Li Haozheng, Zheng Yuanming, Yuan Chunlei, Wang Jiayi, Zhao Xiaying, Yang Ming, Xiong Defei, Yang Yenan, Dai Yunpeng, Gao Yiming, Wang Yuqi, Xue Lei, Wang Gang
State Key Laboratory of Genetics and Development of Complex Phenotypes, School of Life Sciences and Zhongshan Hospital, Fudan University, Shanghai, China.
School of Biological Sciences, The University of Hong Kong, Hong Kong, China.
Cell Discov. 2025 Aug 19;11(1):69. doi: 10.1038/s41421-025-00820-1.
A hallmark of aging is chronic systemic inflammation, which is exacerbated by the hypersecretory aging phenotype known as the senescence-associated secretory phenotype (SASP). How the SASP is initiated to accelerate tissue inflammation and aging is an outstanding question in aging biology. Here, we showed that phosphorylation of the Mediator subunit MED15 at T603 is able to control the SASP and aging. Transforming growth factor-β selectively induces CDK1-mediated MED15 T603 phosphorylation to control SASP gene expression. The MED15 T603 dephosphorylated mutant (T603A) inhibits the SASP and cell senescence, whereas the T603 phosphorylation-mimicking mutant (T603D) has the opposite effect. Mechanistically, forkhead box protein A1 preferentially binds to unphosphorylated but not phosphorylated MED15 at T603 to suppress SASP gene expression. Notably, aging mice harboring dephosphorylated mutation in this phosphosite exhibit improved learning and memory through the attenuation of the SASP across tissues. Overall, our study indicates that MED15 T603 phosphorylation serves as a control switch for SASP production, which underlies tissue aging and cognitive decline and provides a novel target for age-related pathogenesis.
衰老的一个标志是慢性全身炎症，而被称为衰老相关分泌表型（SASP）的分泌亢进衰老表型会加剧这种炎症。SASP如何启动以加速组织炎症和衰老，是衰老生物学中一个尚未解决的问题。在这里，我们表明，中介体亚基MED15在T603位点的磷酸化能够控制SASP和衰老。转化生长因子-β选择性地诱导CDK1介导的MED15 T603磷酸化，以控制SASP基因表达。MED15 T603去磷酸化突变体（T603A）抑制SASP和细胞衰老，而T603磷酸化模拟突变体（T603D）则具有相反的效果。从机制上讲，叉头框蛋白A1优先结合未磷酸化而非T603位点磷酸化的MED15，以抑制SASP基因表达。值得注意的是，在该磷酸位点携带去磷酸化突变的衰老小鼠，通过减轻全身组织的SASP，表现出学习和记忆能力的改善。总体而言，我们的研究表明，MED15 T603磷酸化作为SASP产生的控制开关，是组织衰老和认知衰退的基础，并为与年龄相关的发病机制提供了一个新的靶点。
