Antioxidant Supplementation for Aging-Related Vascular Dysfunction

Overseen By Matthew J Rossman, PhD

Age: 18+

Sex: Any

Trial Phase: Phase 2

Sponsor: University of Colorado, Boulder

Disqualifiers: Uncontrolled thyroid disease, others

Prior Safety Data This treatment has passed at least one previous human trial

Compensation: Varies

Number of Visits: Unknown

Duration: 12 weeks

112 Participants Needed

Trial Summary

What is the purpose of this trial?

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.

Will I have to stop taking my current medications?

The trial information does not specify whether you need to stop taking your current medications. It's best to discuss this with the trial coordinators or your doctor.

What evidence supports the effectiveness of the drug MitoQ for improving age-related vascular dysfunction?

Research shows that MitoQ, a mitochondrial-targeted antioxidant, improved vascular function in healthy older adults by reducing oxidative stress and arterial stiffness. In a study, participants taking MitoQ had a 42% improvement in blood vessel function compared to those taking a placebo. ^{1 2 3 4 5}

Is MitoQ safe for humans?

MitoQ has been tested in humans and is generally well tolerated, with studies showing no significant safety concerns, even at higher doses. It has been used in trials with healthy older adults without causing harmful effects, and a study found that high doses did not increase kidney injury markers. ^{1 2 6 7 8}

How does the drug MitoQ differ from other treatments for aging-related vascular dysfunction?

MitoQ is unique because it specifically targets mitochondria to reduce oxidative stress, which is a key factor in age-related vascular dysfunction. This mitochondrial-targeted approach helps improve blood vessel function and reduce artery stiffness, which is different from other treatments that may not focus on the mitochondria. ^{1 2 3 9 10}

Research Team

Douglas R Seals, PhD

Principal Investigator

University of Colorado, Boulder

Eligibility Criteria

This trial is for men and women aged 60 or older who are mentally fit (with a mini-mental exam score of at least 21), not alcohol dependent, have had stable weight recently, and aren't heavily involved in vigorous aerobic activities. Those with uncontrolled thyroid disease or recent blood donations are excluded.

Inclusion Criteria

Willing to accept random assignment to condition

Body mass index <40 kg/m2

Ability to provide informed consent

Exclusion Criteria

Blood donation within 8 weeks prior to enrolling in the study

My thyroid condition is not under control.

Regular vigorous aerobic (>6 bouts/week, >60 min/bout at a workload >6 METS)

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive oral MitoQ (20 mg/day) or placebo for 3 months to improve endothelial function and assess effects on aortic stiffness

12 weeks

Regular visits for monitoring and assessments

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

Treatment Details

Interventions

• MitoQ
• Placebo

Trial Overview The study tests if MitoQ, an antioxidant targeting mitochondria, can improve vascular function by reducing oxidative stress in the elderly when taken orally for three months compared to a placebo. The effects on endothelial function and aortic stiffness will be measured.

Participant Groups

Group I: MitoQ, 20 mg/day Experimental Treatment 1 Intervention

Each MitoQ capsule contains 20 mg of mitoquinol mesylate. Dosage: 20 mg orally per day for 3 months.

Group II: Placebo Placebo Group 1 Intervention

Matched placebo capsules.

Who Is Running the Clinical Trial?

University of Colorado, Boulder

Lead Sponsor

Trials

128

Recruited

29,600+

National Institute on Aging (NIA)

Collaborator

Trials

1,841

Recruited

28,150,000+

Findings from Research

In a study involving 20 healthy older adults, 6 weeks of oral supplementation with the mitochondrial-targeted antioxidant MitoQ significantly improved endothelial function, as indicated by a 42% increase in brachial artery flow-mediated dilation compared to placebo.

MitoQ was well tolerated and also reduced aortic stiffness and plasma oxidized LDL levels, suggesting its potential as a therapeutic strategy for age-related vascular dysfunction.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Chronic Supplementation With a Mitochondrial Antioxidant (MitoQ) Improves Vascular Function in Healthy Older Adults. Rossman, MJ., Santos-Parker, JR., Steward, CAC., et al.[2022]

The ongoing phase IIa clinical trial is investigating the efficacy of MitoQ, a mitochondrial-targeted antioxidant, in improving vascular function in 90 healthy older adults aged 60 and above, with a focus on nitric oxide-mediated dilation as the primary outcome.

Initial evidence from a previous pilot study suggested that MitoQ may enhance vascular function by reducing mitochondrial reactive oxygen species, which are linked to age-related vascular dysfunction.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Mitochondrial-targeted antioxidant supplementation for improving age-related vascular dysfunction in humans: A study protocol. Murray, KO., Berryman-Maciel, M., Darvish, S., et al.[2022]

Aging leads to significant molecular and cellular changes in blood vessels, which are linked to increased oxidative stress and inflammation, contributing to vascular diseases in elderly patients.

Practical interventions such as anti-inflammatory treatments, regular exercise, dietary changes, and caloric restriction mimetics may help prevent or improve age-related vascular dysfunction.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Mechanisms of vascular aging: new perspectives. Ungvari, Z., Kaley, G., de Cabo, R., et al.[2022]

In a study involving 1162 healthy participants over an average of 7.2 years, daily low-dose antioxidant supplementation was associated with a higher percentage of carotid plaques compared to a placebo group (35.2% vs. 29.5%).

The study found no significant benefits of antioxidant supplementation on common carotid intima-media thickness or arterial stiffness, suggesting that long-term use may not improve vascular health.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Effects of long-term daily low-dose supplementation with antioxidant vitamins and minerals on structure and function of large arteries. Zureik, M., Galan, P., Bertrais, S., et al.[2016]

Vascular dysfunction, which includes issues like endothelial dysfunction and stiffening of arteries, is a significant risk factor for cardiovascular disease (CVD), making it a key target for prevention and management strategies.

Mitochondrial function plays a crucial role in maintaining vascular health, and impairments in this function can lead to increased CVD risk; both lifestyle changes and pharmaceutical interventions targeting mitochondrial health may help improve vascular function.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Mitochondrial contributions to vascular endothelial dysfunction, arterial stiffness, and cardiovascular diseases. Kirkman, DL., Robinson, AT., Rossman, MJ., et al.[2022]

MitoQ, a mitochondrial-targeted antioxidant, was found to increase respiration in cells using complex I substrates and enhance glucose oxidation while reducing fat oxidation, indicating its role in altering fuel selectivity in intact cells.

The study demonstrated that MitoQ interacts with complex I in a way that increases reactive oxygen species (ROS) production, suggesting that its effects are more complex than previously thought and depend on the type of substrate used.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Mitochondrial targeted coenzyme Q, superoxide, and fuel selectivity in endothelial cells. Fink, BD., O'Malley, Y., Dake, BL., et al.[2021]

MitoQ, a mitochondria-targeted antioxidant, significantly reduced nitrotyrosine concentration, indicating its potential to alleviate oxidative stress associated with aging, based on a meta-analysis of 27 studies involving 190 animals.

The intervention also improved mitochondrial membrane potential, suggesting that MitoQ may support healthier mitochondrial function as we age.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The Effect of MitoQ on Aging-Related Biomarkers: A Systematic Review and Meta-Analysis. Braakhuis, AJ., Nagulan, R., Somerville, V.[2023]

Acute high-dose MitoQ supplementation (100-160 mg) in 32 healthy adults showed no significant changes in urinary biomarkers associated with kidney injury, suggesting it is not nephrotoxic.

The study's results support the safety of MitoQ for further research on its effects related to mitochondrial oxidative stress, as it did not affect kidney function or injury markers in the short term.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Acute High Dose MitoQ Does not Increase Urinary Kidney Injury Markers in Healthy Adults. Linder, BA., Stute, NL., Hutchison, ZJ., et al.[2023]

Chronic supplementation with the mitochondria-targeted antioxidant MitoQ significantly improves endothelial function in older adults by enhancing nitric oxide production and reducing mitochondrial oxidative stress, as shown in a clinical trial with 19 participants.

MitoQ treatment leads to lower levels of oxidized low-density lipoprotein (oxLDL) in the plasma, which is crucial for the observed improvements in endothelial function, indicating that changes in the circulating environment play a key role in its efficacy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Chronic mitochondria antioxidant treatment in older adults alters the circulating milieu to improve endothelial cell function and mitochondrial oxidative stress. Murray, KO., Ludwig, KR., Darvish, S., et al.[2023]

An oral antioxidant cocktail consisting of vitamins C, E, and alpha-lipoic acid significantly reduced circulating free radicals by approximately 98% at rest and 85% during exercise in a study of 25 healthy young males.

Despite the reduction in free radicals, the antioxidant cocktail led to decreased vasodilation during exercise compared to a placebo, suggesting that free radicals may play a beneficial role in normal vascular function during physical activity.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Exercise-induced brachial artery vasodilation: role of free radicals. Richardson, RS., Donato, AJ., Uberoi, A., et al.[2020]

References

1. United States pubmed.ncbi.nlm.nih.gov

Chronic Supplementation With a Mitochondrial Antioxidant (MitoQ) Improves Vascular Function in Healthy Older Adults. [2022]

2. Switzerland pubmed.ncbi.nlm.nih.gov

Mitochondrial-targeted antioxidant supplementation for improving age-related vascular dysfunction in humans: A study protocol. [2022]

3. United States pubmed.ncbi.nlm.nih.gov

Mechanisms of vascular aging: new perspectives. [2022]

4. United States pubmed.ncbi.nlm.nih.gov

Effects of long-term daily low-dose supplementation with antioxidant vitamins and minerals on structure and function of large arteries. [2016]

5. United States pubmed.ncbi.nlm.nih.gov

Mitochondrial contributions to vascular endothelial dysfunction, arterial stiffness, and cardiovascular diseases. [2022]

6. United States pubmed.ncbi.nlm.nih.gov

Mitochondrial targeted coenzyme Q, superoxide, and fuel selectivity in endothelial cells. [2021]

7. United States pubmed.ncbi.nlm.nih.gov

The Effect of MitoQ on Aging-Related Biomarkers: A Systematic Review and Meta-Analysis. [2023]

8. United States pubmed.ncbi.nlm.nih.gov

Acute High Dose MitoQ Does not Increase Urinary Kidney Injury Markers in Healthy Adults. [2023]

9. United States pubmed.ncbi.nlm.nih.gov

Chronic mitochondria antioxidant treatment in older adults alters the circulating milieu to improve endothelial cell function and mitochondrial oxidative stress. [2023]

10. United States pubmed.ncbi.nlm.nih.gov

Exercise-induced brachial artery vasodilation: role of free radicals. [2020]