cGAS loss curbs senescence without extending killifish lifespan
The cGAS protein triggers inflammation when it detects cytosolic DNA, contributing to chronic inflammation in aging. In killifish, knocking out cGAS reduced age-related cellular senescence but did not extend lifespan. This highlights the dual role of cGAS in both harmful inflammation and beneficial DNA repair.
The cGAS protein serves dual roles: it triggers inflammation when detecting cytosolic DNA, yet also influences nuclear DNA repair, including inhibiting homologous recombination. In killifish, CRISPR-based cGAS knockout reduced senescence markers, dampened age-related gene expression changes, and preserved proliferative capacity, but failed to alter overall lifespan. This suggests cGAS's inflammatory contribution to aging is not a primary lifespan determinant, while its DNA repair functions may be essential. Notably, species-specific cGAS variants—like naked mole rat cGAS in mice—can improve repair and reduce aging impact, whereas certain human variants lower inflammation, highlighting context-dependent effects.
This finding could reshape how anti-aging therapies targeting inflammation are evaluated, as reducing cGAS activity may improve healthspan without extending longevity. Patients with chronic inflammatory conditions might see symptom relief, but expectations for lifespan gains may need adjustment. The dual nature of cGAS also cautions against broad inhibition, potentially guiding more selective interventions that preserve DNA repair while curbing harmful inflammation.