2. Academic Validation
  3. Comparative analysis of senolytic drugs reveals mitochondrial determinants of efficacy and resistance

Comparative analysis of senolytic drugs reveals mitochondrial determinants of efficacy and resistance

  • Nat Aging. 2026 Feb;6(2):316-328. doi: 10.1038/s43587-025-01057-z.
Masahiro Wakita 1,  Koyu Ito 1 2,  Kaho Fujii 1,  Dai Sakamoto 1,  Takumi Mikawa 3,  Sho Sugawara 4,  Xiangyu Zhou 4,  Jeong Hoon Park 1,  Hideka Miyagawa 1,  Daisuke Motooka 1,  Emi Ogasawara 5,  Naotada Ishihara 5,  Akiko Takahashi 4 6,  Hiroshi Kondoh 3,  Eiji Hara 7 8 9
Affiliations

Affiliations

  • 1 Research Institute for Microbial Diseases (RIMD), The University of Osaka, Suita, Japan.
  • 2 Shiga University of Medical Science, Otsu, Japan.
  • 3 Graduate School of Medicine, Kyoto University, Kyoto, Japan.
  • 4 Cancer Institute, Japanese Foundation for Cancer Research, Tokyo, Japan.
  • 5 Graduate School of Science, The University of Osaka, Toyonaka, Japan.
  • 6 Graduate School of Pharmaceutical Sciences, The University of Tokyo, Tokyo, Japan.
  • 7 Research Institute for Microbial Diseases (RIMD), The University of Osaka, Suita, Japan. [email protected].
  • 8 Immunology Frontier Research Center, The University of Osaka, Suita, Japan. [email protected].
  • 9 Center for Infectious Diseases Education and Research, The University of Osaka, Suita, Japan. [email protected].
PMID: 41611832 DOI: 10.1038/s43587-025-01057-z
Abstract

Cellular senescence contributes to aging and disease, and senolytic drugs that selectively eliminate senescent cells hold therapeutic promise. Although over 20 candidates have been reported, their relative efficacies remain unclear. Here we systematically compared 21 senolytic agents using a senolytic specificity index, identifying the Bcl-2 Inhibitor ABT263 and the BET inhibitor ARV825 as most effective senolytics across fibroblast and epithelial senescence models. However, even upon extended treatment with these most potent senolytics, a proportion of senescent cells remained viable. We found that senolytic resistance was driven by maintenance of mitochondrial integrity through V-ATPase-mediated clearance of damaged mitochondria. Imposing mitochondrial stress via metabolic workload enhanced the senolytic efficacies of ABT263 and ARV825 in vitro, and in mouse models, ketogenic diet adoption or SGLT2 inhibition similarly potentiated ABT263-induced and ARV825-induced senolysis, reducing metastasis and tumor growth. These findings suggest that mitochondrial quality control is a key determinant of resistance to ABT263-induced and ARV825-induced senolysis, providing a possible framework for rational combination senotherapies.

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