The role and mechanisms of the cGAS-STING signaling pathway in age-related pathophysiological processes: challenges and therapeutic strategies.
TL;DR
The mechanisms of cGAS-STING activation in aging-including mitochondrial DNA leakage, nuclear envelope disruption, and retrotransposon activation-and its role in driving cellular senescence and the senescence-associated secretory phenotype (SASP) are reviewed.
Abstract
Agingis characterized by chronic low-grade inflammation ("inflammaging"), a key driver of functional decline and age-related diseases. The cGAS-STING pathway, which senses cytosolic DNA, has emerged as a central mediator of this sterile inflammation. Here, we systematically review the mechanisms of cGAS-STING activation in aging-including mitochondrial DNA leakage, nuclear envelope disruption, and retrotransposon activation-and its role in driving cellular senescence and the senescence-associated secretory phenotype (SASP). We examine the pathway's pathological contributions across multiple systems, including the nervous, cardiovascular, musculoskeletal, metabolic, reproductive, and sensory systems. We also discuss therapeutic strategies targeting cGAS-STING, encompassing small-molecule inhibitors, natural products, nanomedicine, and gene therapy. Furthermore, we integrate AlphaFold3-based structural modeling and CB-DOCK2 molecular docking analyses to characterize the binding modes and affinities of key inhibitors (e.g., H-151, RU.521, VBIT-4, Mdivi-1) to cGAS, STING, VDAC1, and DRP1, providing a structural rationale for their therapeutic potential. Finally, we address current challenges, including tissue-specific effects and pathway complexity, and highlight future directions for translating these insights into clinical interventions for aging and age-associated disorders.