FBS Colloquia No.422Laboratory of Cancer Biology

Overcoming Senolytic Drug Resistance in Senescent Cells through Mitochondrial Control


Cellular senescence is a stable state of cell-cycle arrest induced by potentially oncogenic stresses, including telomere erosion, oxidative stress, radiation, and oncogene activation. While senescence suppresses tumorigenesis by preventing the proliferation of damaged cells, senescent cells also exert detrimental effects through the secretion of pro-inflammatory factors collectively known as the senescence-associated secretory phenotype (SASP), thereby contributing to tissue dysfunction and age-related diseases. Consequently, senolytic drugs, which selectively eliminate senescent cells, have emerged as promising therapeutic agents for aging-associated diseases. However, despite the identification of more than 20 candidate senolytics, their relative efficacy, specificity, and mechanisms of resistance have not been systematically evaluated. Here, we quantitatively compared 21 senolytic agents and identified the Bcl-2 inhibitor ABT263 and the BET inhibitor ARV825 as the most potent and selective senolytics across fibroblast and epithelial models. Nevertheless, a subset of senescent cells survived prolonged treatment with these agents. We found that this resistance is mediated by V-ATPase-dependent mitochondrial quality control through the clearance of damaged mitochondria. Shifting cellular metabolism from glycolysis toward OXPHOS increased mitochondrial stress and markedly enhanced the senolytic activities of ABT263 and ARV825 both in vitro and in mouse models. Notably, metabolic interventions using a ketogenic diet or SGLT2 inhibitors similarly potentiated senolysis and suppressed tumour growth and metastasis. These findings identify mitochondrial quality control as a key determinant of senolytic resistance and suggest a promising strategy for metabolism-based combination senotherapies.