Examination of health benefits
Several observational studies suggest that diets rich in antioxidant nutrients – particularly vitamins C and E, and beta-carotene – or supplements containing one or more of these nutrients are associated with a reduction in the risk of age-related chronic diseases, including some forms of cancer, cardiovascular, eye, and neurodegenerative diseases (13-18). These relatively consistent results stimulated the initiation of several large-scale, randomized controlled trials (19-24); the overall results of most of them have been presented as equivocal or null.
With regard to the efficacy of antioxidant supplementation in RCTs the health benefits are statistically significant, mainly in those populations generally characterized at risk for micronutrient deficiencies, including those micronutrients contributing to the antioxidant defense network (25). This relationship may suggest that dietary supplementation for the prevention or treatment of chronic diseases is likely to be most effective in those with inadequate intakes, though absent of overt deficiency syndromes.
Experts have suggested that the reasons for contradictory findings are linked to the “ Randomized Controlled Trials ” (RCTs) design (25-28). Most RCTs conducted so far have:
- examined the effect of antioxidant supplements on secondary prevention of disease. In contrast, most observational studies have investigated primary prevention. Thus, while adequate amounts of dietary or supplemental antioxidants consumed over a long period of time by healthy individuals may effectively prevent or delay development of chronic diseases, treating patients diagnosed with these diseases with antioxidant supplements no longer may provide significant benefit.
- assessed the effects of antioxidant treatment in conjunction with standard multi-drug therapy, which may obliterate the potentially beneficial effects of the antioxidant studied.
- not determined antioxidant levels, such as plasma levels of vitamins C and E, or oxidative stress levels at the beginning of the study and following supplementation. Without such data, it is impossible to know whether the supplementation had the intended effect of increasing antioxidant and/or decreasing oxidative stress levels in the subjects studied.
- tested the efficacy of supplements with only one or two antioxidant nutrients in multifactorial diseases. Thus, the trials may not have fully benefited from the dynamic interrelationships between these nutrient and other components (e.g. further micronutrients) of the antioxidant defense network.
In general, RCTs have limitations in testing the efficacy and safety of nutrients as they were developed for drugs. While drug interventions are designed to cure a disease, not produced by their absence; nutrients prevent dysfunction that would result from their inadequate intake (29). In addition, drug effects are generally intended to be acute, large, and with a specific target for action, while nutrient effects are typically chronic, modest, and polyvalent in scope. Moreover, drug effects can be tested against a non-exposed (placebo) contrast group, whereas it is impossible and/or unethical to attempt a zero intake group for nutrients (30). Nonetheless, RCTs are currently considered the ”gold standard” for evaluating dietary interventions and, thus, receive the attention of most meta-analyses on this topic.
The efficacy of antioxidant micronutrient intake in health promotion depends on the initial status of the antioxidant defense network and the level of oxidative stress in each subject. Moreover, the dose(s) of the micronutrient(s) and the concentration threshold for action of each nutrient is of relevance. The threshold for adequate intake of any nutrient as well as its blood and tissue levels are recognized as dependent on an individual’s specific requirements as affected by parameters such as age, sex, health status, lifestyle, and genetic factors (see also “Micronutrient insufficiency: Also a matter of genes”). Reducing disease risk and slowing down disease progression by adequate antioxidant intake is a long-term approach.