Laboratory of Cell Signaling, Graduate School of Pharmaceutical Sciences, The University of Tokyo, Tokyo, Japan.
Cell Signaling and Stress Responses Laboratory, Advanced Research Institute (ARIS), Tokyo Medical and Dental University, Tokyo, Japan.
Commun Biol. 2024 Jun 5;7(1):691. doi: 10.1038/s42003-024-06386-0.
Cellular senescence is a stress-induced, permanent cell cycle arrest involved in tumor suppression and aging. Senescent cells secrete bioactive molecules such as pro-inflammatory cytokines and chemokines. This senescence-associated secretory phenotype (SASP) has been implicated in immune-mediated elimination of senescent cells and age-associated chronic inflammation. However, the mechanisms regulating the SASP are incompletely understood. Here, we show that the stress-responsive kinase apoptosis signal-regulating kinase 1 (ASK1) promotes inflammation in senescence and aging. ASK1 is activated during senescence and increases the expression of pro-inflammatory cytokines and chemokines by activating p38, a kinase critical for the SASP. ASK1-deficient mice show impaired elimination of oncogene-induced senescent cells and an increased rate of tumorigenesis. Furthermore, ASK1 deficiency prevents age-associated p38 activation and inflammation and attenuates glomerulosclerosis. Our results suggest that ASK1 is a driver of the SASP and age-associated chronic inflammation and represents a potential therapeutic target for age-related diseases.
细胞衰老是一种应激诱导的、永久性的细胞周期停滞，涉及肿瘤抑制和衰老。衰老细胞分泌生物活性分子，如促炎细胞因子和趋化因子。这种衰老相关的分泌表型（SASP）与免疫介导的衰老细胞清除和与年龄相关的慢性炎症有关。然而，调节 SASP 的机制尚不完全清楚。在这里，我们表明应激反应激酶凋亡信号调节激酶 1（ASK1）促进衰老和衰老过程中的炎症。ASK1 在衰老过程中被激活，并通过激活 p38 增加促炎细胞因子和趋化因子的表达，p38 是 SASP 的关键激酶。ASK1 缺陷小鼠表现出诱导性致癌基因衰老细胞清除受损和肿瘤发生率增加。此外，ASK1 缺乏可防止与年龄相关的 p38 激活和炎症，并减轻肾小球硬化。我们的结果表明，ASK1 是 SASP 和与年龄相关的慢性炎症的驱动因素，代表了与年龄相关疾病的潜在治疗靶点。
