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

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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.