Nicotinamide riboside as an Enhancer of Exercise Therapy in hypertensive older adults: The NEET Trial

摘要 超过80%的老年人患有高血压，其中高收缩压(SBP)的患病率更高 使他们处于心血管(CV)疾病和死亡的高危状态。因为降低SBP的药物治疗 与低血压、晕厥和肾功能障碍等副作用相关的药物非常需要 有效的生活方式--可替代药物治疗的老年人群降压干预措施。而当 有氧运动是控制SBP和预防心血管疾病的推荐生活方式干预措施 当然，在老年人中，它在血管组织重塑方面的效果较差，因为 动脉僵硬，导致SBP控制效率较低。烟酰胺腺嘌呤生物利用度降低 二核苷酸(NAD+)是脱乙酰酶Sirtuin1(SIRT1)的辅助因子，可能与年龄相关的血管有关 通过氧化应激和一氧化氮(NO)减少而导致的功能障碍。运动诱导NAD+-的过度表达 依赖的SIRT1提高了NO的生物利用度。临床前证据表明，血管功能不良 老年小鼠对运动的反应改善是由于NAD+水平不足以刺激SIRT1 活动。重要的是，NAD+水平的补充诱导了血管重构，改善了血管 并能降低小鼠的SBP。因此，这项研究的一个目标是测试有氧运动的组合 运动和烟酰胺核苷，一种补充NAD+水平的化合物，以优化运动的SBP- 对老年高血压患者的降压效果。初步的人体临床试验表明，烟酰胺核苷 补充(1,000毫克/天)是安全的，并显示出更高的降低SBP和动脉僵硬的潜力 在SBP升高的参与者中。因为我们有临床前证据表明，将NAD+补充与 运动是改善血管功能的理想策略，我们的中心假设是 有氧运动训练联合补充烟酰胺核苷可降低SBP 与单独锻炼相比，高血压老年人更有效。我们将招募45名参与者，65年后 老年人服用：(1)每天1,000毫克的烟酰胺核苷，外加每周3天的有监督的、以中心为基础的 步行锻炼，或(2)相同的锻炼计划加安慰剂，或(3)每天1000毫克 单独的烟酰胺核苷。所有参与者都将接受日间持续SBP和动脉僵硬。 分别在基线和6周时测量脉搏波速度。升高的SBP将被确定为 通过24小时血压计测量，白天的平均值超过130毫米汞柱。据我们所知，这 这项研究将是首次尝试用烟酰胺核苷加强老年高血压患者的运动治疗 成年人。我们认为烟酰胺核苷是改善血管的“缺失的一块拼图”。 老年人的血管重塑和SBP管理。这项初步研究的初步证据可能支持一个完整的- 高血压老年患者的第三阶段临床试验。这一系列研究的最终目标是找到 改善运动在老年人中降低SBP效果的辅助策略。

ABSTRACT More than 80% of older adults have hypertension, with higher prevalence of high systolic blood pressure (SBP) putting them at high risk for cardiovascular (CV) disease and death. Because drug therapy that lowers SBP is associated with side effects such as hypotension, syncope, and kidney dysfunction, there is a great need for effective lifestyle SBP-lowering interventions for the older population that can replace drug therapy. While aerobic exercise is a recommended lifestyle intervention for controlling SBP and preventing CV disease naturally, in older adults it has been shown to be less effective in vascular-tissue remodeling because of arterial stiffness, resulting in less efficient SBP control. Reduced bioavailability of nicotinamide adenine dinucleotide (NAD+), a cofactor for the deacetylase sirtuin1 (SIRT1), may contribute to age-related vascular dysfunction via oxidative stress and reduced nitric oxide (NO). Exercise-induced overexpression of NAD+- dependent SIRT1 improves the bioavailability of NO. Preclinical evidence suggests that poor vascular-function improvement in response to exercise in older mice is caused by insufficient NAD+ levels to stimulate SIRT1 activity. Importantly, replenishment of NAD+ levels induced vascular remodeling, improved vascular function, and reduced SBP in mice. An objective of this study, therefore, is to test a combination of aerobic exercise and nicotinamide riboside, a compound that replenishes NAD+ levels, to optimize exercise's SBP- lowering effect in hypertensive older adults. Initial human clinical trials demonstrated that nicotinamide riboside supplementation (1,000 mg/day) was safe and showed a higher potential to reduce SBP and arterial stiffness in participants with elevated SBP. As we have preclinical evidence that combining NAD+ replenishment with exercise is an ideal strategy for improving vascular function, our central hypothesis is that the intervention of aerobic-exercise training combined with nicotinamide riboside supplementation will reduce SBP in hypertensive older adults more effectively than will exercise alone. We will enroll 45 participants 65 years and older into either: (1) 1,000 mg/day of nicotinamide riboside plus 3 days/week of supervised, center-based walking exercise, or (2) the same exercise program combined with placebo, or (3) 1,000 mg/day of nicotinamide riboside alone. All participants will undergo daytime continuous SBP and arterial-stiffness measurements by pulse-wave velocity at baseline and at 6 weeks. Elevated SBP will then be determined as daytime average above 130 mmHg, measured by the 24-hour blood-pressure device. To our knowledge, this study will be the first attempt to enhance exercise therapy with nicotinamide riboside in hypertensive older adults. We believe that nicotinamide riboside is “the missing piece of the puzzle” in improving vascular remodeling and SBP management in older adults. Preliminary evidence from this pilot study may support a full- scale Phase III clinical trial in hypertensive older adults. The ultimate goal of this line of research is to find adjuvant strategies to improve the exercise's SBP-lowering effects in older adults.