Cardiovascular diseases (CVD) remain the leading cause of morbidity and mortality worldwide (Martin et al. 2024). Aging is the primary risk factor for CVD development, which is preceded by the stiffening of the aorta (Chirinos et al. 2019). Aortic stiffness is an independent predictor of future CVD and serves as a therapeutic target to mitigate CVD risk with aging (Chirinos et al. 2019).
Stiffening of the aorta is a key antecedent to cardiovascular diseases (CVD) with aging. Age-related aortic stiffening is driven, in part, by cellular senescence—a hallmark of aging defined primarily by irreversible cell cycle arrest. In this study, we assessed the efficacy of 25-hydroxycholesterol (25HC), an endogenous cholesterol metabolite, as a naturally occurring senolytic to reverse vascular cell senescence and reduce aortic stiffness in old mice
We found that short-term (5d) treatment with 25HC reduced aortic stiffness in vivo, assessed via aortic pulse wave velocity (p = 0.002) to a similar extent as GCV. Ex vivo 25HC exposure of aorta rings from the old p16-3MR GCV-treated mice did not further reduce elastic modulus (measure of intrinsic mechanical stiffness), demonstrating that 25HC elicited its beneficial effects on aortic stiffness, in part, through the suppression of excess senescent cells. Improvements in aortic stiffness with 25HC were accompanied by favorable remodeling of structural components of the vascular wall (e.g., lower collagen-1 abundance and higher α-elastin content) to a similar extent as GCV. Moreover, 25HC suppressed its putative molecular target CRYAB, modulated CRYAB-regulated senescent cell anti-apoptotic pathways, and reduced markers of cellular senescence. The findings from this study identify 25HC as a potential therapy to target vascular cell senescence and reduce age-related aortic stiffness.