Cellular senescence is triggered by various distinct stresses and characterized by a permanent cell cycle arrest. Senescent cells secrete a variety of inflammatory factors, collectively referred to as the senescence-associated secretory phenotype (SASP). The mechanism(s) underlying the regulation of the SASP remains incompletely understood. Here we define a role for innate DNA sensing in the regulation of senescence and the SASP. We find that cyclic GMP-AMP synthase (cGAS) recognizes cytosolic chromatin fragments in senescent cells. The activation of cGAS, in turn, triggers the production of SASP factors via stimulator of interferon genes (STING), thereby promoting paracrine senescence. We demonstrate that diverse stimuli of cellular senescence engage the cGAS-STING pathway in vitro and we show cGAS-dependent regulation of senescence following irradiation and oncogene activation in vivo. Our findings provide insights into the mechanisms underlying cellular senescence by establishing the cGAS-STING pathway as a crucial regulator of senescence and the SASP.

中文翻译：

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通过 cGAS 对胞质染色质片段的先天免疫感应可促进衰老。


细胞衰老是由各种不同的应激引发的，其特征是永久性的细胞周期停滞。衰老细胞分泌多种炎症因子，统称为衰老相关分泌表型（SASP）。 SASP 监管的机制仍不完全清楚。在这里，我们定义了先天 DNA 传感在衰老和 SASP 调节中的作用。我们发现环 GMP-AMP 合酶 (cGAS) 识别衰老细胞中的胞质染色质片段。 cGAS 的激活反过来又通过干扰素基因刺激物 (STING) 触发 SASP 因子的产生，从而促进旁分泌衰老。我们证明细胞衰老的多种刺激在体外参与 cGAS-STING 通路，并且我们在体内展示了照射和癌基因激活后衰老的 cGAS 依赖性调节。我们的研究结果通过建立 cGAS-STING 通路作为衰老和 SASP 的关键调节因子，为细胞衰老的机制提供了见解。