cGAS-deficient mice display premature aging associated with derepression of LINE1 elements and inflammation.

John C Martinez, Francesco Morandini, Cheyenne Rechsteiner, Lucinda Fitzgibbons, Natasha Sieczkiewicz, Xiaoyan Liao, Weijie He, Sung Jae Bae, Michael E Meadow, Eric Hillpot, Joseph Cutting, Victoria Paige, Max Zacher, Seyed Ali Biashad, Matthew Simon, Ines Meula-Zarzuela, Mario D Cordero, Martin S Taylor, John M Sedivy, Andrei Seluanov, Vera Gorbunova

Translational Biomedical Sciences Program, University of Rochester Medical Center, Rochester, NY, USA.Translational Biomedical Sciences Program, University of Rochester Medical Center, Rochester, NY, USA. · pubmed

Paper

Abstract

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.

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Research summary

The paper demonstrates that cGAS maintains nuclear heterochromatin and suppresses LINE1 retrotransposons independently of its cytoplasmic DNA-sensing role, and that loss of this function leads to premature aging phenotypes. This is relevant because it identifies a novel, non-canonical mechanism of aging (epigenetic instability and retrotransposon derepression) driven by a key innate immune sensor, suggesting that cGAS inhibition might have complex, potentially detrimental effects on genomic stability and lifespan that must be considered in geroprotective strategies.

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