Mitochondrial-targeted antioxidant supplementation for improving age-related vascular dysfunction in humans

线粒体靶向抗氧化剂补充剂可改善人类与年龄相关的血管功能障碍

• 批准号: 10319609
• 负责人: DOUGLAS R SEALS
• 金额: $ 58万
• 依托单位: UNIVERSITY OF COLORADO
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-01-01 至 2025-12-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10319609
• 关键词: Acute; Adult; Aftercare; Age; Age-Years; Aging; Antioxidants; Aorta; Arteries; Biochemical; Biological; Biological Assay; Biomedical Research; Biopsy; Blood Vessels; Cardiovascular Diseases; Carotid Arteries; Cause of Death; Cells; Chronic; Clinical; Clinical Trials; Crossover Design; Development; Disease; Dose; Double-Blind Method; Elderly; Endothelial Cells; Endothelium; Exhibits; Exposure to; Health; High Prevalence; Human; Impairment; Inner mitochondrial membrane; Laboratories; Link; Lipoprotein (a); Measures; Mediating; Mitochondria; Molecular; Molecular Profiling; Mus; Oral; Oxidative Stress; Phase; Physiologic pulse; Pilot Projects; Placebo Control; Placebos; Plasma; Positioning Attribute; Prevalence; Production; Randomized; Reactive Oxygen Species; Research; Research Technics; Risk; Serum; Site; Subgroup; Supplementation; Therapeutic; Translating; Translational Research; Translations; Ultrasonography; Vascular Diseases; Vascular Endothelium; Woman; age related; arterial stiffness; base; brachial artery; cardiovascular disorder risk; cardiovascular risk factor; circulating biomarkers; clinical application; demographics; design; drinking water; effective intervention; endothelial dysfunction; fitness; improved; in vivo; indexing; innovation; insight; men; mitochondrial fitness; novel; novel strategies; novel therapeutic intervention; older men; older women; oral supplementation; oxidized low density lipoprotein; pre-clinical; preservation; tonometry; treatment duration; ubiquinol; young adult

Project Summary The vast majority of cardiovascular diseases (CVD) occur in men and women ≥60 years of age. Changes in the demographics of aging in the U.S. predict progressive increases in CVD without effective intervention. Vascular dysfunction, including endothelial dysfunction as assessed by reduced endothelium-dependent dilation (EDD) and stiffening of the large elastic arteries (i.e., aortic and carotid artery stiffening), is a major mechanism of increased risk of CVD in older adults. Excess production of reactive oxygen species by mitochondria (mtROS) has emerged as a central feature of vascular oxidative stress with aging and driver of age-related vascular dysfunction. As such, identifying novel strategies to decrease mtROS and improve vascular function, to ultimately reduce the risk of age-related CVD, is an important biomedical objective. MitoQ is a mitochondria-targeted antioxidant that accumulates at the inner mitochondrial membrane where it is optimally positioned to reduce mtROS. Preclinical findings from our laboratory showed that 4 weeks of oral MitoQ supplementation completely restored EDD in old mice, ameliorated mtROS-associated suppression of EDD, and was associated with reduced arterial mtROS, oxidative stress and improved mitochondrial health. MitoQ therapy also reduced aortic stiffness in old mice. We recently took the first step in translating these findings in a small pilot study of older adults (n=20). We found that supplementation with MitoQ was well-tolerated, improved endothelial function and reduced plasma levels of oxidized low-density lipoprotein, a circulating biomarker of oxidative stress. Consistent with our preclinical findings, preliminary mechanistic assessments in subsets of our subjects suggest that improved endothelial function with MitoQ is mediated by reduced endothelial cell mtROS production, associated reductions in tonic mtROS-related suppression of EDD, and improved mitochondrial health, linked in part to changes in circulating factors in the serum induced by chronic MitoQ supplementation. Lastly, MitoQ reduced aortic stiffness in older adults who exhibited age-related aortic stiffening at baseline. Here we propose a randomized, placebo-controlled, double-blind clinical trial (PA-19-055) to establish oral MitoQ (20 mg/day; MitoQ, Ltd.) for 6 months vs. placebo (n=56/group) for improving endothelial function in older men and women (≥60 years), and determine the mechanisms by which MitoQ improves endothelial function. We also propose to assess the effect of MitoQ on arterial stiffness. Hypothesis 1: Oral MitoQ supplementation will improve vascular endothelial function in healthy older adults. Hypothesis 2: Improvements in endothelial function with oral MitoQ supplementation in older adults will be mediated by reduced mtROS-related suppression of EDD and associated with reduced endothelial cell ROS production, vascular and systemic oxidative stress, and improved endothelial markers of mitochondrial health. Hypothesis 3: Oral MitoQ supplementation will reduce arterial stiffness in older adults.

项目摘要 绝大多数心血管疾病(心血管疾病)发生在60岁的男性和女性≥。变化 在美国老龄化的人口统计学中预测，在没有有效干预的情况下，心血管疾病会逐渐增加。 血管功能障碍，包括内皮依赖性降低所评估的内皮功能障碍 大弹性动脉的扩张(EDD)和硬化(即，主动脉和颈动脉硬化)是主要的 老年人心血管疾病风险增加的机制。细菌产生过量的活性氧物质 随着年龄的增长，线粒体(MtROS)已成为血管氧化应激的中心特征和驱动因素 与年龄相关的血管功能障碍。因此，确定减少mtRO和改善mtRO的新策略 血管功能，最终降低与年龄相关的心血管疾病的风险，是一个重要的生物医学目标。 MitoQ是一种线粒体靶向抗氧化剂，积聚在线粒体膜的内层， 它处于降低mtROS的最佳位置。我们实验室的临床前研究结果显示，4周的 口服MitoQ完全恢复老年小鼠EDD，改善mtROS相关 抑制EDD，并与动脉mtROS减少、氧化应激减少和改善有关 线粒体健康。MitoQ疗法也降低了老年小鼠的主动脉僵硬。我们最近迈出了第一步 在一项针对老年人(n=20)的小型先导性研究中翻译了这些发现。我们发现这种补充剂 MitoQ耐受性良好，改善了内皮功能，降低了血浆氧化低密度水平 脂蛋白，氧化应激的循环生物标记物。与我们的临床前研究结果一致，初步 我们受试者亚组的机械性评估表明，使用MitoQ改善内皮功能是 内皮细胞mtROS产生减少，与紧张性mtROS相关的减少 抑制EDD，改善线粒体健康，部分与循环因子的变化有关 慢性补充MitoQ诱导的血清。最后，MitoQ降低了老年人的主动脉僵硬 在基线时表现出与年龄相关的主动脉僵硬。 在这里，我们提出了一项随机、安慰剂对照、双盲临床试验(PA-19-055)来建立 口服MitoQ(每天20毫克；MitoQ，Ltd.)6个月与安慰剂(n=56/组)相比，改善血管内皮功能 老年男性和女性(≥60岁)，并确定MitoQ改善内皮细胞的机制 功能。我们还建议评估MitoQ对动脉僵硬的影响。 假设1：口服MitoQ补充剂将改善健康老年人的血管内皮功能。 假设2：口服MitoQ可改善老年人的内皮功能 MtROS相关的EDD抑制减少并与内皮细胞ROS减少相关 生产、血管和全身氧化应激，以及改善线粒体健康的内皮标记物。 假设3：口服MitoQ补充剂将降低老年人的动脉僵硬。