Tier 3 — preclinical

Fisetin, a potential skin rejuvenation drug that eliminates senescent cells in the dermis

Kento Takaya, Toru Asou, Kazuo Kishi
Biogerontology 2024 25(1):161–175

Bibliography

PubMed
PMID 37736858
DOI
10.1007/s10522-023-10064-9
Funding
Supported by JSPS KAKENHI grant JP22K19589. The funders had no role in study design, data collection, analysis, interpretation, manuscript writing or publication decisions.
Competing interests
The authors declared no competing interests.

Study snapshot

DesignIn vitro senescence experiments in human dermal fibroblasts plus a mouse/human chimeric whole-skin graft model.
ModelPrimary human dermal fibroblasts with several senescence induction methods; whole skin from four healthy elderly men aged 86–91 transplanted subcutaneously into nude mice.
SampleHuman skin from 4 elderly male donors; paired graft segments produced four control and four fisetin-treated chimeric models. Cell experiments used multiple technical/biological replicates.
InterventionIn vitro fisetin across 0.1–200 micromolar concentrations. In the chimeric model, fisetin 20 mg/kg/day intraperitoneally for 30 consecutive days versus vehicle.
Duration30 days of in vivo fisetin dosing; grafts retrieved four weeks after the end of dosing.
EndpointsSenescent human dermal fibroblast viability; Apoptosis pathways; SA-β-gal and p16INK4a; SASP factors including interleukins and MMPs; Dermal collagen density and histology

What the study showed, in plain terms

This study tested fisetin against senescent human skin fibroblasts and in an unusual chimeric model in which skin from elderly men was grafted into nude mice. Fisetin selectively killed senescent fibroblasts in the laboratory and reduced senescence markers in the human skin grafts.

Fisetin-treated grafts also showed denser collagen and lower SASP-related inflammatory and matrix-degrading signals. Because the treatment was given to mice and the human skin was grafted tissue, this is not a human anti-aging skincare or supplement trial.

Key findings

  • Fisetin selectively reduced viability of senescent human dermal fibroblasts through caspase-mediated apoptosis.
  • Aged human skin grafts treated in the chimeric mouse model showed fewer SA-β-gal- and p16-positive dermal cells.
  • Collagen density increased while SASP-associated interleukins and matrix metalloproteinases decreased.

What this study can and cannot tell us

  • No direct human treatment trial was performed; fisetin was administered intraperitoneally to mice carrying human skin grafts.
  • Skin samples came from only four elderly male donors, so sex and age generalizability are unknown.
  • The subcutaneous graft model could not adequately evaluate visible outcomes such as wrinkles, texture or elasticity in living human skin.

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Fisetin is a senotherapeutic that extends health and lifespan
Yousefzadeh MJ et al. · EBioMedicine · 2018
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Chisato Kubo et al. · Frontiers in Cell and Developmental Biology · 2020

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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