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

烟酰胺核苷作为老年高血压患者运动疗法的增强剂：NEET 试验

• 批准号: 9808164
• 负责人: Robert T Mankowski
• 金额: $ 19.7万
• 依托单位: UNIVERSITY OF FLORIDA
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-09-01 至 2021-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9808164
• 关键词: Address; Adjuvant; Aerobic Exercise; Age; Aging; Biological Availability; Blood Pressure; Blood Vessels; Blood capillaries; Cardiovascular Diseases; Cardiovascular system; Cessation of life; Clinical Trials; Deacetylase; Devices; Diagnosis; Diastolic blood pressure; Double-Blind Method; Elderly; Endothelium; Enhancers; Enrollment; Event; Exercise; Exercise Therapy; Goals; High Prevalence; Hour; Human; Hypertension; Hypotension; Individual; Intervention; Life Style; Martens; Measurement; Measures; Mus; Myocardial Infarction; Nicotinamide Mononucleotide; Nicotinamide adenine dinucleotide; Nitric Oxide; Older Population; Oxidative Stress; Participant; Pharmaceutical Preparations; Pharmacotherapy; Phase II Clinical Trials; Phase III Clinical Trials; Physiologic pulse; Pilot Projects; Placebos; Public Health; Randomized; Research; Risk; Risk Factors; Sampling Studies; Supervision; Supplementation; Syncope; Testing; Tissues; Vascular Diseases; Vascular remodeling; Walking; Woman; age related; aged; arterial stiffness; atherosclerosis risk; base; blood pressure reduction; blood pressure regulation; cardiovascular disorder prevention; cardiovascular disorder risk; cofactor; density; dietary supplements; endothelial dysfunction; exercise program; exercise training; flexibility; functional improvement; high risk; human old age (65+); improved; kidney dysfunction; lifestyle intervention; men; nicotinamide-beta-riboside; novel; overexpression; peripheral blood; pre-clinical; prevent; recruit; response; screening; side effect; targeted treatment; treatment group; trend

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.

抽象的 超过80％的老年人患有高血压，高收缩压（SBP）的患病率更高 使他们处于心血管疾病和死亡的高风险。因为降低SBP的药物治疗是 与副作用（例如低血压，晕厥和肾脏功能障碍）相关，非常需要 可以替代药物疗法的老年人群的有效生活方式降低SBP干预措施。尽管 有氧运动是针对控制SBP和防止CV疾病的推荐生活方式干预措施 自然，在老年人中，由于有效率 动脉刚度，导致效率较低的SBP控制。烟酰胺腺嘌呤的生物利用度降低 Dinucleotide（NAD+）是脱乙酰基酶Sirtuin1（SIRT1）的辅助因子，可能有助于与年龄有关的血管 通过氧化应激和一氧化氮减少（NO）功能障碍。运动引起的NAD+ - 依赖的SIRT1提高了NO的生物利用度。临床前证明血管功能不良 响应老鼠的运动的改善是由NAD+水平不足引起的，以刺激SIRT1 活动。重要的是，补充NAD+水平诱导的血管重塑，改善了血管 小鼠的功能和降低的SBP。因此，这项研究的一个目的是测试有氧的组合 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- 高血压老年人的降低作用。最初的人类临床试验表明烟酰胺核糖剂 补充（1,000毫克/天）是安全的，并且显示出降低SBP和动脉刚度的较高潜力 在SBP升高的参与者中。因为我们有临床前证明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 有氧运动训练与补充烟酰胺核苷相结合将减少SBP 高血压老年人比单独运动更有效。我们将注册45名参与者65年，并且 年龄较大：（1）1,000毫克/天的烟酰胺核苷加3天/周的监督，基于中心的 步行练习，或（2）相同的锻炼计划与安慰剂结合，或（3）1,000 mg/天 烟酰胺核苷。所有参与者都将经历白天连续的SBP和动脉状态 基线和6周时通过脉冲波速度测量。然后将升高的SBP确定为 通过24小时的血压装置测量的白天平均水平以上是130 mmHg。据我们所知，这个 研究将是在高血压较老的烟酰胺核苷增强运动疗法的首次尝试 成年人。我们认为，烟酰胺核苷是改善血管的“难题的缺失” 老年人的改建和SBP管理。这项试验研究的初步证据可能支持全面 高血压老年人的量表III期临床试验。这一研究的最终目标是找到 辅助策略以改善运动对老年人的SBP降低作用。