Fisetin as Senolytic Agent — Aging
Naturally occurring flavonoid with potent senolytic activity, clearing senescent cells in preclinical models; the AFFIRM trial is evaluating clinical efficacy in humans.
Overview
Fisetin (3,3',4',7-tetrahydroxyflavone) is a bioactive flavonoid found naturally in strawberries, apples, persimmons, onions, and cucumbers. It has emerged as one of the most potent naturally occurring senolytic compounds — agents that selectively induce apoptosis in senescent cells while sparing normal cells. Cellular senescence, the irreversible growth arrest accompanied by a pro-inflammatory secretory phenotype (SASP), accumulates with aging and drives age-related pathology including fibrosis, atherosclerosis, osteoarthritis, and neurodegeneration. In a landmark 2018 study published in EBioMedicine by the Mayo Clinic group, fisetin was identified as the most potent senolytic among 10 flavonoids tested, reducing senescent cell burden in aged mice and extending median and maximum lifespan by approximately 10%. Fisetin achieves senolysis primarily by inhibiting the anti-apoptotic BCL-2 family proteins (BCL-xL, BCL-2) that senescent cells depend on for survival, activating caspase-3-mediated apoptosis. It also suppresses the PI3K/AKT/mTOR survival pathway in senescent cells. The AFFIRM trial (Fisetin to Relieve Frailty, Inflammation, and Related Measures in Older Adults), a Phase 2 randomized controlled trial at the Mayo Clinic, is evaluating intermittent high-dose fisetin (20 mg/kg for 2 consecutive days per month) for its effects on frailty, inflammatory markers, and senescent cell burden. Results are anticipated and will be pivotal for clinical translation.
Indications
- Emerging evidence: Senolytic therapy — clearance of senescent cells
- Preclinical: Lifespan and healthspan extension in aged mice
- Under investigation: AFFIRM trial for frailty in older adults
- Preclinical: Reduction of SASP inflammatory markers
- Preclinical: Neuroprotective effects in Alzheimer disease models
- Preclinical: Attenuation of osteoarthritis and fibrotic disease
Mechanism of Action
Fisetin inhibits anti-apoptotic proteins BCL-xL and BCL-2 that senescent cells depend on for survival, disrupting their resistance to programmed cell death
Dosing
| Compound | Dose | Frequency | Notes |
|---|---|---|---|
| Fisetin | 100 mg | Once daily | Low dose for general flavonoid antioxidant support |
| Fisetin | 500 mg | Once daily for 2 consecutive days/month | Intermittent senolytic protocol — lower dose approach |
| Fisetin | 20 mg/kg (~1400 mg for 70 kg) | 2 consecutive days per month | AFFIRM trial protocol — intermittent high-dose senolytic |
Evidence Grade
GRADE C
Safety & Contraindications
- Generally well tolerated as a dietary flavonoid with long history of food consumption
- High-dose intermittent protocols (1-2 g/day for 2 days) tolerability data still emerging from AFFIRM trial
- Poor oral bioavailability (~5-10%) — high doses needed for systemic senolytic effects
- Potential CYP3A4 and CYP2C9 inhibition at high doses — monitor drug interactions
- Theoretical concern of excessive senescent cell clearance affecting tissue repair
- Avoid in pregnancy; insufficient safety data for chronic high-dose use