Nicotinamide mononucleotide supplementation reverses vascular endothelial dysfunction and large elastic artery stiffness in old mice (698.10)

Abstract

Reduced bioavailability of nicotinamide adenine dinucleotide (NAD+), a cofactor for the deacetylase sirtuin1 (SIRT1), may contribute to age‐related vascular dysfunction via oxidative stress and reduced nitric oxide (NO). We hypothesized that boosting NAD+ with the precursor nicotinamide mononucleotide (NMN) might reverse these adverse effects of aging. Old (O: 26 mo, n=14) C57 male mice had impaired ex vivo carotid artery endothelium‐dependent dilation (EDD) to acetylcholine (ACh, 60 ± 5 vs. 82 ± 3%) and NO‐mediated EDD (max dilation to ACh ‐ max dilation to ACh + L‐NAME, 37 ± 4 vs. 69 ± 5%), and increased aortic pulse wave velocity (aPWV, 467 ± 18 vs. 359 ± 8 cm/s) and elastic modulus (EM, 5899 ± 731 vs. 3307 ± 288 kPa, all p<0.05) (indices of arterial stiffness) vs. young (Y; 6 mo, n=12). In O treated with NMN (300 mg/kg/d in drinking water, 8 w) (n=10), EDD (89 ± 3%), NO‐mediated EDD (61 ± 5%), aPWV (364 ± 14 cm/s) and EM (3694 ± 315 kPa) all were improved (p<0.05 vs. O). Aorta from O had reduced expression (WB) of SIRT1 (0.7 ± 0.1 vs. 1.0 ± 0.1 AU, p=0.05 vs. Y) and increased nitrotyrosine (NT) (oxidant modification) (8.7 ± 1.1 vs. 1.0 ± 0.3 AU, p<0.05 vs. Y). In O, NMN restored SIRT1 (1.1 ± 0.1 AU) and reduced NT (4.7 ± 0.7 AU) (both p<0.05 vs. O). Increasing NAD+ bioavailability may be a novel therapy for reversing age‐related vascular dysfunction by reducing oxidative stress and restoring NO signaling.Grant Funding Source: Supported by NIH AG013038 and AG000279