Laboratory of Genetics and Genomics, National Institute on Aging, National Institutes of Health, Baltimore, MD, USA.
Translational Gerontology Branch, National Institute on Aging Intramural Research Program, National Institutes of Health, Baltimore, MD, USA.
Nat Aging. 2023 Oct;3(10):1237-1250. doi: 10.1038/s43587-023-00480-4. Epub 2023 Sep 4.
Sublethal cell damage can trigger senescence, a complex adaptive program characterized by growth arrest, resistance to apoptosis and a senescence-associated secretory phenotype (SASP). Here, a whole-genome CRISPR knockout screen revealed that proteins in the YAP-TEAD pathway influenced senescent cell viability. Accordingly, treating senescent cells with a drug that inhibited this pathway, verteporfin (VPF), selectively triggered apoptotic cell death largely by derepressing DDIT4, which in turn inhibited mTOR. Reducing mTOR function in senescent cells diminished endoplasmic reticulum (ER) biogenesis, triggering ER stress and apoptosis due to high demands on ER function by the SASP. Importantly, VPF treatment decreased the numbers of senescent cells in the organs of old mice and mice exhibiting doxorubicin-induced senescence. Moreover, VPF treatment reduced immune cell infiltration and pro-fibrotic transforming growth factor-β signaling in aging mouse lungs, improving tissue homeostasis. We present an alternative senolytic strategy that eliminates senescent cells by hindering ER activity required for SASP production.
亚致死性细胞损伤可引发衰老，这是一种复杂的适应性程序，其特征是生长停滞、抗细胞凋亡和衰老相关分泌表型（SASP）。在这里，全基因组 CRISPR 敲除筛选揭示了 YAP-TEAD 通路中的蛋白影响衰老细胞活力。相应地，用抑制该通路的药物——维替泊芬（VPF）处理衰老细胞，可选择性地通过去抑制 DDIT4 来触发凋亡性细胞死亡，而 DDIT4 反过来又抑制 mTOR。降低衰老细胞中的 mTOR 功能会减少内质网（ER）的生物发生，由于 SASP 对 ER 功能的高需求，导致 ER 应激和凋亡。重要的是，VPF 处理减少了老年小鼠和表现出多柔比星诱导衰老的小鼠器官中的衰老细胞数量。此外，VPF 处理减少了衰老小鼠肺部中的免疫细胞浸润和促纤维化转化生长因子-β信号，改善了组织内稳态。我们提出了一种替代的衰老细胞溶解策略，通过阻碍 SASP 产生所需的 ER 活性来消除衰老细胞。
