CAS Key Laboratory of Tissue Microenvironment and Tumor, Innovation Center for Intervention of Chronic Disease and Promotion of Health, Shanghai Institute of Nutrition and Health, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai, China.
Key Laboratory of Urban Environment and Health, Institute of Urban Environment, Chinese Academy of Sciences, Xiamen, China.
Aging Cell. 2021 Oct;20(10):e13483. doi: 10.1111/acel.13483. Epub 2021 Sep 29.
The senescence-associated secretory phenotype (SASP) is a striking characteristic of senescence. Accumulation of SASP factors causes a pro-inflammatory response linked to chronic disease. Suppressing senescence and SASP represents a strategy to prevent or control senescence-associated diseases. Here, we identified a small molecule SR9009 as a potent SASP suppressor in therapy-induced senescence (TIS) and oncogene-induced senescence (OIS). The mechanism studies revealed that SR9009 inhibits the SASP and full DNA damage response (DDR) activation through the activation of the NRF2 pathway, thereby decreasing the ROS level by regulating the expression of antioxidant enzymes. We further identified that SR9009 effectively prevents cellular senescence and suppresses the SASP in the livers of both radiation-induced and oncogene-induced senescence mouse models, leading to alleviation of immune cell infiltration. Taken together, our findings suggested that SR9009 prevents cellular senescence via the NRF2 pathway in vitro and in vivo, and activation of NRF2 may be a novel therapeutic strategy for preventing cellular senescence.
衰老相关分泌表型（SASP）是衰老的一个显著特征。SASP 因子的积累会引起与慢性疾病相关的炎症反应。抑制衰老和 SASP 是预防或控制与衰老相关疾病的一种策略。在这里，我们鉴定出一种名为 SR9009 的小分子，它是治疗诱导的衰老（TIS）和致癌基因诱导的衰老（OIS）中的一种有效的 SASP 抑制剂。机制研究表明，SR9009 通过激活 NRF2 通路抑制 SASP 和全 DNA 损伤反应（DDR）的激活，从而通过调节抗氧化酶的表达降低 ROS 水平。我们进一步发现，SR9009 能有效预防辐射诱导和致癌基因诱导的衰老小鼠模型中的细胞衰老，并抑制 SASP，从而减轻免疫细胞浸润。总之，我们的研究结果表明，SR9009 通过体外和体内的 NRF2 通路预防细胞衰老，激活 NRF2 可能是预防细胞衰老的一种新的治疗策略。
