Nature agingAug 26, 2026

Mice lacking cGAS show early aging linked to activation of repetitive DNA and inflammation

Longevity & Aging Weekly Brief ↗PubMed ↗DOI ↗OA ↗

Updated Aug 28, 2026

Abstract

cGAS knockout mice exhibit an accelerated-aging phenotype with increased inflammation and reduced lifespan.

cGAS knockout mice have a shortened median lifespan and heightened frailty compared to wild-type mice.
Increased transcription of long interspersed nuclear element 1 (LINE1) retrotransposons is observed in cGAS knockout mice.
Decreased DNA methylation on LINE1 elements and elevated levels of cytoplasmic LINE1 complementary DNA contribute to inflammation.
A smoothed H3K9me3 chromatin landscape and greater chromatin accessibility are present in cells from cGAS knockout mice.
cGAS is implicated in maintaining heterochromatin organization in the nucleus, beyond its role as a DNA sensor.

Simplified

Aging-associated inflammation is a driver of multiple age-associated diseases. Cyclic GMP-AMP synthase (cGAS) contributes to inflammaging by responding to endogenously-derived cytoplasmic DNA in aged cells. Although cGAS-knockout (KO) mice are viable, their aging has not been characterized. Unexpectedly, we found that cGAS KO mice exhibit an accelerated-aging phenotype, with induction of inflammation in multiple organs. cGAS KO mice display shortened median lifespan and increased frailty relative to wild-type mice. They show increased transcription of long interspersed nuclear element 1 (LINE1) retrotransposons, decreased DNA methylation on LINE1 elements and high levels of cytoplasmic LINE1 complementary DNA, which triggers inflammation, and this phenotype is recapitulated by cGAS knockdown in vitro. Furthermore, cells from cGAS KO mice show a smoothed H3K9me3 chromatin landscape and increased chromatin accessibility. In summary, our results show that cGAS functions to maintain heterochromatin organization in the nucleus, independent of its cytoplasmic role as a DNA sensor or its catalytic activity, with implications for geroprotective strategies targeting this pathway.