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by Gert E. Schuitemaker, PhD
There are few subjects on which opinions are as divided as nutrition. Nearly everyone agrees: an excellent diet with lots of fruits and vegetables is healthy and will prevent many diseases. Such a diet is chock full of essential nutrients and antioxidants. Then, how come condemnation of supplemental antioxidants gets so much press coverage worldwide?
How antioxidants work
Oxygen is necessary for life, but on the other hand it inevitably generates reactive molecules throughout all the tissues of the body. These free radicals are dangerous for any cell because they can damage essential molecules such as DNA and the enzymes necessary for proper function of the cell. Antioxidants capture these reactive free radicals and safely convert them back to normal. Although the body does produce antioxidant molecules, these work together with antioxidants that are delivered by the diet, mainly from fruit and vegetables but also from supplements.
Antioxidants can be divided into several groups. In addition to the 'classic' antioxidants vitamin C, vitamin E and selenium, another group includes the carotenoids, such as beta-carotene, lycopene, lutein and astaxanthin. Another subgroup comprises the flavonoids found in most fruits. All these antioxidants are molecules that plants use to protect themselves against environmental factors as solar radiation, heat, toxic chemicals, molds, etc. But these antioxidants also protect animal life. Antioxidants protect all life on earth - plants, animals and humans - against the damaging effects of oxygen radicals, which are always formed in an oxygenated environment. Over eons of time all living forms evolved together and thus depend on each other for survival. So it happened that fruit and vegetables, especially rich in antioxidants, are needed for humans and animals to preserve their health.
Meta-analysis and manipulation
Dr. James Watson, a Nobel Laureate wrote a treatise on metastatic cancers in which he briefly mentioned dietary supplements: 'Free-radical-destroying antioxidative nutritional supplements may have caused more cancers than they have prevented'.  In a few words Dr. Watson condemned the view of double Nobel Laureate Linus Pauling on the effects of cancer and the antioxidant vitamin C. Deplorably, he used the case of Dr. Pauling to support his theory: 'At the time of his death from prostate cancer in 1994, at the age of 93, Linus was taking 12 g of vitamin C every day. In light of the recent data strongly hinting that much of late-stage cancer's untreatability may arise from its possession of too many antioxidants, the time has come to seriously ask whether antioxidant use much more likely causes than prevents cancer.'
Moreover to disqualify the use of dietary supplements as protection against cancer, Watson referred in the same paragraph to a questionable study, performed by a team of researchers led by Dr. Goran Bjelakovic, a professor at the University of Nis (Serbia and Montenegro) and published in the Journal of the American Medical Association (JAMA). The study consisted of a meta-analysis of the research literature. This statistical analysis method, virtually sacrosanct in the world of medical science, is considered the most secure because it combines the results of multiple scientific studies. However, the selection of studies for inclusion makes this method prone to bias. Moreover, the selected studies are often very different with divergent aims and different populations. Sometimes there is no discrimination between healthy persons and sick patients. One recent meta-analysis attracted worldwide media attention, leading to alarming headlines such as "Antioxidant supplements may increase the risk of death." The researchers concluded from this meta-analysis that the antioxidants beta carotene, vitamin A, and vitamin E may increase the risk of mortality.
Scientists know better
The Bjelakovic meta-analysis study demonstrably violated universal methodological rules. Sharp criticism came from scientists around the world, including some from prestigious research institutions such as Harvard University. In a NY Times article, Dr. Bruce Ames, professor of Biochemistry at the University of California Berkeley, said: "You just can't do this kind of study with something like cancer, which can take 20 years to develop in an initially healthy person." The Times added comment that "it was naive of scientists and consumers to hope that the relatively short-term addition of one or two antioxidants would be enough to counteract decades of poor diet and inadequate exercise, not to mention the genome."
The Linus Pauling Institute noted that two important studies with positive results of antioxidants were completely ignored by the Bjelakovic-group.[4,5] From these and other comments, it is clear that antioxidants continue to be considered essential to health.
It just seems implausible that antioxidants should be killing you by several different means," said Dr. Jeffrey Blumberg, a nutrition professor at Tufts. "I don't buy it." 
"Most of these patients already had disease, so the conclusions simply aren't relevant to a healthy population." said Dr. Andrew Shao, vice president of the Council for Responsible Nutrition, a trade group for the supplement industry. 
Bias in medical journals
The question arises as to why leading medical journals, such as JAMA, would publish Bjelakovic's flimsy meta-analysis. The answer may be related to a study published in 2008, which evaluated the content of eleven major medical journals, including JAMA. The authors scrutinized one year's copies of each journal. They found that publications with more pharmaceutical adverts contained fewer articles on food supplements. Furthermore, any such articles that were published tended to be of lower quality and to present a negative opinion of the effectiveness and safety of nutritional products. For example, 67% of articles on dietary supplements in publications with more pharmaceutical adverts reached a negative verdict regarding supplement safety. By contrast, this percentage was only 4% in the journals with fewer pharmaceutical advertisements. Also, in those periodicals with the most pharmaceutical adverts, the effectiveness of nutritional supplements was 50% more likely to be reported as negative. You can judge for yourself whether or not the need to attract pharmaceutical adverts appears to influence the content of medical journals.
The Bjelakovic meta-analysis prompted much media distortion worldwide. "Supplements containing antioxidants may increase the risk of death," was just about the average headline. Yet, starting from the same studies it is straightforward to derive a new analysis that is more balanced. An international team of scientists, led by Professor Hans Biesalski of the University of Hohenheim in Germany and Professor Jeffrey Blumberg of Tufts University (USA), subjected the same 66 studies to a renewed analysis. These researchers followed a different research methodology, based on a risk/benefit analysis. This meant the researchers looked for more than the one-sided risk of mortality. They also considered the known benefits of nutrients. Thus, the 66 studies were divided into three groups according to their subjects: those that studied healthy people, those whose patients had suffered one episode of illness and needed to avoid a subsequent episode, and those whose patients were ill and were being treated therapeutically with antioxidants.
The Biesalski group reached conclusions quite contrary to those of Bjelakovic. Of the 66 studies, 36% showed that antioxidant supplementation resulted in a positive health outcome, 60% were neutral, and only 4% gave negative results. Antioxidant supplementation was found to be especially effective in healthy populations for reducing risk of disease in subjects that tended to be malnourished.
Biesalski's analysis is supported by many clinical studies. Dr. Ralph Moss replies in the Townsend Letter to the Watson paper. He states: 'Prof. Watson should have grounded his paper in clinical reality by citing actual examples of antioxidant use in patients with cancer, especially those with advanced-stage cancers.' Regarding the protective action of antioxidant supplements against cancer in healthy humans, the arguments of Dr. Watson were solely built on the Bjelakovic meta-analysis. Also Watson did not mention the Biesalski analysis. So, again, no media attention on the latter.
From many studies over the past five decades, antioxidants are known to prevent cancer and other age-related diseases especially when taken long-term by healthy people. In cancer patients or those at great risk of cancer, antioxidants in appropriate doses can also be of great benefit in treatment, taken in consultation with a nutrition-aware doctor.
Thus, the best advice for maintaining health continues to be: eat an excellent diet (whole grains, dark green leafy vegetables, fruits, and nuts, with minimal amounts of meat), avoid processed foods that lack essential nutrients, and supplement with adequate doses of essential vitamins, nutrients and antioxidants such as vitamins C and E, zinc, carotenoids and flavonoids.
1. Watson J. Oxidants, antioxidants and the current incurability of metastatic cancers. Open Biol 2013, 3(1), 120144.
2. Bjelakovic G, Nikolova D et al. Mortality in randomized trials of antioxidant supplements for primary and secondary prevention. Systematic review and meta-analysis JAMA 2007; 297:842-857.
4. Gruppo Italiano per lo Studio della Sopravvivenza nell'Infarto miocardico. Dietary supplementation with n-3 polyunsaturated fatty acids and vitamin E after myocardial infarction: results of the GISSI-Prevenzione trial. Lancet. 1999; 354:447-55.
5. Blot WJ, Li JY et al. Nutrition intervention trials in Linxian, China: supplementation with specific vitamin/mineral combinations, cancer incidence, and disease-specific mortality in the general population. J Natl Cancer Inst. 1993; 85:1483-92
6. Kemper KJ, Hood KL. Does pharmaceutical advertising affect journal publication about dietary supplements? BMC Complement Altern Med 2008; 8:11
7. Biesalski HK, Grune T et al. Reexamination of a Meta-Analysis of the Effect of Antioxidant Supplementation on Mortality and Health in Randomized Trials. Nutrients 2010; 2(9):929-949.
8. Moss R. Do antioxidants harm cancer patients? A reply to prof. Watson. Townsend Letter 2013; 357(4):38-41.
9. Hickey S, Saul, AW (2008) Vitamin C: The Real Story. Basic Health Publications. ISBN-13: 978-1591202233.
10. Gonzalez MJ, Miranda-Massari JR, Saul AW (2009) I Have Cancer: What Should I Do? Your Orthomolecular Guide for Cancer Management. Basic Health Publications. ISBN-13: 978-1591202431.