The antioxidant myth: a medical fairy tale
 
 05 August 2006 
 NewScientist.com news service 
Lisa Melton 

 
 

 
Cranberry capsules. Green tea extract. Effervescent vitamin C. Pomegranate 
concentrate. Beta carotene. Selenium. Grape seed extract. High-dose vitamin 
E. Pine bark extract. Bee spit.
You name it, if it's an antioxidant, we'll swallow it by the bucket-load. 
According to some estimates around half the adults in the US take antioxidant 
pills daily in the belief they promote good health and stave off disease. We 
have become antioxidant devotees. But are they doing us any good? Evidence 
gathered over the past few years shows that at best, antioxidant supplements 
do little or nothing to benefit our health. At worst, they may even have the 
opposite effect, promoting the very problems they are supposed to stamp out.
It's little surprise that antioxidants have acquired a reputation as miracle 
health supplements. As long ago as the 1950s, scientists discovered that many 
diseases - including heart disease, strokes, cancer, diabetes, cataracts, 
arthritis and neurodegenerative disorders such as Parkinson's and Alzheimer's 
- were linked to damage caused by highly destructive chemicals called free 
radicals.
Free radicals are compounds with unpaired electrons that stabilise themselves 
by oxidising other molecules - including proteins, carbohydrates, lipids and 
DNA. In the process they often create more free radicals, sparking off a 
chain of destruction. Oxidative damage accompanies most, if not all, diseases 
and has even been proposed as a direct cause of some including lung cancer, 
atherosclerosis and Alzheimer's.
Free radicals are an unavoidable hazard of being alive. We live in an 
oxygen-rich atmosphere, and radicals, particularly reactive oxygen species 
(ROS), are natural by-products of respiration. "One per cent of the oxygen we 
consume turns into ROS," says biochemist Barry Halliwell from the National 
University of Singapore. "It doesn't sound like much but humans are big 
animals and we breathe a lot. Over a year a human body makes 1.7 kilograms of 
ROS." Exposure to X-rays, ozone, tobacco smoke, air pollutants, microbial 
infections, industrial chemicals and intensive exercise also trigger free 
radical production.
In the 1980s, however, a potential weapon against free radical damage appeared 
on the horizon. Scientists had known for a long time that people whose diets 
are rich in fruits and vegetables have a lower incidence of heart disease, 
diabetes, dementia, stroke and certain types of cancer - the very diseases 
that are associated with free radical damage. Now there was an explanation. 
Fruits and vegetables are a rich source of antioxidants that can neutralise 
free radicals by donating electrons to them.
Green plants are full of antioxidants for good reason. They are especially 
vulnerable to oxidative stress since they produce pure oxygen during 
photosynthesis. To protect themselves they manufacture an assortment of 
potent antioxidants.
And so a hypothesis was born: dietary antioxidants are free-radical sponges 
that can stave off the diseases of old age. It was a great idea. "Putting two 
and two together, scientists assumed that these antioxidants were protective, 
and that taking them as supplements or in fortified foods should decrease 
oxidative damage and diminish disease," says Halliwell, who pioneered 
research into free radicals and disease. "It was simple: we said free 
radicals are bad, antioxidants are good."
The concept helped spawn a colossal supplements industry. According to the US 
National Institutes of Health (NIH), more than half of US adults take some 
form of vitamin or mineral supplement at a total cost of $23 billion a year. 
The bewildering range of supplements on the shelves makes it hard to say how 
much of this expenditure goes on antioxidants, but the NIH says it is 
probably a "large proportion". And their popularity just keeps on growing. 
SPINS, a market research firm based in San Francisco, estimates that the 
antioxidant market has grown by 18 per cent in the past year alone.
The best known antioxidants are vitamin E (also known by its chemical name 
tocopherol), vitamin C, and two broad classes of plant chemicals called 
polyphenols (including flavonoids) and carotenoids (including beta carotene 
and lycopene). Most supplements touted as antioxidants contain at least one 
of these, often as a pure chemical and sometimes as a concentrated plant 
extract.
Since the early 1990s scientists have been putting these compounds through 
their paces, using double-blind randomised controlled trials - the gold 
standard for medical intervention studies. Time and again, however, the 
supplements failed to pass the test. True, they knock the wind out of free 
radicals in a test tube. But once inside the human body, they seem strangely 
powerless. Not only are they bad at preventing oxidative damage, they can 
even make things worse. Many scientists are now concluding that, at best, 
they are a waste of time and money. At worst they could be harmful.
The first antioxidant to produce disappointing results was beta carotene. Once 
a star among supplements, beta carotene pills were recommended to smokers to 
protect them against lung cancer. This was largely based on the observation, 
made in the 1970s, that people who ate a lot of carrots - which contain large 
quantities of beta carotene - had some protection against cancer.
In 1992 researchers at the US National Cancer Institute set about testing beta 
carotene. They recruited more than 18,000 people at high risk of developing 
lung cancer, either because they smoked or had been exposed to asbestos, and 
gave around half of them beta carotene supplements. The trial was supposed to 
run for six years, but the researchers pulled the plug two-thirds of the way 
through after discovering, to their surprise and horror, that those taking 
supplements were faring worse than the controls. Their lung cancer rate was 
28 per cent higher, and the overall death rate was up 17 per cent. "It was a 
shock. It not only did no good but had the potential to do harm," Halliwell 
says.
The researchers couldn't be sure that these increases were not caused by 
chance, and beta carotene capsules are still widely sold as an antioxidant. 
Further trials, though, have strengthened the evidence that beta carotene 
supplements not only fail to protect people against cancer but can also 
increase the risk of lung cancer in smokers. In May of this year an expert 
panel convened by the NIH concluded that there was no evidence to recommend 
beta carotene supplements for the general population, and strong evidence to 
recommend that smokers avoid it.
It's a similar story with the world's most popular antioxidant. Vitamin E shot 
to fame in the early 1990s, after two large studies involving more than 
127,000 people in total found that those with a diet high in vitamin E were 
significantly less likely to develop cardiovascular disease. The first study 
followed 87,245 female nurses for eight years; it found that the top 20 per 
cent with respect to vitamin E consumption had a 41 per cent lower incidence 
of cardiovascular disease than the bottom 20 per cent (New England Journal of 
Medicine, vol 328, p 1444). The second study, involving 39,910 male health 
professionals, found a similar reduction in heart disease risk (New England 
Journal of Medicine, vol 328, p 1450).
The researchers, based at Harvard Medical School and Harvard School of Public 
Health, even had a plausible mechanism. Evidence was emerging that one of the 
causes of heart disease was free radical damage to LDLs, tiny packages of 
lipid and protein that circulate in the bloodstream, delivering fatty acids 
to cells. It turned out that adding vitamin E to blood samples in the test 
tube made LDL more resistant to oxidation. Perhaps this was how vitamin E 
prevented heart disease. "At the biochemical level, the rationale sounded so 
good - at that time," says Roland Stocker, a biochemist at the University of 
New South Wales in Sydney, Australia.
Use of vitamin E supplements soared. In 1990, almost nobody took vitamin E; by 
the end of the decade an estimated 23 million US citizens were knocking back 
daily doses.
On the back of these positive results, other researchers set up large studies 
using vitamin E supplements. The results, however, have been almost 
universally disappointing. Only one experiment - the Cambridge heart 
antioxidant study (CHAOS) - found a positive effect, a 77 per cent reduced 
risk of heart attack. Several others found no protective effect and one even 
concluded that vitamin E increased the risk of heart failure.
Time for a rethink?
Other trials designed to test whether vitamin E supplements could prevent 
cancers, such as the ATBC study in Finland, also came in negative. Vitamin E 
also did not halt the progression to Alzheimer's disease in people with mild 
cognitive impairment.
What is more, when scientists went looking for evidence that vitamin E 
protected LDL against oxidation in the body, not just in the test tube, they 
found none - except in people with vitamin E deficiency (Journal of the 
American Medical Association, vol 285, p 1178). In fact, despite good 
evidence that vitamin E is a powerful antioxidant in the test tube, there is 
now serious doubt that it acts the same way in the body. "Vitamin E is not an 
antioxidant. In fact it must be protected against oxidation," says Angelo 
Azzi, a biochemist at Tufts University in Boston, Massachusetts. He points 
out that vitamin E exists in eight different forms in nature, all of which 
function as antioxidants in the test tube. Yet the body only uses one form, 
alpha tocopherol, which is pulled out of the bloodstream by a highly 
specialised protein in the liver. All the other forms are excreted. Azzi 
argues that evolution is unlikely to have gone to such great lengths simply 
to obtain an antioxidant from the diet. "There are millions of antioxidants," 
he says.
Vitamin E is clearly doing something in the body - it is an essential part of 
the diet and deficiency leads to neurological problems - but whatever it's 
doing, it's not an antioxidant.
There is even some evidence that vitamin E supplements can be harmful. Last 
year, a team led by Edgar Miller of the Johns Hopkins Medical Institutions in 
Baltimore made headline news when they amalgamated the results of 19 separate 
trials and concluded that high doses of vitamin E increase overall mortality 
(Annals of Internal Medicine, vol 142, p 37) - though this conclusion remains 
controversial. "It's flawed," asserts Azzi. "We re-analysed the data and 
there is no change in mortality." "Most people agree that there is no good 
evidence that large doses are harmful," adds Stocker.
Vitamin C is another disappointment. "People are still trying to defend it, 
but you don't get an effect on free radical damage unless you start with 
people with a vitamin C deficiency," says Halliwell. "I think it is a lost 
cause." In fact, results from a vast US trial probing the links between diet 
and health, called the Women's Health Study, suggest that vitamin C 
supplements may accelerate atherosclerosis in some people with diabetes.
One class of antioxidants that remains relatively unresearched is polyphenols. 
What little evidence there is comes from epidemiological studies, some of 
which suggest that polyphenols prevent disease and others of which do not. 
While polyphenols act as antioxidants in the test tube, it is not clear that 
they are absorbed into the bloodstream, and if they are, they are swiftly 
metabolised. For example, 95 per cent of a flavonoid called resveratrol - the 
one found in red wine - is destroyed by our digestive system before it enters 
circulation.
"Just because a food with a certain compound in it is beneficial to health, it 
does not mean a pill with the same compound in is"
The conclusion is becoming clear: whatever is behind the health benefits of a 
diet rich in fruits and vegetables, you cannot reproduce it by taking 
purified extracts or vitamin supplements. "Just because a food with a certain 
compound in it is beneficial, it does not mean a nutraceutical [with the same 
compound in] is," said Paul Coates, who works in the Office of Dietary 
Supplements at NIH.
Yet the fact remains that people eating diets abundant in vitamin C, vitamin 
E, polyphenols and carotenoids are less likely to suffer heart attacks, 
vascular disease, diabetes and cancer. One explanation is that these people 
have a generally healthier lifestyle - they exercise more and smoke less, for 
example. For now, no one knows for sure.
Tough vegetables
There are some ideas. Halliwell still believes that antioxidants are at least 
partly responsible. He argues that because the polyphenols, carotenoids and 
vitamins in fruit and vegetables are bound into tough, fibrous material, they 
hang around in the stomach and colon, where they can neutralise free 
radicals. The gastrointestinal tract, especially the stomach with its highly 
acidic environment, is constantly generating reactive oxygen species from 
food. Supplements may not replicate this effect because they are digested too 
quickly.
Andrew Shao from the Council for Responsible Nutrition, a supplement industry 
trade association based in Washington DC, argues along similar lines. He says 
that pulling a nutrient out of context and testing it in a clinical trial is 
not appropriate. "Antioxidants should not be expected to perform as drugs," 
he insists. "That's simply not how nutrients work. They work in concert with 
each other."
There's yet another, more intriguing explanation. Among the leading sources of 
dietary antioxidants are tea and coffee, and there is some evidence that 
green tea in particular is linked with health benefits including reduced risk 
of cancer and cardiovascular disease. Oddly, though, Halliwell has discovered 
that tea and coffee are also bursting with reactive oxygen species in the 
form of hydrogen peroxide.
"Every time you drink a cup of coffee it's a dilute bowl of hydrogen 
peroxide," says Halliwell. The hydrogen peroxide is there because of the 
presence of the antioxidants - "antioxidants" is really just another way of 
saying reducing agent, which can react with oxygen in the water to produce 
hydrogen peroxide. Think platinum blond, and you get the picture of what you 
might be drinking.
But if free radicals are bad for us, how come coffee and tea might be 
beneficial? One possibility is that they can help nudge our own internal 
antioxidant systems into action. "There has been a considerable rethink as to 
what free radicals are doing," says Malcolm Jackson, a biochemist at the 
University of Liverpool, UK. He believes that in the right quantities 
radicals can be positively health-enhancing, prompting our cells to fire up 
their own internal defence machinery: a battery of radical-busting enzymes 
such as catalase and superoxide dismutase. "Cells are very good at protecting 
themselves against minor stresses, as long as they are not excessive," says 
Jackson. "The question is: should we be quenching free radicals at all?"
If it turns out that antioxidants in food work because they generate 
health-promoting quantities of free radicals, that would be an ironic 
turnaround. It may also explain why supplements and extracts don't seem to 
work or may even be dangerous: the doses are too high, and produce too many 
free radicals.
For now, the advice is simple. "Stick to flavonoid-rich foods, red wine in 
moderation, tea, fruits and vegetables," says Halliwell. "Don't start taking 
high-dose supplements or heavily fortified foods, until we know more."
From issue 2563 of New Scientist magazine, 05 August 2006, page 40-43

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