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

项目摘要 绝大多数心血管疾病（CVD）发生在≥60岁的男性和女性中。变化 在美国老龄化的人口统计学中，预测CVD在没有有效干预的情况下会逐渐增加。 血管功能障碍，包括内皮功能障碍，通过降低内皮依赖性 大弹性动脉的扩张（EDD）和硬化（即，主动脉和颈动脉硬化），是一个主要的 老年人CVD风险增加的机制。活性氧物质的过量产生 线粒体（mtROS）已成为血管氧化应激的中心特征， 与年龄相关的血管功能障碍因此，确定减少mtROS和改善线粒体损伤的新策略， 血管功能，以最终降低年龄相关CVD的风险，是一个重要的生物医学目标。 MitoQ是一种以线粒体为靶点的抗氧化剂，它积累在线粒体内膜上， 它被最佳地定位以减少mtROS。我们实验室的临床前研究结果显示， 口服MitoQ补充完全恢复了老年小鼠的EDD，改善了mtROS相关的 抑制EDD，并与动脉mtROS减少，氧化应激和改善 线粒体健康MitoQ治疗还降低了老年小鼠的主动脉僵硬度。我们最近迈出了第一步 在一项针对老年人的小型试点研究（n=20）中，我们发现， MitoQ耐受性良好，改善了内皮功能，降低了血浆氧化低密度脂蛋白水平。 脂蛋白，氧化应激的循环生物标志物。与我们的临床前研究结果一致，初步 我们受试者亚组的机制评估表明，MitoQ改善内皮功能是 通过减少内皮细胞mtROS的产生介导， 抑制EDD，改善线粒体健康，部分与循环因子的变化有关， 慢性MitoQ补充诱导的血清。最后，MitoQ降低了老年人的主动脉僵硬度 在基线时表现出年龄相关的主动脉硬化。 在此，我们提出了一项随机、安慰剂对照、双盲临床试验（PA-19-055），以确定 口服MitoQ（20 mg/天; MitoQ，Ltd.）6个月与安慰剂（n=56/组）相比， 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对动脉僵硬度的影响。 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：老年人口服MitoQ补充剂可改善内皮功能， 通过减少线粒体ROS相关的EDD抑制介导，并与减少内皮细胞ROS相关 生产，血管和全身氧化应激，并改善线粒体健康的内皮标志物。 假设3：口服MitoQ补充剂将降低老年人的动脉僵硬度。

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.