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

项目摘要 超过90%的心血管疾病（CVD）和认知障碍/痴呆发生在男性中， 女性>50岁。美国年龄人口统计学的变化预测， 没有有效的循证干预措施的疾病。与年龄相关的收缩压升高 血压（SBP）是导致中年和老年人这些疾病风险增加的主要因素 (MA/O）成人。收缩压的增加主要是由于大的弹性动脉硬化，如 颈动脉-股动脉脉搏波速度（CFPWV）增加，反映主动脉硬化。主动脉 随着年龄的增长，硬化由结构和功能（血管平滑肌张力增加）介导 氧化应激和慢性低度炎症刺激的动脉壁变化。 新的血压指南将偶然（静息）SBP 120-129 mmHg描述为“升高”，SBP 130-139 mmHg描述为“升高”。 mmHg作为“1期高血压”，因为这些水平占CVD和其他疾病风险增加的大部分 BP影响的衰老障碍。重要的是，约50%的年龄>50岁的成年人的SBP在这些范围内。的 在这些范围内降低SBP的一线治疗是基于生活方式的治疗。在这种情况下，我们已经表明， 热量限制（CR）降低了老年小鼠和超重/肥胖MA/O人类的SBP和CFPWV， 但粘附性差，CR降低了肌肉和骨量。因此，我们已经证明， 提高NAD+的生物利用度以刺激SIRT-1，一种“CR模拟”方法， 最近，我们在一项MA/O的小型试点研究中迈出了将这些发现转化为现实的第一步。 成人（n=24）。我们发现，补充烟酰胺核苷，一种天然的， NAD+的前体和新型CR模拟物，耐受性良好，并增加了总体NAD+的生物利用度。 在基线SBP为120-139 mmHg的亚组（n=13）中，SBP（-8 mmHg）和CFPWV降低。 在此，我们提出了一项随机、安慰剂对照、双盲、单中心IIa期临床试验， 评估口服烟酰胺核苷的安全性和有效性（500 mg胶囊，每日2次; NIAGEN®; ChromaDex Inc.）在MA/O男性和女性中，与安慰剂（n=59/组）相比，降低SBP和主动脉僵硬度3个月 （50-79岁），SBP在升高/1期高血压（120-139 mmHg）范围内。我们假设 治疗将是安全的，耐受性良好，并将降低SBP和CFPWV，与全身性 NAD+生物利用度和血管收缩因子、氧化应激和炎症的减少。 目的1：测量烟酰胺核苷与安慰剂治疗前后的偶然SBP（主要结局）; 目的2：测定治疗前后24小时动态SBP和CFPWV（次要结局）; 目的3：确定烟酰胺核苷与安慰剂治疗的安全性和耐受性; 目的4：测量全身NAD+和NAD+相关代谢物浓度，以及循环 治疗前后血管收缩因子、氧化应激和炎症标志物。

Project Summary More than 90% of cardiovascular diseases (CVD) and cognitive impairment/dementia occur in men and women >50 years of age. Changes in age demographics in the U.S. predict progressive increases in these disorders without effective, evidence-based interventions. The age-related increase in systolic blood pressure (SBP) is a major factor driving the increased risk of these disorders in later middle-aged and older (MA/O) adults. This increase in SBP is due primarily to stiffening of the large elastic arteries, as indicated by increased carotid-femoral pulse wave velocity (CFPWV), which reflects stiffening of the aorta. Aortic stiffening with aging is mediated by structural and functional (increased vascular smooth muscle tone) changes in the arterial wall stimulated by oxidative stress and chronic low-grade inflammation. New BP guidelines describe a casual (resting) SBP of 120-129 mmHg as “elevated” and SBP of 130-139 mmHg as “stage 1 hypertension”, as these levels account for much of the increased risk of CVD and other BP-influenced disorders of aging. Importantly, ~50% of adults age >50 have SBP within these ranges. The first-line treatment for lowering SBP in these ranges is lifestyle-based therapy. In this context, we have shown that caloric restriction (CR) reduces SBP and CFPWV in older mice and in overweight/obese MA/O humans, but adherence is poor and CR reduces muscle and bone mass. As a result, we have since shown that boosting NAD+ bioavailability to stimulate SIRT-1, a “CR mimetic” approach, reduces CFPWV and oxidative stress in old mice, and we recently took the first step in translating these findings in a small pilot study of MA/O adults (n=24). We found that supplementation with nicotinamide riboside, a natural, commercially available precursor of NAD+ and novel CR mimetic, was well-tolerated and increased NAD+ bioavailability in the overall group, and reduced SBP (-8 mmHg) and CFPWV in a subgroup (n=13) with baseline SBP of 120-139 mmHg. Here we propose a randomized, placebo controlled, double-blind, single-site phase IIa clinical trial to assess the safety and efficacy of oral nicotinamide riboside (500 mg capsules 2x/day; NIAGEN®; ChromaDex Inc.) for 3 months vs. placebo (n=59/group) for decreasing SBP and aortic stiffness in MA/O men and women (50-79 years) with SBP in the elevated/stage 1 hypertension (120-139 mmHg) range. We hypothesize that treatment will be safe and well-tolerated, and will reduce SBP and CFPWV, as related to increases in systemic NAD+ bioavailability and reductions in vasoconstrictor factors, oxidative stress and inflammation. Aim 1: To measure casual SBP (primary outcome) before/after nicotinamide riboside vs. placebo treatment; Aim 2: To measure 24-hour ambulatory SBP and CFPWV (secondary outcomes) before and after treatment; Aim 3: To determine the safety and tolerability of treatment with nicotinamide riboside vs. placebo; Aim 4: To measure systemic NAD+ and NAD+–related metabolite concentrations, as well as circulating markers of vasoconstriction factors, oxidative stress and inflammation before and after treatment.