Dietary restriction mitigates vascular aging, modulates the cGAS-STING pathway and reverses macrophage-like VSMC phenotypes in progeroid DNA-repair-deficient Ercc1?/- mice

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?/- 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?/- 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?/- aortic tissue and were both reduced by DR. In vitro, cisplatin-induced DNA damage activated the cGAS-STING pathway in Ercc1?/- 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. Overall design: To investigate the underlying molecular mechanism of vascular aging and the effect of dietary restriction, we performed RNA sequencing on the aortic arch of Ercc1?/- mice and wildtype littermates at 6 weeks of age (ad libitum diet) and at 22 weeks of age (after either being subjected to an ad libitum diet or 30% dietary restriction). Next, differential expression analysis was performed to compare the RNA expression in Ercc1?/- aortas to the RNA expression in wildtype aortas at the different ages and to compare the RNA expression in aortas from mice on dietary restriction to the aortas of mice on an ad libitum diet.