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Antioxidant Hype and Reality

A new study by lead author Shelly Gray and published in the latest issue of the Journal for the American Geriatric Society, found no effect from taking Vitamin C or E, either alone or in combination, on the risk of dementia or Alzheimer’s disease after 5.5 years. Vitamins C and E were chosen because they both have significant antioxidant activity, and so this study was partly to test the hypothesis that oxidative stress causes or contributes to dementia.

The science behind the role of oxidative stress in aging and neurodegenerative disorders and the modulation of oxidative stress by nutritional antioxidants is complex and has not yielded many confident therapeutic recommendations. And yet, by contrast, antioxidants are sold to the public with dramatic health claims as if they were well established. It is common for marketing hype to out pace scientific reality, especially when the science is complex and preliminary so that there is as yet no firm scientific consensus.

For background, oxidative stress refers to the production in the cells of the body of certain oxygen-based compounds, collectively called reactive oxygen species (ROS), that are highly reactive. Some of these compounds are simply waste products of cell metabolism. Others serve a useful purpose, such as nitric oxide that is used in neurotransmission. What these ROS compounds have in common is that they react with proteins, DNA, and other cell components and cause damage.

The body has evolved a natural defense against the onslaught of ROS. These compounds are called free radical scavengers or antioxidants (such as the protein superoxide dismutase) and their job is to gobble up ROS before they can damage cells.

In the last two decades our increasing knowledge of oxidative stress and natural antioxidants has led to a great deal of legitimate scientific speculation about the role of ROS in degenerative disorders and even natural aging. Even conservative and responsible scientists dared dream that antioxidants might cure everything from Alzheimer’s disease to old age.

Before scientists could even write their research grants, however, there emerged from this “irrational exuberance” a cottage industry of antioxidant products marketed as if they were the very elixir of life. But two decades later a complex picture has emerged – and continues to emerge. At this point what does the evidence say about oxidative stress and antioxidants?

Of course this is many separate questions that must be addressed individually. First let us consider the basic science. We have learned a great deal about the various kinds of cellular damage caused by ROS. This includes damage to mitochondrial function (mitochondria are the energy factories of cells) and also to DNA, which is likely at least partly responsible for cellular aging. We have also found the products of oxidative damage in virtually all neurodegenerative diseases, like ALS and Parkinson’s disease.

So, if anything, the basic science plausibility of antioxidants has increased over time. There is no question that oxidative damage is occurring as part of neurodegenerative diseases. But biological symptoms are frustratingly complex and often mock our simplistic explanations. It is possible, for example, that oxidative damage may be more of a consequence of the cellular damage that occurs than a cause of it. Therefore antioxidants may not necessary stop the cellular damage.

Medicine also seems to follow the law of unintended consequences. For example, it is also possible that antioxidants may decrease the beneficial actions of some oxidative agents. Heat shock proteins, which are proteins that function, in part, by activating protective cell functions, are themselves activated by oxidative stress. It is possible that therefore, that exogenous antioxidants might decrease some protective function activated by heat shock proteins.

In other words – the regulation of ROS and oxidative stress in the body may be more of a balancing act than any simplistic notion of oxidative stress being all bad and antioxidants being all good. So nutritional antioxidants may have some benefits but at the same time disrupt certain metabolic balances. And yet, in disease states this balance may already be broken, and therefore antioxidants may have the potential to correct excessive oxidative stress.

Ultimately we need clinical evidence to make any conclusions about the health benefits, if any, of nutritional antioxidants. We simply need to see what the net effects of these substances are in actual people. On this score the scientific evidence is highly mixed and has yet to yield a clear benefit for any antioxidant, but this has not been ruled out either.

A recent review of clinical studies of antioxidants in Alzheimer’s disease (AD) concluded that the evidence is “ambiguous”, while still recommending them largely because they are low risk. More definitive trials were recommended, like the study I referred to above which shows no benefit for prevention of AD.

The evidence for antioxidants in ALS is largely negative. In Parkinson’s disease (PD) the picture is a bit more complex. There is some evidence that eating Vitamin E rich foods may help prevent PD but not Vitamin E supplements. So perhaps it is something other than the Vitamin E in these foods that is of benefit, or perhaps eating healthy foods is simply a marker for some other variable that protect against PD. In other words, the evidence is ambiguous.

In general research into antioxidants as treatment for the various neurodegenerative diseases has been disappointingly negative. But hope is not gone. There are enough preliminary positive results, as well as positive animal and preclinical data, to fuel antioxidant enthusiasm for years. Some argue that we simply have not found the right antioxidant or the proper dosing. Vitamin E, for example, does not cross over into the brain significantly so perhaps an antioxidant with more brain penetration would work better.

These are all very legitimate points, and I think it is reasonable to continue to conduct clinical research with antioxidants, although the lackluster clinical evidence has reduced my optimism. It may even be reasonable for patients with neurodegenerative disorders to take antioxidants in the hopes there will be some modest benefit – as long as they understand that they should still be considered experimental, and that while they are generally low risk, at high doses there may be (and probably are) unknown risks. Some trials, for example, have shown a possible adverse effect from Vitamin E in treating heart disease.

The use of antioxidant supplements and the consuming of foods high in natural antioxidants for routine health maintenance needs to be considered completely separately from the use of antioxidants in treating specific diseases. But here the evidence is also ambiguous. The difficulty here is that most studies are epidemiological and don’t control for many variables, such as the effects having a generally healthful diet. A danish meta analysis published one year ago in JAMA even showed that the use of certain antioxidants was associated with a higher mortality rate. All of this evidence, good and bad, is preliminary. Long term, prospective, definitive trials are simply lacking.

Conclusion

Oxidative stress and the effects of antioxidants are an important and interesting aspect of human physiology. We have already learned a great deal, but it seems like just enough to understand that we still have a great deal more to learn. It is clearly playing some role in aging and many diseases, but likely a more complex one than we initially assumed. Antioxidants may one day play an important role in the treatment of certain diseases or in routine health maintenance, but so far there is insufficient evidence to make any confident predictions or to make specific recommendations.

However, when it comes to the marketing hype for antioxidant products I can make a clear recommendation – healthy skepticism.

Posted in: Herbs & Supplements

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11 thoughts on “Antioxidant Hype and Reality

  1. James Fox says:

    How I do love rational, reasonable, and informed discussions about health issues that are a part of every day conversations with friends and family, in health literature and the general media. Again thanks for all your efforts and willingness to take on what seems to have become a substantial avocation. I’m greatly anticipating the the TAM 6 conference in LasVegas.

  2. Joe says:

    It seems that every sCAM product “detoxifies, enhances the immune system, and is loaded with antioxidants.” Indeed, just about everything is an antioxidant when compared to something like fluorine.

    Your observation that vitamin E does not cross the blood-brain barrier is important. If one could identify, with certainty, that anti-oxidation would be therapeutic in some situation; a drug must get to that site. That increases my skepticism of claims of anti-oxidants.

  3. Joe says:

    Also, the antioxidant has to have an adequate reducing potential, and a mechanism for action. For example, hydrogen and oxygen can definitely participate in a RedOx reaction, yet they can be sealed in a chamber indefinitely without reacting.

  4. drval says:

    Great post!

  5. daedalus2u says:

    A good overview of antioxidants. This is a special area of my research. A state of oxidative stress is a low NO state and vice versa. They can be thought of as complementary metabolic states. I have a more extreme view, that essentially all oxidative stress is self-produced by physiology, even in pathologic situations such as Alzheimer’s and congestive heart failure, and that dietary antioxidants (beyond nutritive amounts) are either of essentially zero value or are harmful (for people with otherwise normal physiology).

    Oxidative stress is one of the major signals that trigger ischemic preconditioning. That is a protective state which can be induced by brief intermittent episodes of ischemia or hypoxia some time before a longer episode. Ischemic preconditioning can put an organ into a state where it can survive ischemic insults that would otherwise be fatal. My interpretation of many of the neurodegenerative diseases is that they are caused by ischemic preconditioning that has gone on for too long because the signal to end ischemic preconditioning hasn’t happened (I think that signal is an increase in NO above a certain level).

    If cells could survive in the ischemic preconditioned state long term, they would have evolved to do so (because that state consumes less ATP) and that would become the new “default” physiological state. That hasn’t happened, so there must be something incompatible with being in the ischemic preconditioned state long term.

    Superoxide is the main agent of oxidative stress. It is produced by the reduction of O2 by a single electron. It is an anion so it is confined by lipid membranes. Mitochondria produce a great deal of superoxide (a few % of O2 consumed), but it is produced in the mitochondrial matrix, there are 2 lipid membranes it has to go through to get out, and there is ~150 mV potential across one of them keeping anions inside. I think that very little superoxide gets out (as superoxide). It is dismutated to H2O2 which is uncharged and can diffuse out. Because superoxide is an anion, oxidative stress due to high superoxide levels are local, that is the effects of high superoxide are confined to local cellular compartments inside of lipid membranes. The low NO that oxidative stress produces is global because NO diffuses everywhere even into high superoxide compartments where it is consumed.

    Superoxide can’t be used as a signaling molecule between cells because it doesn’t pass through cell membranes. Ischemic preconditioning is invoked in a tissue compartment, so cells need to communicate their state of oxidative stress to each other. NO does pass through cell membranes and superoxide reacts with NO at essentially diffusion limited kinetics. A state of high superoxide is then a state of low NO and vice versa. In the case of ischemic preconditioning, there is hysteresis that maintains physiology in the state it is in. Cells can make superoxide in unlimited quantities; NO production is much more limited, and more complicated because NO does pass through membranes, NO in all tissue compartments is “coupled” to NO in every other tissue compartment (which makes NO physiology quite complex). I think that cells need an external source of NO to “stand down” from the ischemic preconditioned state. The details of that are not well understood.

  6. psamathos says:

    Healthy skepticism is especially important when vastly overpriced juice cocktails are being marketed with claims that they are full of antioxidants. Yet eating an apple will likely have more or as much antioxidant content at a fraction of the cost. I guess you can’t make much money off of the “apple a day” plan, though.

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