Dietary restriction mitigates vascular aging, modulates the cGAS-STING pathway and reverses macrophage-like VSMC phenotypes in progeroid DNA-repair-deficient Ercc1Δ/- mice
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA1251075 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR33150544_1.fastq.gz | Fastqsanger.gz | |||
| SRR33150544_2.fastq.gz | Fastqsanger.gz | |||
| SRR33150545_1.fastq.gz | Fastqsanger.gz | |||
| SRR33150545_2.fastq.gz | Fastqsanger.gz | |||
| SRR33150546_1.fastq.gz | Fastqsanger.gz |
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Project description: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 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.
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Project description:DNA-protein crosslinks (DPCs) are severe DNA lesions that disrupt replication, transcription, and genome stability. However, their role in development and aging remains poorly understood. Here, we show that impaired SPRTN function, a metalloprotease essential for DPC repair during replication and mitosis, leads to DNA damage, mitotic abnormalities, and activation of the immune system. Notably, micronuclei formed upon SPRTN deficiency frequently contain DPCs, exhibit nuclear envelope rupture, and accumulate unrepaired DNA, thereby facilitating activation of the cGAS-STING pathway. Using a Sprtn knock-in mouse model of Ruijs Aalfs progeria syndrome, we demonstrate that chronic cGas-Sting activation drives inflammation, innate immune responses, and embryonic lethality. Surviving mice display a continuum of aging phenotypes from embryogenesis into adulthood. Genetic or pharmacological inhibition of cGas-Sting rescues embryonic viability and ameliorates progeroid features, linking DPC-induced innate immune activation to lifespan defects. Our findings uncover a previously unrecognized role for DPCs in coupling early developmental failure to premature aging.
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