Well Aging Research Center, DGIST, Daegu 42988, Korea.
Department of Medicine, Catholic University of Daegu School of Medicine, Daegu 42472, Korea.
Aging (Albany NY). 2020 May 7;12(9):8221-8240. doi: 10.18632/aging.103135.
The selective removal of senescent cells by senolytics is suggested as a potential approach to reverse aging and extend lifespan. Using high-throughput screening with replicative senescence of human diploid fibroblasts (HDFs), we identified a novel senolytic drug R406 that showed selective toxicity in senescent cells. Using flow cytometry and caspase expression analysis, we confirmed that R406 caused apoptotic cell death along with morphological changes in senescent cells. Interestingly, R406 altered the cell survival-related molecular processes including the inhibition of phosphorylation of the focal adhesion kinase (FAK) and p38 mitogen-activated protein kinase (MAPK) in senescent cells. This pattern was not observed in other known senolytic agent ABT263. Correspondingly, apoptotic cell death in senescent cells was induced by simultaneously blocking the FAK and p38 pathways. Taken together, we suggest that R406 acts as a senolytic drug by inducing apoptosis and reducing cell attachment capacity.
通过衰老细胞清除剂选择性地清除衰老细胞被认为是一种逆转衰老和延长寿命的潜在方法。我们使用人二倍体成纤维细胞（HDFs）的复制性衰老进行高通量筛选，鉴定出一种新型的衰老细胞清除剂 R406，它在衰老细胞中表现出选择性毒性。通过流式细胞术和半胱天冬酶表达分析，我们证实 R406 导致衰老细胞发生凋亡性细胞死亡，同时伴有形态学变化。有趣的是，R406 改变了与细胞存活相关的分子过程，包括抑制衰老细胞中粘着斑激酶（FAK）和丝裂原活化蛋白激酶（MAPK）的磷酸化。在其他已知的衰老细胞清除剂 ABT263 中未观察到这种模式。相应地，通过同时阻断 FAK 和 p38 途径诱导衰老细胞中的凋亡性细胞死亡。综上所述，我们认为 R406 通过诱导细胞凋亡和降低细胞附着能力来发挥衰老细胞清除剂的作用。
