The case against antioxidants

Antioxidant supplements are probably ineffective.  They may even be hazardous to your health.

Many people take daily supplements that include antioxidants such as Vitamins A, C, and E; beta carotene, coenzyme Q10, and alpha lipoic acid. I used to be one of them, convinced of the theory that supplementation with antioxidants is an effective way to neutralize harmful free radicals.  These free radicals, also called ROS or “reactive oxygen species”, can cause oxidative damage to cells and organs, and have been implicated in the pathogenesis of degenerative diseases such as cancer, heart disease, and Alzheimer’ disease.

However, study after study not only fails to show a consistent benefit, but in many cases documents positive harm from taking antioxidants. While I continue to believe that antioxidant supplementation is helpful in certain isolated cases of acute infection, tissue damage, or a damaged or aged metabolism, for most of us antioxidants are probably worthless. In fact, antioxidant supplements can interfere with and weaken the body’s inherent ability to mount an effective defense against oxidative damage and its contribution toward degenerative diseases.

I’ve resisted this conclusion because I could not make sense of it.  That is…until I came across recent research into the biochemistry and genetic regulation of the antioxidant response element (ARE). Fortunately the ARE provides us with an in-built adaptive stress response that combats oxidative stress and inflammation The ARE makes the need for antioxidants in the diet unnecessary — other than to keep our food fresh. Surprisingly, antioxidant supplements can impair our adaptive stress response.  But there’s much we can do to strengthen this response.

Fruits, vegetables and green tea. One of the strongest arguments for taking antioxidant supplements is the observation that consumption of fruits and vegetables reduces the levels of oxidative damage and associated degenerative diseases. This has been shown in both epidemiological studies and observational studies.  Similar benefits have been associated with the consumption of certain herbal compounds rich in polyphenols, such as green tea, garlic and curcumin.  The assumption has always been that these benefits can be attributed to the fact that many fruits, vegetables and herbs are rich sources of naturally occurring antioxidants. Therefore, it only makes sense that if you can’t get enough fruits and vegetables in your normal diet, supplementation with purified chemical forms of these antioxidants can boost those benefits.  But it turns out that the protective effects of fruits and vegetables are most likely not due to their antioxidant content, which is probably too weak and inconsistent to explain the health benefits.

But before discussing the real reason that fruits and vegetables have health benefits, let’s review what is known about supplementation with antioxidants.

Antioxidant supplementation studies. It may surprise you that numerous of clinical trials and metabolic studies show no benefit, or even harm, from using antioxidant supplements:

These results were at first puzzling to me.  How can it be that administering the same antioxidant chemicals ubiquitous in “protective” fruits, vegetables and herbs — the same chemicals which have been shown to neutralize oxidants in the test tube — appear to be ineffective or even harmful when taken as dietary supplements? What’s going on here?

The endogenous antioxidant defense. What is missing in the above picture is the role of our body’s own innate defenses system for handling toxic chemicals like free radicals. While our immune system handles invading organisms and large proteins, another system is needed to deal with chemical toxins. It’s called the xenobiotic metabolism; “xenobiotic” is from the Greek and Latin roots for “foreign to the organism”.  It consists of three “waves” of protective enzymes which neutralize dangerous chemicals, designated: Phase I, Phase II, and Phase III.  In Phase I the “xenobiotic response element” (XRE) chemically modifies the foreign toxins, which can sometimes make them even more reactive oxidants.  In Phase II, a set of antioxidant enzymes known as the “antioxidant response element” (ARE) neutralizes these toxins, including free radicals. Phase III involves further modifications and excretion.

The ARE is your body’s own endogenous antioxidant defense.  And it is far more powerful and effective than any antixodants you consume orally at mounting a defense against free radicals.  The ARE system is activated by the presence of oxidants in specific tissues in the body. These oxidative toxins are detected by transcription factors, most importantly Nrf2 (Nuclear factor (erythroid-derived 2)-like 2).

Nrf2 has been called the “master redox switch”.  It turns on a series of cytoprotective genes, which have been nicknamed “vitagenes” by U. Massachusetts toxicologist and hormesis researcher Edward Calabrese. These vitagenes upregulate the production of endogenous antioxidant enzymes that combat oxidative stress and inflammation. Collectively, they are known as the Phase II antioxidant enzymes:

  • glutathione transferase
  • glutathione peroxidase
  • glucuronysyl transferase
  • quinone reductase
  • epoxide hydrolase
  • superoxide dismutase
  • gamma glutamylcysteine

So how can it be that supplementing with antioxidants can actually dampen the body’s internal antioxidant defense system?

Homeostatic compensation. As we’ve seen time and again in this blog, the body is an adaptive system.  The organism adjusts to maintain a relatively constant state: homeostasis. Provide it with external “help” and it will reduce the effort in building its own internal defenses.  Just as using corrective lenses will weaken the eye’s inherent ability to focus, and avoiding exposure to allergens will prevent the adaptive immune system from developing, it turns out that chronic consumption of exogenous antioxidants reduces the “pressure” on your adaptive stress response — specifically your ARE system — to gear up its own endogenous antioxidant defense system by producing adequate amounts of the the Phase II enzymes.  In biological terms, taking antioxidants leads to homeostatic downregulation of the antioxidant response element.  This actually makes biological sense:  Why should the organism expend precious energy and resources building a defense system if the defense is provided for “free” through diet or supplements?

A number of studies bear out this compensatory effect:

So it appears that, by consuming more antioxidants, we become dependent upon them and perversely reduce our innate ability to detoxify. With any let-up in the constant supply of external defenses, we become more vulnerable to oxidative and inflammatory attack. And the externally supplied antioxidants themselves are in any case much less effective than the endogenous ones.

But if the endogenous antioxidant defense system is so potent, what steps can we take to build it up?

Plant toxins to the rescue. Nature exhibits a wonderful phenomenon called “biological arms races”.  To defend against predators, plants or animals develop defenses, and often this involves the production of biological “poisons”.  To defend themselves againts pests and parasites, plants have evolved a set of mildly toxic substances that discourage, sicken, or even kill predators, from microbes and insets to mammals.  These toxic substances typically taste bad and can be irritating.  However, predators evolve to be able to tolerate at least some of these plant toxins, at least in moderate amounts.  They do this by developing detoxification systems.  Which is exactly what the ARE is!

Some plant toxins are too poisonous and deadly.  But, as Nietzsche said: “That which does not kill us makes us stronger”.  Biologically speaking, this is the principle of hormesis advocated on this blog, the principle by which small amounts of a stressor activates and strengthens our internal defenses, but excessive levels of the same stressor overwhelms these defenses.  Our ARE anti-toxin system will develop in response to virtually any toxic compound.  In principle, you could strengthen it by ingesting all kinds of chemical poisons. But why play roulette?  Humans have grown up for eons consuming a fairly regular supply of certain plants to which they have become habituated, plants that contain tolerable amounts of toxins which moderately stimulate the adaptive stress response, but not sufficiently to kill us.  Of course, there are still poisonous plants and mushrooms which exceed this threshold, so there is a continuum.  And probably some people and populations can tolerate more than others of certain plant toxins. But some of these plant toxins are well enough tolerated by most of us to prove reliably beneficial.

What are the good plant toxins? We refer to them as “phytochemicals” or “phytonutrients”.

There are a nearly infinite number of phytonutrients, most of them unknown and uncharacterized.  But a number of them have been studied for their impact on upgregulating the Phase II enzymes of the the ARE system, as Mattson et. al. have detailed..  Many of these compounds fall into the chemical class of polyphenols, more specifically flavonoids.  They are typically pigmented, bitter or spicy tasting molecules. A partial list includes:

  • resveratrol – from red grapes, which turns on sirtuins and has broad cardiovascular, memory and anti-aging benefits
  • sulforaphone – from broccoli, which turns on antioxidant and anticancer enzymes in the skin, arteries and stomach
  • curcumin – from tumeric, inhibits transcription factors and kinases involved in cancer and inflammation
  • green tea - a rich but variable source of bioflavinoids which have been shown to have anticancer and cardioprotective effects

Other polyphenolics that stimulate that Phase II enzyme system have been found in garlic, rosemary, ginko, bee propilis, and even…coffee!

What may have confused many researchers is that these polyphenolic flavonoid compounds in many cases have antioxidant properties.  This fact may have led to drawing the mistaken conclusion that they work because they are antioxidants in their own right.  And yet this antioxidant effect is not consistent — polyphenols and other phytochemicals sometimes function as pro-oxidants, dependent on the context and dosage.  I believe the evidence for their being hormetic stimulants of the endogenous ARE system is stronger than the case for thinking of them as antioxidants.   For example:

Am I the only one challenging the paradigm that fruits and vegetables are good for us because they are rich in antioxidants?  Certainly not. Stephan Guyenet has likewise challenged this explanation, and highlighted the hormetic properties of plant polyphenols in an excellent two-part series on his Whole Health Source blog:

In his article, Guyenet mentions the interesting phenomenon that the hormetic effects of polyphenols tend to be non-specific:

One of the most interesting effects of hormesis is that exposure to one stressor can increase resistance to other stressors. For example, long-term consumption of high-polyphenol chocolate increases sunburn resistance in humans, implying that it induces a hormetic response in skin. Polyphenol-rich foods such as green tea reduce sunburn and skin cancer development in animals.

Another researcher who has come to similar conclusions as me is Robert Rountree.  If you had trouble following the science here and you have 90 minutes to spare, please do yourself a favor and click here listen to this extremely informative, lucid, and humorously entertaining lecture by Rountree that was presented at the 2010 Integrative Healtcare Symposium.  Unfortunately this is an audio recording so you’ll have to just imagine the slides, but not much is lost without the pictures because Rountree is such a vivid speaker:

CLICK HERE TO LISTEN:

Beyond Antioxidants: Nutrigenomic Regulation of the Adaptive Stress Response

by Dr. Robert Rountree

 

Rountree makes the very powerful point that the skin-protective effect of the sulforaphane in broccoli cannot be explained by its inherent chemical antioxidant properties. He cites a Johns Hopkins study in which broccoli extract applied to the skin of nude mice prevented oxidative damage from UV light for a period of several days, even after it was washed off the skin.  The absorbed sulforaphane could only act as an antioxidant for 30-60 minutes, at best a short-term effect. However, the induced upregulation of antioxidants in the skin protected the skin from UV for two days! To put it in chemistry terms: antioxidants are stoichiometric and used up quickly, whereas the endogenous antioxidant enzyme system is catalytic and long-lasting.

I’ll conclude by considering three interesting questions:

1. Why are there antioxidants and polyphenols in plants, vegetables and herbs?

Rountree suggests a plausible reason for why plants are rich in polyphenols: they act as natural pesticides. As I suggested above, this is part of the evolutionary arms race, and we’ve at least partially adapted to tolerate certain levels of these natural plant toxins.  But what about the antioxidants?  They don’t seem to protect the plant from predators, so why are they there?

I think the most plausible evolutionary reason for the presence of the antioxidants in plants is to protect the seeds in the fruit or vegetable against oxidative damage.  But this doesn’t take much antioxidant, as vegetables and fruit are relative “static” seed protectors.  They aren’t dynamic organisms requiring a long term sustained defense, as is the case with animals.

2.  If antioxidants are useless or even detrimental to our endogenous antioxidant defenses, should I take vitamins?

This is not a simple question, and I’m not your medical practitioner.  But a few things can be said here. First, antioxidant vitamins like Vitamin C (ascorbic acid) and E (tocopherols) are not merely antioxidants. They also perform certain other essential biological functions in processes such as collagen synthesis (Vitamin C), preventing scurvy, and protecting against lipid peroxidation in membranes. However, for these functions only very low amounts of the vitamin are required. By some estimates, 10 mg per day of Vitamin C will prevent scurvy, and 4 mg per day of Vitamin E will ensure good membrane function. The multi-gram  megadoses recommended by advocates of “orthomolecular medicine” such as Linus Pauling are based upon the antioxidant function of these molecules. In light of the studies showing that high levels of exogenous antioxdants suppress our innate endogenous Antioxidant Response Element, these high levels seem to me to be uncalled for, and likely to impair our native ability to handle oxidative stress.  The only exception I would make is in the case of acute or severe infection or illness, or advanced age, where the body’s own immune system and xenobiotic defense system may be compromised or unable to mount a sufficient defense on its own. But routine daily supplementation with antioxidants seems unwise if you are otherwise healthy and eat a good diet.

I’m also only addressing here the antioxidant vitamins and minerals, so this discussion is silent as to the wisdom of supplementation with other vitamins, such as Vitamins A, B and D, which are not classically considered to be antioxidants. Yet I think the general principle of hormesis should always be considered: that which is beneficial at a low or moderate dosage is often detrimental at higher doses. So be careful.

3.  What dietary guidelines can I follow to strengthen my endogenous antioxidant defense system?

What is most exciting for me is that I think I finally have a scientific reason to eat more and varied vegetables, fruits, herbs and spices! Coming from a generally low carb orientation, I’ve made sure to get plenty of protein and fat in my diet from meat, fish, dairy and nuts.  I happen to like broccoli, asparagus, brussell spouts, green and red peppers, and mushrooms, strawberries and blueberries.  But I always thought of them as something to liven up a low carb / Paleo diet with variety, texture and flavor, and perhaps add a little fiber.  I had heard the benefits of “phytonutrients” touted, but never heard a solid scientific reason for their nutritional value.  Thinking of them as hormetic “plant toxins” that help strengthen our internal defenses puts them in a new light.  This suggests a few guidelines to maximize hormetic stimulation of the ARE Phase II enzyme system:

  • eat especially those vegetables and fruits with bright or intense colors (these contain bioflavonoids)
  • eat fruits, skins and seeds which are bitter (these contain glucosinolates)
  • consume teas, herbs and spices which have strong, bitter, or hot flavors
  • to ensure hormesis, vary your choices, and limit the amount and frequency of any single fruit, vegetable or herb

Finally, consider the activation of your in-built detoxification system — your ARE — as just one element of your adaptive stress response capability, which more broadly extends to your immune,  endocrine, nervous, and musculo-skeletal systems, and at a higher level — your psychology and spirit. The more we probe, the more it becomes apparent that we have within ourselves the ability to strengthen our defenses and take on increasing challenge. Relying on external supplements and external crutches is unwise except in the short term. The role of nutrition should be to build us up, not to replace — and thereby weaken — our internal defense, repair and growth capacities.

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40 Comments

  1. Nice post Todd, and thanks for the mention.

    Reply
    • Todd

      Thanks, Stephan. I’ve long admired your Whole Health Source blog and credit you and Robert Rountree with surfacing the alternative hypothesis that hormetic polyphenols, rather than antioxidants, explain the health benefits of many fruits, vegetables and herbs. In the above post I go one step further, arguing that that exogenous antioxidant supplements may actually harm us by causing a compensatory impairment of our endogenous antioxidant detoxification system. The moral of the story is to eat your veggies and drink your green tea, but be skeptical of popping supplement pills.

      Reply
      • marcus volke

        great post but you made a bit of a mistake in your analysis of vitamins. As stephan points out, Vitamin A, C and E DO ACT AS DIRECT ANTIOXIDANTS and maintain high concentrations in the blood, unlike polyphenols which are quickly broken down.
        I would also like to point out that studies have shown that Vitamin A is only toxic at low levels if your vitamin D levels are low. With adequate vitamin D levels, vitamin A is safe at 200,000 IUS, and getting vitamin A from oil-based food sources increases it’s safety threshold ten fold – http://ajcn.nutrition.org/content/78/6/1152.long

        It may also be that the toxicity of vitamin E was related to the fact that synthetic vitamin E uses only half the vitamin E complex – the tocopherols but not the tocotrienols.

        Finally emerging evidence has also found that while polyphenols escape digestion, they are metabolized by our gut bacteria in the small intestine and converted to other compounds which may exert their beneficial effects.

        Hormesis is certainly a part of the picture, but it isn’t the WHOLE picture.

        Reply
        • Todd

          Marcus,

          Thanks for the link.

          But can you point out where I said anything that contradicts your statement that vitamins A, C and E are “direct” antioxidants, and that polyphenols are metabolized? Not sure there is any disagreement.

          When studies find vitamins to be ineffective, defenders often retort that the wrong form of vitamin was used, or that it wasn’t used with all its cofactor vitamins or minerals, or that absorption was faulty, or that something else was missing. Fine, and perhaps they are right. But is our knowledge complete enough to be able to say we know all the necessary cofactors and the proper balance? And is this the same for everyone? I’d rather take my vitamins in the full context of whole foods. In addition, more often than not the problem may lie in other health conditions that impair proper absorption. It seems a bit reductionistic to attempt to stipulate a particular balance of nutrients.

          Somehow our ancestors who ate and exercised well survived and thrived without knowing all these precise ratios.

          Todd

          Reply
  2. Patrea

    Another excellent article. Well done

    Reply
  3. David I

    Very enjoyable and thought-provoking. I’m inclined to believe that the body is perfectly capable of handling it’s own antioxidant production in most cases–although as we age, or adopt less-than optimal diets, that may require supplementation with the substrates the body needs. For example, glutathione seems to be helped along by N-actyl-cystiene, and also by healthy gut flora.

    On the other hand, I’m not sure why you have Coenzyme Q included in a list with A, C, E, and alpha-lipoic acid. True, it does have antioxidant properties, but, as with the polyphenols, there is no reason to believe that’s its main function in the body. (It’s main function in the body is down at the mitochondrial level, and some of the debilitating effects of statin drugs, which also interfere with CoQ production, make it clear how important CoQ production can be in keeping our muscles working.)

    Some of the vitamins you list, such as C, also have important functions apart from their role as antioxidants–and, in fact, their antioxidant behavior may be irrelevant. Consider scurvy: is that really a shortage of antioxidants? If so, why can’t we cure it just by increasing intake of E?

    Vitamin C is vital to repair of elastic tissue and collagen synthesis. I’m old enough, and tough enough on my body, to have experienced many joint and connective-tissue injuries. I have found that I heal much, much faster if I supplement heavily with C, proline, and glycine after an injury. (I also take care to make sure I am using time-release C–otherwise it is eliminated from the body with amazing rapidity.) It is also important for other kinds of wound healing, probably also through its influence on connective tissue synthesis. Once again, its antioxidant properties are probably irrelevant.

    In addition, speaking as an official Old Person (today is my 57th birthday, in fact), I’m not always sure that studies of supplementation on the athletic performance of healthy college students or athletes tells us much about the value of those same supplements in the aging body.

    But I’m with you on the antioxidant issue: I think the research community has wasted a couple of decades by barking up the wrong tree.

    Reply
    • Todd

      Hi David,

      Thanks for your comments. I do agree with you that many “antioxidants” like vitamin C and Co-Q10 have important biological functions that go well beyond their antioxidant function and can be useful in many situations. But I think I acknowledged that in my answer to the second question I posed to myself and answered towards the end of my post:

      …antioxidant vitamins like Vitamin C (ascorbic acid) and E (tocopherols) are not merely antioxidants. They also perform certain other essential biological functions in processes such as collagen synthesis (Vitamin C), preventing scurvy, and protecting against lipid peroxidation in membranes. However, for these functions only very low amounts of the vitamin are required. By some estimates, 10 mg per day of Vitamin C will prevent scurvy, and 4 mg per day of Vitamin E will ensure good membrane function. The multi-gram megadoses recommended by advocates of “orthomolecular medicine” such as Linus Pauling are based upon the antioxidant function of these molecules…The only exception I would make is in the case of acute or severe infection or illness, or advanced age, where the body’s own immune system and xenobiotic defense system may be compromised or unable to mount a sufficient defense on its own. But routine daily supplementation with antioxidants seems unwise if you are otherwise healthy and eat a good diet.

      I also do agree with you that these vitamins and cofactors can be incredibly useful for dealing with acute injury, illnesses (like colds or flu) and other types of healing. I’m just skeptical of their use on a chronic, daily basis at high levels, since I think that can impair your endogeneous antioxidant defenses if taken all the time. Even for “official old persons” like you and me, I’d be careful about chronic overuse. And my other point was to point out that the bioflavinoids and carotenoids in our vegetables may work for reasons other than their properties as chemical antioxidants.

      Todd

      Reply
  4. Kate

    Nice article, Todd. I’ve been told to supplement D, which I pretty much reject, as it’s the end of winter here anyway! I’m going to read the allergies one in a minute. Can’t wait to – sure to be something I can use! By the way, the results of my raw milk experiment are in – much better profile, CHD risk-wise. I’m now a pear instead of an apple, for the first time in my life. Probably caused by years of “healthy” no animal fats eating. ;)

    Reply
    • Todd

      Hi Kate,

      I’m still conflicted about Vitamin D. It’s benefits seem to go well beyond it being an antioxidant (for example it plays a key role in calcium assimilation and bone health), but humans should be able to make plenty of Vitamin D through even brief exposure to sunlight every day or two. When the body makes Vitamin D, it is not a matter of just one or two forms of Vitamin D, but a whole complex, which supplements can’t fully mimic. And yet, if were are not getting sufficient sun exposure, or have some metabolic impairment, supplements could be helpful. I had my own Vitamin D levels tested, and I was low, so at least for now I am taking a supplement. But I’ve got to look into this more, because there may be better alternative ways to boost my levels through diet or getting outdoors more.

      Reply
  5. Adam

    I’ve listened to the linked audio twice now and found it informative, but my skeptic spidey-sense was tingling when Rountree mentioned that microwaves reduce the nutrient value of vegetables. As far as I can tell this is a myth. The audio is not completely clear, but when someone in the audience mentions this, he responds that Helen Something (Vasara? Lasara?) “at Columbia” has done the research. I’ve been unable to figure out who or what research he is referring to. In the mean time, I found this: http://www.uga.edu/nchfp/papers/2003/03iftturnipgreensposter.html which shows that microwaved turnip greens retained MORE, not less, of their nutritional value. Any leads on this research from Columbia?

    Reply
    • Todd

      Adam, I had exactly the same reaction as you did to the microwave comment. Polyphenols are pretty stable molecules. I looked into this all I could find was evidence that microwaving in too much water causes leaching of vitamins and micronutrients from vegetable dishes. But that would also be true if you boil your vegetables on the stovetop! I always microwave my broccoli by placing a small amount of water in the bottom of a covered glass cooking dish and steaming for about 5 minutes. So not much leaching occurs. I can’t find any evidence that the microwaving itself causes any problems.

      I found Rountree’s lecture overall quite illuminating but, like most people, we can always find a few things to disagree with.

      Reply
  6. David I

    Actually, I’m not sure that chronic, repetitive use of anything apart from oxygen is a good thing.

    With any kind of supplements, it think it’s good to take breaks. And with daily caloric intake, be it high or be it low on average, I think it’s good to mix it up. Ditto on exercise. Moderation in all things, including moderation itself.

    One can think of this as an example of hormesis, sionce mixing it up is a kind of mild stress. But I’ve always thought of it as a way of keeping limber, a sort of yoga.

    And I do a lot of yoga. But I also take breaks from that!

    Reply
  7. Great post thanks, totally agree with the hype over antioxidants.

    Reply
  8. Adam

    Tonight I actually stumbled on some more info about the microwaving issue: http://onlinelibrary.wiley.com/doi/10.1002/jsfa.1585/abstract

    “Clear disadvantages were detected when broccoli was microwaved, namely high losses of flavonoids (97%), sinapic acid derivatives (74%) and caffeoyl-quinic acid derivatives (87%). Conventional boiling led to a significant loss of flavonoids (66%) from fresh raw broccoli, while high-pressure boiling caused considerable leaching (47%) of caffeoyl-quinic acid derivatives into the cooking water. On the other hand, steaming had minimal effects, in terms of loss, on both flavonoid and hydroxycinnamoyl derivative contents. Therefore we can conclude that a greater quantity of phenolic compounds will be provided by consumption of steamed broccoli as compared with broccoli prepared by other cooking processes.”

    Reply
    • Todd

      Adam,

      Thanks for the link. I read the full article and learned that in both the boiling and microwaving, the broccoli was submerged and cooked in an equal weight of water, whereas in steaming it was suspended above the water:

      Boiling and steaming were applied using a pressure cooker (Rapid-express, Fagor, Guipuzcua, Spain) containing 150 g of freshly cut raw broccoli and 150 ml of tap water, using two different pressure valves for high and low pressure. The inflorescences were fully dipped in the water for 3 min for high-pressure cooking and 5 min for conventional (low-pressure) cooking, whilst they were suspended above the boiling water for 3.5 min for steaming. A microwave oven (Samsung, Cleveland, UK) operating at full power (1000 W) for 5 min was used for microwaving, with the same amount of broccoli and tap water as above.

      …Also in this treatment, no compounds were detected in the cooking water (Fig 2). As previously mentioned in this work, it is suggested that components in the tissue are more stable than those in water, where they are more degraded. Probably a new microwave cooking treatment without water would lead to lower percentage losses

      …when a short cooking time and no contact with the cooking water (steaming) are combined, the best results will be obtained, with only slight losses of phenolic compounds in the edible part.

      From this, it looks like the main problem with both microwaving or boiling is heating of the flavonoids and phenolics is the presence of bulk water. This suggests that if you use your microwave for “steaming” rather than submerging the vegetables in the water, you may be able to avoid most of the losses. In fact, that’s the way I microwave my broccoli and brussel sprouts — in a seal plastic or glass container with a minimal amount of water on the bottom, just enough to produce steam. (I think you need at least a little water for the steam, or you risk drying out and overcooking the broccoli). You could also consider microwaving for no more than 3.5 minutes (then letting it stand to steam) or microwaving on a lower power setting.

      Reply
  9. Dim

    Please, never stop blogging!
    I learn a lot from your understanding of human metabolism.
    Hormesis is a fascinating reality.
    Thanks for sharing your thoughts.

    Reply
  10. Wow! Excellent Post.

    I’ve wondered about this for a long time, and it’s finally coming more clear to the general public that diet is the best source of antioxidants, not some super dose.

    Foods often work in very synergistic ways, and people fail to account for the fact that no one “eats” vitamin c, they eat broccoli and so on.

    Asker Jeukendrup, has done some similar studies on this and came to pretty much the same conclusion.

    Great work
    -armi

    Reply
  11. John

    I take Protandim. Lifevantage advertizes Protandim as a Nrf2 activator. So, is it worth taking it?

    Reply
    • Todd

      John, I had not heard of Protandim before. Protandim is made by Lifeline Therapeutics and billed as an “antioxidant catalyst” that is a Nrf2 activator, as you say. The manufacturer claims that in clinic studies it upregulates superoxide dismutase, catalase and a broad spectrum of other antioxiidant enzymes. According to Ray Sahelian, it is blend of five herbs: ashwagandha, bacopa, curcumin, green tea, and milk thistle. You can of course obtain these herbs separately, so with Protandim you are paying for the convenience and for the assumption that Lifeline Therapeutics has somehow optimized the ratio of herbs. From what I’ve gleaned, curcumin and green tea are proven Nrf2 activators, but I could find no evidence that the other 3 herbs are Nrf2 activators. So why not make yourself a cup of green tea every day and spice your food with the Indian spice tumeric (curcumin). Tumeric is not hard to find, but it is one of the main ingredients in curry, so you could also just use more curry in your cooking.

      Reply
  12. Todd, what an awesome post. In addition to my performance blog, I run an anti-aging nonprofit in Palo Alto called Smart Life Forum. We have monthly lectures from some of the top minds in aging and orthomolecular research for interested people – about 100 show up every month. Vitamin C has been a frequent topic of discussion, with some of Pauling’s collaborators lecturing in the past.

    Your case against chronic antioxidants makes great sense. After many years of using them at high doses, I take far fewer now than I used to, but I still rely on D3 and large doses of C. The C is there because of the collagen effect (I don’t buy the 10mg number) and for the synthesis of glutathione in the liver. I also take liposomal glutathione (this one: http://www.upgradedself.com/Body-Upgrades/Lipoceutical-Glutathione/flypage.tpl.html ) because it increases blood glutathione levels similar to what an IV does. (I’ve done lots of IVs too.) It is amazingly effective to turn around stress and sickness from very long flights or lack of sleep (or both.)

    But what sticks out most in my mind from your post is what’s missing: ozone therapy. Introducing ozone either rectally, vaginally, aurally, dissolved in drinking water, intravenously, or through the skin has a profound healing effect on the entire body. It’s used for cancer and AIDS treatment in areas where drugs are scarce, with Cuba being the hotbed of research right now. For one year, I used ozone every night for 15 minutes (never breathe the stuff!). I’ve already very extensively biohacked myself, but the boost in performance and wellness that came from that was profound. After a year of it, my wellness levels rose dramatically, and I don’t use it more than once every couple weeks anymore. There are three competing theories about why it works. The first is that it’s donating electrons to quell inflammation (it is shockingly effective on nerve inflammation). The 2nd is that it sterilizes the surfaces it penetrates with O3 which “bugs” can’t fight (but our cells can, by upregulating SOD and glutathione…) The third theory is that the increased SOD and glutathione production is the cause. In any case, the ozone setup was the highest return health investment I’ve made in years, less than $450 for everything.

    Reply
    • Todd

      Many moons ago, I supplemented with Vitamin C, but it always seemed to provide at best a short-term benefit, and taking it chronically did nothing for me. I actually met Linus Pauling in the 80s when I was a student at Stanford and had a lengthy discussion with him about Vitamin C at the time. It struck me that as brilliant as he was, he had an almost religious commitment to the efficacy of ascorbic acid that derived from its chemical antioxidant properties, and that he did not appreciate adequately its biological properties and the adaptive response that ensues when one consumes megadoses.

      While you may be right that there are ways to “supercharge” your metabolism with supplemental glutiathione or ozone, I’m increasingly dubious of any such approach for anything other than a short term intervention in cases of dire need. I’m hesitant to become dependent on ANY external source of “metabolic help” that I have to administer exogenously every day or every week, because I want to build up my endogenous capabilities and defenses in a long-term, sustainable manner. What happens when you’ve been supplementing and suddenly withdraw the ozone, D3 or Vitamin C? And while I agree that glutathione is a good thing, my sense is that we want it “at the right place and right time”, not necessarily at sustained high levels in the blood.

      Regarding the theoretical reasons for using ozone, while excess inflammation and oxidation is bad, I think there is an optimum. I’m not sure I really want to totally quell inflammation, oxidation, and the presence of microorganisms, because these are signals to build up your endogenous defenses. The one point you make that attracts me is that you are able to get by with less ozone now than you did in the beginning; that suggests some type of positive adaptive response that goes beyond the three theories you mention. Perhaps that suggests a role for ozone as a useful pro-oxidant?

      Even though I’m pushing back a bit on some of your points here, Dave, I’m very interested in your biohacking experiments. Since we are both in Palo Alto, we must get together to discuss further.

      Reply
  13. In my understanding, antioxidants are quite useful for our body as long as those antioxidants are gained from natural resources such as herbs. I personally don’t trust pills.

    Reply
  14. WDMLL

    I find what you are saying puzzling when it comes to my life experiences.

    I’m going to be seventy years old. I exercise (weights, aerobics and stretching on a daily basis). As a result I have a muscular body. I believe I have an active mind. At times, I still get stressed out. So I’m into meditation, and biofeedback. My wife and I eat fruits, vegetables, nuts, fish (weekly) and etc., on a daily basis. We normally each drink a glass of wine almost daily.

    As for HRV, if I’m reading my numbers right, I have good HRV variability for my age (more like a healthy active person of 50).

    When it comes to supplements, I take more than my share. Like fish oil, vitamin D, E, C plus multivitamins, you name it and I’m probably taking it. But I watch my yearly blood chemistry results, making changes when needed (a number of changes have resulted in better numbers). Monitor my blood pressure (under control), pulse and blood oxygen%.

    I try to keep up with current affairs, and what is going on in the world. I follow medical and health trends. I keep my Doctor informed as to what supplements I’m taking.

    I have several publications under my belt (I worked in Forensics for over thirty years).

    We have a mountain cabin at ten thousand feet, which we visit two to four times a month. So we are maintaining two homes, travelling and enjoying life.

    I know that life does not go on forever, but I’m going to give it my best try.

    Reply
    • Todd

      Hi WDMLL,

      You sound like you are in great shape, so I won’t argue with success. But I’m not sure exactly what is puzzling to you. You exercise your mind and body, eat a mostly “paleo” diet, and enjoy wine. And you meditate. You take a lot of supplements, including antioxidants. And your health is excellent, both objectively and subjectively.

      But what is the cause of your good health? Besides the supplements you take, you are doing a number of things that I would expect to improve your health. So you can’t necessarily attribute your good health to antioxdants. It could very well be the exercise, diet or meditation. It could also be the non-antioxidant supplements, like fish oil. The only way to know for sure is to do a controlled experiment — eliminate or cut back on the antioxidants, but continue with everything else. One problem with such an experiment is that it typically takes weeks or months to notice an effect from vitamins or other supplements. But why not try it for 3 months? Keep doing everything else — the diet, exercise, wine, meditation and fish oil — but cut out all those pills. Even if you believe in antioxidants and vitamins, you are getting more than enough from your diet. And the phytonutrients in vegetables and fruits would stimulate your own endogenous antioxidant production, if you were not inhibiting that by taking so many pills. There is very little risk to this experiment. If you start feeling worse or see any deterioration in your HRV, blood pressure or blood markers, then resume the antioxidants. Either way, you’ll learn whether you really need them or not based on your own experience, not what somebody else wrote.

      Your lifestyle is remarkably similar to that of your ancestors of several thousand years ago — except for all the pills. Art DeVany, who is a bit older than you — is one of the fittest people I know, and his lifestyle is similar to yours, but without all the supplements. You might find his book “The New Evolution Diet” to be an inspiration.

      Regards,

      Todd

      Reply
      • WDMLL

        My blood chemistry yearly results have put up a red flag a time or two, over the years. So I made the necessary changes after consulting multiple sources of literature. I then made the necessary changes and noted the changes on the next blood chemistry essay and how my body responded.

        If it sounds like a shotgun approach, to take supplements, eat healthy, workout, use meditation and biofeedback, it works for me. My body is the laboratory in which these tests are being monitored.

        And as for the articles on what is bad or good for you, I have been involved in presenting papers and publishing scientific articles or books for a number of years. There are a lot of bias and non bias articles out there. You have to weed out what is valid and not valid. Remember, as in all science, there is a lot of money involved in health and medical publishing.

        What is good for me may not be good for you. Each human body is a separate laboratory environment.

        I’ll venture to say, as in all sciences, what is invalid now, may not be in the future. Einstein once stated the universe was not expanding.

        Reply
  15. amit

    Amazing stuff! Not sure I agree with such a non-mainstream viewpoint, but the post is still highly informative.
    small typo:
    Finally, the consider the activation –> finally, consider the activation

    Reply
  16. german

    I generally disagree with the findings of these studies and seriously doubt their neutrality.
    You rarely hear of studies with positive outcomes (on vitamins and antioxidants) in the media. They often don’t even get a chance to get published in many journals.
    Here you can find a review of intravenous vitamin C and its usefulness with cancer patients: http://www.translational-medicine.com/content/pdf/1479-5876-9-25.pdf
    There is also an interesting case New Zealand. A man with H1N1, viral pneumonia und leukemia was able to fully recover with IV vitamin C: http://www.3news.co.nz/Living-Proof/tabid/371/articleID/171328/Default.aspx?ArticleID=171328

    I know this is quite different from taking a pill, but it’s definitely an interesting topic and should motivate us not to discard vitamins and antioixdants as a treatment for diseases too easily.
    Also, it is quite interesting that animals which are able to synthesize vitamin C rarely have problems with their heart. Man, primates, and guinea pigs cannot synthesize vitamin C and often suffer from heart diseases.

    There are also some promising results regarding CoQ 10 supplementation:
    http://en.wikipedia.org/wiki/Coenzyme_Q10#Supplementation_benefits (I know it’s wikipedia… :P)

    Many people believe that vitamin deficiencies are rare. That is not the case and it’s been shown. Around 40% (age: 26-83) of the population have a vitamin B12 deficiency:
    http://www.ars.usda.gov/is/pr/2000/000802.htm
    (you can find more on this in the book ‘Could It Be B12?’)
    Here is a video of a woman, whose multiple sclerosis was actually a B12 deficiency: http://www.youtube.com/watch?v=Kir2quaVaGQ
    I gave my mother some B12 (1000mcg per day) and after a month her hair loss stopped and her mood improved. (hair loss in women is very frequently a B12 deficiency).

    Niacin (vitamin B3) is proven and also used in conventional medicine to raise HDL cholesterol. (Unfortunately, it causes flushing. It usually decreases and goes away after longer usage)

    Vitamins and antioxidants are not the holy grail. But it’s definitely worth looking into.
    One of the biggest problems with these studies are the supplements themselves. What kind of quality do they have? (e.g. what kind of vitamin E was used?)

    Reply
  17. Andrea

    I am not sure if you are still checking these replies, but I would like to know how you would advise someone to stop long term use of supplementation. I have been taking 1000mg Vit C and a low dose raw food multi daily for some time now and am concerned if I stop my own defenses may be so weak from long term use that I may be at risk of getting sick or an illness.

    Reply
    • Todd

      Andrea,

      It’s hard to give advice on this, because so much depends upon your individual situation. My advice would be to experiment: Taper off your vitamin C over a week, and simultaneously add back phytonutrients, particularly my favorites: curcumin (found in turmeric or curry) and sulforophane (found in broccoli, brussel sprouts and other cruciferous vegetables). In general, eat a LOT more vegetables that are dark green or brightly colored or strongly flavored. Also, minimize intake of sugars (including those “hidden” in sodas, fruit and fruit juices, ketchup, granola and other snacks) because these suppress your endogenous antioxidant response.

      A good test for how you are doing is to monitor your frequency of colds or flus, how quickly you heal from minor cuts and bruises, and how fast you recover from soreness or strains resulting from exercise or exertion. Resistance and rapid recovery from these stresses is evidence of a strong endogenous antioxidant defense. Observe your own health closely and be honest with yourself. Try this for a month or two and see how it goes. If you see an improvement or no problems, then it is evident that you have not been disadvantaged by cutting out your antioxidant supplements.

      Todd

      Reply
  18. Massimo B.

    Perhaps not all the antioxidands have the same effect. For example, if you search on Google with the keywords “autophagy vitamin C” you will found several studies on the stimulatory effect of vitamin C on autophagy.

    Massimo

    Reply
  19. Rodrigo Q.

    In the antioxidant supplementation studies:

    “A Kansas State University study showed that administering antioxidants during exercise can impair muscle function by suppressing hydrogen peroxide, a key signaling compound. This can lead to reduced blood flow in the muscle”

    “A study comparing chemical Vitamin C with oranges containing an equivalent amount of Vitamin C given to test subjects showed that the blood from those who ingested the oranges could neutralize hydrogen peroxide (an oxidant) but those who ingested Vitamin C tablets failed to do so.”

    They seem contradictory, as in the first one seems to say the supplementation neutralized hydrogen peroxide (supposedly something negative) , and on the second one it says that hydrogen peroxide was not suppressed (which is implied as something something negative as well).

    Reply
    • Todd

      Hi Rodrigo,

      I’m not sure there is any real contradiction in what these studies are saying. The conditions of the studies were quite different. Serena Guarnieri, the lead author of the Italian study comparing oranges to pure Vitamin C, is quoted as concluding that her study suggests there are other other components of oranges beyond Vitamin C — probably phytochemicals such as cyanidin-3-glucoside, flavanones and carotenoids — that may provide most of the in vivo antioxidant effect. It’s also a matter of magnitude. The amount of pure vitamin C or oxidants was likely sufficient to interfere with hydrogen peroxide signalling in the KSU study, but too weak to significantly neutralize the amount of peroxide in the blood of the subjects in the Italian study.

      Todd

      Reply
  20. Shauna

    What do you think of green powder instead of vitamin supplements. Green powder is just high vitamin veggies that have been dehydrated and ground into powder?
    I do like reading stories on longevity. Like the story of Jeanne Calment https://en.wikipedia.org/wiki/Jeanne_Calment the oldest documented lady to ever live. She apparently drank lots of red wine, used lots of olive oil and ate pounds of chocolate every week.
    Well the diet of one person is not a lot to go on, but even a study of the Bluezones diet, showed that the longest lived people in the world ate a good amount of fresh fruit and veggies. Plus other factors like fresher foods and less processed foods and water with a higher mineral content probably contributed lots to their lifespan.
    I agree with you, because I also don’t like drugstore supplements. I like to get my dose in smaller amounts through diet. I do take Vitamin D3 however. I live in Canada and work night shift so I am certain to be lacking in it.
    I love your blog. It is always interesting and thought provoking.
    Cheers

    Reply
  21. Jared

    Hi just wondering about how you feel about na-Rala use to stress the natural antioxidant defence system? Cheers

    Reply
  22. Darryl

    Alpha-lipoic acid is fairly potent both as an in vitro antioxidant and in in vivo studies, and the reason may be because its also an adaptive stress response inducer:

    Cao, Zhuoxiao, et al. “Induction of endogenous antioxidants and phase 2 enzymes by α-lipoic acid in rat cardiac H9C2 cells: protection against oxidative injury.” Biochemical and biophysical research communications 310.3 (2003): 979-985.

    Suh, Jung H., et al. “Decline in transcriptional activity of Nrf2 causes age-related loss of glutathione synthesis, which is reversible with lipoic acid.” Proceedings of the National Academy of Sciences of the United States of America 101.10 (2004): 3381-3386.

    Jia, Zhenquan, et al. “Potent upregulation of glutathione and NAD (P) H: quinone oxidoreductase 1 by alpha-lipoic acid in human neuroblastoma SH-SY5Y cells: protection against neurotoxicant-elicited cytotoxicity.” Neurochemical research 33.5 (2008): 790-800.

    Reply
  23. John Mikroulis

    Just a quick correction: “xenobiotic” is not Latin; it’s Greek.

    Reply
  24. BSotoSF

    I keep seeing the “antioxidants don’t work” oversimplification story getting peddled everywhere now, and it’s getting tiring. The story’s distortion is that there’s a deluge of human studies supporting the steady moderate intake of full-spectrum polyphenols in the prevention and treatment of a wide range of maladies, but that curiously never made it into the widely criticized Copenhagen study these anti-antioxidant cranks weirdly keep referring to.

    The problem is the few studies the anti-antioxidant crowd are basing their cynicism on have quite literally only ever found trivial but error-prone numbers associated with ‘vitamin exclusive’ antioxidant intake (e.g. Vitamin A, B, C, D, E), but not polyphenol antioxidants (flavonoids, catechins).

    So we know that consuming egregious amounts of vitamin antioxidants may do nothing or hurt us, and we know moderate polyphenol antioxidants intake has the ability to profoundly helps us. Yet the message somehow got trimmed to, “antioxidants don’t work.”

    There’s something both concerning and hysterical about authors who fancy themselves realists who have unwittingly fixated on malformed narratives based on limited, frequently flawed study, and outright factual omission. As a consequence of this lazy thinking, they’re misinforming the public, and undermining their own credibility.

    Reply
  25. oneException

    6 months on alpha lipoic acid for insulin resistance and it has worked better than pharma drugs with no side effects. I have hereditary severe liver disease resulting in several different serious health conditions. My tops are now normal, along with fasting cholesterol. These are results medical profs said were impossible. I have avoided taking cholesterol medicine because doves said my liver couldn’t handle it. My asthma is gone so I can exercise, great improvements for someone really very sick. Vitamins a, c, e were not well tolerated, vitamin d did not work for me. So, for people deciding whether to take some horrible RX drug vs a more natural solution, yes. I hope now SoME day I can maintain on diet alone, but until then, this is a big improvement. Perhaps we can start to look at supplements not as something we need to take forever, but to get from point a to b. Isn’t ala from curcumin so why is curcumin okay and not ala?

    Reply
  26. JaredW

    This is a very intersting link and I am sure David knows his stuff and his ethics are good

    http://geronova.com/science-blog/greatest-recent-finding-in-lipoic-acid-research/

    Reply

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