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.

项目摘要绝大多数心血管疾病（CVD）发生在≥60岁的男女。更改在美国衰老的人口统计中，预测CVD的渐进性增加而无需有效干预。血管功能障碍，包括内皮依赖性减少的内皮功能障碍大弹性动脉的扩张（EDD）和僵硬（即主动脉和颈动脉僵硬）是主要的老年人CVD风险增加的机制。通过线粒体（MTROS）已成为血管氧化应激的核心特征，并具有衰老和驱动力与年龄有关的血管功能障碍。因此，确定新的策略以减少MTRO并改善血管功能最终降低了与年龄相关的CVD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，可在内部线粒体膜上积聚它在减少MTROS方面是最佳位置。我们实验室的临床前发现表明4周口服MITOQ补充完全恢复了老鼠的EDD，改善了MTROS相关的 EDD的抑制，与动脉MTROS减少，氧化应激相关并改善线粒体健康。 MITOQ治疗还降低了老鼠的主动脉僵硬。我们最近迈出了第一步在对老年人的小型试点研究中翻译这些发现（n = 20）。我们发现补充 Mitoq耐受良好，改善的内皮功能，血浆氧化的低密度水平降低脂蛋白，氧化应激的循环生物标志物。与我们的临床前发现一致对我们受试者子集的机械评估表明，Mitoq的内皮功能提高了通过减少的内皮细胞MTROS产生介导的，及相关的MTROS相关的减少抑制EDD并改善了线粒体健康，部分与循环因素的变化有关补充慢性Mitoq诱导的血清。最后，Mitoq降低了老年人的主动脉僵硬他在基线时暴露了与年龄有关的主动脉僵硬。在这里，我们提出了一项随机，安慰剂对照的双盲临床试验（PA-19-055）建立口服MITOQ（20 mg/day; Mitoq，Ltd。）持续了6个月，而安慰剂（n = 56/组）用于改善内皮功能老年男性和女性（≥60岁），并确定Mitoq改善内皮的机制功能。我们还建议评估Mitoq对动脉刚度的影响。假设1：补充口服MITOQ将改善健康老年人的血管内皮功能。假设2：在老年人中补充口服MITOQ的内皮功能的改善将是通过降低MTROS相关的EDD抑制并与内皮细胞ROS减少相关的介导生产，血管和全身性氧化物胁迫，以及改善线粒体健康的内皮标记。假设3：补充口服MITOQ将降低老年人的动脉僵硬。