Tier 3 — preclinical

Fisetin Supplementation Attenuates Premature Vascular Aging Induced by Doxorubicin via Suppression of Cellular Senescence and Mitochondrial Oxidative Stress

Mary A. Darrah, Sophia A. Mahoney, Ravinandan Venkatasubramanian, Nicholas S. VanDongen, Katelyn R. Ludwig, Douglas R. Seals, Matthew J. Rossman, Zachary S. Clayton
Aging Cell 2026 25(5):e70535

Bibliography

PubMed
PMID 42144546
PubMed Central
PMC13180696
DOI
10.1111/acel.70535
Funding
Supported by NIH grants including F31 HL165885, R21 AG078408 and K99 HL159241, and American Heart Association award 23CDA1056582, with additional support described in the paper.
Competing interests
The authors declared no conflicts of interest.

Study snapshot

DesignControlled mouse intervention with parallel mechanistic experiments in primary human aortic endothelial cells.
ModelYoung adult male and female p16-3MR mice exposed to doxorubicin, plus doxorubicin-induced senescence in human aortic endothelial cells.
SampleMouse groups: sham-vehicle n=13, sham-fisetin n=12, doxorubicin-vehicle n=11, doxorubicin-fisetin n=14.
InterventionFisetin 100 mg/kg/day by oral gavage using an intermittent senolytic schedule: 1 week on, 2 weeks off, 1 week on, after doxorubicin exposure.
DurationIntermittent four-week dosing paradigm with sacrifice 1–2 weeks after the final fisetin dose.
EndpointsEndothelium-dependent dilation; Aortic stiffness; Vascular cellular senescence; SASP expression; Nitric oxide bioavailability; Mitochondrial oxidative stress; Human endothelial-cell senescence

What the study showed, in plain terms

Doxorubicin can accelerate vascular aging by increasing cellular senescence, inflammation and mitochondrial oxidative stress. In this study, intermittent oral fisetin improved vascular function in young mice exposed to doxorubicin and reduced multiple markers linked to senescence and oxidative stress.

Parallel experiments in human aortic endothelial cells supported the same mechanism. The paper strengthens the preclinical vascular case for fisetin, but it does not show that fisetin prevents chemotherapy-related cardiovascular disease in people.

Key findings

  • Fisetin reversed doxorubicin-induced endothelial dysfunction and aortic stiffening in mice (both p<0.001).
  • Vascular senescence and SASP signaling were reduced, with higher nitric-oxide bioavailability and lower mitochondrial oxidative stress.
  • Fisetin also reduced senescence in doxorubicin-exposed human aortic endothelial cells in vitro.

What this study can and cannot tell us

  • The in vivo efficacy data come from mice, not patients exposed to doxorubicin.
  • The 100 mg/kg intermittent mouse dose and gavage formulation cannot be directly translated into a consumer supplement dose.
  • Human endothelial-cell experiments provide mechanistic support but do not reproduce whole-body human pharmacokinetics or cardiovascular outcomes.

Related papers in the corpus

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Senolytic treatment with fisetin reverses age-related endothelial dysfunction partially mediated by SASP factor CXCL12
Sophia A. Mahoney et al. · Aging Cell · 2026
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Intermittent Supplementation With Fisetin Improves Physical Function and Decreases Cellular Senescence in Skeletal Muscle With Aging: A Comparison to Genetic Clearance of Senescent Cells and Synthetic Senolytic Approaches
Kevin O. Murray et al. · Aging Cell · 2025
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Fisetin is a senotherapeutic that extends health and lifespan
Yousefzadeh MJ et al. · EBioMedicine · 2018

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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