GLSP mitigates vascular aging by promoting Sirt7-mediated Keap1 deacetylation and Keap1-Nrf2 dissociation

Background and Purpose: Vascular aging is a prior marker of human aging and a significant contributor to atherosclerosis and vascular calcification. However, there are limited pharmacological options available to mitigate vascular aging. Thus, understanding the mechanisms underlying vascular aging and age-related atherosclerosis and vascular calcification is crucial. This study investigates the targets of vascular aging and elucidates the role and mechanisms of Ganoderma lucidum spore powder (GLSP) in mitigating vascular aging and aging-associated atherosclerosis as well as vascular calcification. Methods: The anti-vascular aging effects of GLSP was determined in aged C57BL/6J mice and the targets of GLSP was identified through transcriptome sequencing. Additionally, the protective effects of GLSP on the aged vasculature were assessed by examining atherosclerosis in apoE^-/- mice and vascular calcification in VD₃ and nicotine-induced mice. In vitro, the protective effects of GLSP triterpenes against vascular aging and calcification was determined in vascular smooth muscle cells (VSMCs). Results: GLSP exerted anti-vascular aging effects by regulating the cell cycle and senescence-associated secretory phenotype (SASP), mitigating DNA damage, reducing oxidative stress, improving mitochondrial function and modulating metabolic levels. Furthermore, GLSP improved vascular aging-associated atherosclerosis and vascular calcification in vivo. Mechanistically, RNA sequencing revealed an upregulation of Sirt7 expression after GLSP treatment. Sirt7 inhibitor exacerbated VSMCs senescence and calcification in senescent VSMCs and abolished the anti-senescence and the inhibitory effect of GLSP triterpenes on VSMCs senescence and calcification. Innovatively, we found that Sirt7 interacted with Keap1 and facilitated Keap1 deacetylation, which promoted Keap1-Nrf2 dissociation and consequently enhanced Nrf2 nuclear translocation and activation. Conclusion: GLSP alleviates vascular aging by exerting antioxidant effects through the activation of the Sirt7-Nrf2 axis, providing a promising new strategy for delaying vascular aging, atherosclerosis and vascular calcification.