Clinical trial NCT04851288: Mitochondrial-targeted Antioxidant Supplementation for Improving Age-related Vascular Dysfunction in Humans
Official title: Mitochondrial-targeted Antioxidant Supplementation for Improving Age-related Vascular Dysfunction in Humans
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE2
Conditions: Aging
Lead sponsor: University of Colorado, Boulder
Sponsor class: OTHER
Collaborators: name: National Institute on Aging (NIA)
First posted: 2021-04-20
Enrollment: 112
Sex: ALL
Minimum age (years): 60
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: yes
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: OTHER

Brief summary: The majority of cardiovascular diseases (CVD) occur in men and women ≥60 years of age. 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 ROS (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 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. A recent small pilot study of older adults (n=20) 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 the preclinical findings, preliminary mechanistic assessments in subsets of subjects from the pilot study suggested that improved endothelial function with MitoQ was 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.

The investigators are conducting a randomized, placebo-controlled, double-blind clinical trial to establish oral MitoQ (20 mg/day; MitoQ, Ltd.) for 3 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. The investigators will also assess the effect of MitoQ on aortic stiffness.


Eligibility criteria: Inclusion Criteria:

* Age 60 years and over
* Ability to provide informed consent
* Willing to accept random assignment to condition
* Body mass index \<40 kg/m2
* Weight stable in the prior 3 months (\<2 kg weight change) and willing to remain weight stable throughout the study
* Free from alcohol dependence or abuse,
* Mini-mental stage examination score ≥21

Exclusion Criteria:

* Uncontrolled thyroid disease
* Regular vigorous aerobic (\>6 bouts/week, \>60 min/bout at a workload \>6 METS)
* Blood donation within 8 weeks prior to enrolling in the study

Primary outcomes:
measure: Change from baseline in endothelial function at 3 months
timeFrame: 3 months
Secondary outcomes:
measure: Change from baseline in suppression of endothelial function by mitochondrial oxidative stress at 3 months
timeFrame: 3 months
measure: Change from baseline in aortic stiffness at 3 months
timeFrame: 3 months
Other outcomes:
measure: Change from baseline in serum exposure-induced endothelial cell reactive oxygen species production at 3 months
timeFrame: 3 months
measure: Change from baseline in endothelial cell markers of oxidative stress and mitochondrial health from baseline at 3 months
timeFrame: 3 months
measure: Change from baseline in carotid artery stiffness at 3 months
timeFrame: 3 months
measure: Change from baseline in circulating marker of oxidative stress at 3 months
timeFrame: 3 months
measure: Change from baseline in cerebrovascular reactivity at 3 months
timeFrame: 3 months
measure: Change from baseline in mitochondrial oxidative stress-mediated suppression of cerebrovascular reactivity at 3 months
timeFrame: 3 months
measure: Change from baseline in internal carotid artery dilation at 3 months
timeFrame: 3 months
measure: Change from baseline in mitochondrial oxidative stress-mediated suppression of internal carotid artery dilation at 3 months
timeFrame: 3 months
measure: Change from baseline in total cerebral blood flow at 3 months
timeFrame: 3 months
measure: Change from baseline in serum exposure-induced brain endothelial cell nitric oxide and mitochondrial reactive oxygen species production at 3 months
timeFrame: 3 months
Locations:
city: Boulder
country: United States
facility: University of Colorado Boulder
state: Colorado
Study officials:
affiliation: University of Colorado, Boulder
name: Douglas R Seals
role: PRINCIPAL_INVESTIGATOR
References:
citation: Murray KO, Berryman-Maciel M, Darvish S, Coppock ME, You Z, Chonchol M, Seals DR, Rossman MJ. Mitochondrial-targeted antioxidant supplementation for improving age-related vascular dysfunction in humans: A study protocol. Front Physiol. 2022 Sep 15;13:980783. doi: 10.3389/fphys.2022.980783. eCollection 2022.