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

PROJECT SUMMARY Aging is the primary risk factor for mild cognitive impairment (MCI), Alzheimer’s disease and related dementias. Cerebrovascular dysfunction (i.e., reduced cerebrovascular reactivity and cerebral blood flow) is a key mechanism contributing to the increase in risk with aging and is largely mediated by decreases in the

vasodilatory molecule nitric oxide (NO), leading to impaired cerebrovascular dilation. Excessive reactive oxygen species production by mitochondria (mtROS) is a major contributor to cerebrovascular dysfunction as mtROS can reduce bioavailable NO and impair cerebral endothelial cell (EC) function. Because the aging

population and prevalence of MCI and dementias are projected to increase in coming years, establishing novel strategies to decrease mtROS to improve cognitive and cerebrovascular function in older adults is an important biomedical research goal to reduce the risk of MCI, Alzheimer’s disease and related dementias.

MitoQ is a mitochondrial-targeted antioxidant biochemically modified to accumulate in the inner mitochondrial membrane where it is optimally positioned to reduce mtROS. We reported in an NIA R21-funded pilot clinical trial that 6 weeks of MitoQ treatment in older adults improves peripheral vascular endothelial function

(brachial artery flow-mediated dilation) by reducing mtROS-related suppression of endothelial function. We also found that MitoQ treatment-induced changes in the circulating milieu (plasma) evoke improvements in human aortic EC function, as shown by higher acetylcholine-stimulated NO production and lower basal mtROS

bioactivity in ECs treated with plasma from subjects after MitoQ supplementation vs. placebo. Our parent award is a larger, NIA R01-funded (AG067730) randomized, placebo-controlled clinical trial assessing 3 months of MitoQ treatment for improving peripheral vascular function in older adults. To explore

the possible effects of MitoQ on cognitive and cerebrovascular function, we utilized subjects enrolled in the parent trial to obtain preliminary data that suggest MitoQ treatment may improve fluid cognition (i.e., the domain of cognition most heavily influenced by aging and Alzheimer’s disease) and cerebrovascular

function vs. placebo. We propose to leverage the R01-funded trial to determine the efficacy of MitoQ supplementation for improving fluid cognition and cerebrovascular function in older adults and provide insight into possible mechanism(s) contributing to these improvements. This research is highly relevant to

Alzheimer’s disease and related dementias as it will evaluate a novel clinical intervention for improving cognitive and cerebrovascular function in asymptomatic older adults, a group disproportionately burdened by MCI, Alzheimer’s disease and related dementias. Leveraging our ongoing clinical trial will

stimulate research in Alzheimer’s disease and related dementias by providing initial evidence for the efficacy of dietary supplementation with MitoQ as an innovative prevention strategy for decreasing dementia risk and promoting translation of this promising alternative intervention to other at-risk groups.