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

项目总结/摘要 导致冠状病毒疾病的严重急性呼吸道综合征冠状病毒（SARS-CoV）-2 2019 （COVID-19）对老年人的影响不成比例，60岁及以上的人明显 增加感染风险、发病率和死亡率的严重程度。这种随着年龄增长而增加的脆弱性是由于 部分更大的全身炎症和氧化应激，受损的一氧化氮（NO）介导的内皮细胞 功能障碍和烟酰胺腺嘌呤二核苷酸（NAD+）缺乏。作为 这些新的“老年保护策略”：1）改善COVID-19的基线风险因素概况; 2） 恢复NAD+水平，抑制炎症和氧化应激，提高NO生物利用度/内皮细胞 感染期间诱导的功能障碍对于降低老年人COVID-19的严重程度/致死率至关重要。 我们最近表明，长期补充（6周）烟酰胺核苷，一种天然的饮食， 复合物，提高老年人的NAD+生物利用度。然后，我们将这项试点研究的结果转化为 一项由国家免疫局资助的（R 01 AG 061514）IIa期随机临床试验，评估了3个月的 烟酰胺核苷治疗老年人降低收缩压和主动脉僵硬度 基线SBP升高至1级高血压范围。这项为期5年的临床试验目前处于第2年。 COVID-19的发病机制包括NAD+缺乏、过度炎症、过度活性氧 物种（ROS）的生物活性，肺和全身NO介导的内皮功能障碍。我们的初步 在老年人中的结果表明，烟酰胺核苷减少促炎细胞因子的产生， 外周血单个核细胞（PBMC），降低内皮ROS生物活性，增加内皮NO 生产，并改善体内全身血管内皮功能。然而，这些有希望的初步 这些发现必须在更大的队列中得到证实，以确定烟酰胺核苷的潜在疗效 补充剂作为老年保护策略，用于预防和治疗老年人的COVID-19。 本行政补充文件的目的是解决NIA的主要研究目标 NOT-AG-20-022中的老年病学和临床老年学分部：药理学评价 可预防或减轻发病率和/或改善老年人感染后健康的干预措施 感染了SARS-CoV-2这将通过以下方式实现：1）评估PBMC炎性细胞因子产生 在烟酰胺核苷处理和与特异性NAD+途径代谢物孵育之前/之后; 2） 评价浸泡在受试者血清中的人肺动脉内皮细胞的离体内皮功能 有/无COVID-19样炎症和氧化应激±保护性NAD+代谢物;和3）评估 用烟酰胺核苷处理体内全身内皮功能。预期的结果将建立 烟酰胺核苷作为一种有前途的老年保护策略：a）降低SARS-CoV-2感染的风险; B） 抑制导致COVID-19发病的多种途径;以及c）帮助老年人感染后恢复。

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 in part 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 preliminary results 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 initial findings 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 NIA Division 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.