Senescent cells are more susceptible to reductive stress-induced cell death: implications for senolytic research.
Proliferating cells can enter an irreversible state of cell-cycle arrest known as cellular senescence. The accumulation of senescent cells contributes to organismal ageing and age-related pathologies. Consequently, therapeutic strategies have emerged to selectively eliminate senescent cells (senolytics). Our previous work suggested that senescent mouse myoblasts are more susceptible to reductive stress-induced cell death than proliferating cells. Here, we replicated these findings in human LHCN-M2 myoblasts, demonstrating a biphasic dose-response relationship with cell death, wherein low concentrations were associated with reduced cell death in both proliferating and senescent cells, whereas higher concentrations selectively induced cytotoxicity in senescent cells. We propose that many identified natural senolytic compounds may exert their in vitro activity, at least in part, through the induction of reductive stress due to their antioxidant properties. These findings have important implications for understanding senolytic mechanisms and guiding the future development of senescence-targeting therapies.