The autophagy enhancer spermidine reverses arterial aging

Abstract

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.

Nicotinamide mononucleotide supplementation reverses vascular dysfunction and oxidative stress with aging in mice

“…As established in our previous work (Rippe et al ., 2010; Sindler et al ., 2011; Fleenor et al ., 2013; LaRocca et al ., 2013), aging in the control animals was associated with an impairment in ex vivo carotid artery EDD in response to acetylcholine due to reduced NO‐mediated dilation (Fig. 1A,B).…”

“…2A), indicating excessive superoxide‐mediated endothelial dysfunction with aging. To further assess the influence of aging and NMN treatment on oxidative stress in arteries, aortas were used because of the greater amount of tissue provided for biochemical assay, as described previously (Sindler et al ., 2011; Donato et al ., 2013; LaRocca et al ., 2013; Gano et al ., 2014). Consistent with the results of the pharmacological‐function experiments with TEMPOL, compared with young mice, aortas from old animals exhibited increased superoxide production, directly assessed by electron paramagnetic resonance (EPR) spectroscopy (Fig.…”

“…We have observed reductions in aortic collagen in old mice subjected to other short‐term late‐life behavioral or pharmacological interventions (Fleenor et al ., 2010, 2012a, 2013; LaRocca et al ., 2013), although not in every case (Fleenor et al ., 2012b). Interestingly, NMN also induced a partial restoration of aortic elastin to levels not significantly different from young control animals.…”

“…Aging in control animals was associated with marked increases in both aortic superoxide production and nitrotyrosine abundance (Fig. 2B,C), as we have reported previously (Rippe et al ., 2010; Sindler et al ., 2011; Fleenor et al ., 2012a, 2013; Donato et al ., 2013; LaRocca et al ., 2013). In response to NMN supplementation, we observed a normalization of aortic superoxide production and a marked reduction in nitrotyrosine abundance in old mice.…”

“…Superoxide production in the thoracic aorta was measured using EPR spectroscopy, as previously described (Sindler et al ., 2011; Fleenor et al ., 2012b; LaRocca et al ., 2013). One‐millimeter aortic segments, free of perivascular fat and other surrounding tissue, were incubated for 1 h at 37 °C in Krebs–Hepes buffer with the superoxide‐specific spin probe 1‐hydroxy‐3‐methoxycarbonyl‐2,2,5,5‐tetramethylpyrrolidine (CMH; 0.5 m m ; Enzo Life Sciences, Inc., Farmington, NY, USA) for detection of whole‐cell superoxide production.…”