Aging
Conditions
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.
Interventions
DIETARY_SUPPLEMENTMitoQ
MitoQ is a biochemically modified form of ubiquinol
DIETARY_SUPPLEMENTPlacebo
Each placebo capsule contains inert excipient and is identical in appearance
Sponsors
National Institute on Aging (NIA)
University of Colorado, Boulder
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
OTHER
Masking
TRIPLE (Subject, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
60 Years to No maximum
Healthy volunteers
Yes
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change from baseline in endothelial function at 3 months | 3 months | Brachial artery flow-mediated dilation |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change from baseline in suppression of endothelial function by mitochondrial oxidative stress at 3 months | 3 months | Change in brachial artery flow-mediated dilation with acute, supratherapeutic MitoQ (160mg) |
| Change from baseline in aortic stiffness at 3 months | 3 months | Carotid-femoral pulse wave velocity |
Other
| Measure | Time frame | Description |
|---|---|---|
| Change from baseline in circulating marker of oxidative stress at 3 months | 3 months | Oxidized LDL levels in blood |
| Change from baseline in cerebrovascular reactivity at 3 months | 3 months | Change in middle cerebral artery blood velocity in response to hypercapnia |
| Change from baseline in mitochondrial oxidative stress-mediated suppression of cerebrovascular reactivity at 3 months | 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 |
| Change from baseline in serum exposure-induced endothelial cell reactive oxygen species production at 3 months | 3 months | Endothelial cell whole-cell (CellROX) and mitochondria-specific (MitoSOX) reactive oxygen species levels after treatment with serum from subjects |
| Change from baseline in mitochondrial oxidative stress-mediated suppression of internal carotid artery dilation at 3 months | 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 |
| Change from baseline in total cerebral blood flow at 3 months | 3 months | Total cerebral blood flow |
| Change from baseline in serum exposure-induced brain endothelial cell nitric oxide and mitochondrial reactive oxygen species production at 3 months | 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 |
| Change from baseline in internal carotid artery dilation at 3 months | 3 months | Dilation of the internal carotid artery in response to hypercapnia |
| Change from baseline in endothelial cell markers of oxidative stress and mitochondrial health from baseline at 3 months | 3 months | Endothelial cell protein expression of nitrotyrosine and Fis1 |
| Change from baseline in carotid artery stiffness at 3 months | 3 months | Carotid artery beta-stiffness index |
Countries
United States
Outcome results
None listed