Fisetin
3,3',4',7-tetrahydroxyflavone
The senolytic with the best animal data and the most anticipated unpublished trials. Mayo has run them, enrolment is done, and nobody has seen the results.
Preclinical only
Sold as a dietary supplement. Not an approved drug. Under investigation in FDA-cleared academic trials for frailty and for sepsis in elderly patients, none of which has reported.
What it is
Fisetin is a flavonoid found in strawberries, apples and onions. Its interest is as a senolytic: a compound that selectively kills senescent cells, which accumulate with age, stop dividing, and secrete an inflammatory mixture known as the senescence-associated secretory phenotype.
Clearing them in mice improves healthspan and, in some protocols, lifespan. Of the senolytics screened by the Mayo Clinic group, fisetin was the most effective, which is why it became the one tested in humans.
The animal evidence is good
Fisetin reduces senescent cell burden across multiple tissues in mice and extends both health and lifespan in aged animals. Recent work continues to reproduce the mechanism in specific systems, including reversal of age-related endothelial dysfunction mediated through a SASP factor, and protection against premature vascular ageing from doxorubicin.
That is a coherent, replicating body of preclinical work with an identified mechanism. By the standards of this site it is a strong preclinical position.
The human trials exist and have not reported
This is the honest state of things and it is frustrating.
AFFIRM is a phase 2b double-blind placebo-controlled trial at Mayo, FDA-cleared, giving oral fisetin at 20 mg/kg/day for two days in pulsed monthly doses to elderly women with multimorbidity, measuring senescent cell burden, frailty and inflammation. It has enrolled and it is not unblinded. STOP-Sepsis is a multicentre randomised trial in elderly patients with sepsis, intended to inform a larger phase 3.
The only published human work is a small pilot in COVID-19 in skilled nursing facilities, which was a trial of convenience during a pandemic rather than a test of the ageing hypothesis.
So fisetin sits at preclinical on this site, not because the research is weak, but because the human results that would move it are sitting unpublished. That may change, and this page carries a review date for exactly that reason.
The dose gap is the practical problem
Trial protocols use roughly 20 mg/kg for two days at a time, monthly. For an 80 kg adult that is around 1600 mg in a day, pulsed.
Commercial supplements are typically 100 to 500 mg taken daily and continuously. That is a lower peak dose delivered on the opposite schedule, and it matches no protocol under investigation. If the senolytic mechanism depends on reaching a concentration that triggers apoptosis in senescent cells, continuous low dosing may be the one regimen that does neither the clearing nor the resting.
Practical notes
- Bioavailability is poor and formulation-dependent. Plain fisetin absorbs badly. Liposomal and phospholipid formulations claim improvements that are rarely quantified in humans.
- Pulsed is the studied design. Daily dosing is a supplement-industry convention imported onto a drug class whose entire rationale is intermittency.
- This is the senolytic most likely to graduate. If AFFIRM reads out positive it moves tiers. Until it reads out, the animal data is what there is.
Side effects and warning signs
Commonly reported
- Generally well tolerated in the small published human work
- Gastrointestinal discomfort at the high pulsed doses
- Long-term safety in humans is uncharacterised
Stop and get medical help
- Senolytics clear cells by inducing apoptosis in stressed cells, and the consequences of doing that repeatedly in a healthy person over years are unknown
- Interaction potential with drugs metabolised by CYP enzymes, since flavonoids inhibit several of them and fisetin doses used in trials are far above dietary levels
Sources
From the community
Discussion for this compound concentrates in r/longevity and r/Biohackers.
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