Nicotinamide riboside supplementation for treating elevated systolic blood pressure and arterial stiffness in middle-aged and older adults

PROJECT SUMMARY/ABSTRACT The severe acute respiratory syndrome coronavirus (SARS-CoV)-2 that causes Coronavirus Disease 2019 (COVID-19) disproportionately affects older adults such that individuals 60 years and older have markedly increased risk of infection, severity of morbidity, and mortality. This increased vulnerability with aging is due inpart to greater systemic inflammation and oxidative stress, impaired nitric oxide (NO)-mediated endothelial dysfunction, and nicotinamide adenine dinucleotide (NAD+) deficiency both at baseline and post-infection. As such, novel "geroprotective strategies" that: 1) improve baseline risk factor profile for COVID-19; and 2) restore NAD+ levels, inhibit inflammation and oxidative stress, and improve NO bioavailability/endothelial dysfunction induced during infection, are essential for reducing severity/lethality of COVID-19 in older adults. We recently showed that chronic supplementation (6 weeks) with nicotinamide riboside, a natural dietary compound, boosts NAD+ bioavailability in older adults. We then translated the results of this pilot study into an NIA-funded (R01 AG061514) phase IIa randomized clinical trial assessing the efficacy of 3 months of nicotinamide riboside treatment for lowering systolic blood pressure (SBP) and aortic stiffness in older adults with baseline SBP in the elevated to stage 1 hypertension range. This 5-year clinical trial is currently in year 2. The pathogenesis of COVID-19 includes NAD+ deficiency, hyper-inflammation, excessive reactive oxygen species (ROS) bioactivity, and pulmonary and systemic NO-mediated endothelial dysfunction. Our preliminar yresults in older adults suggest that nicotinamide riboside reduces pro-inflammatory cytokine production in peripheral blood mononuclear cells (PBMC), decreases endothelial ROS bioactivity, increases endothelial NO production, and improves in vivo systemic vascular endothelial function. However, these promising initialfindings must be confirmed in a larger cohort to establish the potential efficacy of nicotinamide riboside supplementation as a geroprotective strategy for prevention and treatment of COVID-19 in older adults. The purpose of this administrative supplement is to address a major research objective for the NIADivision of Geriatrics and Clinical Gerontology in NOT-AG-20-022: The evaluation of pharmacological interventions that may prevent or mitigate morbidity and/or improve post-infection health in older adults exposed to SARS-CoV-2. This will be accomplished by: 1) assessing PBMC inflammatory cytokine production before/after nicotinamide riboside treatment and incubation with specific NAD+-pathway metabolites; 2) evaluating ex vivo endothelial function in human pulmonary artery endothelial cells bathed in subject serum with/without COVID-19-like inflammatory and oxidative stress ± protective NAD+ metabolites; and 3) assessing in vivo systemic endothelial function with nicotinamide riboside treatment. The expected results will establish nicotinamide riboside as a promising geroprotective strategy for: a) reducing risk of SARS-CoV-2 infection; b) inhibiting multiple pathways driving COVID-19 morbidity; and c) aiding post-infection recovery in older adults.