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

基本信息

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
项目类别：
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

项目摘要

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.

项目概要绝大多数心血管疾病（CVD）发生在≥60岁的男性和女性身上。美国老龄化人口统计数据预测，如果没有有效干预，心血管疾病将逐渐增加。血管功能障碍，包括通过减少内皮依赖性来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）是主要的活性氧生成过多导致老年人 CVD 风险增加的机制。线粒体（mtROS）已成为血管氧化应激与衰老和驱动因素的核心特征因此，确定减少 mtROS 和改善的新策略。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 是一种靶向线粒体的抗氧化剂，在线粒体内膜上积累，其中我们实验室的临床前研究结果表明，4 周后，它处于减少 mtROS 的最佳位置。口服 MitoQ 补充剂完全恢复老年小鼠的 EDD，改善 mtROS 相关 EDD 的抑制，并与动脉 mtROS 减少、氧化应激和改善有关 MitoQ 疗法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）中转化这些发现时，我们发现补充 MitoQ 耐受性良好，可改善内皮功能并降低血浆氧化低密度水平脂蛋白，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。对我们部分受试者的机制评估表明，MitoQ 改善内皮功能是由内皮细胞 mtROS 产生减少介导，与强直性 mtROS 相关的相关减少抑制 EDD 并改善线粒体健康，部分与循环因子的变化有关长期补充 MitoQ 引起的血清最后，MitoQ 降低了老年人的主动脉僵硬度。基线时表现出与年龄相关的主动脉硬化。在此，我们提出一项随机、安慰剂对照、双盲临床试验 (PA-19-055) 来建立口服 MitoQ（20 毫克/天；MitoQ, Ltd.）6 个月与安慰剂（n=56/组）相比，用于改善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由 mtROS 相关的 EDD 抑制减少介导，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志物。假设 3：口服 MitoQ 补充剂将减少老年人的动脉僵硬度。