Abstract
Accumulation of senescent fibroblasts, chronic inflammation, and collagen remodeling due to aging-related secretory phenotypes have been hypothesized to cause age-related skin aging, which results in wrinkles and loss of skin elasticity, thus compromising appearance attractiveness. However, the rejuvenating effects of removing senescent cells from the human skin and the efficacy of related therapeutic agents remain unclear. Here, we investigated the effects of fisetin, a potential anti-aging component found in various edible fruits and vegetables, on senescent human dermal fibroblasts (HDFs) and aging human skin. Senescence was induced in primary HDFs using long-term passaging and treatment with ionizing radiation, and cell viability was assessed after treatment with fisetin and a control component. A mouse/human chimeric model was established by subcutaneously transplanting whole skin grafts from aged individuals into nude mice, which were treated intraperitoneally with fisetin or control a component for 30 d. Skin samples were obtained and subjected to senescence-associated-beta-galactosidase staining; the extent of aging was evaluated using western blotting, reverse transcription-quantitative PCR, and histological analysis. Fisetin selectively eliminated senescent dermal fibroblasts in both senescence-induced cellular models; this effect is attributable to cell death induction by caspases 3, 8, and 9-mediated endogenous and exogenous apoptosis. Fisetin-treated senescent human skin grafts showed increased collagen density and decreased senescence-associated secretory phenotypes (SASP), including matrix metalloproteinases and interleukins. No apparent adverse events were observed. Thus, fisetin could improve skin aging through selective removal of senescent dermal fibroblasts and SASP inhibition, indicating its potential as an effective novel therapeutic agent for combating skin aging.
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The datasets generated during and/or analyzed during the current study are available from the corresponding author on reasonable request.
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Acknowledgements
The authors thank the laboratory members for their technical assistance with the experiments.
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This research was funded by JSPS KAKENHI (grant number: JP 22K19589).
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Conceptualization, KT, TA, KK; formal analysis, KT; investigation, KT; writing—original draft preparation, KT; supervision, TA and KK.
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The protocol for animal experiments was reviewed and approved by the Institutional Animal Care and Use Committee of Keio University School of Medicine (approval number: 13072-(2)). Human skin sampling complied with ethical guidelines for life science and medical research involving human subjects. All procedures involving human subjects were approved by the University Institutional Review Board (IRB No. 1101-116-353), and volunteers provided written informed consent.
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Takaya, K., Asou, T. & Kishi, K. Fisetin, a potential skin rejuvenation drug that eliminates senescent cells in the dermis. Biogerontology 25, 161–175 (2024). https://doi.org/10.1007/s10522-023-10064-9
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DOI: https://doi.org/10.1007/s10522-023-10064-9