Cytosolic DNA sensing pathway in senescence and aging: Underlying mechanisms and targeted interventions

The global increase in the older population presents major healthcare challenges due to increased prevalence of age-related diseases. Cellular senescence is a defining feature of aging, and the cyclic GMP-AMP synthase (cGAS) and stimulator of interferon genes (STING) pathway plays a central role in orchestrating the inflammatory responses linked to senescent cells. This pathway detects cytosolic self-DNA arising from genomic instability and mitochondrial dysfunction, triggering inflammatory programs including the senescence-associated secretory phenotype (SASP). Recent studies reveal an age-dependent impairment in the canonical cGAS-STING activation, while a non-canonical signaling mode emerges that maintains chronic inflammation and senescence phenotypes. These mechanistic insights underscore the dual role of cGAS-STING in innate immunity and senescence-associated inflammation, linking DNA sensing to tissue degeneration in aging. This review aims to comprehensively summarize the underlying molecular mechanisms by which the cGAS-STING pathway regulates cellular senescence and aging. It also highlights how this axis contributes to age-related pathologies, and discusses current advances in targeted interventions that modulate this pathway. Given its critical role, the cGAS-STING axis represents a promising therapeutic target for ameliorating chronic inflammation, delaying senescence, and improving healthspan in an aging society.