Systemic LINE ‐1 RNA in Plasma Extracellular Vesicles Drives Neuroinflammation and Cognitive Dysfunction via cGAS ‐ STING Pathway in Aging

ABSTRACT Aging is characterized by systemic inflammation and progressive cognitive decline, yet the molecular pathways linking peripheral aging signals to central nervous system dysfunction remain elusive. Here, we identify plasma extracellular vesicle (EV)‐derived long interspersed nuclear element‐1 (LINE‐1) RNA as a potent systemic aging factor mediating neuroinflammation and cognitive impairment in humans and mice. Plasma EV LINE‐1 RNA levels markedly increase with age and strongly correlate with established brain aging biomarkers, including neurofilament light chain (NFL). Utilizing mouse models, we demonstrate that EVs from aged individuals penetrate the blood–brain barrier, deliver LINE‐1 RNA to microglia, and initiate cGAS‐STING signaling, leading to pronounced neuroinflammation, neuronal damage, and impaired cognition. Pharmacological blockade of LINE‐1 reverse transcription by 3TC or inhibition of STING signaling with H151 significantly ameliorates these age‐associated deficits. Notably, aged peripheral tissues, especially brain and lung, emerge as primary sources of pro‐aging EVs enriched with LINE‐1 RNA, revealing a novel mechanism of inter‐organ communication in aging. Our findings position EV‐derived LINE‐1 RNA and its downstream cGAS‐STING pathway as critical systemic drivers of brain aging, presenting promising therapeutic targets for mitigating cognitive decline and age‐related neurodegenerative diseases.