The cGAS-STING pathway in senescence and aging-related diseases: mechanisms and therapeutic opportunities

Abstract

The cGAS-STING pathway acts as a critical molecular hub connecting genomic instability with cellular senescence. Functioning as a key regulator of the innate immune system, this pathway detects aberrant cytoplasmic DNA to activate downstream inflammatory responses, thereby playing a pivotal role in aging-related diseases. This review systematically explores the core mechanisms by which the cGAS-STING pathway regulates cellular senescence, emphasizing its role in triggering senescence through the recognition of DNA damage signals (e.g., oxidative stress, telomere dysfunction) and promoting paracrine senescence effects via the production and release of the senescence-associated secretory phenotype (SASP). We focus on the crosstalk between this pathway and current research hotspots, including the hypoxic microenvironment, ammonia-induced cell death, neutrophil extracellular trap (NET) formation, and macrophage polarization, uncovering its intricate molecular network in cellular senescence regulation. Moreover, this review provides an in-depth analysis of the cGAS-STING pathway's pathological contributions and molecular mechanisms in aging-related diseases, along with a summary of potential therapeutic strategies targeting this pathway, based on recent advances. These findings provide a critical theoretical framework for understanding cellular senescence mechanisms and advancing anti-aging interventions.