Tier 3 — preclinical

Fisetin Clears Senescent Cells Through the Pi3k-Akt-Bcl-2/Bcl-xl Pathway to Alleviate Diabetic Aortic Aging

Xiao-Man Ji, Xin-Xin Dong, Jia-Peng Li, Guang-Jie Tai, Shu Qiu, Wei Wei, Ceaser Wankumbu Silumbwe, Davaadagva Damdinjav, Joseph Nicolao Otieno, Xiao-Xue Li, Ming Xu
Phytotherapy Research 2025 39(6):2757-2775

Bibliography

PubMed
PMID 40259678
DOI
10.1002/ptr.8507
Funding
Supported by the National Natural Science Foundation of China (grant 82373870).
Competing interests
The authors declared no conflicts of interest.

Study snapshot

DesignControlled mouse intervention with vascular functional, histological and molecular analyses plus in vitro endothelial-cell experiments.
ModelHigh-fat-diet/streptozotocin type 2 diabetes mouse model, naturally aged mice, and senescent endothelial-cell models.
SampleReported vascular experiments commonly used n=6 per group; sample size varied by assay.
InterventionChronic intermittent fisetin in mice, including 50, 100 and 200 mg/kg dose exploration and a 100 mg/kg regimen used with metformin in the diabetic model; cell experiments used micromolar fisetin concentrations.
DurationUp to 12 weeks in the diabetic mouse experiments, with intermittent fisetin exposure.
EndpointsAortic cellular-senescence burden; SASP factors; Aortic histology and remodelling; Vasomotor function; PI3K-Akt-Bcl-2/Bcl-xL signalling; Endothelial-cell apoptosis; Metformin-plus-fisetin vascular effects

What the study showed, in plain terms

In diabetic and naturally aged mice, chronic intermittent fisetin reduced vascular markers of cellular senescence and improved measures of aortic structure and function. Cell experiments suggested that inhibition of PI3K-Akt survival signalling and downstream Bcl-2/Bcl-xL pathways contributed to selective death of senescent endothelial cells.

The study strengthens the mechanistic vascular-senolytic case for fisetin, but it is preclinical. The findings do not establish that oral fisetin clears vascular senescent cells or improves cardiovascular outcomes in people with diabetes.

Key findings

  • Fisetin reduced aortic senescence markers and SASP signalling in mouse models of diabetic and natural vascular aging.
  • Fisetin improved vasomotor function and measures of vascular remodelling in the mouse experiments.
  • In vitro work supported a PI3K-Akt-Bcl-2/Bcl-xL pathway as one mechanism for selective apoptosis of senescent endothelial cells.
  • Fisetin plus metformin produced stronger vascular effects than metformin alone in the diabetic mouse model, a preclinical combination finding only.

What this study can and cannot tell us

  • The efficacy findings are from mouse and cell models rather than a human clinical trial.
  • Mouse doses and intermittent treatment schedules cannot be directly converted into an evidence-based human supplement regimen.
  • The metformin-combination result does not establish a clinically useful or safe fisetin-metformin combination in people.

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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