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In the present study, we determined the efficacy of oral intermittent treatment (1\u2009week on\u20142\u2009weeks off\u20141\u2009week on) with the natural flavonoid senolytic fisetin to improve frailty and grip strength in old mice. Further, the effects of fisetin on physical function were evaluated in young mice. We performed bulk RNA sequencing of quadricep skeletal muscle to determine the cell senescence\u2010related signaling pathways modulated by fisetin. We also assessed the relative effects of fisetin on frailty and grip strength with aging in comparison with two other well\u2010established approaches for the removal of senescent cells: (1) genetic\u2010based clearance of excess senescent cells in old p16\u20103MR mice, a model that allows for clearance of p16\u2010positive (p16+) senescent cells, and (2) oral intermittent treatment with the synthetic pharmacological senolytic ABT\u2010263 in old mice. We found that fisetin mitigated the adverse changes in frailty and grip strength with aging. Fisetin had no effects in young mice. The improvements in frailty and grip strength in old mice were accompanied by favorable modulation of the skeletal muscle transcriptome, including lower abundance of cellular senescence\u2010related genes (e.g., <jats:italic>Cdkn1a<\/jats:italic> and <jats:italic>Ddit4<\/jats:italic>). Improvements in frailty and grip strength with fisetin were comparable to those observed with genetic\u2010based clearance of excess p16+ senescent cells and treatment with ABT\u2010263. Taken together, our findings provide proof\u2010of\u2010concept support for fisetin as a senolytic strategy to improve physical function with aging.<\/jats:p>","DOI":"10.1111\/acel.70114","type":"journal-article","created":{"date-parts":[[2025,5,29]],"date-time":"2025-05-29T00:00:28Z","timestamp":1748476828000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":21,"title":["Intermittent Supplementation With Fisetin Improves Physical Function and Decreases Cellular Senescence in Skeletal Muscle With Aging: A Comparison to Genetic Clearance of Senescent Cells and Synthetic Senolytic Approaches"],"prefix":"10.1111","volume":"24","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-1863-0708","authenticated-orcid":false,"given":"Kevin O.","family":"Murray","sequence":"first","affiliation":[{"name":"Department of Integrative Physiology University of Colorado Boulder  Boulder Colorado 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