GAS deficient mice display premature aging associated with loss of chromatin organization, derepression of LINE1 elements and induction of inflammation [Cut & Tag]

Cyclic GMP-AMP Synthase (cGAS) is a cytosolic DNA sensor that functions to activate interferon response upon detecting viral DNA in the cytoplasm. cGAS is also implicated in induction of inflammaging by responding to endogenous signals such as damaged DNA or LINE1 cDNA which forms in aged cells. While cGAS knockout mice are viable their aging has not been examined.

Unexpectedly, we found that cGAS knockout mice exhibit accelerated aging phenotype associated with induction of inflammation and DNA damage signaling. Cells from cGAS knockout mice showed increased overall chromatin accessibility, particularly on LINE1 (L1) transposons and inflammation genes. Transcription of L1 elements was also increased associated with high levels of cytoplasmic L1 DNA and expression of ORF1 protein.