Senescent cells: an emerging target for diseases of ageing

Abstract

Chronological age represents the single greatest risk factor for human disease. One plausible explanation for this correlation is that mechanisms that drive ageing might also promote age-related diseases. Cellular senescence, which is a permanent state of cell cycle arrest induced by cellular stress, has recently emerged as a fundamental ageing mechanism that also contributes to diseases of late life, including cancer, atherosclerosis and osteoarthritis. Therapeutic strategies that safely interfere with the detrimental effects of cellular senescence, such as the selective elimination of senescent cells (SNCs) or the disruption of the SNC secretome, are gaining significant attention, with several programmes now nearing human clinical studies.

Oxidation resistance 1 is a novel senolytic target

“…Resistance to apoptosis and oxidative stress is a hallmark of SCs (Childs, Baker, Kirkland, Campisi & Van Deursen, 2014; Childs et al., 2017) that can be exploited to develop senolytic agents that selectively kill SCs, assuming that the molecules that mediate the resistance can be identified. Indeed, we and others have recently discovered that the upregulation of the antiapoptotic Bcl‐2 family proteins is primarily responsible for the resistance of SCs to apoptosis, and Bcl‐2/xl/w inhibitors such as ABT‐263 are potent senolytic agents (Chang et al., 2016; Yosef et al., 2016; Zhu et al., 2016).…”

“…However, senescent cells (SCs) accumulate if they cannot be removed rapidly by the immune system due to immune dysfunction and/or a sustained, overwhelming increase in SC production. This occurs during aging or under certain pathological conditions (Childs et al., 2017; Muñoz‐Espín & Serrano, 2014). Under these circumstances, SCs can be detrimental and play a causal role in aging, age‐related diseases, and chemotherapy‐ and radiotherapy‐induced side effects, in part through the expression of the senescence‐associated secretory phenotype (Childs et al., 2017; Muñoz‐Espín & Serrano, 2014).…”

“…This occurs during aging or under certain pathological conditions (Childs et al., 2017; Muñoz‐Espín & Serrano, 2014). Under these circumstances, SCs can be detrimental and play a causal role in aging, age‐related diseases, and chemotherapy‐ and radiotherapy‐induced side effects, in part through the expression of the senescence‐associated secretory phenotype (Childs et al., 2017; Muñoz‐Espín & Serrano, 2014). This hypothesis is supported by recent studies demonstrating that the genetic clearance of SCs prolongs the lifespan of mice and delays the onset of several age‐related diseases and disorders in both progeroid and naturally aged mice (Baker et al., 2011, 2016).…”

“…Since the first senolytic was published (Zhu et al., 2015), twelve molecular targets have been identified (Childs et al., 2017), including the prosurvival Bcl‐2 family proteins (Chang et al., 2016; Yosef et al., 2016; Zhu et al., 2016) and forkhead Box O4 (FOXO4) (Baar et al., 2017). These findings led to the discovery of a few senolytic agents, including ABT‐263 and ABT‐737, two Bcl‐2/xl/w inhibitors, and FOXO4‐DRI, a peptide molecule that interferes with the interaction of FOXO4 and p53.…”

Social stress shortens lifespan in mice

“…Overall, data in human and animal models call attention to the urgent need to understand how different stressors accelerate and/or offset aging and associated chronic diseases (Childs et al., 2017; Gil & Withers, 2016; López‐Otín, Blasco, Partridge, Serrano & Kroemer, 2013). Nevertheless, in spite of available evidences on the mechanisms regulating aging and stress responses (Koolhaas et al., 2011; McEwen, 2007; Prather et al., 2015) and the profound effect of stress on pathophysiology (Bartolomucci, 2007; McEwen, 2007), this association is not mechanistically understood nor has its causation been explored in animal models thus far.…”