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

Natalie E Picciotto,Douglas R Seals,Lindsey B Gano,Christopher R Martens,Lawrence C Johnson,Kathryn F Mills,Amy L Sindler,Shin‐Ichiro Imai

doi:10.1111/acel.12461

Natalie E Picciotto, Douglas R Seals + Show 6 more

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https://doi.org/10.1111/acel.12461

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Abstract

SummaryWe tested the hypothesis that supplementation of nicotinamide mononucleotide (NMN), a key NAD + intermediate, increases arterial SIRT1 activity and reverses age‐associated arterial dysfunction and oxidative stress. Old control mice (OC) had impaired carotid artery endothelium‐dependent dilation (EDD) (60 ± 5% vs. 84 ± 2%), a measure of endothelial function, and nitric oxide (NO)‐mediated EDD (37 ± 4% vs. 66 ± 6%), compared with young mice (YC). This age‐associated impairment in EDD was restored in OC by the superoxide (O2−) scavenger TEMPOL (82 ± 7%). OC also had increased aortic pulse wave velocity (aPWV, 464 ± 31 cm s−1 vs. 337 ± 3 cm s−1) and elastic modulus (EM, 6407 ± 876 kPa vs. 3119 ± 471 kPa), measures of large elastic artery stiffness, compared with YC. OC had greater aortic O2− production (2.0 ± 0.1 vs. 1.0 ± 0.1 AU), nitrotyrosine abundance (a marker of oxidative stress), and collagen‐I, and reduced elastin and vascular SIRT1 activity, measured by the acetylation status of the p65 subunit of NFκB, compared with YC. Supplementation with NMN in old mice restored EDD (86 ± 2%) and NO‐mediated EDD (61 ± 5%), reduced aPWV (359 ± 14 cm s−1) and EM (3694 ± 315 kPa), normalized O2− production (0.9 ± 0.1 AU), decreased nitrotyrosine, reversed collagen‐I, increased elastin, and restored vascular SIRT1 activity. Acute NMN incubation in isolated aortas increased NAD + threefold and manganese superoxide dismutase (MnSOD) by 50%. NMN supplementation may represent a novel therapy to restore SIRT1 activity and reverse age‐related arterial dysfunction by decreasing oxidative stress.

Highlights

Cardiovascular diseases (CVD) remain the leading cause of morbidity and mortality in developed nations (Mortality & Causes of Death, 2014), and advancing age is the primary risk factor for CVD (Lakatta & Levy, 2003)
We observed an age-related increase in heart mass and a decrease in fat and muscle mass, which were not altered with nicotinamide mononucleotide (NMN) treatment
We and others have shown that lifelong caloric restriction (CR) prevents (Csiszar et al, 2009; Donato et al, 2013) and short-term CR reverses (Rippe et al, 2010) the age-associated decline in endothelial function and that these effects are associated with enhanced arterial SIRT1 activity

Summary

We tested the hypothesis that supplementation of nicotinamide mononucleotide (NMN), a key NAD+ intermediate, increases arterial SIRT1 activity and reverses age-associated arterial dysfunction and oxidative stress. Old control mice (OC) had impaired carotid artery endothelium-dependent dilation (EDD) (60 Æ 5% vs 84 Æ 2%), a measure of endothelial function, and nitric oxide (NO)-mediated EDD (37 Æ 4% vs 66 Æ 6%), compared with young mice (YC). This age-associated impairment in EDD was restored in OC by the superoxide (OÀ2 ) scavenger TEMPOL (82 Æ 7%). Supplementation with NMN in old mice restored EDD (86 Æ 2%) and NO-mediated EDD (61 Æ 5%), reduced aPWV (359 Æ 14 cm sÀ1) and EM (3694 Æ 315 kPa), normalized OÀ2 production (0.9 Æ 0.1 AU), decreased nitrotyrosine, reversed collagen-I, increased elastin, and restored vascular SIRT1 activity.

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