Tier 2 — strong

Fisetin as a senotherapeutic agent — evidence and perspectives for age-related diseases

Tavenier J, Nehlin JO, Houlind MB, Rasmussen LJ, Tchkonia T, Kirkland JL, Andersen O, Rasmussen LJH

Mechanisms of Ageing and Development 2024 Volume 222, article 111995

Bibliography

DOI: 10.1016/j.mad.2024.111995
PubMed: PMID 39384074
Funding: Capital Region of Denmark's Research Funds (A7537 to LJHR; A7238 to JT), Beckett-Fonden (23-2-10655), Brødrene Hartmanns Fond (A39435), Hvidovre Hospital's Research Foundation (A240). J.L.K. and T.T. supported by NIH grants R37AG013925 and R33AG061456, the Connor Fund, Robert J. and Theresa W. Ryan, and the Noaber Foundation.
Competing interests: J.L.K. and T.T.: Patents on senolytic drugs held by Mayo Clinic, where both were employed before their move to Cedars-Sinai. Reviewed under Mayo Clinic Conflict of Interest policies. O.A.: Invented a patent concerning suPAR and risk stratification, owned by Copenhagen University Hospital Hvidovre and licensed to ViroGates A/S. Other authors declare none.

Study snapshot

Design	Narrative review of in vitro, animal, and human clinical trial evidence.
Model	Review scope: fifty-plus in vitro studies across cardiovascular, musculoskeletal, hepatic, nervous, and renal cell lines; twenty-plus animal studies; thirty clinical studies in humans (four with published results, remainder ongoing).
Sample	Thirty clinical studies catalogued; four with published outcomes (n=192 stroke trial largest).
Intervention	Fisetin dosing paradigms reviewed span 20 mg/kg/day intermittent (two consecutive days, most common in ongoing trials) to 100 mg/day continuous (chemotherapy adjunct, stroke, healthy volunteer cohorts) to 200–800 mg/day (Gulf War Illness trial).
Duration	Reviews acute two-day, weekly-cycle intermittent, and continuous daily dosing schedules.
Endpoints	Cellular senescence markers (p16, p21, SA-β-gal); Senescence-associated secretory phenotype factors; Disease-specific clinical outcomes across trial indications

What the study showed, in plain terms

This is a comprehensive review, not a new experiment. Its authors — a group that includes James Kirkland and Tamara Tchkonia, the researchers who originally identified fisetin as a senolytic — catalogued every published in vitro study, animal study, and human clinical trial of fisetin as a senotherapeutic and assessed what the evidence collectively shows.

The verdict is measured. In cultured cells, fisetin selectively kills some but not all types of senescent cells, with sensitivity depending on how the senescence was induced and which cell type is studied. In animal models spanning aged wild-type mice, progeroid mice, aged sheep, and disease-specific models across kidney, liver, cardiovascular, musculoskeletal, and immune systems, fisetin reduces markers of cellular senescence and often improves organ-level outcomes.

The human evidence is limited. As of the review's publication, only four trials had published results. A stroke trial and a colorectal cancer adjunct trial showed modest reductions in inflammation markers. A recent cohort study of healthy volunteers self-dosing 100 mg/day showed reductions in circulating senescence markers. Most of the thirty registered clinical trials are still ongoing.

The review also identifies the outstanding open questions: optimal dosing, whether the intermittent "hit-and-run" paradigm works in humans, drug-drug interactions relevant to polypharmacy in older adults, and the low oral bioavailability that limits how much fisetin actually reaches circulation.

Key findings

Thirty registered clinical trials of fisetin identified as of publication, spanning musculoskeletal disorders, geriatric syndromes, infectious diseases, cardiovascular disease, and cancer. Four trials had published results; most were ongoing.
Published human results: a stroke trial (n=192) supplementing tissue plasminogen activator with 100 mg/day fisetin showed improved outcomes and reduced MMP-2, MMP-9, and CRP versus placebo. A colorectal cancer trial (n=21) with 100 mg/day fisetin during chemotherapy showed greater IL-8 reduction. A Gulf War Illness trial (200–800 mg/day) showed no symptom improvement. A healthy volunteer cohort self-dosing 100 mg/day showed reduced serum senescence-associated secretory phenotype factors and reduced senescent peripheral blood mononuclear cell percentage.
Most ongoing trials use a 20 mg/kg/day intermittent dosing paradigm — two consecutive days per month or per cycle — reflecting the "hit-and-run" senolytic hypothesis that continuous dosing is not required.
In vitro evidence supports selective senolytic activity across cardiovascular, musculoskeletal, skin, hepatic, neural, and renal cell types, but with variable potency depending on senescence induction method. Fisetin is not universally senolytic — some senescent cell types resist it, and different senolytics target different senescent cell populations.
In vivo animal evidence shows fisetin reduces senescent cell burden across multiple organs and improves organ-level function, with lifespan extension replicated in some genetic backgrounds (C57BL/6:FVB) but not others (UM-HET3, per Harrison et al. 2023).
Fisetin has favourable safety in animal models across acute and chronic dosing up to nine months. Reported human side effects are mild and gastrointestinal. However, fisetin inhibits multiple cytochrome P450 enzymes (CYP2C9, CYP2C19, CYP1A2, CYP2D6, CYP3A4, CYP2C8), raising drug-drug interaction concerns in polypharmacy populations.
Oral bioavailability is low. Peak plasma concentration after 1000 mg oral dose is approximately 0.01 μg/mL, with 1.14-hour half-life. Novel formulations (self-nano emulsifying systems, hybrid hydrogels) improve bioavailability substantially but require further clinical validation.

What this study can and cannot tell us

This is a narrative review, not a systematic review or meta-analysis. The authors did not use pre-registered search strategies or formal quality assessment tools. Reader should treat conclusions as informed synthesis rather than statistical summary.

Author conflict-of-interest disclosures are substantial. Two authors (Kirkland and Tchkonia) hold senolytic drug patents through Mayo Clinic. One author (Andersen) holds a suPAR-related patent licensed to a commercial entity. Both conflicts are disclosed clearly in the paper. The review's overall framing of fisetin as a promising senotherapeutic aligns with the commercial interests of the patent holders — this does not invalidate the evidence catalogued but warrants reader awareness.

Most cited human trials had not published results at review time. Conclusions about human efficacy remain provisional pending trial completions. The single cohort study showing SASP factor reductions in healthy volunteers (Hambright 2024) was a sub-analysis of self-dosed participants, not a controlled trial.

The review does not address one important gap: no head-to-head human comparison exists between fisetin and other senolytic candidates. Whether fisetin's specific senolytic profile is clinically preferable to alternatives is not yet known.

Tier 3

Fisetin is a senotherapeutic that extends health and lifespan

Yousefzadeh MJ et al. · EBioMedicine · 2018