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Antioxidants and Exercise: More Harm Than Good?

Multivitamin supplementation has been getting a rough ride in the literature, as evidence emerges that routine supplementation for most is, at best, unnecessary. Some individual vitamins are earning their own unattractive risk/benefit profiles: Products like folic acid, calcium, and beta-carotene all seem inadvisable for routine supplementation in the absence of deficiency or medical indication. Vitamin E, already on the watch list,  looks increasingly problematic, with data recently published confirming the suspected association of supplementation with an elevated risk of prostate cancer.

Reading through the vitamin posts here at SBM, one issue comes through repeatedly: The danger of assuming therapeutic benefits in the absence of confirmatory evidence. Vitamin supplement have the patina of safety and of health, a feature that’s reinforced when you purchase them: You don’t need a prescription, you don’t get counseled on their use, and there isn’t a long list of frightening potential side effects to accompany the product. You can pull a bottle off the shelf, and take any dose you want. After all, how harmful can vitamins be when you can buy 5 pounds of vitamin C at a time, or vitamin E capsules in a 1000-pack?  But the research signals seem to be getting stronger, and most are pointing in the same direction: what we though we knew about antioxidants was based on simplistic hypotheses about nutrition and health. And while we thought we were doing ourselves good with antioxidant supplements, we may have been doing harm.

I have vitamin confession to make, like Harriet Hall did a few years ago. I too was a panacea-seeking antioxidant-taker. As background, I’m a marathon runner and occasional triathlete. Several years ago, I was training for an Ironman triathlon, and banking 20+ hours of intense exercise per week. That may sound absurd to many (it does to me, now that I have kids) but that kind of training is necessary for the long races. So what did the pharmacist-wannabe-triathlete with access to discounts do? He stocked up on the fancy bottles of multivitamins, the “endurance” version, of course — with extra antioxidants. Why did I supplement? I wanted to maximize my workouts, speed recovery, and minimize downtime and the risk of injury. Oxidation sounds bad — like a rusting car. Anti-oxidants sounded like the ultimate in preventative medicine. My workouts may have been more extreme, but the practice of supplementing if you exercise is common among athletes.

As it turns out, not only were the antioxidants likely ineffective, they may have compromised some of the gains I was seeking with all that training. That I didn’t evaluate the evidence at the time was my critical-thinking blind spot. Over the the past several years, more data on antioxidants and exercise have emerged.  A recent review article, profiled by sports & science blogger Alex Hutchinson at his blog Sweat Science, was an opportunity to get caught up on the evidence. And there’s a lot, nicely summarized by Tina-Tinkari Peternelj and Jeff S. Coombes in this month’s Sports Medicine: Antioxidant Supplementation during Exercise Training: Beneficial or Detrimental?

Let me address the biggest limitation of the paper first. This is just a review paper — not a systematic review. While the authors describe using systematic search strategy, there’s no methodology described for the articles selected, nor is there a systematic appraisal of the literature selected.  And as Travis Saunders at the excellent Obesity Panacea blog recently pointed out, a review article with the right amount of cherry picking can be used to support even the most implausible hypothesis, such as the potential benefits of smoking to distance runners. I couldn’t locate any published systematic reviews on this topic, so perhaps it’s more appropriate to consider the paper as a launching point for a review, but not a definitive statement on the evidence.

Why antioxidants?

There’s good epidemiologic data to suggest that a diet rich in foods that are naturally high in antioxidants is associated with better health outcomes. So if some antioxidants are good, more might be better, right? At a minimum, supplements might allow the kale-haters to get all the health benefits their cruciferous-vegetable-loving friends could be enjoying.

Oxidation (electron loss) and reduction (electron gains) are ubiquitous in biochemical reactions. While oxygen is essential to life, the outputs of respiration have the potential to do cellular damage in the form of “reactive oxygen species” or ROS. The ROS can damage cell membranes and other components. The imbalance is sometimes called “oxidative stress.” Antioxidants work to eliminate the oxidative stress by neutralizing ROS when they develop, preventing cell damage. We have evolved complex systems to produce several antioxidants (e.g., glutathione, uric acid, coenzyme q-10) endogenously — the process is too critical to rely solely on the consumption of dietary antioxidants like vitamin C, vitamin E, and beta-carotene, which also play a role in managing ROS.

The antioxidant-exercise hypothesis is simple: exercise more, breathe more, oxidize more.  Exercise can also damage muscle tissue.  So the idea of boosting the antioxidant reserves to offset the perceived negative effects of exercise emerged. The expected results: better workouts and faster recovery. But like the t-shirt says, it’s a bit more complicated than that.

So let’s look at the data in the paper. The authors found 150 studies, but most were small and had weak methodologies:

As commonly found in sports nutrition research, the vast majority do not adhere to all the accepted features of a high-quality trial (e.g. placebo-controlled, double-blind, randomized design with an intent-to-treat analysis). Indeed, most studies fail to provide sufficient detail regarding inclusion and exclusion criteria, justification of sample size, adverse events, data gathering and reporting, randomization, allocation and concealment methods, and an assessment of blinding success. The poor quality of the majority of studies in this field increases the possibility for bias and needs to be always considered when evaluating the findings.

Summarizing the data is complicated by different supplements, different endpoints, varied durations and doses, and a lack of hard outcomes. The most common endpoint was some measure of oxidative stress, and on balance (though not always consistently) the data suggest that antioxidants do reduce this parameter. It’s been shown with vitamin C, vitamin E, beta carotene, and other antioxidants.  Good news? Not really. It’s an endpoint without any demonstrated relationship to something meaningful — like performance or recovery.

Evaluations of the effects of antioxidant supplements on exercise-induced muscle damage are disappointing. The usual research approach is to look at measures of muscle damage in the bloodstream — enzymes like creatine kinase, which are a indicator of cell rupture. But the evidence is mixed — there’s no strong evidence to suggest supplements have any meaningful effect on muscle damage. What’s more concerning is that some studies have suggested that supplements may induce muscle injury and actually delay recovery.

So do antioxidants have any acute benefits on exercise? Should I be selecting the energy bar with extra vitamins?  The data are more consistent here — there does not appear to be strong evidence of a performance-enhancing effect when antioxidants are consumed during exercise.  With some exceptions, single ingredient and multiple-product supplements including vitamins E, C, coenzyme Q10, quercetin and polyphenol resveratrol have generally failed to demonstrate consistent effects in animal and human studies.  Again, the quality of the studies and the lack of reproduction of many of the trials precludes firm conclusions.

Let’s consider the post-workout period now, and it’s here where we get to the most concerning data. Antioxidant supplements seem to be working against the beneficial cardiovascular effects of exercise. Mechanisms could include:

  • Promoting, rather than reducing, oxidative stress: In some cases, supplements appear to raise indicators of inflammation, rather than reduce them.
  • Reducing the ability to adapt to exercise-induced oxidative stress: Cells will naturally adapt to increases in ROS by upregulating endogenous enzyme systems. Supplements may inhibit this endogenous adaptation.
  • Affecting physiologic processes like muscle contraction and insulin sensitivity: Supplementation, by affecting the concentration of ROS, may interfere with muscle function and recovery from the effects of exercise. A study by Ristow identified that supplementation with vitamins E and C inhibited the usual insulin-sensitizing effects of exercise. The result, for diabetics that exercise and take antioxidants, could mean an elimination of the expected benefits.

So what does the science say about antioxidants and exercise?

Simple solutions can be the wrong ones. Surrogate endpoints, like those that measure oxidative stress, can’t be extrapolated to infer positive health effects in the absence of confirmatory data.   Like other areas of CAM, our ability to draw conclusions is limited by a lack of good data. The evidence is inconsistent and generally unimpressive when it comes to the effects of antioxidant supplements on exercise. So we’re challenged to make decisions based on incomplete information. In light of what we know about antioxidants and exercise, the trend in the data is strongly suggestive of zero benefit, at best, with the real possibility that there may be negative consequences to supplementation. Overlay the epidemiologic evidence that looks at mortality, cancer, and other outcomes, and the attractiveness of antioxidant supplements drops even further. The best advice for those that exercise seems to be to focus on consuming a diet rich in fruits and vegetables, and leaving the antioxidant bottles on the shelf. There appears to be little that is complementary about them.

Reference

ResearchBlogging.orgPeternelj TT, & Coombes JS (2011). Antioxidant Supplementation during Exercise Training: Beneficial or Detrimental? Sports medicine (Auckland, N.Z.), 41 (12), 1043-69 PMID: 22060178

Posted in: Herbs & Supplements, Science and Medicine

Leave a Comment (35) ↓

35 thoughts on “Antioxidants and Exercise: More Harm Than Good?

  1. anoopbal says:

    Nice post!

    Scott have you come across Juice Plus? They claim it is processed from whole fruits and hence it is different from multivitamin and includes all the ingredients missing in multivitamins. Their marketing stratergy is that most people don’t get enough fruits and vegetables so they should all take JuicePlus.

  2. anoopbal says:

    And this is an article I wrote about antioxidants and cancer a few years ago: http://www.exercisebiology.com/index.php/site/articles/can_antioxidants_prevent_cancer/

  3. Nikola says:

    While it’s becoming pretty damn clear that antioxidants don’t do any good, I think it might be a stretch to call them harmful, at least based on such a review. Additional muscle injury and delay of recovery may simply be due to the fact that athletes who take such supplements push themselves harder, and perhaps too hard. Without blinding, it’s really hard to tell if there’s actual negative effects.

  4. majkinetor says:

    Nonsense. Here is something from head to get you started in the right direction [positive + neutral studies]:

    http://goo.gl/8XpCK http://goo.gl/X523J http://goo.gl/TUp3W http://goo.gl/7l4Ja http://goo.gl/eXAps http://goo.gl/Yd86w http://goo.gl/e5zvS http://goo.gl/6nKiH

    If that was the case, animals which produce gram amounts of C daily (which is… like… every animal in the world), would fail to adapt to exercise which is ROFLMAO. Also, kids would be very bad at sports due to excessive CoQ10 production.

    While some level of ‘adaptation’ might be prevented with antioxidant, I would be more concerned about injuries which is what typically happens even with safe exercise like walking. Antioxidants, particularly vitamin C promotes fast healing and prevent injuries which are more important then adaptation since if you are injured and ,consequently, can’t exercise because of that, its much more bad for your health and/or professional outcome then exercising and having lower adaptation.

    Most of the studies on Vitamin E “detrimental effects” are rebutted many times (for instance: http://goo.gl/QFjBS http://goo.gl/Exbhm http://goo.gl/PvoJf).

    Vitamin winning again, while you should really devote more time to wine about pharmaceuticals, even the basic ones like paracetamol (fresh: http://goo.gl/ZkXoy, http://goo.gl/qI7f7)

  5. Janet Camp says:

    Even my fast food junkie kids and grandkids love my KALE/beet salad. The trick is to use the lacinato (dinosaur) variety and use it raw–just like cabbage for cole slaw. Use the orange beets, also raw, and grate them–or carrots for beet haters. Add a few dried cranberries or diced apple and a vinegarette made with a little olive oil, some grated ginger (or whatever else you like) and any of a large variety of vinegars or lemon juice. I grow kale almost year round outside my kitchen door (in Wisconsin) and pick as needed. I feed it to my chickens and they have the most beautiful orangy yolks in their eggs from all the Vit A.

    I also substitute kale for spinach in things like spinach lasagne–another thing my carnivore family relish! I wish people would stop referring to kale as though it’s truly the most horrible thing to eat. We will be using up the last of this year’s crop for Thanksgiving dinner–then it’s back to $2.99/lb at the Co-op or else the chard growing in the basement under the grow lights–another tasty and nutritious treat!

    It’s also sad that most people who DO use kale, only juice it. Yuck. The curly kind is more bitter, but good in kale/potato soup.

    Sorry, I know the focus of the article was not kale, but I had to speak up for this much-maligned veggie.

  6. majkinetor says:

    Check out also LPI comment about the review in question:

    http://lpi.oregonstate.edu/news/exercise.html

    Additionally, the insulin sensitivity may stay diminished by the number of reasons, for instance by improvement in beta oxidation pathways (vitamin C – carnitine pathway for example or effect of CoQ10 on energy status) which will promote physiological insulin resistance to conserve glucose for body parts that need it.

  7. majkinetor says:

    If that was the case, animals which produce gram amounts of C daily (which is… like… every animal in the world), would fail to adapt to exercise which is ROFLMAO. Also, kids would be very bad at sports due to excessive CoQ10 production.

    While some level of ‘adaptation’ might be prevented with antioxidant, I would be more concerned about injuries which is what typically happens even with safe exercise like walking. Antioxidants, particularly vitamin C promotes fast healing and prevent injuries which are more important then adaptation since if you are injured and ,consequently, can’t exercise because of that, its much more bad for your health and/or professional outcome then exercising and having lower adaptation.

    Most of the studies on Vitamin E “detrimental effects” are rebutted many times.

    Vitamin winning again, while you should really devote more time to wine about pharmaceuticals, even the basic ones like paracetamol

    PS: I omitted all studies I referenced because otherwise, “my comment awaits moderation”

  8. Nikola says:

    @majkinetor: There’s a limit to how many links you can put into one post without moderation. It’s to prevent spam.

  9. Hi Scott,

    I think when describing “reduction”, you may have meant to say “electron gaining” instead of “oxidation”. The whole “OIL RIG” thing that I only recently learned from Khan Academy :)

    Great article, as always.

    1. Scott Gavura says:

      @Mike. Thanks – fixed.

  10. daedalus2u says:

    Taking antioxidants before exercise is not good and does diminish the effects of exercise by interfering with the signaling. It is not exercise per se that causes beneficial health effects, it is the activation of compensatory pathways by exercise when then remodel physiology into a more healthful state after the exercise is over that produces the beneficial effects. Much of that signaling is due to ROS, and taking antioxidants to the extent that they interfere with that ROS signaling will interfere with the beneficial effects of exercise.

    I used to take large quantities of antioxidants too, now I don’t. There is no prospective human data showing that a diet rich in antioxidants improves health. All the diet studies are from self-selected diets. My hypothesis is that there is an “oxidative stress setpoint”, which physiology regulates, and that diet choice is part of that regulatory system. If you are in bad health, you have a high oxidative stress setpoint and will self-select a diet low in antioxidants so your physiology doesn’t need to destroy them by increasing superoxide generation.

    The main beneficial health effects from a diet rich in antioxidants are not from the antioxidants, it is from the phytotoxins that such a diet also has. Appropriate doses of these phytotoxins stimulates physiology via the process of hormesis to make physiology better and stronger than in the absence of those phytotoxins. Most of those signaling pathways use ROS, superoxide and hydrogen peroxide. These activate the various MAPK and other signaling cascades and the response is better health. A refined diet is bad because the phytotoxins have been removed, not because refining somehow adds “toxins” which are unknown to science.

    In the case of exercise, the signaling goes like this: exercise leads to ROS due to mitochondria overload, blood shear, hypoxia, micro-injuries and a state of oxidative stress. This state of oxidative stress turns off healing to divert ATP to immediate consumption by muscles. The ROS are also mitogens which then triggers compensatory pathways including increased NO which turns off the state of oxidative stress and turns healing back on. It is during the period of rest after the exercise that the repair and remodeling to a higher net capacity happens. If you interfere with the signaling by using antioxidants, then the signaling is not as efficient and it takes more exercise to produce the same benefits.

  11. Jeff says:

    There may not be much evidence for improved performance through antioxidant supplements. However there is evidence antioxidants enhance post-exercise recovery:

    http://www.naturalproductsinsider.com/news/2010/08/antioxidants-endurance-athletes.aspx?nck=1

    Melatonin supplementation ameliorates oxidative stress and inflammatory signaling induced by strenuous exercise in adult human males.

  12. @Janet Camp, reading your comment was like a little vacation. I did not know Kale could taste good. We used the curly kind as a garnish when I did food service. I tasted it once and it was awful/bitter. Since, I have stuck to the spinach, arugula, and mixed lettuce. It’s good to branch out. I will have to try the straight kind of kale.

  13. Jeff says:

    A study by Rostow identified that supplementation with vitamins E and C inhibited the usual insulin-sensitizing effects of exercise. The result, for diabetics that exercise and take antioxidants, could mean an elimination of the expected benefits.

    One study suggests dietary antioxidants improve insulin sensitivity in obese adults:
    http://www.sciencedaily.com/releases/2010/06/100621091205.htm

    Vitamin E, already on the watch list, looks increasingly problematic, with data recently published confirming the suspected association of supplementation with an elevated risk of prostate cancer.

    The SELECT study Mr. Gavura refers to used synthetic DL-alpha tocopherol. There are several studies emphasizing the importance of maintaining high blood levels of all the various components of vitamin E:
    http://www.sciencedaily.com/releases/2010/07/100707102439.htm

  14. daedalus2u says:

    Jeff, the references you link to don’t provide evidence that supports positive effects of antioxidants.

    The extreme exercise paper only looks at acute measures of oxidative stress and simply assumes there are adverse effects. There was no follow up to see if people with higher levels recovered faster or slower. There was no measure of functional recovery or enhancement at all.

    The antioxidant diet example used a diet that contained antioxidants. Such diets also contain phytotoxins which cause expression of repair pathways via hormesis. This is the opposite of what antioxidants do.

    The Alzheimer’s paper was purely association, not necessarily causation. Since they looked at natural vitamin E isomers, the kind gotten from the diet and not supplements, what they are actually “measuring” is (vitamin E ingestion in the diet) minus (vitamin E consumption by physiology). The association could also be due to greater consumption of vitamin E by physiology in patients who were destined to exhibit Alzheimer’s symptoms. Alzheimer’s is notoriously difficult to diagnose early on. A diet rich in natural vitamin E is also rich in phytotoxins. Also the p value was 0.19, not a compelling value.

    If the natural vitamin E was exerting effects via an antioxidant mechanism, then synthetic vitamin E would exert protective effects by the same mechanism. There are multiple studies showing that synthetic or supplemental vitamin E does not have the same protective effects as eating a diet that contains the same amount of vitamin E. A diet rich in vitamin E also is rich in phytotoxins which trigger hormesis.

    The seemingly paradoxical effects attributed to natural vitamin E which synthetic vitamin E does not exhibit may have nothing to do with vitamin E but are more likely due to hormesis from the phytotoxins that accompany the natural vitamin E in a diet rich in natural vitamin E.

  15. DKlein says:

    I graduated 11 years ago from a health-supportive cooking school in NYC that taught natural = better but also provided excellent training in (mostly) vegetarian cooking. The school was and is anti-supplementation because pills were not natural, and because the body “doesn’t know” what to do with, for example, a gram of vitamin C or one of the B vitamins, all at once – it throws things off balance. They teach a little science but don’t go far enough. There was already some research back then about vitamin E and blood clotting problems, so there were already a lot of unknowns. Unfortunately, they also teach a lot about the energy of food and don’t come out and say Rudolf Steiner but he’s there. What is ironic is that science supports their pro-whole foods/anti-supplementation stance better than woo, but TCM and biodynamics seem to fill the classrooms.

    @daedalus2u – This is the first time I’ve heard of phytotoxins being a good thing. I didn’t know they worked that way. In school, we were taught to soak certain beans and grains overnight to remove them. We were warned again over-consumption of tofu because of its phytotoxins. Of course, since finding this site, I’m not sure about anything I’ve “learned” there.

    @Janet Camp – Vegetables in general seem to be maligned but at the same time, people complain their doctors don’t know anything about nutrition. Your beet/kale salad sounds fabulous. Maybe doctors need to pass our recipes :)

    @micheleinmichigan – Kale can be bitter depending on where it is grown and what time of year. Even our rabbit won’t eat it when it gets too bitter and crunchy. You can always boil it until tender. Throw some diced sweet potatoes into the boiling water towards the end of cooking time. In another pan, saute’ some garlic and dried cranberries in some olive oil, add 1-2 Tbs apple juice, drain the kale and potatoes and add them to the saute’ pan. Cook until the apple juice evaporates.

  16. daedalus2u says:

    A good paper on it is here.

    http://www.grc.nia.nih.gov/branches/lns/BestinSmallDoses.pdf

    It is the dose that makes the medicine.

  17. Jeff says:

    @daedalus2u:
    Almost all “vitamin E studies” have used either the natural or synthetic form of alpha-tocopherol. An emerging body of research is just beginning to explain the health benefits of the four forms of tocotrienols.

    Besides many tocotrienol cell studies, there have been a few trials:

    Tocotrienols lower cholesterol in type 2 diabetics (pubmed/16159610)
    Tocotrienols lower cholesterol in animal study (ajcn.org/content/53/4/1042S.abstract)
    Tocotrienols lower cholesterol in human trial (ajcn.org/content/53/4/1021S.long)

    Study Supports prostate Cancer Benefits of Tocotrienols

  18. Ed Whitney says:

    Sound recommendations regarding health practices should be based on known physiologic principles. For example, a fine review article shows that cigarette smoking should be recommended for athletes who are training for high-performance endurance events. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3001541/ has all the details and references. Briefly, smoking is associated with three variables which are correlated with improved performance in long-distance running, cycling, and other endurance sports. These three variables are increased hemoglobin, increased lung volume, and reduced weight. This review article furnishes numerous references from the peer-reviewed literature, and reminds the reader of the adverse effects of some practices which athletes resort to in order to improve their physiological profiles. Altitude training, high altitude pulmonary edema (HAPE), high altitude cerebral edema (HACE), and high altitude flatulent expulsion (HAFE), a little-known syndrome reported at http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1272559/pdf/westjmed00222-0087.pdf. The impeccable logic supporting smoking as an aid to marathon training cannot be refuted.

  19. daedalus2u says:

    Jeff, I looked at those papers and the comparison was the tocotrienol rich mixture against corn oil. That doesn’t demonstrate a specific effect of a mixture over a single isomer at equivalent dose.

    If the effects were mediated through an anti-oxidant effect, then the different vitamin E isomers should have effects proportional to their anti-oxidant properties.

    Usually synthetic vitamin E is given as an ester because the free vitamin is sensitive to oxidation. The ester doesn’t have anti-oxidant properties until it is de-esterified by metabolism. In the animal feed experiments, putting non-esterified vitamin E in the feed as it is prepared would protect the polyunsaturated lipids from peroxidation. Peroxidized lipids are known to raise cholesterol levels. The mineral mix added to the feed contained Fe, Mn and probably Cu (that is says Ca is probably a misprint, Ca is added to the main mix, the amount in the mineral mix would be insignificant, the amount added is around where Cu would be needed). Those metals are well known to catalyze lipid peroxidation. The feed was probably mixed up at the beginning of the experiment and would then became progressively oxidized over the 8 week course in the absence of measures to prevent oxidation which they don’t mention.

    I don’t find fault with their data, there are some additional measurements I would have liked to see, but their data does not support their conclusion that the lower cholesterol is a specific effect of the tocotrienol rich mixture. I think an effect on lipid peroxidation in the feed is a more likely explanation.

    Acute mental stress does raise blood cholesterol levels. Is the cholesterol lowering effect of exercise due to better cholesterol regulation following the stress of exercise? If so, what is the mechanism? If the mechanism is a response to some kind of oxidative stress, then interfering with that oxidative stress signaling with exogenous antioxidants would be expected to worsen the regulation. I have seen no data that is inconsistent with that hypothesis.

  20. Janet Camp says:

    @Michelle

    Try the lacinato (its also called “dinosaur” kale because it’s rather bumpy as I guess dinosaur skin is assumed to be, but now it seems some had feathers!). Regular markets here (Milwaukee) don’t have it, but Whole Foods and our local co-op both carry it year round. It’s very easy to grow as well. It grows on a big stalk and lasts all season.

    I agree that the curly stuff is bitter and is responsible for people hating the stuff.

  21. Chris says:

    Janet Camp:

    I wish people would stop referring to kale as though it’s truly the most horrible thing to eat.

    I do love kale, and chard. I grow the bright lights chard in my yard for decorative and culinary purposes. Along with putting it into lasagna, I like to saute chopped chard and onions until much of the moisture is gone, then pour in beaten egg to make an omelet with fresh thyme.

    One way to not cook healthy kale is something from my husband’s Dutch grandmother. It is very traditional to cook the chopped kale in with the potatoes, and then mash them together. Though the twist is to cook sausage in a bunch of butter, and them pour the resulting butter/sausage fat mixture into the mashed potatoes/kale. It actually makes me a bit ill. We spent a week with his grandparents in a town near Amsterdam, and she literally cooked everything in a pool of butter.

  22. aegimius says:

    Many studies suggest that fruits and vegetables help prevent many different diseases. If it is not the anti-oxidants in fruits and vegetables that are responsible for disease prevention, then what, besides fiber is responsible?

  23. daedalus2u says:

    aegimius, it could be the phytotoxins via hormesis (I have a link to a paper on it upthread), or it could be the nitrate that green leafy vegetables have (a few thousand ppm). Nitrate gets reduced to nitrite on the tongue and that nitrite raises your NO/NOx status.

    It also could be a self-selected diet effect. Essentially all diets are self-selected, healthy people might simply self-select certain foods which then become associated with good health due to the retrospective nature of most diet studies, but it is only association, not causation, or rather the causal mechanism goes the other way.

    If it was antioxidants, then supplementation of antioxidants would work to produce the same health effects. Supplementation doesn’t work to produce the same health effects, the health effects can’t be due to antioxidants.

  24. Harriet Hall says:

    It might not even be anything beneficial in the vegetables. It might be that when they eat more vegetables they are eating less of other foods that are harmful. All speculation until proper studies are done.

  25. Jeff says:

    @daedalus2u: The hormesis paper was interesting – I plan to read it again. In fact there is evidence antioxidants can prevent and even treat some diseases:

    Attenuation of influenza-like symptoms using N-Acetyl-Cysteine

    One cell study (pubmed/19732754) shows that NAC inhibits replication of the H5N1 flu virus

    French adults’ cognitive performance after daily supplementation with antioxidant vitamins

  26. anoopbal says:

    Hi Harriet,

    Wasn’t there a recent study which showed that eating fruits and vegetables do have a significant beneficial effect on cancer as we thought?

    1. Harriet Hall says:

      There is evidence that a diet high in fruits and vegetables correlates with lower cancer incidence. It has not been established that it is the anti-oxidants in the fruits and vegetables that produce the benefit. Studies with anti-oxidant supplements do not appear to produce the same effect. It appears that the subject is more complicated.

  27. @Janet Camp, good to know. I will have to search for the dinosaur kale next time I’m near a grocery store with a good vegetable selection.

  28. daedalus2u says:

    Jeff, attenuation of symptoms is not equivalent to improving recovery.

    Fever (a symptom of infection) actually aids in the resolution of that infection. Essentially all orgnisms with immune systems that have the ability to modulate their temperature use elevated temperature as an infection control strategy, including organisms normally thought to be “cold blooded” like insects, fish and reptiles. When fever is blocked, organisms do not recover from the infection as well.

    In the NAC paper, it seems like more in the NAC group got infected and seroconverted, they just didn’t exhibit symptoms, so they remained ignorant of their infectious condition, and likely spread flu more. This is perhaps not unexpected because part of how the immune system turns itself on is via the respiratory burst which generates oxidative stress signaling. Attenuate that signaling and you will attenuate the ability of physiology to respond. Maybe there would be no adverse effects in most cases, but their might be insufficient immune system response in others. Maybe the reason that a higher percentage of the treatment group seroconverted despite having fewer symptomatic events was that people not taking NAC were able to clear the virus before it reached levels high enough to trigger seroconversion.

    In the cell mediated immune system tests, there was a significant increase in reactivity over the course of the experiment in the NAC group. Exactly what is happening is not clear, but increased reactivity might increase the likelihood of autoimmune disorders. The immune system is self-regulating. If the signaling is being blocked, it is likely that physiology will try to compensate. If the immune system compensates for reduced ROS signaling due to NAC by increasing the “gain” on the system, it may lead to hypersensitivity. Trading off fewer flu symptoms for arthritis or other autoimmune disorders might not be an acceptable trade-off for some.

  29. daedalus2u says:

    Regarding kale, I feel a little surreal, like I am in the movie Repo Man, where the topic of kale seems to keep coming up.

    http://finance.yahoo.com/news/vt-artist-ill-fight-chick-141222247.html

  30. aegimius asks:
    “Many studies suggest that fruits and vegetables help prevent many different diseases. If it is not the anti-oxidants in fruits and vegetables that are responsible for disease prevention, then what, besides fiber is responsible?”

    There are many viable explanations for why, in observational studies, disease incidence is lower in those who report eating fruits and vegetables more and more more regularly.

    These reasonable explanations are not evident when we hav a bias of believing there must be some secret ingredient IN the food items. We keep detecting similar patterns: this or that food is assoc with lower disease incidence in observational studies, but when study designs with more control over biases are conducted, the efefct disappears. Garlic, curcumin, lycopene, anti-oxidants, and other candidates have failed to emerge as the secret ingredient in these diets.

    There are other viable candidate hypotheses. But you have to give up on the bias that the secret must be a secret ingredient.

    For the host of things that are assoc with lower disease incidence and longer life, and the host of things that are bad, the list happens to fall out into those things that facilitate bowel regularity and those that lead to constipation.

    I am not declaring that regularity is the key to a good life, but I am serious that it deserves consideration.

    The bowel cell turnover is supposed to be very high. Any tissue with high cell turnover, or any cell tissue provoked to have high vell turnover, is assoc with cancer. Mesothelioma happens when curved asbestos fibers get hooked in lung tissue, and scarring/turnover/regrowth processes of the tissue cannot get rid of the fibers. Straight asbestos fibers are eliminated in this way.

    All that to say it may be a bad thing to have the bowel work as it has to when constipated, versus when we are “regular.”

    Exercise and drinking more water favor regularity. So, there are two “secret ingredients” that are not in food right there for support of this regulartiy idea.

    Another reasonable hypothesis: A complex diet with fruits and vegetables will regularly be eaten, with some small exceptions, in just one social circumstance: a family context.

    Many of us now are single or have spent time single, and also as part of a family, including a nuclear family and and extended family.

    With the nuclear family, and more wit the extended family, you have a diet closer to what we all recognize as “normal.” There may be health benefits related largely to the social circumstances, and social benefits; healthy diet may be a proxy for healthy, supportive family. Instrumental and emotional support, plus social pressures limiting bad behavior such as skipping meals, smoking, excessive alcohol use, and so on – just think of your life in your extended family and when you were/are off on your own in grad school.

    Yet another explanation is the healthy user effect. People wh happen to be more likely to eat more fruits and vegetables also happen to be those who happen to not smoke, or have quit smoking if they ever smoked, more likely to have received various screenings such as colorectal and mammography, more likely to get the flu shot, more likely to take a daily baby aspirin for cardioprotection, more likely to have a deliberate low fat diet, etc.

    When you start examining this in epidemiologic studies, this is obvious. It is a big challenge because many things are confounded. I believe it is almost impossible statistically to isolate the effects of one of these behaviors since they are all indicators of a behavior pattern. That behavior pattern has been identified as “healthy user.” The well-documented, but not widely recognized, personality trait of “conscientiousness” has at least modest correlation with an amazing host of better health outcomes – this is reviewd in Bogg and Roberts. (2004.) Conscientiousness and health-related behaviors: A meta-analysis of the leading behavioral contributors to mortality. Psychological Bulletin 130: 887-919.

    What is recognized as “healthy user effect” may be heavily related to the “Big Five” personality trait of “conscientiousness.” In psychology, “Big Five” is about the leading, most empirically supported personality trait model going. Google will bring this up, and it is in Wikipedia. The scary part is that these ideas may eventually lead to the discovery that a glass or two of wine a day is not great for your health, but only is a marker for one of these effects.

    So, there are 3 viable hypotheses about diet and morbidity/mortality that do not depend upon a secret ingredient.

    If you begin looking for healthy user effects and social context effects, you will see their fingerprint.

    JAMA nov 2011 just ran an article from Chen et al “Moderate Alcohol Consumption During Adult Life, Drinking Patterns, and Breast Cancer Risk.”

    This has a table with mammography screening compliance by level of alc consumption, and has a table presenting, for those women who did have brest cancer, the stage at diagnosis by alc consumtion level.

    Alc consumption was in five levels: none, very little, 3-6 servings a week, 6- some higher # per week, and an even higher level.

    Mammography rates were the highest for the middle consumption level: women drinking moderately were most adherent to mammography, vs. those at higher and lower levels.

    And so you would guess, and be right: for women with breast cancer, stage at dx was shifted to earlier statges for those at this middle level of alc consumption, vs. the two higher and lower categories.

    This dip effect right in the middle of a continuous measure is striking.

    Sadly, the authors make no mention of this healthy user bias, and the reviewers apparently had nothing to say about it, and the JAMA editors had nothing to say about it.

    I believe the problem is that physicians are trained to be very smart about physiology, and to pay less respect to “lesser,” “softer” science such as psychology and sociology. So, authors, reviewers, and editors do not see this healthy user effect that is quite obvious to me, a person with a PhD in a touchy-feely soft-science discipline.

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