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

PubMed
PMID 30279143
PubMed Central
PMC6197652
DOI
10.1016/j.ebiom.2018.09.015
Funding
NIH grants P01 AG043376 (P.D.R., L.J.N.), U19 AG056278 (P.D.R., L.J.N., W.L.L.), R24 AG047115 (W.L.L.), R37 AG013925 (J.L.K.), R21 AG047984 (J.L.K.), P30 DK050456 (Adipocyte Subcore, J.L.K.); Glenn Foundation/American Federation for Aging Research BIG Award (J.L.K.); Glenn/AFAR support (L.J.N., C.E.B.); Ted Nash Long Life and Noaber Foundations (J.L.K.); Connor Group (J.L.K.); Robert J. and Theresa W. Ryan (J.L.K.); Minnesota Partnership Grant AMAY-UMN#99-P004610401-1 (J.L.K., E.A.A.).
Competing interests
J.L.K., T.T., Y.Z., M.X. and T.P. disclosed financial interests related to the research. Mayo Clinic held patents on senolytic drugs (PCT/US2016/041646). The work was reviewed by the Mayo Clinic Conflict of Interest Review Board and conducted under Mayo Clinic conflict-of-interest policies; the other authors reported no relevant financial conflict.

Study snapshot

DesignMulti-part preclinical/translational study: in-vitro flavonoid screening in senescent murine and human fibroblast systems; intermittent/chronic fisetin interventions in progeroid Ercc1−/Δ and naturally aged wild-type mice; ex-vivo human omental adipose-tissue explants.
ModelErcc1−/− mouse embryonic fibroblasts and IMR90 human fibroblasts; Ercc1−/Δ p16-luciferase progeroid mice; aged C57BL/6 and F1 C57BL/6:FVB mice; human greater-omental adipose explants from three women aged 55–66 years.
SampleVaried by experiment: progeroid mouse cohorts generally n=4–10 per group/time point; acute aged wild-type adipose experiment n=6–7 per group; late-life lifespan cohort n=8–9 per group; human adipose explants n=3 donors; in-vitro assays used replicate cultures rather than an enrolled clinical sample.
InterventionFisetin in cell/explant assays (including 20 μM for human adipose explants); 500 ppm dietary fisetin (about 60 mg/kg/day in the progeroid dietary experiment) given intermittently or chronically; 100 mg/kg/day oral gavage for 5 days in aged mice; 500 ppm diet from 85 weeks of age through lifespan follow-up.
DurationModel-dependent: 24–48 h cell exposure; human adipose explants 48 h fisetin followed by 24 h drug-free conditioned-medium collection; progeroid intermittent diet at 6–8 and 12–14 weeks or chronic exposure; acute aged-mouse gavage for 5 days; lifespan diet initiated at 85 weeks and continued through end of life.
EndpointsSenescence burden and markers (SA-β-gal/C12FDG, p16Ink4a, p21Cip1); SASP/inflammatory factors in tissues, blood and human adipose explants; Cell-type-specific senescence in adipose tissue by CyTOF; Age-related histopathology and organ-homeostasis markers; Median and maximum mouse lifespan

What the study showed, in plain terms

This 2018 paper is a foundational preclinical fisetin study. The authors screened a panel of flavonoids in senescent murine and human fibroblast systems and found fisetin had the strongest senotherapeutic activity in the screen. Importantly, the cellular mechanism was not uniform: in some models fisetin reduced senescence markers without clear evidence of killing the cells, while prior endothelial-cell work supported apoptosis. The paper therefore supports senotherapeutic activity, but not universal senolytic cell killing across all senescent cell types.

The investigators then tested fisetin in progeroid Ercc1−/Δ mice and naturally aged wild-type mice. Intermittent or chronic dietary fisetin reduced p16/p21 and SASP-related markers in several tissues, and a five-day 100 mg/kg oral-gavage course reduced senescence markers in white adipose tissue of 22–24-month-old mice. In a separate late-life lifespan experiment, mice began a 500 ppm fisetin diet at 85 weeks of age; the small cohort (8–9 mice per group) showed longer median and maximum lifespan and lower age-related pathology scores than controls.

The study also treated human omental adipose-tissue explants from three women aged 55–66 years with 20 μM fisetin ex vivo and observed reductions in senescence-associated β-galactosidase activity and several secreted inflammatory factors. This was not a human supplementation trial: no participant ingested fisetin, and the study does not establish an effective oral dose, human senescent-cell clearance, healthspan benefit, or lifespan extension.

Key findings

  • In the flavonoid screen, fisetin was the most effective compound at reducing the fraction of senescence-associated β-galactosidase-positive Ercc1−/− mouse embryonic fibroblasts at 5 μM; activity was also dose-dependent in MEFs and IMR90 human fibroblasts.
  • In p16-luciferase Ercc1−/Δ progeroid mice, intermittent 500 ppm dietary fisetin suppressed the p16-linked luciferase signal, including during the four-week interval off fisetin, consistent with a durable senotherapeutic effect.
  • Chronic dietary fisetin reduced p16, p21 and multiple SASP-related transcripts in adipose tissue, spleen, liver, kidney and peripheral CD3+ T cells of progeroid mice.
  • In naturally aged mice, 100 mg/kg/day oral fisetin for five days reduced SA-β-gal-positive cells in inguinal white adipose tissue and reduced selected p16-expressing progenitor, T-cell, natural-killer-cell and endothelial populations; not every senescent-like cell population was reduced.
  • Human omental adipose-tissue explants from three women treated ex vivo with 20 μM fisetin showed reduced senescence-associated β-galactosidase activity and lower secretion of several inflammatory/SASP-associated factors.
  • A late-life lifespan cohort beginning 500 ppm dietary fisetin at 85 weeks of age (8–9 mice per group) showed statistically significant extension of median and maximum lifespan together with lower age-related pathology scores.

What this study can and cannot tell us

  • No in-vivo human efficacy evidence. The human component used adipose-tissue explants from only three surgical donors; participants did not take fisetin.
  • The headline lifespan experiment was very small (8–9 mice per group) and used a specific F1 C57BL/6:FVB background. A later, much larger NIA Interventions Testing Program study in genetically heterogeneous UM-HET3 mice did not reproduce a lifespan benefit with either continuous or intermittent fisetin at the tested regimens, and did not show reduced p16-positive cells in the sampled tissues.
  • The mechanism was cell-type and model dependent. In Ercc1−/− MEFs, fisetin reduced senescence markers without evidence of cell killing; the authors explicitly discuss senolytic versus senomorphic possibilities. Some senescent-like macrophage and dendritic-cell populations were not cleared.
  • Mouse exposure was high relative to ordinary dietary intake: the study used 100 mg/kg/day by gavage for acute treatment and 500 ppm chow (approximately 60 mg/kg/day in the progeroid dietary experiment). These regimens do not define an equivalent effective human supplement dose.
  • Multiple experiments used different mouse strains, dosing schedules, tissues and endpoints with modest group sizes, so the study should be read as a collection of converging preclinical experiments rather than one definitive replicated lifespan trial.
  • Five authors disclosed financial interests related to the work, and Mayo Clinic held patents on senolytic drugs (PCT/US2016/041646). The conflicts were formally reviewed and disclosed, but they remain relevant when weighing translational claims.

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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