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cGAS-STING signaling in aging and age-related diseases: therapeutic promise and precaution.

Yingying Xu·Weidong Wu·Yifan Guo·Wenhong Wang·Jingsheng Zhu·Weihua Xiao
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Abstract

Endogenous cytoplasmic DNA (cytoDNA) is increasingly recognized as a mediator of tissue dysfunction and disease progression during aging. As a major cytosolic DNA-sensing pathway, the cyclic GMP-AMP synthase-stimulator of interferon genes (cGAS-STING) pathway can translate aging-associated cytoDNA accumulation into innate immune and inflammatory programs. This review summarizes the evolutionary and signaling features of the cGAS-STING cascade and critically discusses its crosstalk with aging-associated intracellular molecular threats, including nuclear genomic and chromatin stress, mitochondrial dysfunction, oxidative-metabolic stress, and defective clearance of nucleic acids or damaged organelles. We further synthesize evidence linking dysregulated cGAS-STING activation to inflammatory remodeling, senescence-associated changes, cell injury, fibrosis, and tissue dysfunction, while highlighting the context-dependent roles of this pathway across physiological aging and ARDs. Finally, we discuss the therapeutic potential and limitations of cGAS-STING modulation, emphasizing that successful translation will require context-defined therapeutic windows, tissue- and cell-specific targeting, subcellular compartmentalization, and long-term safety assessment.

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HumansAgingNucleotidyltransferasescGAS-STING Signaling PathwayAnimalsMembrane ProteinsSTING ProteinCyclic Guanosine Monophosphate-Adenosine Monophosphate SynthaseSignal TransductionAging-related diseasesCytosolic DNATherapeutic modulationcGAS–STING signalingJournal ArticleReview

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Yingying Xu, Weidong Wu, Yifan Guo, Wenhong Wang, Jingsheng Zhu, Weihua Xiao. 2026-08-24. cGAS-STING signaling in aging and age-related diseases: therapeutic promise and precaution.. https://doi.org/10.1007/s12272-026-01633-w

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