How might antioxidant supplements increase all-cause mortality?

As a graduate student, I had the good fortune of meeting Dr Don Coffey, a professor of Urology, Oncology, Pharmacology, and Molecular Sciences at the Johns Hopkins School of Medicine, one of the most creative and humble scientists I have known.
I recall him telling a lunchtime gathering of us wide-eyed trainees that American graduate students don’t think about their experiments enough; that is, one should spend some 10-20% of the time it took to do the experiment thinking about the results, especially if the results are not what you expected.
The exercise he challenged us to do for “failed” experiments is to ask, “If this [result] is true, what does it imply?”
So, I thought of the good Dr Coffey last week when a highly-discussed paper appeared in JAMA describing a meta-analysis of antioxidant use in primary and secondary disease prevention trials. The surprising outcome was that, for some antioxidants like beta-carotene, vitamin A, and vitamin E, the relative risk of mortality increased between 4 and 16%. (abstract here but full article requires subscription). Vitamin C or selenium were associated with no change in mortality.
The findings in this paper generated a great deal of ruckus in the news, was attacked by industry-funded trade groups, and is already a CME module on Medscape.
But very few pixels have been expended on how antioxidants might be increasing mortality if indeed the findings are true.
The very short two-fold answer is 1) that some antioxidants can be converted into more active pro-oxidants when sopping up free radicals and 2) free radicals are not always bad and, in fact, play important physiological defense roles in fighting infections and cancer.

Calling a compound an antioxidant is tricky business because one has to consider what happens to the so-called antioxidant in the process of making another molecule less reactive. Vitamin E is a perfect example of an antioxidant that can be turned into a pro-oxidant. If the pro-oxidant form of vitamin E is not reduced by another antioxidant, it can be damaging.
In terms of fighting infection, granulocytes normally produce an oxidative burst to help kill invading bacteria. Could interfering with this process with antioxidant vitamins worsen the progression of life-threatening infections?
Moreover, reactive oxygen species also mediate the mitochondrial pathway of apoptosis, or programmed cell death. While we often associate this process with how anticancer drugs work, normal apoptosis is also the reason that we don’t have a greater incidence of cancer – cells that have accumulated so much DNA damage that cannot be repaired (from sunlight, dietary carcinogens, etc.) are triggered to undergo apoptosis so that they don’t become cancer cells.
Mind you, these are each oversimplified explanations of steps where inappropriate action of an antioxidant could contribute to mortality and, for the most part, are theoretical.
So, while much more debate will continue on the drawbacks of the study design and the responses by supplement stakeholders (see this great essay by David Michaels for a discussion), it does pay to think for a moment or two what the JAMA study might be telling us about antioxidant supplementation and the perceived promise of improved health.

11 thoughts on “How might antioxidant supplements increase all-cause mortality?

  1. I think it’s simpler than that. The harmless ones, selenium and Vitamin C are water soluble. The harmful ones, A, E and beta carotene, are all lipid soluble.
    Seems kind of obvious what the problem is here. Anything, in excess, can be harmful. If you’re supplementing on fat soluble vitamins you simply can not clear the excess effectively, and build up levels that are toxic for any number of reasons, maybe not even related to their intended anti-oxidant effect.
    Vit C and Selenium, you just piss these out. Not that selenium doesn’t have it’s own specific toxicity, but you’d have to take a pretty hefty loading dose in order to overwhelm your system, and far lower than the 50 a day that is the typical supplementation.

  2. Abel , sorry, but you err badly by omission.
    {quote]describing a meta-analysis of antioxidant use in primary and secondary disease prevention trials.[/quote]
    Compare please, to the actual words. Mortality is being analyzed, not disease prevention; that’s why all the studies that had no deaths were discarded !
    Mortality in Randomized Trials of Antioxidant Supplements for Primary and Secondary Prevention

  3. Brain, yes, mortality is being examined in the meta-analysis but the data are culled from published studies of antioxidant use in primary and secondary disease prevention trials. You’ve got to read further than the title to get this information. From the Methods section of the paper:

    We included all primary and secondary prevention trials in adults randomized to receive beta carotene, vitamin A, vitamin C, vitamin E, or selenium vs placebo or no intervention. Parallel-group randomized trials and the first period of crossover randomized trials were included. Trials including general or healthy populations were classified as primary prevention. Trials including participants with specific disease were classified as secondary prevention. We excluded tertiary prevention (treatment) trials, like trials on acute, infectious, or malignant diseases except nonmelanoma skin cancer.

    Moreover, if you examine Figure 2, some trials were indeed included where there were no deaths in the antioxidant group and one or two deaths in the placebo group (Jacobson 2000; Richer 2004).
    No study is perfect, but my opinion is that the authors did their best to provide as much balance as possible given the limitations of a meta-analysis.

  4. Thank you for your reply, Abel.
    I appreciate that one may hold an opposing view and discuss this issue here sensibly.
    Would you be so kind as to indulge me, an untrained observer of this, in a more-in depth examination of this meta analysis? There’s more here than meets the eye, it seems !
    After all, we are talking [i]only[/i] about mortality and the various, sometimes mixed substances , not about the substances and disease control. Correct ?

  5. Abel, as I said, unfortunately I am a layperson, and some of the technical terms are not in my lexicon, and so I may need help if I use a wrong term, and I may have some misconceptions too.
    Am I mistaken to have said that studies that had no deaths were excluded? I had thought that the placebo groups were included in any particular study, and so a death in the placebo group equaled a death in the study.
    That would be how any study got used, because a death occurred – a not unlikely occurrence due to the makeup of many of the study groups – comprised of aged or sick people.
    Seems to me that including studies of people that are sick, and giving them some incredibly high doses for a short time, with mixed substances, would always produce such startling results, even if H2O drinking was the subject of meta analysis.

  6. I think it was CRN (Council for Responsible Nutrition) who suggested that studies with no deaths were excluded from the meta-analysis. However, I cannot find that statement anywhere in the text of the paper.
    You could spend a whole semester-long class on the pros and cons of meta-analyses. The bottom line is that the authors had no control as to how the studies were conducted and a limitation is that meta-analyses often have to compare apples and oranges in order to get the statistical power of large populations to see a difference one way or the other. To do a prospective study of similar populations (over 180,000 patients) would cost in the tens or hundreds of millions of dollars. I do agree that one limitation is that the studies selected were not done in otherwise healthy volunteers, although I would hesitate to say that all of the studies were in “sick” patients. For example, one study was in patients with angina – my grandmother lived 35 years with angina.

  7. I can think of another reason for increased deaths for those taking anti-oxidants-
    That they would rely upon the pills to work for them and not change their unhealthy lifestyles, which then means that they think they’ll be ok but in fact they will not be.

  8. Thank you for your reply, Abel !
    I have a couple of questions regarding your reply, and a link that may help ID some areas to look for. The link has a crude, inappropriate name for JAMA, unfortunately. It is the leads for info that interest me, not the politics or inappropriate language used. I will not link, but can supply if requested.
    To your points made in reply; you said
    “The bottom line is that the authors had no control as to how the studies were conducted and a limitation is that meta-analyses often have to compare apples and oranges in order to get the statistical power of large populations to see a difference one way or the other.”
    Abel, Agreed that the authors had no control over the original studies. What they did have control over would be the method used to select which studies were appropriate, to study their interest.
    They also had control over analysis methods, and interpretation of results. Is that correct ? that would be their responsibility I would think.
    You also said this:
    “I do agree that one limitation is that the studies selected were not done in otherwise healthy volunteers, although I would hesitate to say that all of the studies were in “sick” patients. For example, one study was in patients with angina – my grandmother lived 35 years with angina”
    Abel, if most were studies with sick patients, or elderly, wouldn’t that in itself be what I was referring to, as tending to possibly show very different results than would be expected for the people the sound byte is bing aimed at in media and mainstream med websites ? the view being originally given is that “all things being equal”…which “all things” would not be, if most patients were not in normal health to begin with.
    this is what I’m getting at. the media and all mainstream websites seem to play it as if “all thing” were equal, not mentioning the weaknesses of method in order to say something meaningful..and this , to me, resembles creating an artifact.
    You said:
    ” For example, one study was in patients with angina – my grandmother lived 35 years with angina.”
    Abel, that example could be questionable, I feel. Disregarding the potential of single anecdotes to provide anything resembling good evidence in medicine,and just taking it at face value, one could ask if she and your mom birthed at young age, if the angina started early, and she died relatively early, or many other questions that may alter the significance of the statement. Also, by genetics, if they are a long-lived line, perhaps even 70 years is short of her normal potential – maybe it’s a line of survivors to 95..if you see what I mean.
    all together, if my bletherings point to a resemblance of the real situation, then my next thought is that the trumpeted “results” seem to be offering a very skewed outlook on what really was studied, and what it all means.
    If this is correct, then I think
    it signals an attempt to mislead has occurred, quite the opposite of the outlook given in mainstream, that opposition to this is coming from obviously biased and invested quarters – and so the obvious inferences should be drawn : ) something I feel you referred to,in a way. Perhaps he opposite reference would have been more appropriate, that this just showed Big Pharma invested interest being blasted out regardless of the real meanings to be drawn from the study results.
    Overall, it leaves a dissatisfied feeling, to me; as if someone tried to pull a fast one on the general public. Certainly not something to aid generaal understanding of the subject of supplements.
    Any comments would be very well appreciated, and thank you Abel ! I will try to post some leads from the site I mentioned.

  9. Abel, I’ll abridge this to shorten and avoid posting the entirety. please remove if this is unacceptable, apologies in advance. Regards, Brain
    …published a hit piece … antioxidant vitamins. JAMA’s Systematic Review and Meta-Analysis of beta carotene, vitamin A, and vitamin E concluded that taking supplements of them increases one’s chances of death by 5%.
    The…media gleefully ran stories…with headlines like “Vitamins Can Kill You.”
    …What these folks did…out of the close to…thousand clinical …studies, they cherry picked 68 that showed what …wanted.
    And they had to lie about many of those in order to force the data to fit their pre-ordained conclusion.
    Register to read more…
    ..example…they claim 30 deaths as a result of this study: Brown BG, Zhao XQ, Chait A, et al. Simvastatin and niacin, antioxidant vitamins, or the combination for the prevention of coronary disease. N Engl J Med. 2001;345: 1583-1592.
    Yet…study actually shows only one death in the placebo group, one death in the drug (Simvastatin) plus antioxidant group, and no deaths in the group given only antioxidants.
    Note that this particular study was for people taking statins. While statins can effectively reduce cholesterol …, one grave side effect is they …reduce…Coenzyme Q (CoQ10) which protects the…mitochondria..from F.R. damage.
    Although the necessity of CoQ10 supplementation with statin use is known, the JAMA folks picked studies that didn’t do so.
    Virtually all 68 of JAMA’s …picked studies are like this – …people in the studies are ill and using a variety of drugs. Further…are single-use studies of only one, possibly two, antioxidants. Any bona-fide researcher knows…need a chain of antioxidants to progressively reduce free radical energy levels in a series of downward steps.
    Now – why would JAMA do this? Because JAMA gets its revenues not from subscriptions but from ads placed by Big Pharma –
    Big Pharma bought this phony anti-antioxidant “review,” bought its placement in JAMA, and bought a major publicity campaign to make sure it was headline news.
    Appendix: Here is a sample of clinical studies not included in the JAMA cherry-picked negative-studies-only review. There are hundreds more. This sample was provided by Life Extension Foundation.
    1. A study involving…29,092 male smokers aged 50-69 years followed prospectively for 19 years showed…men with the highest serum alpha-tocopherol levels had a 28% lower risk of total and cause-specific mortality than did those with the lowest levels, and a 21%, 29%, and 30% lower risk of deaths due to cancer, cardiovascular disease, and other causes. [Wright ME, Lawson KA, Weinstein SJ, Pietinen P, Taylor PR, Virtamo J, Albanes D. Higher baseline serum concentrations of vitamin E are associated with lower total and cause-specific mortality in the Alpha-Tocopherol, Beta-Carotene Cancer Prevention Study. Am J Clin Nutr. 2006 Nov;84(5):1200-7.]
    2. study …3,254 people (1,260 males and 1,994 females)… 39 to 85 years followed from 1989 to 1995 showed…higher serum levels of carotenoids with pro-vitamin A activity significantly reduces the risk of mortality from cardiovascular disease and colorectal cancer. [Ito Y, Suzuki K, Ishii J, Hishida H, et al. A population-based follow-up study on mortality from cancer or cardiovascular disease and serum carotenoids, retinol and tocopherols in Japanese inhabitants. Asian Pac J Cancer Prev. 2006 Oct-Dec;7(4):533-46.]
    3. A study in aging women…showed those with…lowest levels of alpha- and beta-carotene, lutein/zeaxanthin, and total carotenoids were significantly more likely to have increasing IL-6 levels over…period of 2 years, and those aging women with the lowest selenium levels had a significantly higher 54% risk of death over a 5-year period. [Walston J, Xue Q, Semba RD, Ferrucci L, Cappola AR, Ricks M, Guralnik J, Fried LP. Serum antioxidants, inflammation, and total mortality in older women. Am J Epidemiol. 2006 Jan 1;163(1):18-26.] in patients with aggressive, small cell lung cancer showed a clinically significant 35% decreased risk of death associated with antioxidant supplement use after adjustment for tumor stage and other risk factors. [Jatoi A, Williams BA, Marks R, Nichols FC, Aubry MC, Wampfler J, Yang P. Exploring vitamin and mineral supplementation and purported clinical effects in patients with small cell lung cancer: results from the Mayo Clinic lung cancer cohort. Nutr Cancer. 2005;51(1):7-12. ]
    5. A study…1,168 elderly men and women followed for 10 years showed that plasma carotene concentrations were associated with a 21% lower mortality risk for every 0.39 micromol/L increase in plasma carotene, a 41% lower mortality risk for cancer, and a 17% lower risk of mortality due to cardiovascular disease. [Buijsse B, Feskens EJ, Schlettwein-Gsell D, Ferry M, Kok FJ, Kromhout D, de Groot LC. Plasma carotene and alpha-tocopherol in relation to 10-y all-cause and cause-specific mortality in European elderly: the Survey in Europe on Nutrition and the Elderly, a Concerted Action (SENECA). Am J Clin Nutr. 2005 Oct;82(4):879-86.]…evaluated…effect…Vitamin E, beta carotene, and vitamin C on prostate cancer risk…over 29,000 men during 8 years of follow-up showed…supplemental beta-carotene intake at a dose level of at least 2000 micrograms per day was associated with a highly significant 52% decreased prostate cancer risk in men with low dietary beta-carotene intake as well as a dramatic, 71% decreased risk of advanced prostate cancer with increasing dose and duration of supplemental vitamin E. [Kirsh VA, Hayes RB, Mayne ST, Chatterjee N, Subar AF, Dixon LB, Albanes D, Andriole GL, Urban DA, Peters U; PLCO Trial. Supplemental and dietary vitamin E, beta-carotene, and vitamin C intakes and prostate cancer risk. J Natl Cancer Inst. 2006 Feb 15;98(4):245-54.]…1,214 persons age 75-84 for over 4 years showed …those people with the lowest vitamin C plasma levels ( 66 micromol/L) had a mortality risk nearly 50% less. [Shetty PS, Breeze E, Fletcher AE. Antioxidant vitamins and mortality in older persons: findings from the nutrition add-on study to the Medical Research Council Trial of Assessment and Management of Older People in the Community. Am J Clin Nutr. 2003 Nov;78(5):999-1010.]…examined vitamin E and vitamin C supplement use in relation to mortality risk in 11,178 persons aged 67-105 years (Established Populations for Epidemiologic Studies of the Elderly) in 1984-1993 showed that vitamin E reduced the risk of all-cause mortality by 34%, reduced the risk of coronary disease mortality by 47%, ..simultaneous use.. vitamins E and C…associated with…42% lower risk of total mortality and 53% lower risk of coronary mortality. [Losonczy KG, Harris TB, Havlik RJ. Vitamin E and vitamin C supplement use and risk of all-cause and coronary heart disease mortality in older persons: the Established Populations for Epidemiologic Studies of the Elderly. Am J Clin Nutr. 1996 Aug;64(2):190-6.] (Chicago Western Electric Study) that followed… 1,800 middle-aged men over…30-year period showed that during 46,102 person-years of follow-up the risk of fatal stroke was 29% lower in the group taking the highest amount …vitamin C and beta-carotene. [Daviglus ML, Orencia AJ, Dyer AR, Liu K, Morris DK, Persky V, Chavez N, Goldberg J, Drum M, Shekelle RB, Stamler J. Dietary vitamin C, beta-carotene and 30-year risk of stroke: results from the Western Electric Study. Neuroepidemiology. 1997;16(2):69-77.
    One study showed that in 3,318 persons with esophageal dysplasia, a precursor to esophageal cancer, significantly lower total and cancer mortality risk was observed in those Chinese receiving beta-carotene, vitamin E, and selenium, and a whopping 55% decrease in mortality due to cerebrovascular disease. [Blot WJ, Li JY, Taylor PR, Guo W, Dawsey SM, Li B. The Linxian trials: mortality rates by vitamin-mineral intervention group. Am J Clin Nutr. 1995 Dec;62(6 Suppl):1424S-1426S.]
    A second study in 29,584 adult Chinese followed from March 1986-May 1991 showed a significantly lower total mortality among those receiving supplementation with beta carotene, vitamin E, and selenium, with a significant 23% reduction in stomach cancer in this high-risk population. [Blot WJ, Li JY, Taylor PR, Guo W, Dawsey S, Wang GQ, Yang CS, Zheng SF, Gail M, Li GY, 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 Sep 15;85(18):1483-92.]
    11. A study in 1,078 pregnant women infected with HIV given daily multivitamin supplements including vitamins A, C, and E showed reductions in risk of death, reduction in risk of HIV progression, and reduction in viral load. [Fawzi WW, Msamanga GI, Spiegelman D, Wei R, Kapiga S, Villamor E, Mwakagile D, Mugusi F, Hertzmark E, Essex M, Hunter DJ. A randomized trial of multivitamin supplements and HIV disease progression and mortality. N Engl J Med. 2004 Jul 1;351(1):23-32.]…15,419 children over one year showed…risk of death in…group supplemented with synthetic vitamin A (8,333 IU daily) was 54% less. [Rahmathullah L, Underwood BA, Thulasiraj RD, Milton RC, Ramaswamy K, Rahmathullah R, Babu G. Reduced mortality among children in southern India receiving a small weekly dose of vitamin A. N Engl J Med. 1990 Oct 4;323(14):929-35.]…lung cancer patients over age 60 showed that those patients taking supplements including antioxidant vitamins like A, C, and E had…dramatic 68% increase in survival, from only 11 months in non-users to an astounding 41 months for the vitamin users (median survival). [Jatoi A, Daly BD, Kramer G, et al…cross-sectional study of vitamin intake in postoperative non-small cell lung cancer patients. J Surg Oncol. 1998 Aug;68(4):231-6.]
    14study…showed daily oral administration of high-dose vitamin A (300,000 IU daily)…as effective in reducing… number of lung cancers related to tobacco consumption and improved disease-free interval in patients surgically-treated for stage I lung cancer. [Pastorino U, Infante M, Maioli M, Chiesa G, Buyse M, Firket P, Rosmentz N, Clerici M, Soresi E, Valente M, et al. Adjuvant treatment of stage I lung cancer with high-dose vitamin A. J Clin Oncol. 1993 Jul;11(7):1216-22.] in 595 critically-ill ICU patients showed… supplemental vitamin C and vitamin E reduced…risk of multiple organ system failure by an amazing, statistically significant 57% along with…shorter duration of mechanical ventilation and length of ICU stay. [Nathens AB, Neff MJ, Jurkovich GJ, Klotz P, Farver K, Ruzinski JT, Radella F, Garcia I, Maier RV. Randomized, prospective trial of antioxidant supplementation in critically ill surgical patients. Ann Surg. 2002 Dec;236(6):814-22.]

  10. Abel, I am now wondering if I have been directed to discuss this matter within a site that is a shill site for BIG PHARMA. Your misleading opening comments, and your non-response now, tend to indicate that I should take this possibility as a likely.
    Are you able to logically discount the accusations
    that this study was a paid-for hit job, and supporters are either ignorant or willfully decieving the public ? \
    Thanks, Brain

  11. Brain, I do not exactly understand what you are insinuating but I have no connnection to Big Pharma and have no stake in the veracity of this study. I merely questioned that if the results were indeed true, how might antioxidants increase mortality?
    If you have questions about the paper being a paid hit job, you might care to directly contact the two lead authors of the JAMA study who are in Serbia and Denmark, respectively. Their e-mail addresses are in this JNCI commentary they wrote on the topic. You can then ask the authors why the 15 papers cited by the Life Extension Foundation were not included in their analysis. I have absolutely no information on your accusations.

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