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Peer-reviewedCC BY-NC-NDNature Aging

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

  • John C. Martinez1,2,3
  • Francesco Morandini1,4
  • Cheyenne Rechsteiner1,4
  • Lucinda Fitzgibbons1,4
  • Natasha Sieczkiewicz1,4
  • Xiaoyan Liao5,4
  • Weijie He1,4
  • Sung Jae Bae1,4
  • Michael E. Meadow1,4
  • Eric C. Hillpot1,4
  • Joseph Cutting1,4
  • Victoria Paige1,6
9 more authors
  • Max Zacher1,4
  • Seyed Ali Biashad1,4
  • Matthew A. Simon1
  • Inés Muela‐Zarzuela7
  • Mario David Cordero7
  • Martin S. Taylor8
  • John M. Sedivy8
  • Andrei Seluanov9,10
  • Vera A. Gorbunova11,12,13
13 affiliations
  1. 1Department of Biology, University of Rochester, Rochester, NY, USA
  2. 2Translational Biomedical Sciences Program, University of Rochester Medical Center, Rochester, NY, USA
  3. 3University of Rochester Medical Center
  4. 4University of Rochester
  5. 5Department of Surgical Pathology, University of Rochester Medical Center, Rochester, NY, USA
  6. 6Brown University
  7. 7Department of Molecular Biology and Biochemical Engineering, Universidad Pablo de Olavide, Seville, Spain
  8. 8Department of Molecular Biology, Cell Biology, and Biochemistry, Brown University, Providence, RI, USA
  9. 9Department of Biology, University of Rochester, Rochester, NY, USA. [email protected]
  10. 10Department of Medicine, University of Rochester Medical Center, Rochester, NY, USA. [email protected]
  11. 11Department of Biology, University of Rochester, Rochester, NY, USA. [email protected]
  12. 12Department of Medicine, University of Rochester Medical Center, Rochester, NY, USA. [email protected]
  13. 13Translational Biomedical Sciences Program, University of Rochester Medical Center, Rochester, NY, USA. [email protected]
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Abstract

Aging-associated inflammation, or 'inflammaging" is a driver of multiple age-associated diseases. Cyclic GMP-AMP Synthase (cGAS) is a cytosolic DNA sensor that functions to activate interferon response upon detecting viral DNA in the cytoplasm. cGAS contributes to inflammaging by responding to endogenous signals such as damaged DNA or LINE1 (L1) 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. Transcription of L1 elements was increased in both cGAS knockout mice and in cGAS siRNA knockdown cells associated with high levels of cytoplasmic L1 DNA and expression of ORF1 protein. Cells from cGAS knockout mice showed increased chromatin accessibility and decreased DNA methylation on L1 transposons. Stimulated emission depletion microscopy (STED) showed that cGAS forms nuclear condensates that co-localize with H3K9me3 heterochromatin marks, and H3K9me3 pattern is disrupted in cGAS knockout cells. Taken together these results suggest a previously undescribed role for cGAS in maintaining heterochromatin on transposable elements. We propose that loss of cGAS leads to loss of chromatin organization, de-repression of transposable elements and induction of inflammation resulting in accelerated aging.

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Cite

BibTeXRIS
BibTeX
@article{martinez2026cgasdeficient,
  title = {{cGAS-deficient mice display premature aging associated with derepression of LINE1 elements and inflammation}},
  author = {John C. Martinez and Francesco Morandini and Cheyenne Rechsteiner and Lucinda Fitzgibbons and Natasha Sieczkiewicz and Xiaoyan Liao and Weijie He and Sung Jae Bae and Michael E. Meadow and Eric C. Hillpot and Joseph Cutting and Victoria Paige and Max Zacher and Seyed Ali Biashad and Matthew A. Simon and Inés Muela‐Zarzuela and Mario David Cordero and Martin S. Taylor and John M. Sedivy and Andrei Seluanov and Vera A. Gorbunova},
  journal = {Nature Aging},
  year = {2026},
  month = aug,
  doi = {10.1038/s43587-026-01206-y},
  url = {https://doi.org/10.1038/s43587-026-01206-y},
  note = {CC BY-NC-ND},
}
RIS
TY  - JOUR
TI  - cGAS-deficient mice display premature aging associated with derepression of LINE1 elements and inflammation
AU  - John C. Martinez
AU  - Francesco Morandini
AU  - Cheyenne Rechsteiner
AU  - Lucinda Fitzgibbons
AU  - Natasha Sieczkiewicz
AU  - Xiaoyan Liao
AU  - Weijie He
AU  - Sung Jae Bae
AU  - Michael E. Meadow
AU  - Eric C. Hillpot
AU  - Joseph Cutting
AU  - Victoria Paige
AU  - Max Zacher
AU  - Seyed Ali Biashad
AU  - Matthew A. Simon
AU  - Inés Muela‐Zarzuela
AU  - Mario David Cordero
AU  - Martin S. Taylor
AU  - John M. Sedivy
AU  - Andrei Seluanov
AU  - Vera A. Gorbunova
PY  - 2026
DA  - 2026/08/25
JO  - Nature Aging
DO  - 10.1038/s43587-026-01206-y
UR  - https://doi.org/10.1038/s43587-026-01206-y
AB  - Aging-associated inflammation, or 'inflammaging" is a driver of multiple age-associated diseases. Cyclic GMP-AMP Synthase (cGAS) is a cytosolic DNA sensor that functions to activate interferon response upon detecting viral DNA in the cytoplasm. cGAS contributes to inflammaging by responding to endogenous signals such as damaged DNA or LINE1 (L1) 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. Transcription of L1 elements was increased in both cGAS knockout mice and in cGAS siRNA knockdown cells associated with high levels of cytoplasmic L1 DNA and expression of ORF1 protein. Cells from cGAS knockout mice showed increased chromatin accessibility and decreased DNA methylation on L1 transposons. Stimulated emission depletion microscopy (STED) showed that cGAS forms nuclear condensates that co-localize with H3K9me3 heterochromatin marks, and H3K9me3 pattern is disrupted in cGAS knockout cells. Taken together these results suggest a previously undescribed role for cGAS in maintaining heterochromatin on transposable elements. We propose that loss of cGAS leads to loss of chromatin organization, de-repression of transposable elements and induction of inflammation resulting in accelerated aging.
SN  - 2662-8465
ER  -