Fisetin Supplements Reverse Age-Related Muscle Decline as Effectively as Genetic Senescent Cell Clearance

Aging drives an accumulation of senescent cells in skeletal muscle that secretes pro-inflammatory factors (the senescence-associated secretory phenotype, SASP), contributing to muscle weakness and frailty. While pharmaceutical senolytics like dasatinib+quercetin or ABT-263 have shown promise, safe and broadly accessible alternatives are needed. Fisetin, a flavonoid found in strawberries and other foods, has emerged as a candidate natural senolytic, but its impact on skeletal muscle function had not been directly tested.

This study enrolled young (6–8 months) and old (27–29 months) male and female C57BL/6 mice across three parallel intervention arms: (1) oral intermittent fisetin (50 mg/kg/day), (2) genetic clearance of p16+ senescent cells via ganciclovir in p16-3MR transgenic mice, and (3) oral intermittent ABT-263 (50 mg/kg/day). All drug regimens used an intermittent schedule of 1 week on, 2 weeks off, 1 week on. Frailty was quantified with a validated 31-point index and forelimb grip strength was measured directly. Bulk RNA sequencing of quadriceps muscle was performed in the fisetin study to map transcriptomic changes.

Fisetin significantly reduced frailty scores and improved grip strength in old mice but had no detectable effect in young mice, consistent with a mechanism requiring excess senescent cell burden. RNA sequencing revealed that fisetin favorably remodeled the skeletal muscle transcriptome in old animals, most notably reducing expression of senescence-related genes Cdkn1a (p21) and Ddit4, and broadly suppressing cell cycle arrest and SASP-related pathways. These molecular findings align with a direct senolytic or senomorphic action in muscle tissue.

Comparison across the three intervention arms showed that fisetin's improvements in frailty and grip strength were statistically comparable to those achieved by precise genetic deletion of p16+ cells and by ABT-263 treatment. This equivalence is notable because genetic clearance is a highly targeted gold-standard approach, and ABT-263 is a potent BCL-2/BCL-XL inhibitor with known myelotoxicity concerns in humans. Fisetin's similar efficacy without apparent toxicity strengthens its translational case.

These preclinical findings provide proof-of-concept that intermittent fisetin supplementation can meaningfully reverse age-associated skeletal muscle dysfunction through reduction of cellular senescence, with a safety and accessibility profile well-suited for eventual human trials.