cGAS-STING signaling in brain aging and neurodegeneration: molecular links and therapeutic perspectives

Abstract

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 (SASP). 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 cGAS-STING pathway. 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.