Mice lacking cGAS, a protein that detects DNA outside the nucleus, showed disrupted genome packaging, activation of LINE1 mobile elements, and shorter lifespans
Mice lacking cGAS, a protein that detects DNA outside the nucleus, showed disrupted genome packaging, activation of LINE1 mobile elements, and shorter lifespans
A Nature Aging study published on August 25, 2026 compared 76 mice with cGAS genetically disabled and 99 control animals. Their median lifespans were 1.64 years and 2.01 years, respectively. The authors traced how loss of the protein weakens the dense packaging of DNA and releases LINE1 elements, repetitive genomic sequences that can generate new copies of themselves.
cGAS usually acts in the cytoplasm, where it detects double-stranded DNA and initiates an inflammatory signal. The authors therefore expected its removal to reduce age-related inflammation.
“We initially expected mice without cGAS to live longer and remain healthy for longer. Instead, we found the opposite.”
At 18 months, mice with cGAS disabled had a higher frailty index, a scale based on visible signs of aging, including coat condition, posture, and tremor. The researchers found inflammation or fibrosis in the lungs, liver, and pancreas. In fibrosis, normal tissue is replaced by dense connective tissue. Ovarian fibrosis was already greater at nine months. They then looked for the cellular sequence of events linking these findings.
LINE1 is normally kept silent. Cells lacking cGAS had higher levels of LINE1 RNA, its ORF1p protein, and LINE1 DNA copies in the cytoplasm. Genes associated with inflammation were also more active. The authors attribute this pattern to the accumulation of LINE1 cDNA.
The authors compared several interventions to distinguish loss of the protein itself from loss of its usual signaling activity. RU.521 blocks the production of cGAMP, the signaling molecule generated by cGAS. The March study on PEP also inhibited cGAS activity and thereby reduced cGAMP production. Reducing cGAS increased LINE1, whereas blocking cGAMP production did not. LINE1 also remained suppressed in mice lacking STING, which transmits the cGAS signal, and in mice lacking the PYHIN family of DNA sensors. Restoring cGAS in primary cells from mice lacking cGAS reduced the levels of LINE1 and the inflammatory gene IL-1β. These controls link the increase in LINE1 to the loss of cGAS itself rather than to the interruption of a single downstream signal.
The authors then examined the nucleus, where DNA is packaged into chromatin. Densely packed regions help keep repetitive sequences silent. Measurements of DNA accessibility identified 1 392 regions that had become substantially more open, including young LINE1 families. DNA methylation, a chemical mark associated with suppression, decreased in 84 families of repetitive elements. Microscopy and analysis of H3K9me3, a marker of dense chromatin, showed that this mark had become more diffusely distributed throughout the nucleus. Together, these measurements link the loss of cGAS to weaker chromatin packaging and link that change to LINE1 activation.
Human skin connective tissue cells in which cGAS was reduced for three days also showed increased levels of RNA from the human LINE1 variant L1HS and increased ORF1p protein. The authors measured organism-level signs of aging in mice. Interventions designed to reduce inflammatory cGAS signaling can be evaluated by testing whether they preserve the protein’s nuclear function, which keeps LINE1 suppressed.