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The intersection of TREX1, cGAS, STING and the DNA damage theory of aging
Kate M Jones1,2, Samuel D Chauvin1,2, Jonathan J Miner1,2,3,4,5
1Division of Rheumatology, Department of Medicine, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, United States.
Abstract:
Genetic syndromes of immune dysregulation have opened a door toward understanding mechanisms linking inflammation, premature aging, and normal aging. Here, we discuss new insights into the relationship between DNA damage, premature senescence, and nucleic acid-sensing pathways that detect or regulate DNA damage. First, we review mechanisms by which the DNA exonuclease TREX1 negatively regulates the cytosolic DNA sensor cGAS and its downstream effector STING, and we propose a model of TREX1-mediated DNA damage and cellular senescence that implicates age-related, inducible TREX1 expression in the context of genetic disease and inflamm-aging. Our central thesis is that two TREX1-associated diseases-Aicardi-Goutières syndrome (AGS) and retinal vasculopathy with cerebral leukoencephalopathy (RVCL or RVCL-S), historically regarded as inflammatory conditions-can serve as models for research into mechanisms of premature aging.
Insights
Genetic syndromes reveal how DNA damage and inflammation link to premature aging. Studying Aicardi-Goutières syndrome and RVCL offers insights into cellular senescence and inflamm-aging mechanisms.
Area of Science:
- Immunology
- Genetics
- Aging Research
Background:
- Genetic immune dysregulation syndromes offer insights into inflammation, premature aging, and normal aging processes.
- DNA damage, premature senescence, and nucleic acid-sensing pathways are key areas of investigation.
- TREX1 (a DNA exonuclease) plays a crucial role in regulating cytosolic DNA sensors like cGAS and STING.
Purpose of the Study:
- To explore the relationship between DNA damage, cellular senescence, and nucleic acid-sensing pathways.
- To propose a model of TREX1-mediated DNA damage and cellular senescence.
- To investigate Aicardi-Goutières syndrome (AGS) and retinal vasculopathy with cerebral leukoencephalopathy (RVCL/RVCL-S) as models for premature aging research.
Main Methods:
- Review of mechanisms involving TREX1, cGAS, and STING.
- Development of a model for TREX1-mediated DNA damage and senescence.
- Analysis of genetic diseases (AGS and RVCL/RVCL-S) as models for aging.
Main Results:
- TREX1 negatively regulates the cGAS-STING pathway.
- Age-related, inducible TREX1 expression may link genetic disease and inflamm-aging.
- AGS and RVCL/RVCL-S serve as valuable models for studying premature aging mechanisms.
Conclusions:
- TREX1-associated genetic diseases provide a framework for understanding premature aging.
- Cellular senescence and DNA damage pathways are implicated in aging.
- Further research into these syndromes can elucidate fundamental aging processes.
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