Antioxidants — time to reconsider the principles? Part 1

For around six decades, we have indulged in a passionate love affair with ‘antioxidants’.  It seems we just can’t get enough of these seemingly miraculous compounds that are claimed to prevent disease, prolong our lives and keep us young.  Although that love affair has been souring for more than 20 years in scientific circles, the casual reader and consumer might be oblivious to this — and for a good reason — due to the plethora of available information.

In this series, we break down all you need to know about antioxidants, beginning with this article on their basic features.

Antioxidants were not created equal

‘Antioxidants’ are all individual in their properties; in their cellular compartmentalisation, in their ability to cross cell membranes, in the speed with which they undergo chemical reactions (kinetics), in their solubility, in their bioavailability, in their interactions with other molecules and in their ability to act as messengers, sending signals which initiate critical processes.

In addition, many such as ascorbate have far more significant roles in human biochemistry than in quenching free radicals. We have tended to assume that because these compounds are capable of quenching free radicals in test tubes, they are doing the same in living cells; this erroneous assumption has led us down many a blind alley in both research and in clinical application.

Although ascorbate as one example, is capable of quenching free radicals (more correctly termed reactive oxygen species and reactive nitrogen species), it is not particularly efficient at doing so at the primary level; there are far more targeted molecules designed to keep oxidative species in proper redox balance. The common practice of megadosing ascorbate at hundreds of times the recommended dietary intake (apart from diverging markedly from a ‘natural medicine’ model), is like using a shotgun to hit the bulls eye – a scattered, rather wasteful and non-targeted approach. There is a much more targeted solution which I will discuss further on.

Misnomers?

Many compounds we categorise as ‘antioxidants’ are really molecules with unique bioactivity, quite unrelated to any potential for them to act as free radical ‘sponges’. This misunderstanding has largely arisen because these compounds were shown in laboratory in vitro studies to quench free radicals. It was some time before it was realised that quenching free radicals in a test tube could not be replicated for clinical advantage in a living human being. In the interim, the popular notion that these compounds behave as antioxidants in vivo has stuck, a misconception arguably fuelled by industry!

A case in point is Vitamin E which has been extensively researched by Angelo Azzi at Tufts University. Azzi’s conclusions can be paraphrased as saying, “Vitamin E is clearly doing something in the body – it is an essential part of the diet and deficiency leads to neurological dysfunction – but whatever it is doing, it is NOT doing it as an antioxidant¹!  In an earlier paper², Azzi described how α-tocopherol modulates 2 major signal transduction pathways and alters regulation of 5 gene families associated with lipid uptake, cell proliferation and platelet aggregation to define the most clinically significant of its roles.

Why do so many vitamin trials fail?

This change in our understanding of what these molecules do helps us to see why so many studies which have used Vitamin E as a clinical intervention tool have failed. They have failed because they are looking for an outcome related to Vitamin E’s supposed antioxidant properties; outside the test tube, these are minimal.

A 2001 study³ looked at the effects of escalating doses of Vitamin E from 200 to 2000 IU per day for 8 weeks on lipid peroxidation in healthy adults. They concluded, “Our results question the potential benefit of the reportedly widespread use of Vitamin E supplementation in healthy individuals.”  This paper reports on many other studies which similarly showed no clinical effect.

A similar conclusion was drawn in a well-designed study⁴ which investigated the long term effects of supplementation of Vitamin C, Vitamin E and β-carotene for primary prevention of Type 2 diabetes. The conclusion drawn was that ‘there were no significant overall effects to show that these supplements in any way prevented the development of diabetes in 8171 women over 9 years’. One must surely conclude that even though oxidative stress is clearly associated with the cellular dysfunction typical of diabetes, these vitamins simply aren’t interacting at this level.

A fundamentally-flawed theory?

What these studies and others are showing us is that our basic premise on what these essential substances do biochemically, is fundamentally flawed. We know that diseases like cardiovascular disease, diabetes, kidney disease and neurodegenerative diseases (and dozens more) are underpinned by oxidative stress. We also know that individuals who consume a diet rich in ‘antioxidant’ nutrients enjoy superior health. We have then assumed that if we dose with the known antioxidants as supplements (Vitamins C, E, beta- carotene, NAC, the plant polyphenols and others), we will take control of the oxidative stress and reduce disease risk.

The research continues to show again and again that the clinical benefits are just not there. At best, we must conclude that the results are inconsistent. Essentially, we are sending in the wrong man for the job! It is just like calling the electrician to fix your blocked drains – the electrician is a very competent tradesman but drains are not his forte. Whatever benefits a whole food diet confers on the health of individuals, it is clearly much more than the effect of the ‘antioxidant’ vitamins.

In our next post, we will be looking at where the antioxidant story began. Stay tuned!

References

1. Azzi A Molecular mechanism of alpha-tocopherol action Free Radical Biology and Medicine 2007; 43:16-21

2. Azzi A et al Vitamin E Mediates Cell Signalling and Regulates Gene Expression Ann NY Acad Sci 2004;1031:86-95

3. Meagher EA et al Effects of Vitamin E on Lipid Peroxidation in Healthy Persons JAMA 2001;285:1178-1182

4. Song Y et al. Effects of Vitamins C and E and β-carotene on the risk of Type 2 Diabetes in women at high risk of cardiovascular disease: a randomised controlled trial Am J Clin Nutr 2009;90:429-37