cGAS-STING signaling may connect brain aging, cellular senescence, neuroinflammation, and neurodegenerative disease processes.
Evidence
This review synthesizes molecular links between cytoplasmic DNA sensing, IFN-I and NF-kB signaling, , CNS aging, and neurodegeneration.
Caveat
The abstract presents mechanistic and therapeutic perspectives rather than direct clinical evidence that targeting cGAS-STING improves neurodegenerative outcomes.
Simplified
Aging is a major risk factor for neurodegenerative diseases, yet the underlying mechanisms linking aging to neurodegeneration remain incompletely understood. The cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) pathway plays a critical role in sensing mislocalized cytoplasmic DNA, triggering innate immune responses such as type I interferon (IFN-I) and NF-κB signaling, and promoting senescence-associated secretory phenotypes (). In the aging central nervous system (CNS), cellular senescence is accompanied by mitochondrial DNA (mtDNA) leakage, nuclear DNA damage, and other changes that may aberrantly activate the . This activation drives neuroinflammation, potentially increasing susceptibility to neurodegenerative diseases or exacerbating pre-existing pathology. Conversely, neurodegenerative disease-related processes-such as pathological protein aggregation-can further stimulate cGAS-STING signaling, amplifying inflammatory cascades and accelerating cellular senescence. This review explores the molecular mechanisms linking cGAS-STING activation to neurodegeneration and discusses potential therapeutic strategies targeting this pathway.
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