Loss of killifish cGAS attenuates age-related signatures but does not affect organismal life span

Abstract The cGAS/STING pathway is a central innate immune signaling pathway responsive to cytosolic DNA. Chronic activation of this pathway promotes numerous age-related pathologies, but its impact on lifespan remains unknown. Here we engineer a cGAS knockout (KO) in the turquoise killifish Nothobranchius furzeri to assess effects on physiology and aging. In cultured fibroblasts, cGAS deficiency results in elevated DNA damage but reduces radiation-induced senescence and enhances cellular proliferation. In vivo, cGAS KO attenuates DNA damage-induced transcriptional responses in young fish, and blunts age-associated transcriptional changes in old fish, consistent with dampening of senescence and aging. Accordingly, old cGAS KO animals exhibit lower levels of senescence-associated β-galactosidase activity and higher levels of cell proliferation, without detectable differences in immune infiltration. Despite these attenuated aging signatures, lifespan is not extended. Together, these findings reveal that while cGAS loss alleviates senescence and age-related signatures, additional mechanisms constrain longevity.