Fisetin — The Senolytic Flavonoid
Fisetin is a flavonoid found in strawberries, apples, and persimmons. It is one of the most potent natural senolytics — compounds that selectively clear senescent ('zombie') cells that accumulate with age and drive chronic inflammation.
Mechanism of Action
Fisetin activates apoptosis in senescent cells via the PI3K/Akt pathway while sparing healthy cells. It also inhibits mTOR, activates SIRT1, reduces NF-κB-mediated SASP (senescence-associated secretory phenotype), and crosses the blood-brain barrier to reduce neuroinflammation.
Human Trial Evidence
A 2018 EBioMedicine study (Yousefzadeh et al.) showed fisetin extended median and maximum lifespan in mice by 10% and reduced senescent cell burden across multiple tissues. A 2021 pilot human trial (Mayo Clinic) in older adults with frailty showed 20 mg/kg/day for 2 consecutive days reduced senescent cell markers in adipose tissue.
Dosing Protocol
100–500 mg/day for daily maintenance. 'Pulse dosing' protocols (used in Mayo Clinic trial): 20 mg/kg/day for 2 consecutive days per month. Best taken with fat for absorption. Often combined with quercetin for synergistic senolytic effect.
Safety & Contraindications
Well-tolerated in human trials. No serious adverse events at doses up to 20 mg/kg/day. Fisetin inhibits CYP3A4 at high doses — potential interactions with drugs metabolized by this enzyme. Avoid during pregnancy.