Why Senescent Cells Are Resistant to Apoptosis: An Insight for Senolytic Development

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.

Microgravity-induced stress mechanisms in human stem cell-derived cardiomyocytes

“…Interestingly, we identified by our Metascape analysis that 27 genes belonging to the p53 pathway and 8 genes belonging to TOR pathway whose expression was suppressed in SMG-CMs (see Table S3 and Table S7 A). Normally, these pathways are involved in cell death processes but senescent cells, in general, are resistant to apoptosis and cell death (for review see ( Hu et al., 2022 ). Therefore, we may speculate that the SMG-CMs suppressed genes associated with these pathways preventing senescent CMs from apoptosis and cell death.…”

Cellular senescence is a key mediator of lung aging and susceptibility to infection

“…When senescent cells fail to be detected and cleared, they begin to cause dysfunction. Senescent cells engage various pathways to enforce resistance to apoptosis via a variety of pathways as reviewed by others ( 7 ), collectively termed senescent cell anti-apoptotic pathways (SCAPs). Engagement of SCAPs furthers the accumulation of these cells, which can have deleterious effects on the microenvironments where senescent cells are found and beyond.…”

Development of Olaparib-Resistance Prostate Cancer Cell Lines to Identify Mechanisms Associated with Acquired Resistance

“…Interestingly, the chemical structure of the ROCKi hydroxyfasudil contains the benzamide pharmacophore of PARPi and inhibits the activity of PARP1 and PARP2 by 27% and 50%, respectively [ 51 ]. It is already known that senescent cells are resistant to apoptosis by decreasing the expression of pro-apoptotic proteins and increasing the expression of anti-apoptotic proteins [ 52 ]. We identified two pro-apoptotic genes, GRAMD4 and sirtuin-3 ( SIRT3 ), with decreased gene expression suggesting a possible negative regulation of apoptosis in the PC OR cell lines.…”