# Dietary Restriction Mitigates Vascular Aging, Modulates the cGAS‐STING Pathway and Reverses Macrophage‐Like VSMC Phenotypes in Progeroid DNA‐Repair‐Deficient Ercc1Δ /− Mice

## TL;DR

Dietary restriction reduces vascular aging in DNA repair-deficient mice by modulating the cGAS-STING pathway and reversing harmful cell changes.

## Contribution

The study identifies the cGAS-STING pathway as a key driver of DNA damage-related vascular aging and shows how dietary restriction can reverse it.

## Key findings

- Dietary restriction reduced macrophage-like vascular smooth muscle cells and STING1 expression in Ercc1Δ/− mice.
- cGAS-STING pathway activation was observed in DNA-damaged Ercc1Δ/− vascular smooth muscle cells but not in wildtype cells.
- RNA sequencing showed dietary restriction reversed gene expression changes linked to vascular aging.

## 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 Ercc1

Δ/−
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 Ercc1

Δ/−
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 Ercc1

Δ/−
aortic tissue and were both reduced by DR. In vitro, cisplatin‐induced DNA damage activated the cGAS‐STING pathway in Ercc1

Δ/−
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.

Dietary restriction mitigates vascular aging in DNA‐repair‐deficient Ercc1

Δ/−
mice by reducing extracellular matrix remodeling, inflammation, oxidative stress, and switching of vascular smooth muscle cells to a macrophage‐like phenotype. Our findings suggest that the cGAS‐STING pathway plays a key role in vascular aging and that the benefits of dietary restriction may result from reducing its activation. Created in BioRender. Van der pluijm, I. (2025) https://BioRender.com/iwpqncu.