A range of mitochondrially targeted antioxidant compounds have been developed over the past decade or more: SkQ1, SS-31, and MitoQ, the subject of the trial here. The present consensus in the research community is that ordinary antioxidants are probably, on balance, somewhat harmful if used over the long term. They sabotage the oxidative signaling need for the beneficial response to exercise, for example. Mitochondrially targeted antioxidants, on the other hand, appear to modestly slow aging in a range of species, and have proven an effective treatment for some conditions characterized by inflammation and oxidative stress, meaning the excessive production of oxidative molecules and resultant damage to molecular machinery. It can be debated on a case by case basis as to the degree to which this is a compensatory treatment versus addressing a specific causative issue in any given condition.

Mitochondria in cells generate oxidative molecules in the course of producing chemical energy stores to power cellular processes. Moderately raised production can result in overall benefits, because cells react with increased housekeeping activities. Greatly increased production is harmful, however, and appears as aging progresses due to the accumulation of mitochondrial damage. It raises the level of oxidized lipids in the bloodstream, a contributing factor in atherosclerosis. It can cause cells to become dysfunctional, though the details are varied and tissue specific. It can spur chronic inflammation. In this trial, it is interesting to see confirmation of these various themes, with a focus on the vascular system in aging, though I think the pulse wave velocity data is mixed at best. The reduction in oxidized LDL cholesterol is more interesting, and more compelling when one considers that this outcome is the goal of statin drugs.

Cardiovascular diseases (CVDs) remain the leading cause of morbidity and mortality in developed societies. Advancing age is the primary risk factor for CVD, which is largely mediated by adverse changes to arteries. Two features of vascular aging that are key antecedents to CVD are the development of endothelial dysfunction, as assessed by reduced endothelium-dependent dilation (EDD), and stiffening of the large elastic arteries. Vascular dysfunction with age is a consequence of excessive superoxide-related oxidative stress, much of which is of mitochondrial origin. Given the projected increase in CVD prevalence in the coming decades, driven mainly by increases in the number of middle-aged and older (MA/O) adults, identifying novel strategies that reduce excess mitochondrial reactive oxygen species (mtROS) to improve vascular function and reduce CVD risk in this population is a biomedical priority. MitoQ is a mitochondria-targeted antioxidant consisting of the naturally occurring antioxidant ubiquinol attached to a lipophilic cation; the lipophilicity and positive charge of this compound enable it to cross cell membranes and accumulate in the matrix facing the surface of the mitochondrial inner membrane where it is optimally positioned to reduce mtROS. MitoQ is now available as a dietary supplement and recently was administered chronically (3 weeks) to healthy young adults without adverse effects. However, presently, the efficacy of chronic MitoQ supplementation for improving vascular function in healthy MA/O adults is unknown. Accordingly, we sought to translate our preclinical findings to humans by conducting the first randomized, double-blind, placebo-controlled clinical trial with MitoQ in healthy late MA/O humans. MitoQ was well tolerated, and plasma MitoQ was higher after the treatment versus placebo period. Brachial artery flow-mediated dilation was 42% higher after MitoQ versus placebo; the improvement was associated with amelioration of mitochondrial reactive oxygen species-related suppression of endothelial function. Aortic stiffness (measured via carotid-femoral pulse wave velocity) was lower after MitoQ versus placebo in participants with elevated baseline levels. Plasma oxidized LDL (low-density lipoprotein), a marker of oxidative stress, also was lower after MitoQ versus placebo. These findings in humans extend earlier preclinical observations and suggest that MitoQ and other therapeutic strategies targeting mitochondrial reactive oxygen species may hold promise for treating age-related vascular dysfunction.

Link: https://doi.org/10.1161/HYPERTENSIONAHA.117.10787