Dietary fisetin does not improve physical function or muscle contractility in naturally aging female mice

Abstract Objectives Fisetin has shown promise as a potential antioxidant, anti-inflammatory, senolytic, and senomorphic agent. However, important research gaps remain, particularly concerning fisetin’s effects on physical function and muscle contractility. Therefore, this study aimed to explore the effect of fisetin in a preclinical model of aging. Methods Ninety-nine female C57BL/6 mice (19–26 months old) were randomly assigned to either a control group or a fisetin-supplemented chow (500 ppm) group for 12 weeks. Physical function was assessed by measuring walking speed, grip strength, distance to exhaustion, and voluntary activity both before and after supplementation. Ex vivo skeletal muscle contractility was evaluated in the soleus and extensor digitorum longus muscles following the intervention period. Mice were sub-analyzed by chronological and biological age to assess the effect of fisetin. Results Baseline physical function testing revealed functional decline with both increased chronological and biological age. Fisetin did not produce meaningful system-level benefits: there was no difference in survival between groups, and no improvements in endurance, strength, or most contractile outcomes when grouping mice by chronological or biological age. Conclusions Our results suggest that the skeletal muscle of naturally aging mice may not experience sufficient stress to measure an effect on survival, physical function, or muscle contractility with fisetin supplementation.