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Purpose: Regular calorie restriction (CR) improves endothelial function and lowers aortic stiffness in older mice and humans; however, adherence to sustained CR remains poor, and possibly unsafe in normal weight older adults. Nicotinamide adenine dinucleotide (NAD+) is an important signaling molecule involved in the beneficial effects of CR and we have recently demonstrated that boosting NAD+ reverses these measures of arterial aging in older mice. The purpose of this study was to determine if supplementation with nicotinamide riboside (NIAGEN®; ChromaDex, Inc.), a naturally occurring precursor to NAD+, would similarly improve vascular function with aging in humans. Methods: Healthy middle-aged and older adults (65 ± 2 yrs, n = 24) received oral NIAGEN® (500 mg, 2x/day) and placebo capsules for six weeks each in a randomized, placebo-controlled crossover study. Blood pressure (BP), aortic stiffness (carotid-femoral pulse wave velocity [PWV]), and endothelial function, (brachial artery flow-mediated dilation [FMD]), were measured at the end of each intervention phase. Results: NIAGEN® safely and effectively raised circulating levels of NAD+ and related metabolites. Although no effect was observed on endothelial function, NIAGEN® significantly lowered PWV as well as systolic (SBP) and diastolic blood pressure (DBP) in all subjects (P < 0.05). When separated by baseline BP status, the BP-lowering effect of NIAGEN® was observed in pre-hypertensive (pHTN, n = 13) but not normotensive (N = 11) individuals (P < 0.01). Interestingly, NIAGEN® was lowered in all subjects regardless of baseline BP status. Conclusion: Chronic NIAGEN® supplementation lowers SBP in pHTN older adults and reduces aortic stiffness, independent of baseline blood pressure status.

The gut microbiome, an emerging mediator of host physiological function, is adversely altered by aging and many diseases, termed “gut dysbiosis.” One consequence of gut dysbiosis is elevated circulating levels of the gut-derived metabolite trimethylamine N-oxide (TMAO), which has been directly linked to cardiovascular (CV) risk, including the development of atherosclerosis. However, it is unknown whether TMAO mediates arterial dysfunction that precedes the onset of clinical disease, and if so, the underlying mechanisms. Purpose: To determine whether TMAO independently induces large elastic artery stiffening and endothelial dysfunction via increased superoxide-related oxidative stress. Method: Twenty young (6 mo) male C57BL/6 mice were fed a chemically-defined choline (0.08–0.09%) diet supplemented without (Control; N = 9) or with (N = 11) 0.12% TMAO for 6 months. Arterial stiffness was assessed as aortic pulse wave velocity (aPWV). Endothelial function was evaluated ex vivo as carotid artery endothelium-dependent dilation (EDD) to increasing doses of acetylcholine (10−9 to 10−4M) in the absence or presence of the superoxide dismutase mimetic TEMPOL. Results: TMAO increased aPWV (Control: 392 ± 20 vs. TMAO: 483 ± 32 cm/sec, p = 0.04) and impaired EDD (peak dilation, Control: 93.7 ± 3.2 vs. TMAO: 79.9 ± 3.4%, p = 0.01). Suppression of oxidative stress with TEMPOL restored EDD in TMAO-treated animals (peak dilation: 92.1 ± 4.7%, p = 0.46 vs. Control). Conclusions: TMAO independently induces large elastic artery stiffening and endothelial dysfunction in mice. Dysfunction appears to occur through increases in oxidative stress. These data may explain, at least in part, why TMAO increases CV risk and provide a potential target for prevention/treatment of arterial dysfunction. Supported by R01 HL134887 & T32 HL007822.