Elimination of physiological senescent cutaneous cells in a novel p16-dependent senolytic mouse model impacts lipid metabolism in skin aging

IF 16.4 1区化学 Q1 CHEMISTRY, MULTIDISCIPLINARY

Accounts of Chemical Research Pub Date : 2024-09-16 DOI:10.1111/gtc.13163

Yuma Sugiyama, Yoichiro Kawabe, Tanenobu Harada, Yu Aoki, Keiko Tsuji, Daijiro Sugiyama, Mitsuo Maruyama

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引用次数: 0

Abstract

The evidence of the correlation between cellular senescence and aging has increased in research with animal models. These models have been intentionally generated to target and regulate cellular senescent cells with the promoter activity of p16^Ink4a or p19^Arf, genes that are highly expressed in aging cells. However, the senolytic efficiency in various organs and cells from these models represents unexpected variation and diversity in some cases. We have generated a novel knock-in model, p16tdT-hDTR mice, which possess tdTomato and human diphtheria toxin receptor (hDTR) downstream of Cdkn2a, an endogenous p16^Ink4a gene. We successfully demonstrated that p16-derived tdTomato and hDTR expressions are observed in these mouse embryo fibroblasts and following treatment with diphtheria toxin (DT) eliminates those cells. Furthermore, we demonstrated the efficacy of eliminating p16-positive cells in vivo, and also observed a tendency to decrease their cutaneous SA-β-gal activity after subcutaneous DT injection into p16tdT-hDTR mice. In particular, comprehensive gene expression analysis in skin revealed that upregulated genes related to lipid metabolisms with aging exhibited remarkable expressions under the senolysis. These results clearly unveiled p16-positive senescent cells contribute to age-related changes in skin.

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在新型 p16 依赖性衰老小鼠模型中消除生理性衰老皮肤细胞会影响皮肤老化过程中的脂质代谢

在动物模型研究中，细胞衰老与衰老之间相关性的证据越来越多。这些动物模型是有意识地利用衰老细胞中高表达基因 p16Ink4a 或 p19Arf 的启动子活性来靶向和调控细胞衰老。然而，这些模型在不同器官和细胞中的衰老效率在某些情况下存在意想不到的差异和多样性。我们生成了一种新的基因敲入模型--p16tdT-hDTR小鼠，它在内源性p16Ink4a基因Cdkn2a的下游具有tdTomato和人白喉毒素受体（hDTR）。我们成功地证明，在这些小鼠胚胎成纤维细胞中观察到了 p16 衍生的 tdTomato 和 hDTR 表达，并在用白喉毒素（DT）处理后消除了这些细胞。此外，我们还证明了在体内消除 p16 阳性细胞的功效，并观察到 p16tdT-hDTR 小鼠皮下注射 DT 后，其皮肤 SA-β-gal 活性呈下降趋势。特别是，皮肤中的综合基因表达分析表明，与脂质代谢相关的基因随衰老而上调，在衰老过程中表现出显著的表达。这些结果清楚地揭示了 p16 阳性衰老细胞导致了皮肤与年龄相关的变化。

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来源期刊

Accounts of Chemical Research 化学-化学综合

CiteScore

31.40

自引率

1.10%

发文量

312

审稿时长

2 months

期刊介绍： Accounts of Chemical Research presents short, concise and critical articles offering easy-to-read overviews of basic research and applications in all areas of chemistry and biochemistry. These short reviews focus on research from the author’s own laboratory and are designed to teach the reader about a research project. In addition, Accounts of Chemical Research publishes commentaries that give an informed opinion on a current research problem. Special Issues online are devoted to a single topic of unusual activity and significance. Accounts of Chemical Research replaces the traditional article abstract with an article "Conspectus." These entries synopsize the research affording the reader a closer look at the content and significance of an article. Through this provision of a more detailed description of the article contents, the Conspectus enhances the article's discoverability by search engines and the exposure for the research.