Abstract
The skin’s protective functions are compromised over time by both endogenous and exogenous aging. Senescence is well-documented in skin phenotypes, such as wrinkling and sagging, a consequence of the senescence-associated secretory phenotype (SASP) that involves the accumulation of senescent fibroblasts, chronic inflammation, and collagen remodeling. Although therapeutic approaches for eliminating senescent cells from the skin are available, their efficacy remains unclear. Accordingly, we aimed to examine the effects of dasatinib in combination with quercetin (D + Q) on senescent human skin fibroblasts and aging human skin. Senescence was induced in human dermal fibroblasts (HDFs) using approaches such as long-term passaging, ionizing radiation, and doxorubicin treatment. The generated senescent cells were treated with D + Q or vehicle. Additionally, a mouse-human chimera model was generated by subcutaneously transplanting whole-skin grafts of aged individuals onto nude mice. Mouse models were administered D + Q or vehicle by oral gavage for 30 days. Subsequently, skin samples were harvested and stained for senescence-associated beta-galactosidase. Senescence-associated markers were assessed by western blotting, reverse transcription-quantitative PCR and histological analyses. Herein, D + Q selectively eliminated senescent HDFs in all cellular models of induced senescence. Additionally, D + Q-treated aged human skin grafts exhibited increased collagen density and suppression of the SASP compared with control grafts. No adverse events were observed during the study period. Collectively, D + Q could ameliorate skin aging through selective elimination of senescent dermal fibroblasts and suppression of the SASP. Our findings suggest that D + Q could be developed as an effective therapeutic approach for combating skin aging.
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No datasets were generated or analysed during the current study.
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Datasets generated and/or analyzed in the current study are available from the corresponding author upon reasonable request.
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Acknowledgements
This research was funded by the Japan Society for the Promotion of Science KAKENHI (grant number: JP 22K19589).
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This research was funded by the Japan Society for the Promotion of Science KAKENHI (grant number: JP 22K19589). The funders had no role in the study design, collection, analyses, interpretation of data, writing of the manuscript, or decision to publish the results.
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Conceptualization: KT, KK; Formal analysis, KT; Investigation: KT; Writing—original draft preparation, KT; Supervision: 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)). This study was conducted in accordance with the Declaration of Helsinki. Human skin sampling complied with the ethical guidelines for life sciences and medical research involving human subjects. All procedures involving human subjects were approved by the Institutional Review Board of Keio University School of Medicine (IRB No. 1101-116-353).
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Takaya, K., Kishi, K. Combined dasatinib and quercetin treatment contributes to skin rejuvenation through selective elimination of senescent cells in vitro and in vivo. Biogerontology (2024). https://doi.org/10.1007/s10522-024-10103-z
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DOI: https://doi.org/10.1007/s10522-024-10103-z