Cellular Senescence

Cellular senescence is a stress response that imposes an essentially irreversible proliferative arrest on cells while they remain metabolically active. ^{[1] [2]} It is imposed on proliferating cells in response to various stressors and cellular damage, serving as a defense that prevents the replication of damaged cells. ^{[2] [3]} Senescent cells are identified through hallmark features including stable cell-cycle arrest, apoptosis resistance, and biomarkers such as SA-beta-galactosidase, p16 and p21, although no single marker has high sensitivity and specificity. ^{[4] [5]}

Cellular metabolism plays a significant role in the regulation of various signaling processes involved in cell senescence, including the response to DNA damage. ^[6] Beyond exiting the cell cycle, senescent cells undergo phenotypic alterations including metabolic reprogramming, chromatin rearrangement and modulation of autophagy. ^[7] Senescent cells must survive in a nondividing state while protecting themselves from positive feedback loops linked to constant activation of the DNA damage response. ^[1] Mitochondrial dysfunction is a hallmark of senescence that participates in the growth arrest and figures prominently in feedback loops that induce and maintain the senescent phenotype. ^[8]

Cellular senescence is a hallmark of aging, and the steady accumulation of senescent cells in tissues with age has adverse consequences that contribute to aging-related diseases and morbidity. ^[9] Senescence plays a paradoxical, context-dependent role: acute induction protects against cancer and supports tissue remodeling and wound healing, whereas lingering senescent cells drive age-related disorders. ^{[10] [11]} In transgenic mouse models, genetic ablation of senescent cells has established a key role for these cells in driving aging and age-related disease. ^[9]

Targeting senescent cells to delay aging and limit dysfunction, an approach known as senotherapy, is being actively explored. ^{[11] [12]} Senotherapeutics fall into two main classes: senolytics that selectively eliminate senescent cells, and senomorphics that suppress the senescence-associated secretory phenotype and other markers of senescence. ^{[13] [9]} Based on preclinical studies and small clinical trials suggesting benefit, multiple clinical trials of senotherapeutics are under way, but their adaptability to human application has been questioned given the lack of fully specific senescence targeting and the physiological roles of senescence. ^{[9] [14]}