Low-grade inflammation is a hallmark of old age and a central driver of ageing-associated impairment and disease¹. Multiple factors can contribute to ageing-associated inflammation²; however, the molecular pathways that transduce aberrant inflammatory signalling and their impact in natural ageing remain unclear. Here we show that the cGAS–STING signalling pathway, which mediates immune sensing of DNA³, is a critical driver of chronic inflammation and functional decline during ageing. Blockade of STING suppresses the inflammatory phenotypes of senescent human cells and tissues, attenuates ageing-related inflammation in multiple peripheral organs and the brain in mice, and leads to an improvement in tissue function. Focusing on the ageing brain, we reveal that activation of STING triggers reactive microglial transcriptional states, neurodegeneration and cognitive decline. Cytosolic DNA released from perturbed mitochondria elicits cGAS activity in old microglia, defining a mechanism by which cGAS–STING signalling is engaged in the ageing brain. Single-nucleus RNA-sequencing analysis of microglia and hippocampi of a cGAS gain-of-function mouse model demonstrates that engagement of cGAS in microglia is sufficient to direct ageing-associated transcriptional microglial states leading to bystander cell inflammation, neurotoxicity and impaired memory capacity. Our findings establish the cGAS–STING pathway as a driver of ageing-related inflammation in peripheral organs and the brain, and reveal blockade of cGAS–STING signalling as a potential strategy to halt neurodegenerative processes during old age.

低度炎症是老年的标志，也是衰老相关损伤和疾病的主要驱动因素¹。多种因素可能导致衰老相关炎症²；然而，转导异常炎症信号的分子途径及其对自然衰老的影响仍不清楚。^{在这里，我们表明，介导 DNA 3}免疫感应的 cGAS-STING 信号通路是衰老过程中慢性炎症和功能衰退的关键驱动因素。阻断 STING 可抑制衰老人类细胞和组织的炎症表型，减轻多个外周器官和小鼠大脑中与衰老相关的炎症，并改善组织功能。着眼于衰老的大脑，我们发现 STING 的激活会触发反应性小胶质细胞转录状态、神经变性和认知能力下降。受到干扰的线粒体释放的胞质 DNA 会在老小胶质细胞中引发 cGAS 活性，从而定义了 cGAS-STING 信号传导参与衰老大脑的机制。对 cGAS 功能获得性小鼠模型的小胶质细胞和海马的单核 RNA 测序分析表明，cGAS 在小胶质细胞中的参与足以指导与衰老相关的转录小胶质细胞状态，从而导致旁观者细胞炎症、神经毒性和记忆能力受损。我们的研究结果表明，cGAS-STING 通路是周围器官和大脑中与衰老相关的炎症的驱动因素，并揭示了 cGAS-STING 信号传导的阻断是阻止老年神经退行性过程的潜在策略。