Mitochondrial-targeted Antioxidant Supplementation for Improving Age-related Vascular Dysfunction in Humans

Aging Clinical Trial

Official title:

Mitochondrial-targeted Antioxidant Supplementation for Improving Age-related Vascular Dysfunction in Humans

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT04851288
• Other study ID #: 20-0502
• Secondary ID: R01AG066730
• Status: Recruiting
• Phase: Phase 2
• Start date: April 2, 2021
• Est. completion date: December 2025

Study information

• Verified date: February 2024
• Source: University of Colorado, Boulder
• Contact: Hannah Bethke
• Phone: 720-526-2925
• Email: MitoQstudy[@]colorado.edu
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 112
• Est. completion date: December 2025
• Est. primary completion date: August 2025
• Accepts healthy volunteers: Accepts Healthy Volunteers
• Gender: All
• Age group: 60 Years and older

Eligibility

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

Related Conditions & MeSH terms

• Aging

Intervention

Dietary Supplement:
• MitoQ
MitoQ is a biochemically modified form of ubiquinol
• Placebo
Each placebo capsule contains inert excipient and is identical in appearance

Locations

Country	Name	City	State
United States	University of Colorado Boulder	Boulder	Colorado

Sponsors (2)

Lead Sponsor	Collaborator
University of Colorado, Boulder	National Institute on Aging (NIA)

Country where clinical trial is conducted

United States, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Other	Change from baseline in serum exposure-induced endothelial cell reactive oxygen species production at 3 months	Endothelial cell whole-cell (CellROX) and mitochondria-specific (MitoSOX) reactive oxygen species levels after treatment with serum from subjects	3 months
Other	Change from baseline in endothelial cell markers of oxidative stress and mitochondrial health from baseline at 3 months	Endothelial cell protein expression of nitrotyrosine and Fis1	3 months
Other	Change from baseline in carotid artery stiffness at 3 months	Carotid artery beta-stiffness index	3 months
Other	Change from baseline in circulating marker of oxidative stress at 3 months	Oxidized LDL levels in blood	3 months
Other	Change from baseline in cerebrovascular reactivity at 3 months	Change in middle cerebral artery blood velocity in response to hypercapnia	3 months
Other	Change from baseline in mitochondrial oxidative stress-mediated suppression of cerebrovascular reactivity at 3 months	Assessed as the change in cerebrovascular reactivity to hypercapnia following administration of a supratherapeutic dose of MitoQ known to scavenge mitochondrial reactive oxygen species	3 months
Other	Change from baseline in internal carotid artery dilation at 3 months	Dilation of the internal carotid artery in response to hypercapnia	3 months
Other	Change from baseline in mitochondrial oxidative stress-mediated suppression of internal carotid artery dilation at 3 months	Assessed as the change in internal carotid artery dilation to hypercapnia following administration of a supratherapeutic dose of MitoQ known to scavenge mitochondrial reactive oxygen species	3 months
Other	Change from baseline in total cerebral blood flow at 3 months	Total cerebral blood flow	3 months
Other	Change from baseline in serum exposure-induced brain endothelial cell nitric oxide and mitochondrial reactive oxygen species production at 3 months	Brain endothelial cell acetylcholine-induced nitric oxide production (DAR-4M-AM) and mitochondria-specific (MitoSOX) reactive oxygen species levels after treatment with serum from subjects	3 months
Primary	Change from baseline in endothelial function at 3 months	Brachial artery flow-mediated dilation	3 months
Secondary	Change from baseline in suppression of endothelial function by mitochondrial oxidative stress at 3 months	Change in brachial artery flow-mediated dilation with acute, supratherapeutic MitoQ (160mg)	3 months
Secondary	Change from baseline in aortic stiffness at 3 months	Carotid-femoral pulse wave velocity	3 months