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The Evidence Piles Up: Antioxidant Supplements Are Bad For You

You may remember a study that suggested that antioxidant supplement actually negated the effects of exercise in muscle tissue. (The reactive oxygen species generated are apparently being used by the cells as a signaling mechanism, one that you don’t necessarily want to turn off). That was followed by another paper that showed that cells that should be undergoing apoptosis (programmed cell death) could be kept alive by antioxidant treatment. Some might read that and not realize what a bad idea that is – having cells that ignore apoptosis signals is believed to be a common feature in carcinogenesis, and it’s not something that you want to promote lightly.
Here are two recent publications that back up these conclusions. The BBC reports on this paper from the Journal of Physiology. It looks like a well-run trial demonstrating that antioxidant therapy (Vitamin C and Vitamin E) does indeed keep muscles from showing adaptation to endurance training. The vitamin-supplemented group reached the same performance levels as the placebo group over the 11-week program, but on a cellular level, they did not show the (beneficial) changes in mitochondria, etc. The authors conclude:

Consequently, vitamin C and E supplementation hampered cellular adaptions in the exercised muscles, and although this was not translated to the performance tests applied in this study, we advocate caution when considering antioxidant supplementation combined with endurance exercise.

Then there’s this report in The Scientist, covering this paper in Science Translational Medicine. The title says it all: “Antioxidants Accelerate Lung Cancer Progression in Mice”. In this case, it looks like reactive oxygen species should normally be activating p53, but taking antioxidants disrupts this signaling and allows early-stage tumor cells (before their p53 mutates) to grow much more quickly.
So in short, James Watson appears to be right when he says that reactive oxygen species are your friends. This is all rather frustrating when you consider the nonstop advertising for antioxidant supplements and foods, especially for any role in preventing cancer. It looks more and more as if high levels of extra antioxidants can actually give people cancer, or at the very least, help along any cancerous cells that might arise on their own. Evidence for this has been piling up for years now from multiple sources, but if you wander through a grocery or drug store, you’d never have the faintest idea that there could be anything wrong with scarfing up all the antioxidants you possibly can.
The supplement industry pounces on far less compelling data to sell its products. But here are clear indications that a large part of their business is actually harmful, and nothing is heard except the distant sound of crickets. Or maybe those are cash registers. Even the wildly credulous Dr. Oz reversed course and did a program last year on the possibility that antioxidant supplements might be doing more harm than good, although he still seems to be pitching “good” ones versus “bad”. Every other pronouncement from that show is immediately bannered all over the health food aisles – what happened to this one?
This shouldn’t be taken as a recommendation to go out of the way to avoid taking in antioxidants from food. But going out of your way to add lots of extra Vitamin C, Vitamin E, N-acetylcysteine, etc., to your diet? More and more, that really looks like a bad idea.
Update: from the comments, here’s a look at human mortality data, strongly suggesting no benefit whatsoever from antioxidant supplementation (and quite possibly harm from beta-carotene, Vitamin A, and Vitamin E),

35 comments on “The Evidence Piles Up: Antioxidant Supplements Are Bad For You”

  1. a. nonymaus says:

    I’m now taking bets on how long it will be before we see the first cases of self-induced scurvy from people misunderstanding this. More broadly, it seems like, as usual, the dose makes the poison. I would even speculate that there is an optimum anti-oxidant dose dependent on one’s lipid peroxidation status, exposure to things like dietary nitrite, and so on.

  2. SP says:

    Coming soon to the supplement aisle, Dr. Smith’s superoxide pills.

  3. As always, to me the argument here seems to be at least partly a matter of degree. Reactive oxygen radicals are good for you…in moderate amounts. What doesn’t kill you makes you better.

  4. pikolinian says:

    The dose makes the poison…

  5. Paul Brookes says:

    A much more inclusive recent study is this one from Christian Gluud’s group in Copenhagen…, showing no benefit in all-cause mortality for antioxidant supplements across nearly 300k patients (and increased mortality for a sub-set of vitamins). Gluud has been putting out meta-analyses and other clinical trials on this stuff for years now, but nobody seems to take any notice.
    This is old news to anyone who actually works in the field (e.g. the entire membership of SFRBM – the Society for Free Radical Biology & Medicine, which publishes 2 journals devoted to the subject). The umbrella SFRRI (Society for Free Radical Research International) also runs conferences on this topic, and those meetings are routinely populated by Gluud and other speakers who debunk the “ROS bad/antioxidants good” idea.
    The same thing happens every few years with silly headlines like “is the free radical theory of aging dead?” For anyone who’s been living under a rock, it’s been dead for nearly 20 years now. Unfortunately as with most science this stuff takes time to filter down to the masses. One can’t help suspecting that the multi-billion dollar nutritional supplements industry is rather pleased at this lack of public acceptance that their product is a total crock.

  6. Anonymous BMS Researcher says:

    RIP Linus Pauling.

  7. pete says:

    “RIP Linus Pauling.”
    – like smugly kicking a rock from the sides of Mt. Everest

  8. supplement joe says:

    With so many natural antioxidants in the body, depleting by only 3% over the course of a lifetime (avg) the fascination with supplemental anti-oxidants never made sense – they are like fireman standing around with nothing to do – eventually they start fires. Someone might start looking at synthetic sunscreens next – these also cause many more problems than they solve and their use is almost a religion. Keep drinking.

  9. Lane Simonian says:

    It all depends on what you are trying to accomplish. If you want cell survival and in some cases the regeneration of cells, then highly bioavailable antioxidants may be useful (certain neurodegenerative diseases, for instance). If you want to prevent or inhibit oxidation, nitration, inflammation, and DNA strand breakage, then such antioxidants may again be helpful (type 2 diabetes, lupus, rheumatoid arthritis, prevention of cancer, etc.) If you want to kill cancer cells (hopefully without killing other cells) then potent pro-oxidants may be helpful.
    Under conditions of oxidative stress (such as in the presence of transition metals or the over- activation of AMPK), taking certain antioxidants like Vitamin C or resveratrol might not be a good idea. Antioxidants may become pro-oxidants during endurance training or the early stages of Alzheimer’s disease (which might explain why taking Vitamin C actually worsened conditions in people with mild Alzheimer’s disease in one study). The type of antioxidant taken can also make a difference. The alpha version of tocopherol lowers levels of the gamma version of tocopherol–the latter of which is a much better antioxidants. So the results from any study using vitamin E has to at least be partially evaluated based upon what form of Vitamin E was being used.
    I am not a big vitamin supplementation advocate. Most people attain an adequate amount of vitamins through their diet, and if there is a deficiency supplementation may not correct it. More generally, though, antioxidants vary widely in their bioavailability and effectiveness and can be useful or potentially harmful depending on the circumstances. It is important to know which diseases are drive primarily by oxidants and which antioxidants are best suited to treating those diseases.

  10. Interesting! A colleague sent me the lung cancer paper last week. Aside from natural occurring antioxidants (which I eat) and supplements (which I don’t) antioxidants are also used in many packaged foods to prevent fats ‘n oils from going rancid – even more so now that trans fats are out. I think these preservatives are not used in large amounts, but it’s a third source maybe worth mentioning.

  11. gippgig says:

    The latest version of the informationisbeautiful evaluation of supplements (see Dietary Supplements, Charted, March 17, 2010) indicates that there is good evidence that antioxidants are beneficial for heart disease, N-acetylcysteine for mental health & addiction, & melatonin for insomnia for the elderly. Other than that, antioxidants are below the “worth it line”.

  12. gippgig says:

    Are there any good studies on sulforaphane, which induces cells to produce their own antioxidants?

  13. Lane Simonian says:

    Here are a few for you in regards to sulforaphane and neurodegenerative diseases.
    Review Article
    Sulforaphane as a Potential Protective Phytochemical against Neurodegenerative Diseases
    Andrea Tarozzi,1 Cristina Angeloni,1 Marco Malaguti,1 Fabiana Morroni,2 Silvana Hrelia,1 and Patrizia Hrelia2
    1Department for Life Quality Studies, Alma Mater Studiorum, University of Bologna, Corso d’Augusto 237, 47900 Rimini, Italy
    2Department of Pharmacy and Biotechnology, Alma Mater Studiorum, University of Bologna, Via Irnerio 48, 40126 Bologna, Italy
    Received 30 April 2013; Revised 28 June 2013; Accepted 3 July 2013
    Academic Editor: Cláudio M. Gomes
    A wide variety of acute and chronic neurodegenerative diseases, including ischemic/traumatic brain injury, Alzheimer’s disease, and Parkinson’s disease, share common characteristics such as oxidative stress, misfolded proteins, excitotoxicity, inflammation, and neuronal loss. As no drugs are available to prevent the progression of these neurological disorders, intervention strategies using phytochemicals have been proposed as an alternative form of treatment. Among phytochemicals, isothiocyanate sulforaphane, derived from the hydrolysis of the glucosinolate glucoraphanin mainly present in Brassica vegetables, has demonstrated neuroprotective effects in several in vitro and in vivo studies. In particular, evidence suggests that sulforaphane beneficial effects could be mainly ascribed to its peculiar ability to activate the Nrf2/ARE pathway. Therefore, sulforaphane appears to be a promising compound with neuroprotective properties that may play an important role in preventing neurodegeneration.
    Amyloid. 2013 Mar;20(1):7-12. doi: 10.3109/13506129.2012.751367. Epub 2012 Dec 19.
    Amelioration of Alzheimer’s disease by neuroprotective effect of sulforaphane in animal model.
    Kim HV, Kim HY, Ehrlich HY, Choi SY, Kim DJ, Kim Y.
    Author information
    Pathophysiological evidences of AD have indicated that aggregation of Aβ is one of the principal causes of neuronal dysfunction, largely by way of inducing oxidative stresses such as free radical formation. We hypothesized that the known antioxidative attribute of SFN could be harnessed in Alzheimer’s treatment. SFN is an indirect, potent antioxidant derived from broccoli that has previously been found to stimulate the Nrf2-ARE pathway and facilitate several other cytoprotective mechanisms. In this study, administration of SFN ameliorated cognitive function of Aβ-induced AD acute mouse models in Y-maze and passive avoidance behavior tests. Interestingly, we found that the therapeutic effect of SFN did not involve inhibition of Aβ aggregation. While the exact mechanism of interaction of SFN in AD has not yet been ascertained, our results suggest that SFN can aid in cognitive impairment and may protect the brain from amyloidogenic damages.

  14. BG says:

    If I’m interpreting this wrong, someone please let me know:
    On the top of page 6: “(Vitamin E) was administered in chow pellets…at doses of 0.1 and 0.5 g/kg chow (12.5 and 61.5 mg/kg body weight), calculated on the basis of observed daily food intake.”
    I don’t know how much a mouse weighs, but I weigh 70kg. So if they were experimenting on me, I’d be eating 0.875g – 4.3g of Vitamin E per day… that’s alot. Am I understanding this correctly?

  15. passionlessDrone says:

    Hello friends –
    Anyone with access have data on the mouse study that gives us insight into meaningful levels; i.e., did they give the mice a microgram or pound of nac?
    In any case, this discussion reminds me a lot about what I’ve taken from this blog: the locks and keys we know how to force together via pill/supplement/whatever do lots of different things; that is why giving you a boner with Viagra can *also* do lots of other things. Figuring out the right balance is a job where we are still stabbing in the dusk.
    That being said, as pointed out some above, there are indications that antioxidant therapy can be useful in some instances that aren’t about cancer. For example, schizophrenia:
    There are good reasons to think this is biologically plausible relationship.
    So, the question is, is a reduction in schizophrenic symptoms worth an increase in cancer risk? I bet it depends on how schizophrenic symptoms manifest in an individual patient.
    Not to defend supplement advertising or ‘natural’ cures, but a lot of the times on this blog we get a more nuanced view than ‘supplements_are_bad_for_you.php’.

  16. luysii says:

    This is an OK study using biomarkers. However, inference from such studies are always treacherous.
    Here’s a link to two studies in humans (preventing lung cancer with antioxidants, preventing prostate cancer with antioxidants) which were a disaster.
    There’s also a link there to a naturalistic study (again always treacherous) showing that taking vitamin supplementation increases the risk of dying. Also discussed is the infamous HERS study, which was criticized as even unethical to undertake, given the weight of previous naturalistic studies showing that postmenopausal hormones were a good thing.

  17. DTX says:

    A great book that looks at the scientific studies behind many supplement claims is “Do you believe in magic? The sense and nonsense of alternative medicine.” There were educated proponents, such as L Pauling, but what amazed me is the total lack of nutritional & scientic training of most.
    Many brag about their lack of education and this somehow makes them credible to the public.

  18. Lane Simonian says:

    Why don’t antioxidants that appear to work in mice not work in human beings? The authors of this article note three possibilities.
    Autophagy as an essential cellular antioxidant pathway in neurodegenerative disease ☆
    Samantha Giordanoa, b,
    Victor Darley-Usmara, b,
    Jianhua Zhanga, b, c, Corresponding author contact information, E-mail the corresponding author
    Oxidative stress including DNA damage, increased lipid and protein oxidation, are important features of aging and neurodegeneration suggesting that endogenous antioxidant protective pathways are inadequate or overwhelmed. Importantly, oxidative protein damage contributes to age-dependent accumulation of dysfunctional mitochondria or protein aggregates. In addition, environmental toxins such as rotenone and paraquat, which are risk factors for the pathogenesis of neurodegenerative diseases, also promote protein oxidation. The obvious approach of supplementing the primary antioxidant systems designed to suppress the initiation of oxidative stress has been tested in animal models and positive results were obtained. However, these findings have not been effectively translated to treating human patients, and clinical trials for antioxidant therapies using radical scavenging molecules such as α-tocopherol, ascorbate and coenzyme Q have met with limited success, highlighting several limitations to this approach. These could include: (1) radical scavenging antioxidants cannot reverse established damage to proteins and organelles; (2) radical scavenging antioxidants are oxidant specific, and can only be effective if the specific mechanism for neurodegeneration involves the reactive species to which they are targeted and (3) since reactive species play an important role in physiological signaling, suppression of endogenous oxidants maybe deleterious.
    Of these, number two is the most common problem. Even if you choose the best antioxidant to target the right oxidant, there is still the problem of getting that oxidant in sufficient quantities to the right place. That is sometimes a particular challenge when it comes to the brain. At least in the case of Alzheimer’s disease, though, there have been highly concentrated antioxidants (such as eugenol in essential oils via aromatherapy) or combination of antioxidants (such as ferulic acid, syringic acid, vanillic acid, and maltol) in heat-processed ginseng that have reversed the disease in human clinical trials. Somewhere between panacea and poison lies the truth about antioxidants.

  19. Lane Simonian says:

    The next to the last line should have been partially reversed the disease in human clinical trials.

  20. Richard says:

    > Consequently, vitamin C and E supplementation hampered cellular adaptions in the exercised muscles

  21. Erebus says:

    Due to metabolic differences between rodents and men, doses in these small animals need to be converted to a human-equivalent dose (HED). There are some fast-and-loose rules for that here:
    For mice, it’s basically:
    Dm * (3/37) = Dh
    Where Dm is the mouse dose in mg/kg, and Dh is the corresponding HED.
    …So the heavier dose in this antioxidant study of 61.5mg/kg/day/mouse corresponds to roughly 5mg/kg/day in humans. Still a very large dose.

  22. navarro says:

    moderation in all things, even in moderation.

  23. rtw says:

    Found this news item this morning.
    So perhaps its too soon to be bashing Linus Pauling? Perhaps this observation is likely as not entirely due to anti-oxidative processes? As with a lot of chemical entities, it likely has many as yet undetermined cellular interactions/effects. Unfortunately many cancer patients grasp at anything, and I have heard that many subscribe to the use of Vitamin C going so far as to have very high doses infused via IV as an alternative treatment. No clinical trial I am aware of has shown this to be effective, but on the basis of incidental data and news briefs like the one above, some patients will chance it.

  24. Phil says:

    There are no simple answers to this matter because the primary organelle involved, the mitochondrion, is anything but simple. Among many functions, mitochondria are a cellular redox system and as such ROS are an important component. As others have noted above, the efficacy of any antioxidant regimen is highly dependent on the cellular state. For those affected by primary mitochondrial disease (of genetic origin)in which there is pathological mitochondrial dysfunction, antioxidants are an accepted treatment protocol despite limited, ambiguous clinical trial data. A first in class redox modulator for Leigh Syndrome is currently in Phase IIb and other approaches that address oxidative stress are in development. It is an exciting time for researchers and clinicians investigating this area as well as patients affected by mitochondrial disease. We are poised to enter the era of mitochondrial medicine that may well bring a more nuanced perspective on the value of antioxidants to every human being.

  25. MattNY says:

    Something that may be clouding the issue in human vs animal testing is that all other animals make their own vitamin C. Humans, great apes, and guinea pigs do not. Animals make the equivalent of several grams of vitamin C per day, and when sick, make hundreds – a whole bottle of vitamin c per day when scaled up to humans.
    All that happens when you give additional vitamin c to animals that make their own is that they make a little less of their own.
    Do animals that make their own vitamin C not adapt to endurance exercise? I doubt it. Something else is going on.

  26. Anonymous BMS Researcher says:

    @MattNY: excellent point. The discovery that guinea pigs, like humans, get scurvy made the discovery of vitamin C possible.
    It had been known for a long time that certain foods prevented scurvy. The slang term “limey” for somebody from the UK comes from the Royal Navy giving sailors limes because they had learned citrus fruits prevented scurvy. However, the impossibility of giving scurvy to most lab animals made it difficult to find out what nutrient in such foods prevented scurvy. One early theory was acidity because many foods high in vitamin C are also acidic, but 19th century experiments with various acids demonstrated pH alone was not sufficient.

  27. Mike says:

    I think it needs to be said that the amount of vitamin C and E administered to the test subjects was 11 times, and 17 times respectively the recommended daily allowance, as specified by the US Department of Health, National Institute of Health, Office for Dietary Supplements. When the article states that high dosages should be used with caution, they do mean high – very high – dosages.

  28. Bill Taylor says:

    Two Things:
    Very high dosages of anything is bad
    Not all antioxidants are the same – polyphonls are way better for you than a vitamin e pill

  29. Nikolas Britton says:

    Testosterone replacement therapy has a paradoxical effect, for example, sub-fertile males given testosterone injections will stop producing natural endogenous testosterone in the testis and sperm production will literally drop to zero. The reason this happens is there is an endocrine feedback loop.
    I think antioxidants follow a parallel feedback loop, in that, when one takes exogenous antioxidants they circumvent the Keap1-Nrf2 ARE (antioxidant response element) pathway. The Keap1-Nrf2 pathway regulates over 600 cytoprotective genes that confer upon the cell multiple layers of protection. This includes: antioxidant enzymes, conjugating enzymes, proteins that enhance the export of xenobiotics and their metabolites, enzymes that participate in the synthesis and regeneration of glutathione, enzymes that promote the synthesis of reducing equivalents, enzymes that inhibit inflammation, proteins that protect against heavy metal toxicity, proteins that function to repair and remove damaged proteins, and proteins that regulate the expression of other transcription factors and growth factors.
    Through natural selection, I strongly believe the body has all the tools it needs to manage oxidative stress, and I’m of the opinion that taking exogenous antioxidants reduces overall activation of the ARE pathway. As a result of this deactivation of the ARE, it ends up having a net negative effect as all the other cytoprotective genes and systems don’t get activated.
    With that said, the supplements I do take are NAC and Vitamin D3 (calcitriol is a glutathione catalyst), because these are prodrugs for endogenous glutathione that is naturally produced by the body upon activation of ARE. Cysteine is typically a rate limiting factor, so I firmly believe that supplying the body with precursors is one way to maximize our natural cytoprotective systems. The ARE pathway is what everyone needs to get focused on; I see nrf2 activators as taking center stage in the battle against oxidative stress.
    Antidotally, the last time I was taking buckets of antioxidants, one night I got “mildly” drunk, and remember having the worst hangover ever. Hangovers are the result of the body’s inability to clear acetaldehyde. I recall acetaldehyde dehydrogenase, the main way the body neutralizes acetaldehyde, is regulated by ARE; normally I never get hangovers. Taking those various antioxidants I also began to feel seriously ill, I stopped all of them cold turkey when I learned of the ARE feedback loop, and the ill feeling went away quickly after stopping them.

  30. Matt says:

    I take Longvida curcumin supplements to help with a condition I have called Sarcoidosis. Everything I read about curcumin before is positive. Curcumin is a potent polyphonolic antioxident though. Should I be worried now?

  31. Laura says:

    This shouldn’t be taken as a recommendation to go out of the way to avoid taking in antioxidants from food. But going out of your way to add lots of extra Vitamin C, Vitamin E, N-acetylcysteine, etc., to your diet? More and more, that really looks like a bad idea.
    Is it radiated food or non radiated food that we are talking about in here?

  32. Laura says:

    If it wasnt so dramatic, I would just laugh at this article…

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  34. The problem revealed in this article is that we continue attempting to understand the potential benefit or harm of antioxidants through scientific rigor, which isolates substances, subjects and effects and then try to come up with something conclusive.
    There is not a single pharmaceutical drug that does not have adverse side effects or reactions, as well as negative interactions with other drugs and supplements. So highlighting an adverse reaction to antioxidant supplements is a ruse to cover over the general fallacy that we will ever get well with reductionist medicine.
    Antioxidants are pervasive in nature for a reason. There is hardly a plant or food without them! Wake up people 🙂

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