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Cellular senescence and the senescence‐associated secretory phenotype (SASP) contribute to age‐related arterial dysfunction, in part, by promoting oxidative stress and inflammation, which reduce the bioavailability of the vasodilatory molecule nitric oxide (NO). In the present study, we assessed the efficacy of fisetin, a natural compound, as a senolytic to reduce vascular cell senescence and SASP factors and improve arterial function in old mice. We found that fisetin decreased cellular senescence in human endothelial cell culture. In old mice, vascular cell senescence and SASP‐related inflammation were lower 1 week after the final dose of oral intermittent (1 week on—2 weeks off—1 weeks on dosing) fisetin supplementation. Old fisetin‐supplemented mice had higher endothelial function. Leveraging old p16‐3MR mice, a transgenic model allowing genetic clearance of p16INK4A‐positive senescent cells, we found that ex vivo removal of senescent cells from arteries isolated from vehicle‐ but not fisetin‐treated mice increased endothelium‐dependent dilation, demonstrating that fisetin improved endothelial function through senolysis. Enhanced endothelial function with fisetin was mediated by increased NO bioavailability and reduced cellular‐ and mitochondrial‐related oxidative stress. Arterial stiffness was lower in fisetin‐treated mice. Ex vivo genetic senolysis in aorta rings from p16‐3MR mice did not further reduce mechanical wall stiffness in fisetin‐treated mice, demonstrating lower arterial stiffness after fisetin was due to senolysis. Lower arterial stiffness with fisetin was accompanied by favorable arterial wall remodeling. The findings from this study identify fisetin as promising therapy for clinical translation to target excess cell senescence to treat age‐related arterial dysfunction. [ABSTRACT FROM AUTHOR]

The aorta stiffens with aging in both men and women, which predicts cardiovascular mortality. Aortic wall structural and extracellular matrix (ECM) remodeling, induced in part by chronic low-grade inflammation, contribute to aortic stiffening. Male mice are an established model of aortic aging. However, there is little information regarding whether female mice are an appropriate model of aortic aging in women, which we aimed to elucidate in the present study. We assessed two strains of mice and found that in C57BL/6N mice, in vivo aortic stiffness (pulse wave velocity, PWV) was higher with aging in both sexes, whereas in B6D2F1 mice, PWV was higher in old versus young male mice, but not in old versus young female mice. Because the age-related stiffening that occurs in men and women was reflected in male and female C57BL/6N mice, we examined the mechanisms of stiffening in this strain. In both sexes, aortic modulus of elasticity (pin myography) was lower in old mice, occurred in conjunction with and was related to higher plasma levels of the elastin-degrading enzyme matrix metalloproteinase-9 (MMP-9), and was accompanied by higher numbers of aortic elastin breaks and higher abundance of adventitial collagen-1. Plasma levels of the inflammatory cytokines interferon-γ, interleukin 6, and monocyte chemoattractant protein-1 were higher in both sexes of old mice. In conclusion, female C57BL/6N mice exhibit aortic stiffening, reduced modulus of elasticity and structural/ECM remodeling, and associated increases in MMP-9 and systemic inflammation with aging, and thus are an appropriate model of aortic aging in women. NEW & NOTEWORTHY Our study demonstrates that with aging, female C57BL/6N mice exhibit higher in vivo aortic stiffness, reduced modulus of elasticity, aortic wall structural and extracellular matrix remodeling, and elevations in systemic inflammation. These changes are largely reflective of those that occur with aging in women. Thus, female C57BL/6N mice are a viable model of human aortic aging and the utility of these animals should be considered in future biomedical investigations.