神经炎症导致神经元死亡的数量甚至比病理蛋白杀死的神经元更多。cGAS（即环鸟苷酸-腺苷酸合成酶）能检测细胞中的双链DNA，当识别到进入细胞的微生物DNA后，cGAS与之结合并激活自身的酶活性，所产生的信号分子继而激活位于内质网的STING蛋白（即干扰素基因刺激器）；随后，STING信号通路触发免疫反应，诱导一系列与炎症相关的基因表达。cGAS–STING通路是外周器官和大脑衰老相关炎症的驱动因素，并揭示了阻断cGAS-STING信号传导是阻止老年神经退行性过程的潜在策略（试药H-151）。本文是衰老、认知衰退、慢性炎症关联的基础医学研究论文。
(Translated by Baidu: )
Nature: Anti inflammation is the key to anti aging! Immunologists have found a new method to delay cognitive decline: a small molecule inhibitor H-151 (known as the interferon gene stimulator) that blocks STING protein
Neuroinflammation causes even more neuronal death than pathological proteins kill. CGAS (Cyclic Guanylate Adenylate Synthase) can detect double stranded DNA in cells. After recognizing the microbial DNA entering the cell, cGAS binds to it and activates its own enzyme activity. The generated signal molecules then activate the STING protein located in the endoplasmic reticulum (i.e. interferon gene stimulator); Subsequently, the STING signaling pathway triggers an immune response, inducing the expression of a series of genes related to inflammation. The cGAS STING pathway is a driving factor for age-related inflammation in peripheral organs and the brain, and it has been revealed that blocking cGAS STING signaling is a potential strategy to prevent neurodegenerative processes in the elderly (trial drug H-151). This article is a fundamental medical research paper on the association between aging, cognitive decline, and chronic inflammation.
（百度翻訳： ）
《自然》：抗炎症こそアンチエイジング！免疫学者は認知衰退を遅らせる新しい方法を見つけたSTINGタンパク質を遮断する小分子抑制剤H-151（すなわちインターフェロン遺伝子刺激器）
神経炎症によるニューロン死の数は、病理タンパク質によって殺されたニューロンよりも多い。cGAS（すなわちシクログアニル酸−アデノシン合成酵素）は細胞中の二本鎖DNAを検出することができ、細胞に入った微生物DNAを認識した後、cGASはそれと結合して自身の酵素活性を活性化し、発生した信号分子は次に内質網に位置するSTINGタンパク質（すなわちインターフェロン遺伝子刺激器）を活性化する、その後、STINGシグナルパスは免疫反応をトリガし、炎症に関連する一連の遺伝子発現を誘導する。cGAS−STINGパスは末梢器官と脳の老化に関連する炎症の駆動因子であり、cGAS−STING信号伝導を遮断することは老年神経の退行性過程を阻止する潜在的な戦略であることを明らかにした（試薬H−151）。本文は老化、認知衰退、慢性炎症関連の基礎医学研究論文である。
期刊：Nature
发表时间：2023/08/02
数字识别码：10.1038/s41586-023-06373-1
摘要：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.
