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:
- A 2004 American Heart Association meta-analysis of 20 clinical trials showed no benefits for the use of Vitamins C, E and beta carotene in the prevention of heart attacks or strokes, and no reduction in mortality. While they acknowledged that the scientific evidence from observational studies supports the conclusion that “a diet high in food sources of antioxidants and other cardioprotective nutrients” reduces the risk of CVD, they found no support for any benefits from the use of antioxidant vitamin supplements. They did indicate that antioxidant supplementation may be useful in certain critical medical procedures, but not for routine dietary supplementation.
- A 2008 Cochrane Institute meta-analysis of 67 randomised clinical trials on antioxidant supplements (beta-carotene, vitamin A, vitamin C, vitamin E, and selenium) versus placebo or no intervention found no evidence that antioxidant supplements prevent mortality in healthy people or patients with various diseases
- A University of Washington randomized trial showed evidence of positive harm from antioxidants. A cocktail of antioxidants added to the course of patients with high cholesterol and using statin-niacin therapy led to reduced levels of HDL and increased levels of coronary blockage .
- 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 at Cedars-Sinai Heart Institute showed that cardiac stem cells cells that were loaded with high doses of antioxidants developed genetic abnormalities that predispose to the development of cancer.
- 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.
- A 2009 study by German and American researchers found that daily supplementation with 1000 mg Vitamin C and 400 IU Vitamin E during a 4-week exercise program by healthy young men suppressed improvements in insulin sensitivity observed in the non-supplementing control group.
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 Latin 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:
- A metabolic study in houseflies showed that administering Vitamin C (ascorbic acid), Vitamin E (alpha tocopherol) and beta-carotene caused a compensatory depression of activity of key endogeneous antioxidant enzymes includiing superoxide dismutase, catalase, and glutathione. The administration of vitamins C and E also reduced life span. Granted that humans are not the same as flies, but we use the same enzymes to detoxify.
- A study of supplementation of cells with the antioxidant lipoic acid showed that it inhibits the antioxidant adaptive response triggered by treatment with UV-B light The added lipoic acid decreases the intracellular oxidative signals necessary to develop the adaptive response in human mononuclear cells.
- A 2008 study at the University of Valencia showed that Vitamin C supplementation hampered exercise endurance. While Vitamin C reduces ROS levels in short term, it impairs the adaptive response by reducing transcription factors that enable mitochodria production, and inhibiting expression of antioxidant enzymes superoxide dismutase and glutathione peroxidase.
- A 2010 study showed antioxidants can cause neurodegeneration by inhibiting autophagy — an important process for removing damaged cellular material. Inhibition of autophagy by antioxidants has a range of other potential negative consequences.
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:
- A review of cell culture experiments with various polyphenols shows that their mechanisms of action goes beyond their intrinsic antioxidant properties, by indirectly stimulating enzyme transcription through the ARE system.
- Resveratrol seems to have its optimal effect at concentrations too low to be explained by an antioxidant effect. A metabolic study of resveratrol in heart cells, showed that even at very low (micromolar) concentrations, it upregulates endogenous “cytoprotective factors” — antioxidants and phase 2 enzymes such as superoxide dismutase, catalase, glutathione, glutathione reductase, glutathione peroxidase, glutathione S-transferase (GST), and NAD(P)H:quinone oxidoreductase-1 (NOQ1).
- An Israeli study showed that caratenoids in tomatoes activate the ARE transcription system, upregulating the phase II detoxification enzymes in a manner that is not correlated with the antioxidant potential of the caratenoids. However, caratenoids appear to have an optimum level, above which they may be harmful.
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:
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.