Arterial aging, characterized by stiffening of large elastic arteries and the development of arterial endothelial dysfunction, increases cardiovascular disease (CVD) risk. We tested the hypothesis that spermidine, a nutrient associated with the anti-aging process autophagy, would improve arterial aging. Aortic pulse wave velocity (aPWV), a measure of arterial stiffness, was ~20% greater in old (O, 28 months) compared with young C57BL6 mice (Y, 4 months, P < 0.05). Arterial endothelium-dependent dilation (EDD), a measure of endothelial function, was ~25% lower in O (P < 0.05 vs. Y) due to reduced nitric oxide (NO) bioavailability. These impairments were associated with greater arterial oxidative stress (nitrotyrosine), superoxide production, and protein cross-linking (advanced glycation end-products, AGEs) in O (all P < 0.05). Spermidine supplementation normalized aPWV, restored NO-mediated EDD and reduced nitrotyrosine, superoxide, AGEs and collagen in O. These effects of spermidine were associated with enhanced arterial expression of autophagy markers, and in vitro experiments demonstrated that vascular protection by spermidine was autophagy-dependent. Our results indicate that spermidine exerts a potent anti-aging influence on arteries by increasing NO bioavailability, reducing oxidative stress, modifying structural factors and enhancing autophagy. Spermidine may be a promising nutraceutical treatment for arterial aging and prevention of age-associated CVD.

Reductions in arterial SIRT1 expression and activity with aging are linked to vascular endothelial dysfunction. We tested the hypothesis that the specific SIRT1 activator SRT1720 improves endothelial function [endothelium-dependent dilation (EDD)] in old mice. Young (4-9 mo) and old (29-32 mo) male B6D2F1 mice treated with SRT1720 (100 mg/kg body wt) or vehicle for 4 wk were studied with a group of young controls. Compared with the young controls, aortic SIRT1 expression and activity were reduced (P < 0.05) and EDD was impaired (83 ± 2 vs. 96 ± 1%; P < 0.01) in old vehicle-treated animals. SRT1720 normalized SIRT1 expression/activity in old mice and restored EDD (95 ± 1%) by enhancing cyclooxygenase (COX)-2-mediated dilation and protein expression in the absence of changes in nitric oxide bioavailability. Aortic superoxide production and expression of NADPH oxidase 4 (NOX4) were increased in old vehicle mice (P < 0.05), and ex vivo administration of the superoxide scavenger TEMPOL restored EDD in that group. SRT1720 normalized aortic superoxide production in old mice, without altering NOX4 and abolished the improvement in EDD with TEMPOL, while selectively increasing aortic antioxidant enzymes. Aortic nuclear factor-κB (NF-κB) activity and tumor necrosis factor-α (TNF-α) were increased in old vehicle mice (P < 0.05), whereas SRT1720 normalized NF-κB activation and reduced TNF-α in old animals. SIRT1 activation with SRT1720 ameliorates vascular endothelial dysfunction with aging in mice by enhancing COX-2 signaling and reducing oxidative stress and inflammation. Specific activation of SIRT1 is a promising therapeutic strategy for age-related endothelial dysfunction in humans.

Central arterial stiffness increases with sedentary ageing. While near-daily, vigorous lifelong (>25 years) endurance exercise training prevents arterial stiffening with ageing, this rigorous routine of exercise training over a lifetime is impractical for most individuals. The aim was to examine whether a less frequent 'dose' of lifelong exercise training (four to five sessions per week for > 30 min) that is consistent with current physical activity recommendations elicits similar benefits on central arterial stiffening with ageing. A cross-sectional examination of 102 seniors (>60 years old) who had a consistent lifelong exercise history was performed. Subjects were stratified into four groups based on exercise frequency as an index of exercise 'dose': sedentary: fewer than two sessions per week; casual exercisers: two to three sessions per week; committed exercisers: four to five sessions per week; and Masters athletes: six to seven sessions per week plus regular competitions. Detailed measurements of arterial stiffness and left ventricular afterload were collected. Biological aortic age and central pulse wave velocity were younger in committed exercisers and Masters athletes compared to sedentary seniors. Total arterial compliance index (TACi) was lower, while carotid β-stiffness index and effective arterial elastance were higher in sedentary seniors compared to the other groups. There appeared to be a dose-response threshold for carotid β-stiffness index and TACi. Peripheral arterial stiffness was not significantly different among the groups. These data suggest that four to five weekly exercise sessions over a lifetime is associated with reduced central arterial stiffness in the elderly. A less frequent dose of lifelong exercise (two to three sessions per week) is associated with decreased ventricular afterload and peripheral resistance, while peripheral arterial stiffness is unaffected by any dose of exercise.