Antioxidant micronutrients

There is compelling evidence that a diet rich in fruit and vegetables including antioxidant nutrients can help maintain a healthy lifestyle. Current recommendations are that everyone should eat at least five portions of a variety of fruit and vegetables each day to reduce the risk of chronic diseases. However, several national nutrition surveys have shown that the average fruit and vegetable consumption is less than three portions a day (2, 3), with consumption often lower in children (4). Consequently, dietary supplements and fortified foods have been suggested as sources of antioxidants for preventive strategies.

The health promoting effects of antioxidant micronutrients depend on their target locations in the body, which is related to their solubility characteristics. While vitamin C is water soluble (“hydrophilic”) and is therefore especially found in the aqueous sections of the cell and in body fluids, vitamin E (tocopherols), carotenoids and CoQ10 are highly fat soluble (“lipophilic”) and can be found in membranes and lipoproteins. Accordingly, lipophilic antioxidants potentially protect fat-rich tissues and cell parts, such as skin and lipid membranes (6), while hydrophilic antioxidants can protect water-rich tissues (e.g. muscles and internal organs) and cell parts (7). Some antioxidant micronutrients show efficacy in special tissues (e.g. lutein and zeaxanthin in the eye) (8).

However, the fact that @antioxidant micronutrients can help maintain human health and delay disease onset does not imply that the more one consumes the better it is for one’s health. It has been suggested that over-consumption could down-regulate important antioxidants that the body produces, depress parts of the immune system and the normal cellular protective responses to tissue damage (9). In addition, a hypothesis suggests that in some cases, Reactive Oxygen Species (ROS) may have a protective role, e.g. by down-regulating inflammation, which could be counteracted by an administered antioxidant (10). Moreover, it has been speculated as the result of some in vitro studies that antioxidants could also exhibit deleterious pro-oxidant properties under specific conditions unlikely to happen in vivo (11). Furthermore, scientists have speculated that excessive levels of certain antioxidants may contribute to disease development by inducing “reductive stress,” the counterpart of oxidative stress (12); solid data for in vivo effects are currently lacking.

In case of doubt, antioxidant micronutrient consumption according to the recommended dosage is advised.

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.

All-cause or total mortality has been used as a global indicator of safety in many meta-analyses of RCTs with antioxidant supplements (e.g. 32, 33). Critical to the validity of such meta-analyses is the statistical accounting for the variability of the included studies. Including small RCTs with few deaths; attributing deaths occurring after only a few months of antioxidant treatment; as well as combining different nutrients in different forms with a large range of doses in a wide variety of population groups with varying health status can implicate a high risk of bias. Meta-analyses of total mortality not determining the cause of death and thus not eliminating those that lack any biological plausibility to a hypothetical antioxidant (or pro-oxidant) toxicity such as accidental deaths and homicides are of limited validity (25). The risk of mortality in any RCTs of nutrients substantially depends upon the nature of the population studied, including parameters such as advanced age, severe disease status, possible side effects of drug treatments, etc.

Consequently, experts recommend that instead of focusing exclusively on the risk of toxic effects (all-cause mortality) of micronutrients it needs a balanced perspective, also considering overall beneficial study outcomes (25).

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