Department of Dermatology, Seoul National University College of Medicine, Seoul, Korea.
Department of Biomedical Sciences, Seoul National University Graduate School, Seoul, Korea.
J Eur Acad Dermatol Venereol. 2022 Jul;36(7):1125-1135. doi: 10.1111/jdv.18051. Epub 2022 Mar 24.
Skin ageing is caused by numerous factors that result in structural and functional changes in cutaneous components. Research has shown that senescent cells are known to accumulate in skin ageing, however, the role of senescent cells in skin ageing has not been defined.
To elucidate the role of the senescent cell in skin ageing, we evaluated the effect of known senolytic drugs on senescent dermal fibroblasts.
Primary human dermal fibroblasts (HDFs) were induced to senescence by long-term passaging, UV irradiation, and H O treatment. Cell viability was measured after treatment of ABT-263 and ABT-737 on HDFs. Young and aged hairless mice were intradermally injected with drugs or vehicle on the dorsal skin for 10 days. Skin specimens were obtained and reverse-transcription quantitative PCR, western blotting, and histological analysis were performed.
We found that ABT-263 and ABT-737 induced selective clearance of senescent dermal fibroblasts, regardless of the method of senescence induction. Aged mouse skin treated with ABT-263 or ABT-737 showed increased collagen density, epidermal thickness, and proliferation of keratinocytes, as well as decreased senescence-associated secretory phenotypes, such as MMP-1 and IL-6.
Taken together, our results indicate that selective clearance of senescent skin cells can attenuate and improve skin ageing phenotypes and that senolytic drugs may be of potential use as new therapeutic agents for treating ageing of the skin.
皮肤衰老由多种因素引起，导致皮肤成分的结构和功能发生变化。研究表明，衰老细胞在皮肤衰老中会积累，但衰老细胞在皮肤衰老中的作用尚未确定。
为了阐明衰老细胞在皮肤衰老中的作用，我们评估了已知的衰老细胞选择性清除剂对衰老真皮成纤维细胞的影响。
通过长期传代、紫外线照射和 H2O2 处理诱导原代人真皮成纤维细胞（HDFs）衰老。用 ABT-263 和 ABT-737 处理 HDFs 后，测量细胞活力。将药物或载体在无毛小鼠背部皮肤皮内注射，每天 1 次，连续 10 天。取皮肤标本，进行逆转录定量 PCR、western blot 和组织学分析。
我们发现，ABT-263 和 ABT-737 诱导衰老的真皮成纤维细胞选择性清除，而与衰老诱导的方法无关。用 ABT-263 或 ABT-737 处理的衰老小鼠皮肤显示出胶原蛋白密度增加、表皮厚度增加、角蛋白细胞增殖增加，以及衰老相关分泌表型（如 MMP-1 和 IL-6）减少。
综上所述，我们的研究结果表明，选择性清除衰老的皮肤细胞可以减轻和改善皮肤衰老表型，衰老细胞选择性清除剂可能作为治疗皮肤衰老的新治疗剂具有潜在的应用价值。
