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，高收缩压（SBP）的患病率更高 使他们处于心血管（CV）疾病和死亡的高风险中。因为降低SBP的药物治疗 与副作用如低血压、晕厥和肾功能不全相关，非常需要 有效的生活方式SBP降低干预老年人群，可以取代药物治疗。而 有氧运动是控制SBP和预防CV疾病的推荐生活方式干预 自然，在老年人中，由于 动脉僵硬，导致SBP控制效率降低。烟酰胺腺嘌呤的生物利用度降低 去乙酰化酶sirtuin 1（SIRT 1）的辅因子NAD+可能有助于年龄相关的血管内皮细胞凋亡。 通过氧化应激和减少一氧化氮（NO）的功能障碍。脂质体诱导的NAD+- 依赖SIRT 1提高NO的生物利用度。临床前证据表明，血管功能差 老年小鼠对运动反应的改善是由于NAD+水平不足以刺激SIRT 1 活动重要的是，NAD+水平的补充诱导血管重塑，改善血管重塑。 功能，并降低小鼠的SBP。因此，本研究的一个目的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），以优化运动的收缩压- 降低老年高血压患者的血压。最初的人体临床试验表明，烟酰胺核苷 补充（1，000 mg/天）是安全的，并显示出更高的降低SBP和动脉僵硬度的潜力 在SBP升高的参与者中。由于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， 有氧运动训练结合烟酰胺核苷补充将降低SBP， 高血压老年人更有效地将比单独行使。我们将招募45名65岁的参与者， （1）1，000 mg/天的烟酰胺核苷加3天/周的监督，中心为基础的 步行运动，或（2）相同的运动计划与安慰剂相结合，或（3）1,000 mg/天的 单独的烟酰胺核苷。所有参与者将接受日间连续SBP和动脉僵硬度 在基线和6周时通过脉搏波速度测量。然后将SBP升高确定为 白天平均超过130毫米汞柱，由24小时血压装置测量。据我们所知，这 这项研究将首次尝试用烟酰胺核苷加强老年高血压患者的运动疗法。 成年人了我们认为，烟酰胺核苷是改善血管紧张素转换酶活性的“拼图中缺失的一块”。 重塑和老年人SBP管理。这项试点研究的初步证据可能支持全面的- 在老年高血压患者中进行的III期临床试验。这一系列研究的最终目标是找到 辅助策略，以提高运动的SBP降低老年人的影响。

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.