Lay off the antioxidants

I think I've had stuff up before warning you off antioxidant supplements.  Here is another  study -  a Cochrane Review - which says that  current evidence does not support the use of antioxidant supplements.  Indeed certain of them seem to increase mortality.

The abstract is below:

Background:
Our systematic review has demonstrated that antioxidant supplements may increase mortality. We have now updated this review.

Objectives:
To assess the beneficial and harmful effects of antioxidant supplements for prevention of mortality in adults.

Search strategy:
We searched The Cochrane Library, MEDLINE, EMBASE, LILACS, the Science Citation Index Expanded, and Conference Proceedings Citation Index-Science to February 2011. We scanned bibliographies of relevant publications and asked pharmaceutical companies for additional trials.

Selection criteria:
We included all primary and secondary prevention randomised clinical trials on antioxidant supplements (beta-carotene, vitamin A, vitamin C, vitamin E, and selenium) versus placebo or no intervention.

Data collection and analysis:
Three authors extracted data. Random-effects and fixed-effect model meta-analyses were conducted. Risk of bias was considered in order to minimise the risk of systematic errors. Trial sequential analyses were conducted to minimise the risk of random errors. Random-effects model meta-regression analyses were performed to assess sources of intertrial heterogeneity.

Main results:
Seventy-eight randomised trials with 296,707 participants were included. Fifty-six trials including 244,056 participants had low risk of bias. Twenty-six trials included 215,900 healthy participants. Fifty-two trials included 80,807 participants with various diseases in a stable phase. The mean age was 63 years (range 18 to 103 years). The mean proportion of women was 46%. Of the 78 trials, 46 used the parallel-group design, 30 the factorial design, and 2 the cross-over design. All antioxidants were administered orally, either alone or in combination with vitamins, minerals, or other interventions. The duration of supplementation varied from 28 days to 12 years (mean duration 3 years; median duration 2 years). Overall, the antioxidant supplements had no significant effect on mortality in a random-effects model meta-analysis (21,484 dead/183,749 (11.7%) versus 11,479 dead/112,958 (10.2%); 78 trials, relative risk (RR) 1.02, 95% confidence interval (CI) 0.98 to 1.05) but significantly increased mortality in a fixed-effect model (RR 1.03, 95% CI 1.01 to 1.05). Heterogeneity was low with an I2- of 12%. In meta-regression analysis, the risk of bias and type of antioxidant supplement were the only significant predictors of intertrial heterogeneity. Meta-regression analysis did not find a significant difference in the estimated intervention effect in the primary prevention and the secondary prevention trials. In the 56 trials with a low risk of bias, the antioxidant supplements significantly increased mortality (18,833 dead/146,320 (12.9%) versus 10,320 dead/97,736 (10.6%); RR 1.04, 95% CI 1.01 to 1.07). This effect was confirmed by trial sequential analysis. Excluding factorial trials with potential confounding showed that 38 trials with low risk of bias demonstrated a significant increase in mortality (2822 dead/26,903 (10.5%) versus 2473 dead/26,052 (9.5%); RR 1.10, 95% CI 1.05 to 1.15). In trials with low risk of bias, beta-carotene (13,202 dead/96,003 (13.8%) versus 8556 dead/77,003 (11.1%); 26 trials, RR 1.05, 95% CI 1.01 to 1.09) and vitamin E (11,689 dead/97,523 (12.0%) versus 7561 dead/73,721 (10.3%); 46 trials, RR 1.03, 95% CI 1.00 to 1.05) significantly increased mortality, whereas vitamin A (3444 dead/24,596 (14.0%) versus 2249 dead/16,548 (13.6%); 12 trials, RR 1.07, 95% CI 0.97 to 1.18), vitamin C (3637 dead/36,659 (9.9%) versus 2717 dead/29,283 (9.3%); 29 trials, RR 1.02, 95% CI 0.98 to 1.07), and selenium (2670 dead/39,779 (6.7%) versus 1468 dead/22,961 (6.4%); 17 trials, RR 0.97, 95% CI 0.91 to 1.03) did not significantly affect mortality. In univariate meta-regression analysis, the dose of vitamin A was significantly associated with increased mortality (RR 1.0006, 95% CI 1.0002 to 1.001, P = 0.002).

Authors' conclusions:
We found no evidence to support antioxidant supplements for primary or secondary prevention. Beta-carotene and vitamin E seem to increase mortality, and so may higher doses of vitamin A. Antioxidant supplements need to be considered as medicinal products and should undergo sufficient evaluation before marketing.

Keep off the antioxidant supplements

This one has been brewing for a while but now it seems fairly solid -  antioxidant supplements are, at the least, useless.  Stumptuous would like it (beware of the bad language). 

This is an amazing letter

TO THE EDITOR: In a recent paper by Higashida et al. (5), the authors report that very large doses of antioxidant vitamins do not prevent the exercise-induced adaptive responses of muscle mitochondria, GLUT4, and insulin action to exercise. As clearly stated in the paper, their data disagree with those reported by three independent research groups from Germany (14), Australia (17), and Spain (4).

Using a significantly different experimental protocol regarding exercise training intensity and duration, antioxidant supplementation (doses and types of antioxidants), and molecular parameters analyzed (mRNA vs. protein levels), Higashida et al. compared their data with ours and came to exactly the opposite conclusions, i.e., that antioxidant vitamin supplementation does not have an inhibitory effect on the adaptive responses of skeletal muscle to exercise. Regarding our study published in the American Journal of Clinical Nutrition (4), we found a very significant increase (∼186%) in endurance time in rats after training (6 wk), which was dramatically blunted when the animals were supplemented with vitamin C (∼26% increment). Endurance capacity is directly related to mitochondrial content, which is why we decided to determine the mitochondrial biogenesis cascade in skeletal muscle in our animals, and we found that it was significantly hampered. Although we found a dramatic effect of vitamin C on endurance time in animals, we did not find the same effect on V̇O2 max in either the animal study or the human study. This is clearly stated and discussed in the introduction, results, and discussion sections of our paper. However, Higashida et al. did not run any performance tests in their study; moreover, they misquoted a few times the results obtained in our human study. Training studies, including the data published by Higashida et al., conducted to determine whether antioxidant vitamins improve exercise performance, have generally shown that supplementation is useless (3, 7, 13, 18, 20). However, recent evidence shows that they can be worse than useless. Several studies suggest that antioxidants may have detrimental effects on performance. As early as 1971, it was shown that vitamin E supplementation (400 IU/day for 6 wk) caused unfavorable effects on endurance performance in swimmers (15). The authors concluded: “There is no evidence here to suggest that vitamin E has any beneficial effect on endurance performance. Indeed the evidence, if anything, suggests that the vitamin has an unfavourable effect.” Malm and coworkers (10, 11) showed, in two consecutive studies, the deleterious effects of ubiquinone-10 supplementation on the performance of humans after a high-intensity training program. In 2002, it was shown that supplementation of racing greyhounds with 1 g vitamin C/day for 4 wk significantly slowed their speed (12). Moreover, in a human study, the negative effects of ascorbic acid supplementation on the adaptive responses of endogenous antioxidant enzymes and stress proteins were demonstrated (8). Furthermore, it has been shown that supplementation with ascorbic acid to prevent delayed-onset muscle soreness after exercise does not preserve muscle function but hinders the recovery process, thereby being detrimental to future performance (2). Finally, in our animal study, we found that vitamin C supplementation decreases training efficiency because it prevents exercise-induced mitochondrial biogenesis (4). Similar conclusions have been recently achieved by a US-based research group (6). The authors found that inhibition of a free radical-generating enzyme (xanthine oxidase) by allopurinol severely attenuates exercise activation of the mitochondrial biogenesis pathway in skeletal muscle. Thus, in our opinion and contrary to the considerations of Higashida et al., there is growing evidence of the negative effects of antioxidant supplementation in exercise performance in both animal and human studies.

The evidence on the detrimental effects of antioxidant supplementation when given to patients and healthy people (non athletes) is, if possible, more robust. In 2007, Bjerlakovic et al. looked at data from sixty-seven studies on antioxidant supplements and they concluded that beta carotene, vitamin A, and vitamin E supplementation seemed to increase the risk of death (1). This data confirmed previous reports showing that long-term vitamin E supplementation may increase the risk for heart failure in patients with vascular disease or diabetes mellitus (9). When a 6-wk aerobic exercise training program was applied in patients with hypertension, supplementation of antioxidants (vitamins C and E and α-lipoic acid) led to an enhancement of blood pressure and an inhibition of exercise-induced flow-mediated vasodilatation (19). Finally, one of us (M. Ristow) showed that antioxidant supplementation with vitamins C and E prevents the induction of molecular regulators of insulin sensitivity and endogenous antioxidant defense by physical exercise (14).

A significant number of both healthy and sick individuals are taking antioxidant supplements in the belief that these will improve their health and prevent or ameliorate diseases (1). Moreover, a large proportion of athletes, including elite athletes, take vitamin supplements, often large doses, seeking beneficial effects on performance (16). The complete lack of any positive effect of antioxidant supplementation on physiological and biochemical outcomes consistently found in human and animal studies raises questions about the validity of using oral antioxidant supplementation in both health and disease.

The vast majority of experimental evidence clearly advises against this supplementation. Thus, we unreservedly confirm the conclusions derived from our previous research (4, 14) and disagree with Higashida et al. In our opinion, antioxidant supplements are, at the least, useless.