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

ABSTRACT Excess cellular senescence contributes to age‐related increases in frailty and reductions in skeletal muscle strength. In the present study, we determined the efficacy of oral intermittent treatment (1 week on—2 weeks off—1 week 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‐related 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‐established approaches for the removal of senescent cells: (1) genetic‐based clearance of excess senescent cells in old p16‐3MR mice, a model that allows for clearance of p16‐positive (p16+) senescent cells, and (2) oral intermittent treatment with the synthetic pharmacological senolytic ABT‐263 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‐related genes (e.g., Cdkn1a and Ddit4 ). Improvements in frailty and grip strength with fisetin were comparable to those observed with genetic‐based clearance of excess p16+ senescent cells and treatment with ABT‐263. Taken together, our findings provide proof‐of‐concept support for fisetin as a senolytic strategy to improve physical function with aging.