Senescent microglia are a distinct microglial phenotype present in aging brain that have been implicated in the progression of aging and age-related neurodegenerative diseases. However, the specific mechanisms that trigger microglial senescence are largely unknown. Quinolinic acid (QA) is a cytotoxic metabolite produced upon abnormal activation of microglia. Brain aging and age-related neurodegenerative diseases have an elevated concentration of QA. In the present study, we investigated whether QA promotes aging and aging-related phenotypes in microglia and C. elegans. Here, we demonstrate for the first time that QA, secreted by abnormal microglial stimulation, induces impaired mitophagy by inhibiting mitolysosome formation and consequently promotes the accumulation of damaged mitochondria due to reduced mitochondrial turnover in microglial cells. Defective mitophagy caused by QA drives microglial senescence and poor healthspan in C. elegans. Moreover, oxidative stress can mediate QA-induced mitophagy impairment and senescence in microglial cells. Importantly, we found that restoration of mitophagy by mitophagy inducer, urolithin A, prevents microglial senescence and improves healthspan in C. elegans by promoting mitolysosome formation and rescuing mitochondrial turnover inhibited by QA. Thus, our study indicates that mitolysosome formation impaired by QA is a significant aetiology underlying aging-associated changes. QA-induced mitophagy impairment plays a critical role in neuroinflammation and age-related diseases. Further, our study suggests that mitophagy inducers such as urolithin A may offer a promising anti-aging strategy for the prevention and treatment of neuroinflammation-associated brain aging diseases.

中文翻译：

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喹啉酸损害线虫线粒体自噬，促进小胶质细胞衰老和健康寿命不佳：衰老过程受损的机制

衰老小胶质细胞是衰老大脑中存在的一种独特的小胶质细胞表型，与衰老和与年龄相关的神经退行性疾病的进展有关。然而，引发小胶质细胞衰老的具体机制在很大程度上尚不清楚。喹啉酸 (QA) 是小胶质细胞异常激活时产生的细胞毒性代谢物。大脑衰老和与年龄相关的神经退行性疾病的 QA 浓度升高。在本研究中，我们研究了 QA 是否会促进小胶质细胞和线虫的衰老和衰老相关表型。在这里，我们首次证明，由异常小胶质细胞刺激分泌的QA通过抑制线粒体溶酶体形成来诱导受损的线粒体自噬，从而由于小胶质细胞中线粒体周转减少而促进受损线粒体的积累。 QA 引起的线粒体自噬缺陷会导致线虫中的小胶质细胞衰老和健康寿命不佳。此外，氧化应激可以介导 QA 诱导的小胶质细胞线粒体自噬损伤和衰老。重要的是，我们发现通过线粒体自噬诱导剂尿石素 A 恢复线粒体自噬，可以通过促进线粒体溶酶体形成和挽救 QA 抑制的线粒体周转来防止小胶质细胞衰老并改善秀丽隐杆线虫的健康寿命。因此，我们的研究表明，QA 损害的线粒体溶酶体形成是衰老相关变化的一个重要病因。 QA 诱导的线粒体自噬损伤在神经炎症和年龄相关疾病中起着至关重要的作用。此外，我们的研究表明，尿石素 A 等线粒体自噬诱导剂可能为预防和治疗神经炎症相关的脑衰老疾病提供一种有前途的抗衰老策略。