Comparative analysis of senolytic drugs reveals mitochondrial determinants of efficacy and resistance
Open accessAbstract
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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- Authors
- Wakita, M., Ito, K., Fujii, K., Sakamoto, D., Mikawa, T., Sugawara, S., Zhou, X., Park, J. H., Miyagawa, H., Motooka, D., Ogasawara, E., Ishihara, N., Takahashi, A., Kondoh, H., & Hara, E.
- Affiliations
- Research Institute for Microbial Diseases, The University of Osaka (JP)
- Shiga University of Medical Science (JP)
- Kyoto University (JP)
- Japanese Foundation For Cancer Research (JP)
- The University of Osaka (JP)
- Center for Infectious Disease Education and Research, The University of Osaka (JP)
- Corresponding author
- Hara, Eiji
- ORCID
- Venue
- Nature Aging
- Published
- 2026-01-29
- Volume
- 6
- Issue
- 2
- Pages
- 316-328
- ISSN
- 2662-8465 (ISSN-L)
- PMC
- PMC12920139
- OpenAlex
- W7126117731
- Cited by
- 9
- References
- 65
- Citations by year
- 2026: 9
- FWCI
- 41.14
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Locations
- Nature Aging (publishedVersion, cc-by)
- PubMed (publishedVersion)
- PubMed Central (publishedVersion, cc-by)
- Funders
- Japan Agency for Medical Research and Development (JP25gm1710004h0004, JP24ama221114h0003, JP25zf0127008s0104, JP25gm1710013h0002)
- MEXT | Japan Science and Technology Agency (JPMJMS2022)
- MEXT | Japan Society for the Promotion of Science (JP25H00443, JP25K14865, JP25KJ1722)
- Ministry of Education, Culture, Sports, Science and Technology (JPMXP1323015484)
- Mitsubishi Foundation (202012016)
- The University of Osaka OU Master Plan Implementation Project
- Princess Takamatsu Cancer Research Fund
- Topics
- Health Sciences › Medicine › Physiology › Telomeres, Telomerase, and Senescence
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Aging › Genetics, Aging, and Longevity in Model Organisms
- Health Sciences › Medicine › Epidemiology › Autophagy in Disease and Therapy
- Keywords
- senolytics, cellular senescence, navitoclax, mitochondrial quality control, V-ATPase, mitochondrial clearance, mitochondrial stress, ketogenic diet, SGLT2 inhibition, metastasis, tumor growth, fibroblast senescence
- MeSH terms
- Senotherapeutics, Aniline Compounds, Animals, Drug Resistance, Fibroblasts, Humans, Mitochondria, Sulfonamides, Cellular Senescence, Mice, Quinazolinones, Diet, Ketogenic
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
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