk for disease and death. programmed and controlled cell death that regulates growth, development, tissue homeostasis, and tumor suppression. heterogeneous cell state in response to different stress stimuli, characterized by stable cell cycle arrest, as well as morphological, structural, and functional changes, including enhanced expression and secretion of proinflammatory mediators. clinical syndrome observed in older adults that predispose to poor health, onset and progression of diseases and decreased capacity to cope with cellular and tissue stress. conversion from reversible cell cycle arrest (quiescence) to irreversible cell cycle arrest (senescence). period of life where an individual has good health, free of disabilities and diseases. gradual age-associated functional decline of the immune system, especially of the adaptative immune system, that contributes to increased risk of morbidity and mortality. low-grade chronic inflammation, not induced by pathogens, causing higher risk of morbidity and mortality in elderly. measure of populations average survival time between birth and death. cellular senescence originated from dysfunctional mitochondria, likely as a result of the accumulation of ROS. regulated degradation of dysfunctional mitochondria by autophagy. cellular senescence originated in a non-cell autonomous manner via SASP factors secreted by neighboring senescent cells. syndrome or phenotype mimicking premature aging. robust and heterogeneous secretion of soluble modulators by senescent cells, including cytokines, chemokines, growth factors, proteases, and EVs. molecules and strategies that target cellular senescence, which can be classified as senolytics (selective elimination of senescent cells via programmed cell death) and senomorphics/senostatics (modulation of senescence-associated phenotypes without senolysis).