Tier 3 — preclinical

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

PubMed
PMID 39384074
DOI
10.1016/j.mad.2024.111995
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

DesignPeer-reviewed narrative expert review of in-vitro, animal, pharmacokinetic and human fisetin evidence, with a catalogue of ongoing and completed clinical studies.
ModelNo original experimental model. Review scope included cell studies, multiple animal models, pharmacokinetic studies and human clinical/observational evidence relevant to fisetin as a senotherapeutic.
SampleNot applicable as an original study; no pooled participant sample. The review identified 30 human clinical studies involving fisetin, with results available from only four human studies at the time of publication.
InterventionNo intervention administered by the review. It summarizes fisetin regimens ranging from low-dose continuous oral use in published human studies to intermittent high-dose senolytic protocols in ongoing trials, as well as preclinical dosing paradigms.
DurationNot applicable to the review itself; included source studies used acute, repeated intermittent and continuous dosing schedules of varying duration.
EndpointsSenescent-cell burden and senescence/SASP biomarkers; Disease-specific human clinical outcomes and inflammatory markers; Preclinical organ and functional outcomes; Fisetin pharmacokinetics, metabolism and bioavailability; Safety, tolerability, dosing and potential drug interactions; Clinical-trial landscape and candidate outcome measures

What the study showed, in plain terms

This 2024 paper is a narrative expert review of fisetin as a senotherapeutic, not a new clinical trial or a systematic meta-analysis. It synthesizes cell, animal, pharmacokinetic and early human evidence and identified 30 human studies testing fisetin alone or with other interventions; at the time of publication, only four had published human results.

The human evidence summarized by the review was mixed and heterogeneous. A Gulf War Illness trial reported no significant symptom benefit; small colorectal-cancer and acute-stroke studies reported changes in selected inflammatory or disease outcomes; and an uncontrolled sub-analysis of ten healthy people who self-reported taking 100 mg/day fisetin showed reductions in several SASP-associated markers and senescent PBMCs but not senescent T cells. None of these studies established that intermittent high-dose fisetin clears senescent cells in humans.

The review's central conclusion is appropriately cautious: fisetin has substantial preclinical senotherapeutic evidence, but human translation still requires better pharmacokinetic data, validated biomarkers of senescence, dose optimization, drug-interaction assessment, and controlled efficacy trials. Its conclusions should be read as an expert synthesis current to 2024 rather than a pooled estimate of treatment effect.

Key findings

  • The review identified 30 registered/clinical human studies involving fisetin, but only four human studies with published results were available at the time of review.
  • Published human evidence was heterogeneous: Gulf War Illness showed no significant symptom benefit; colorectal-cancer and acute-stroke studies reported selected positive inflammatory or clinical signals; and a small uncontrolled self-dosing cohort reported changes in SASP-associated markers.
  • The review emphasizes that fisetin induces apoptosis in many, but not all, senescent cell types in vitro and that animal findings cannot be assumed to translate uniformly to humans.
  • A major translational constraint is pharmacokinetics: fisetin has low aqueous solubility, rapid metabolism and short systemic persistence, while the clinical exposure needed for senolysis in humans remains unknown.
  • The review highlights potential inhibition of several CYP enzymes (including CYP2C8, CYP2C9, CYP2C19, CYP1A2, CYP2D6 and CYP3A4), making drug-interaction assessment important in older adults with polypharmacy.
  • The authors identify a lack of validated, accessible biomarkers of senescent-cell burden and treatment response as a major obstacle for human senolytic trials.

What this study can and cannot tell us

  • Narrative rather than systematic review. The paper does not report a preregistered systematic-search protocol, formal risk-of-bias assessment, certainty grading, or quantitative meta-analysis, so completeness and weighting of evidence depend on author selection and interpretation.
  • The human evidence available to the review was sparse, small, clinically heterogeneous and generally not designed to demonstrate senescent-cell clearance. The review therefore cannot establish a human anti-aging, healthspan or longevity effect.
  • Its clinical-trial landscape is time-limited to the review period. Trial statuses and results can change after publication and must be checked against current registries and later publications rather than treated as permanently current.
  • The review repeats a conventional-fisetin Cmax of about 0.01 μg/mL from Krishnakumar et al. 2022 as if it followed a 1000 mg conventional dose. Re-review of the underlying pharmacokinetic paper shows that the published comparison values were dose-adjusted because the two formulations delivered very different amounts of fisetin; the original PK paper should therefore be used for exact exposure interpretation rather than this secondary summary.
  • James Kirkland and Tamara Tchkonia disclosed senolytic-drug patent interests held by Mayo Clinic, and Ove Andersen disclosed a suPAR-related patent licensed to ViroGates. These conflicts were disclosed and do not invalidate the review, but they are relevant when weighing interpretation of a field in which the authors are active developers.

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Dr. Khaled Mahmoud, MBBChCritical Care Medicine, Longevity Science & Editorial Direction Dr. Amr Yasser, PhDCardiometabolic, Musculoskeletal, Gut & Bioavailability Dr. Abdulla Mostafa, PhDCellular Senescence, Neurological, Mitochondrial & Brain-Ageing Biology