Mechanisms of cGAS-STING-mediated chronic inflammation and targeted interventions in brain aging

Brain aging is a critical risk factor for various neurodegenerative diseases, with chronic neuroinflammation being one of its core features. The innate immune cGAS-STING signaling pathway, acting as a key sensor of endogenous damage, has emerged as a nexus linking cellular senescence to chronic inflammation. During brain aging, genomic damage and mitochondrial dysfunction facilitate the aberrant accumulation of cytosolic double-stranded DNA. Together with transposable element activation and intercellular propagation of cGAMP, these factors drive sustained activation of the cGAS-STING signaling pathway. This activation not only drives the transcription of interferons and pro-inflammatory cytokines but also accelerates brain functional decline by reshaping neural cell physiology, as manifested by the polarization of glial cells toward a pro-inflammatory phenotype and the release of a senescence-associated secretory phenotype, as well as the induction of cellular stress and apoptosis in neurons, ultimately leading to disruption of synaptic homeostasis and loss of specific neuronal subpopulations. Consequently, targeting the cGAS-STING signaling pathway has emerged as a potential strategy to mitigate brain aging. This review systematically summarizes the sources and mechanisms of cGAS-STING activation during brain aging, with a particular focus on dissecting the molecular mechanisms by which this pathway drives and sustains inflammatory responses and functional remodeling across distinct neural cell types. Furthermore, we explore its implications in age-related neurodegenerative diseases and potential interventional strategies, aiming to provide a theoretical basis and novel perspectives for blocking aging-associated inflammatory cascades in the brain.