Fisetin
The natural senolytic flavonoid with the best safety-efficacy ratio
Definition
Fisetin is a polyphenolic flavonoid present mainly in strawberries (160 μg/g), followed by apples, persimmons, grapes, and onions. It is one of the most promising natural senolytics: in vitro and in animal models, it selectively eliminates senescent cells from multiple tissues (endothelium, liver, kidney, adipose tissue), with a safety profile superior to pharmacological senolytics like Dasatinib. It is the workhorse of senolytic biohacking — accessible, well-tolerated, and with growing preclinical evidence.
Detailed explanation
The Yousefzadeh et al. study (EBioMedicine 2018, University of Minnesota) screened a wide range of potential senolytics in cell cultures and animal models, identifying fisetin as the most effective flavonoid: it significantly reduced senescence markers in multiple tissues and extended median lifespan of aged mice by up to 14%.
Identified mechanisms: selective inhibition of anti-apoptotic proteins (especially BCL-XL and BCL-W) in senescent cells, mTOR downregulation, NF-κB modulation, and direct antioxidant effects.
Human protocols (still experimental): the AFFIRM-LITE clinical trial (Mayo Clinic) is evaluating 20 mg/kg/day for 2 consecutive days every 4 weeks — equivalent to 1,400 mg for a 70 kg person. This intermittent 'hit-and-run' dosing replicates the pattern of pharmacological senolytics.
Bioavailability: pure fisetin has very low oral bioavailability (<3%); modern formulations with liposomes, phospholipids (Phytosome), or micelles improve absorption 4-25-fold. The micronised form with piperine or liposomal is preferred in clinical protocols. Very favourable safety profile; no significant adverse effects documented at nutritional or protocol doses.
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