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Aging is associated with stiffening of the large elastic arteries and consequent increases in systolic blood pressure (SBP), which together increase cardiovascular disease risk; however, the upstream mechanisms are incompletely understood. Using complementary translational approaches in mice and humans, we investigated the role of the gut microbiome-derived metabolite trimethylamine N-oxide (TMAO) in age-related aortic stiffening and increased SBP. Aortic stiffness was measured using carotid-femoral or aortic pulse wave velocity (PWV) in humans and mice, respectively. Study 1: Plasma TMAO concentrations were elevated ( P r 2 =0.15, P r 2 =0.09, P

To determine the efficacy of inorganic nitrite supplementation on endothelial function in humans and mechanisms of action, we performed (1) a randomized, placebo-controlled, parallel-group clinical trial with sodium nitrite (80 mg/day, 12 weeks) in older adults (N=49, 68±1 year) and (2) reverse-translation experiments in young (6 months) and old (27 months) c57BL/6 mice. In the clinical trial, sodium nitrite increased plasma nitrite ( P P P P P P P Registration: URL: https://www.clinicaltrials.gov ; Unique identifier: NCT02393742.

Age-related vascular endothelial dysfunction is a major antecedent to cardiovascular diseases. We investigated whether increased circulating levels of the gut microbiome-generated metabolite trimethylamine-N-oxide induces endothelial dysfunction with aging. In healthy humans, plasma trimethylamine-N-oxide was higher in middle-aged/older (64±7 years) versus young (22±2 years) adults (6.5±0.7 versus 1.6±0.2 µmol/L) and inversely related to brachial artery flow-mediated dilation ( r 2 =0.29, P P G -nitro-L-arginine methyl ester). Acute incubation of carotid arteries with trimethylamine-N-oxide recapitulated these events. Next, treatment with 3,3-dimethyl-1-butanol for 8 to 10 weeks to suppress trimethylamine-N-oxide selectively improved endothelium-dependent dilation in old mice to young levels (peak: 90±2%) by normalizing vascular superoxide production, restoring nitric oxide-mediated dilation, and ameliorating superoxide-related suppression of endothelium-dependent dilation. Lastly, among healthy middle-aged/older adults, higher plasma trimethylamine-N-oxide was associated with greater nitrotyrosine abundance in biopsied endothelial cells, and infusion of the antioxidant ascorbic acid restored flow-mediated dilation to young levels, indicating tonic oxidative stress-related suppression of endothelial function with higher circulating trimethylamine-N-oxide. Using multiple experimental approaches in mice and humans, we demonstrate a clear role of trimethylamine-N-oxide in promoting age-related endothelial dysfunction via oxidative stress, which may have implications for prevention of cardiovascular diseases.

A recent American Heart Association report shows that 34% of US adults ≥20 years of age have hypertension representing ≈86 million adults.1 A substantial increase in the prevalence of hypertension has occurred globally.2 The projected number of individuals with systolic blood pressure of ≥140 mm Hg has doubled from 442 million in 1990 to 874 million in 2015. Hypertension is one of the most prevalent risk factors for cardiovascular disease (CVD).1 Results of the recently concluded SPRINT (Systolic Blood Pressure Intervention Trial) funded by the National Heart, Lung, and Blood Institute showed that among older adults with hypertension but without diabetes mellitus, lowering systolic blood pressure to a target goal of 120 mm Hg, compared with the standard goal of 140 mm Hg, resulted in significantly lower rates of fatal and nonfatal cardiovascular events and death from any cause.3 Some groups such as blacks who display both disproportionately earlier onset and higher prevalence of hypertension have increased risk of blood pressure (BP)–related cardiovascular and renal disease complications compared with non-Hispanic whites. Despite intensive attempts to influence lifestyle changes, nutritional counseling, and intensive antihypertensive drug treatment strategies, ≈14% of all hypertension patients seem to be resistant to antihypertensive interventions.1 Resistant hypertension is defined as BP above goal (>140/90 mm Hg) on ≥3 BP-lowering medications or needing ≥4 medications prescribed at optimal dose to control BP to goal. Thus, both increased prevalence and inability to achieve BP goals in a large patient population with hypertension are creating a tremendous healthcare burden. In addition, no novel antihypertensive drugs have been added to our formulary since 1995, when the first angiotensin receptor antagonist was approved in the United States. The recent attempts to use percutaneous renal artery sympathetic denervation, as a novel means to control hypertension, have been largely unsuccessful to date.4 …