Antioxidants in Translational Medicine


Significance: It is generally accepted that reactive oxygen species (ROS) scavenging molecules or antioxidants exert health-promoting effects and thus their consumption as food additives and nutraceuticals has been greatly encouraged. Antioxidants may be beneficial in situations of subclinical deficiency and increased demand or acutely upon high-dose infusion. However, to date, there is little clinical evidence for the long-term benefit of most antioxidants. Alarmingly, recent evidence points even to health risks, in particular for supplements of lipophilic antioxidants. Recent Advances: The biological impact of ROS depends not only on their quantities but also on their chemical nature, (sub)cellular and tissue location, and the rates of their formation and degradation. Moreover, ROS serve important physiological functions; thus, inappropriate removal of ROS may cause paradoxical reductive stress and thereby induce or promote disease. Critical Issues: Any recommendation on antioxidants must be based on solid clinical evidence and patient-relevant outcomes rather than surrogate parameters. Future Directions: Such evidence-based use may include site-directed application, time-limited high dosing, (functional) pharmacological repair of oxidized biomolecules, and triggers of endogenous antioxidant response systems. Ideally, these approaches need guidance by patient stratification through predictive biomarkers and possibly imaging modalities. Antioxid. Redox Signal. 23, 1130–1143.

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Since the 1970s, oxidative stress has been evoked as a contributor to pathogenesis and thousands of studies have reported protective or therapeutic benefits of antioxidants in cellular and animal models of cardiovascular (43), neurodegenerative (62), and inflammatory diseases (75) and cancer (110) diseases. As a result, antioxidant supplements have been promoted as nutraceuticals and antioxidant vitamins, often with little or no clinical control or evidence.

Failures and risks of antioxidants

However, with the exception of a few studies (50, 53, 67), antioxidants have almost always failed to show a significant effect in long-term clinical trials performed according to the criteria of evidence-based medicine (132). For example, the spin-trapping synthetic antioxidant NXY-059, developed for acute treatment of ischemia injury due to stroke, represents one of the most prominent and costly failures of a synthetic antioxidant ever clinically developed (135). Another example is the recent failure of the 2CARE study on the use of coenzyme Q10 in the largest ever therapeutic trial for Huntington's disease (61b).

In some recent meta-analyses, a beneficial effect of antioxidants was claimed, such as for vitamin C in breast cancer (47), atrial fibrillation (2), stroke (25), or endothelial function (5). However, a more definitive proof of antioxidant benefit would have been required to measure plasma levels of the administered compounds. The latter was also a major limitation in several large clinical trials, for example, the Heart Outcomes Prevention Evaluation (HOPE) (137, 158) and the HOPE-The Ongoing Outcomes (17). Even worse than no effect, chronic use of multivitamins without clinical control, especially lipid-soluble antioxidants at dosages above the upper safety limit, may be associated with increased health risks (Table 1) (13).

Table 1.
Meta-Analyses and Reviews of Chronic Oral Vitamin and Antioxidant Substitution

In sedentary rats, vitamin E administration reduced liver oxidative damage, while in rats submitted to chronic exercise, vitamin E decreased antioxidant levels (148). It remains controversial whether chronic intake of high concentrations of certain antioxidants has a harmful effect on performance and whether this might be due to redox cycling reactions that could even convert an antioxidant into a pro-oxidant (18, 116, 125). Taken together, these observations indicate that to identify efficient redox-based therapeutic strategies, there is first a need to reevaluate the physiological and pathological relevance of reactive oxygen species (ROS), and then to determine whether an antioxidant approach is feasible and in which situations.

Another example of the failure of antioxidant therapy is provided in pre-eclampsia. Some studies have reported a modest increase in oxidative stress biomarker, F2-isoprostane, at late stages of pregnancy (112) as well as low levels of gamma-tocopherol may be considered as a risk factor for pre-eclampsia (63). However, concomitant supplementation with vitamin C and vitamin E did not prevent pre-eclampsia in women at risk and, even worse, this treatment increased the rate of births with low weight (121).

Absorption, distribution, metabolism, and excretion of specific antioxidants are essential aspects of antioxidant therapy that have not been analyzed in detail for many compounds, especially for nutraceuticals. Yet, the pharmacokinetic (bioavailability and frequency of administration) and pharmacodynamic (therapeutic index and onset of action) properties of specific antioxidants are critical to assess their clinical usefulness (11). This is best exemplified with compounds that need to cross the blood–brain barrier (73).

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I take CO-Q10 daily will it affect negatively on my SCA3 ?