Abstract
Cellular senescence is a process that leads to a state of irreversible cell growth arrest induced by a variety of intrinsic and extrinsic stresses. Senescent cells (SnCs) accumulate with age and have been implicated in various age-related diseases in part via expressing the senescence-associated secretory phenotype. Elimination of SnCs has the potential to delay aging, treat age-related diseases and extend healthspan. However, once cells becoming senescent, they are more resistant to apoptotic stimuli. Senolytics can selectively eliminate SnCs by targeting the SnC anti-apoptotic pathways (SCAPs). They have been developed as a novel pharmacological strategy to treat various age-related diseases. However, the heterogeneity of the SnCs indicates that SnCs depend on different proteins or pathways for their survival. Thus, a better understanding of the underlying mechanisms for apoptotic resistance of SnCs will provide new molecular targets for the development of cell-specific or broad-spectrum therapeutics to clear SnCs. In this review, we discussed the latest research progresses and challenge in senolytic development, described the significance of regulation of senescence and apoptosis in aging, and systematically summarized the SCAPs involved in the apoptotic resistance in SnCs.
Highlights
Aging is a time-dependent functional decline that affects most living organisms
For Senescent cells (SnCs), apoptotic resistance can lead to abnormal accumulation, which is detrimental to the organism
It is encouraging to know that several senolytics have been approved for clinical trial and have shown beneficial effects (Niedernhofer and Robbins, 2018; Thoppil and Riabowol, 2019; Kirkland and Tchkonia, 2020)
Summary
Aging is a time-dependent functional decline that affects most living organisms. It is characterized by a progressive loss of physiological integrity, causing impaired function and increased vulnerability to death (López-Otín et al, 2013). A better understanding of the underlying mechanisms for apoptotic resistance of SnCs is likely to provide novel molecular targets for the development of therapeutic senolytics to combat aging and age-related diseases (Figure 1B).
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