Fisetin — Supplements
Flavonoid senolytic with strongest preclinical evidence among polyphenols for clearing senescent cells; 5 active Phase 2 human clinical trials as of 2025.
Overview
Fisetin (3,3',4',7-tetrahydroxyflavone) is a polyphenol flavonoid found in strawberries (the richest dietary source at ~160 mcg/g), apples, persimmons, grapes, onions, and cucumbers. It has emerged as the most potent senolytic flavonoid identified to date, as ranked in a landmark 2018 comparison of 10 flavonoids by the Mayo Clinic group. Senolytics are compounds that selectively eliminate senescent cells — cells that have permanently exited the cell cycle but remain metabolically active and secrete a pro-inflammatory SASP (Senescence-Associated Secretory Phenotype) that drives aging and age-related disease. In preclinical studies, intermittent fisetin treatment reduced senescent cell burden in fat, spleen, liver, kidney, and vasculature, and extended median and maximum lifespan in 24-month-old (equivalent to ~75 human years) mice. Frailty, grip strength, coordination, and tissue homeostasis were all improved. As of 2025, at least 5 active Phase 2 RCTs are recruiting or ongoing (NCT05595499, NCT05758246, NCT06133634, NCT06431932 and others) testing fisetin in breast cancer survivors, elderly sepsis, vascular aging, and frailty. Human pharmacokinetic data confirm measurable fisetin plasma concentrations at 20 mg/kg doses. No completed Phase 2 trial results are yet published as of 2025 — fisetin remains investigational in humans.
Indications
- Biological aging and senescent cell burden reduction (investigational)
- Frailty and physical function in older adults (active clinical trials)
- Vascular aging and endothelial function (investigational)
- Neuroprotection and cognitive aging (preclinical evidence)
- Post-chemotherapy recovery and survivorship (active trials)
Mechanism of Action
Fisetin inhibits pro-survival proteins BCL-2 and BCL-xL that senescent cells depend on for their resistance to apoptosis — reinstating programmed cell death selectively in senescent cells while sparing normal cells (which rely on different survival pathways)
Dosing
| Compound | Dose | Frequency | Notes |
|---|---|---|---|
| Fisetin (research protocol) | 20 mg/kg body weight | Two consecutive days per month | Research dose from Mayo Clinic-led trials; ~1,400 mg/day for 70 kg individual; human trials ongoing |
| Fisetin (supplement dose, low-dose exploratory) | 100–500 mg | Once daily | Commonly used OTC dose; much lower than research protocol; efficacy at this dose unestablished |
Evidence Grade
GRADE C
Safety & Contraindications
- No adverse effects reported in human trials to date (20 mg/kg doses in Phase 1/2 studies) — well tolerated
- Very low oral bioavailability (<10%) due to rapid intestinal metabolism — most plasma fisetin represents glucuronide metabolites; true active compound bioavailability uncertain
- CYP3A4 inhibitor in vitro — theoretical drug interactions at high systemic concentrations; clinical relevance unclear at supplement doses
- Intermittent ('pulse') dosing protocols used in trials — do not use continuously; typical research protocol: 2 consecutive days every 1-2 months (mimicking mouse studies)
- Caution in patients on anticoagulants — quercetin-related flavonoids can have anti-platelet effects
- Do not use in pregnancy or breastfeeding — no safety data
- Important caveat: efficacy in humans is unproven pending Phase 2 trial results; current human supplementation is evidence-anticipating, not evidence-confirmed