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Published on: May 31, 2016
Dietary Restriction Mitigates Vascular Aging, Modulates the cGAS-STING Pathway and Reverses Macrophage-Like VSMC
S J M Stefens1, J van der Linden1, J M Heredia-Genestar1
1Department of Molecular Genetics, Erasmus University Medical Center, Rotterdam, the Netherlands.
Abstract:
Aging is a major risk factor for cardiovascular diseases, and the accumulation of DNA damage significantly contributes to the aging process. This study aimed to identify the underlying molecular mechanisms of vascular aging in DNA-repair-deficient progeroid Ercc1Δ/- mice and to explore the therapeutic effect of dietary restriction (DR). RNA sequencing analysis revealed that DR reversed gene expression of vascular aging processes, including extracellular matrix remodeling, in the Ercc1Δ/- aorta. Notably, this analysis indicated the presence of macrophage-like vascular smooth muscle cells (VSMCs) and suggested cGAS-STING pathway activation. The presence of macrophage-like VSMCs and increased STING1 expression were confirmed in Ercc1Δ/- aortic tissue and were both reduced by DR. In vitro, cisplatin-induced DNA damage activated the cGAS-STING pathway in Ercc1Δ/- VSMCs but not in wildtype VSMCs. These findings identify the involvement of the cGAS-STING pathway in DNA damage-driven vascular aging and underscore the therapeutic benefits of DR for vascular aging. Furthermore, upstream regulator analysis revealed compounds that may replicate the beneficial effects of DR, providing promising leads for further investigation.
Insights
Dietary restriction (DR) reverses vascular aging in mice with DNA repair deficiency by modulating the cGAS-STING pathway. This study identifies macrophage-like vascular smooth muscle cells as a key factor in DNA damage-induced aging.
Area of Science:
- Cardiovascular research
- Molecular biology
- Aging research
Background:
- Aging is a primary risk factor for cardiovascular diseases.
- Accumulated DNA damage is a significant contributor to the aging process.
- Understanding vascular aging mechanisms is crucial for developing interventions.
Purpose of the Study:
- To elucidate molecular mechanisms of vascular aging in DNA-repair-deficient Ercc1Δ/- mice.
- To investigate the therapeutic potential of dietary restriction (DR) in mitigating vascular aging.
- To identify upstream regulators that may mimic DR's beneficial effects.
Main Methods:
- Utilized RNA sequencing on aortas from Ercc1Δ/- mice.
- Confirmed findings through histological analysis of aortic tissue.
- Employed in vitro experiments with VSMCs exposed to DNA-damaging agents.
Main Results:
- Dietary restriction reversed gene expression associated with vascular aging and extracellular matrix remodeling in Ercc1Δ/- aortas.
- Identified macrophage-like vascular smooth muscle cells (VSMCs) and cGAS-STING pathway activation in aging aortas.
- Confirmed that DR reduced macrophage-like VSMCs and STING1 expression; DNA damage activated cGAS-STING in deficient VSMCs but not wildtype.
Conclusions:
- The cGAS-STING pathway is implicated in DNA damage-induced vascular aging.
- Dietary restriction demonstrates significant therapeutic benefits for vascular aging.
- Identified potential compounds that could replicate DR's effects, offering new avenues for research.
