Tier 3 — preclinical

Fisetin is a senotherapeutic that extends health and lifespan

Yousefzadeh MJ, Zhu Y, McGowan SJ, Angelini L, Fuhrmann-Stroissnigg H, Xu M, Ling YY, Melos KI, Pirtskhalava T, Inman CL, McGuckian C, Wade EA, Kato JI, Grassi D, Wentworth M, Burd CE, Arriaga EA, Ladiges WL, Tchkonia T, Kirkland JL, Robbins PD, Niedernhofer LJ

EBioMedicine 2018 Volume 36, pages 18–28

Bibliography

DOI: 10.1016/j.ebiom.2018.09.015
PubMed: PMID 30279143
Funding: US National Institutes of Health (P01 AG043376, U19 AG056278, R24 AG047115, R37 AG013925, R21 AG047984, P30 DK050456), Glenn Foundation/American Federation for Aging Research BIG Award, Ted Nash Long Life and Noaber Foundations, the Connor Group, Robert J. and Theresa W. Ryan, Minnesota Partnership Grant (AMAY-UMN#99)-P004610401–1.
Competing interests: Kirkland JL, Tchkonia T, Zhu Y, Xu M and Pirtskhalava T have a financial interest related to this research. Patents on senolytic drugs (PCT/US2016/041646) are held by Mayo Clinic. The research was reviewed by the Mayo Clinic Conflict of Interest Review Board and conducted under Mayo Clinic Conflict of Interest policies.

Study snapshot

Design	Interventional, controlled, two mouse models plus in vitro screening panel across ten flavonoid compounds.
Model	Ercc1⁻/Δ progeroid mice and aged wild-type C57BL/6:FVB mice; senescent human umbilical vein endothelial cells and mouse embryonic fibroblasts in vitro.
Sample	n=8–9 per group across cohorts; 3 independent in vitro experiments.
Intervention	Fisetin 100 mg/kg oral gavage (acute, 5 consecutive days) or 500 ppm dietary supplementation (chronic, from 85 weeks of age).
Duration	Five consecutive days for acute; chronic dosing from 85 weeks of age through end of life.
Endpoints	Senescent cell burden across multiple tissues; Senescence-associated secretory phenotype markers; Healthspan pathology score; Median lifespan; Maximum lifespan

What the study showed, in plain terms

Fisetin was screened against nine other flavonoids for the ability to selectively kill senescent cells — the aged, dysfunctional cells that accumulate with time and secrete inflammatory signals that damage neighbouring tissue. Fisetin came out most potent, reducing senescent cell counts in mouse and human cell cultures without harming healthy cells.

The researchers then fed fisetin to two groups of mice: a progeroid strain that ages abnormally fast, and normal old mice starting at the equivalent of roughly seventy human years. In both groups, fisetin lowered markers of cellular senescence across multiple tissues — fat, spleen, liver, kidney, and circulating T cells. Old mice given fisetin lived longer and showed less age-related tissue damage on histology.

The mechanism appears to be senolytic — fisetin triggers programmed cell death in senescent cells while leaving healthy cells alone. Because senescent cells are slow to reaccumulate, intermittent dosing produced sustained effects that persisted after the compound had cleared from circulation.

Key findings

Fisetin outperformed nine other flavonoids including quercetin in reducing viability of senescent mouse embryonic fibroblasts at 5 μM concentration.
In aged wild-type mice, dietary fisetin (500 ppm) reduced p16Ink4a expression and senescence-associated secretory phenotype markers across fat, spleen, liver, and kidney tissue.
Late-life intervention starting at 85 weeks of age extended median lifespan and maximum lifespan versus untreated age-matched controls, with statistically significant improvement in composite lesion scores for age-related pathology.
Age-related histopathological damage was reduced in fisetin-fed mice across brain, kidney, liver, lung, and forepaw tissue.
Effects on senescence markers persisted for weeks after fisetin was cleared from circulation, consistent with a hit-and-run senolytic mechanism rather than continuous pharmacological action.
Selective reduction of senescent CD4+ and CD8+ T cells, natural killer cells, and endothelial cells in adipose tissue was confirmed by mass cytometry, without affecting activated macrophages or dendritic cells.

What this study can and cannot tell us

This is a preclinical study. Results in mice — even across two different mouse models — do not translate directly to humans, and the dose used (roughly 60 mg/kg/day dietary or 100 mg/kg oral gavage) is substantially higher on a body-weight basis than what a person would achieve through diet alone.

The lifespan extension finding was not replicated in a later, larger Interventions Testing Program cohort using genetically heterogeneous UM-HET3 mice, as reviewed by Tavenier and colleagues in 2024. Genetic background, study scale, and specific senescence phenotypes appear to matter.

The paper does not address dosing, safety, or efficacy in humans. Human clinical trial data — currently ongoing across multiple indications — is required to draw conclusions applicable to supplementation.

Tier 2

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

Tavenier J et al. · Mechanisms of Ageing and Development · 2024