Antioxidants – A Relook at the Free Radicals Theory
We dose up on antioxidants as if they are the elixir of life. At best, they are probably ineffective. At worse, they may just send you to an early grave.
For Linus Pauling, it all started to go wrong when he changed his breakfast routine. In 1964, at the age of 65, he started adding vitamin C to his orange juice in the morning. It was like adding sugar to Coca Cola, and he believed – wholeheartedly, sometimes vehemently – that it was a good thing.
Before this, his breakfasts were nothing to write about. Just that they happened early every morning before going to work at California Institute of Technology, even on weekends. He was indefatigable, and his work was fruitful.
At the age of 30, for instance, he proposed a third fundamental way that atoms are held together in molecules, melding ideas from both chemistry and quantum mechanics. Twenty years later, his work into how proteins (the building blocks of all life) are structured helped Francis Crick and James Watson decode the structure of DNA (the code of said building blocks) in 1953.
The next year, Pauling was awarded a Nobel Prize in Chemistry for his insights into how molecules are held together. As Nick Lane, a biochemist from University College London, writes in his 2001 book Oxygen, “Pauling… was a colossus of 20th Century science, whose work laid the foundations of modern chemistry.”
But then came the vitamin C days. In his 1970 bestselling book, How To Live Longer and Feel Better, Pauling argued that such supplementation could cure the common cold. He consumed 18,000 milligrams (18 grams) of the stuff per day, 50 times the recommended daily allowance.
In the book’s second edition, he added flu to the list of easy fixes. When HIV spread in the US during the 1980s, he claimed that vitamin C could cure that, too.
In 1992, his ideas were featured on the cover of Time Magazine under the headline: “The Real Power of Vitamins”. They were touted as treatments for cardiovascular diseases, cataracts, and even cancer. “Even more provocative are glimmerings that vitamins can stave off the normal ravages of ageing,” the article claimed.
Sales in multivitamins and other dietary supplements boomed, as did Pauling’s fame.
But his academic reputation went the other way. Over the years, vitamin C, and many other dietary supplements, have found little backing from scientific study. In fact, with every spoonful of supplement he added to his orange juice, Pauling was more likely harming rather than helping his body. His ideas have not just proven to be wrong, but ultimately dangerous.
Pauling was basing his theories on the fact that vitamin C is an antioxidant, a breed of molecules that includes vitamin E, beta-carotene, and folic acid. Their benefits are thought to arise from the fact that they neutralise highly reactive molecules called free-radicals.
In 1954, Rebeca Gerschman then at the University of Rochester, New York, first identified these molecules as a possible danger – ideas expanded upon by Denham Harman, from the Donner Laboratory of Medical Physics at UC Berkeley in 1956, who argued that free radicals can lead to cellular deterioration, disease and, ultimately, ageing.
Throughout the 20th Century, scientists steadily built on his ideas and they soon became widely accepted.
Here’s how it works. The process starts with mitochondria, those tiny combustion engines that sit within our cells. Inside their internal membranes food and oxygen are converted into water, carbon dioxide, and energy. This is respiration, a mechanism that fuels all complex life.
But it isn’t so simple. In addition to food and oxygen, a continuous flow of negatively charged particles called electrons is also required. Like a subcellular stream downhill powering a series of watermills, this flow is maintained across four proteins, each embedded in the internal membrane of the mitochondria, powering the production of the end product: energy.
This reaction fuels everything we do, but it is an imperfect process. There is some leakage of electrons from three of the cellular watermills, each able to react with oxygen molecules nearby. The result is a free radical, a radically reactive molecule with a free electron.
n order to regain stability, free radicals wreak havoc on the structures around them, ripping electrons from vital molecules such as DNA and proteins in order to balance its own charge. Although inconceivably small in scale, the production of free radicals, Harman and many others posited, would gradually take its toll on our entire bodies, causing mutations that can lead to ageing and age-related diseases such as cancer.
In short, oxygen is the breath of life, but it also holds the potential to make us old, decrepit, and then dead.
Shortly after free radicals were linked to ageing and disease, they were seen as enemies that should be purged from our bodies. In 1972, for example, Harman wrote, “Decreasing [free radicals] in an organism might be expected to result in a decreased rate of biological degradation with an accompanying increase in the years of useful, healthy life. It is hoped that [this theory] will lead to fruitful experiments directed toward increasing the healthy human lifespan.”
He was talking about antioxidants, molecules that accept electrons from free radicals thereby diffusing the threat. And the experiments he hoped for were sown, nurtured, and replicated over the next few decades. But they bore little fruit.
In the 1970s and into the 80s, for example, many mice – our go-to laboratory animal – were prescribed a variety of supplementary antioxidants in their diet or via an injection straight into the bloodstream. Some were even genetically modified so that the genes coding for certain antioxidants were more active than non-modified lab mice.
Although different in method, the results were the largely the same: an excess of antioxidants didn’t quell the ravages of ageing, nor stop the onset of disease.
“They never really proved that they were extending lifespan, or improving it,” says Antonio Enriquez from the Spanish National Centre for Cardiovascular Research in Madrid. “Mice don’t care for [supplements] very much.”
What about humans? Unlike our smaller mammalian kin, scientists can’t take members of society into labs and monitor their health over their lifetime, while controlling for any extraneous factors that could bias the results at the end. But what they can do is set up long-term clinical trials.
The premise is pretty simple. First, find a group of people similar in age, location, and lifestyle. Second, split them into two subgroups. One half receives the supplement you’re interested in testing, while the other receives a blank – a sugar pill, a placebo. Third, and crucially to avoid unintentional bias, no one knows who was given which until after the trial; not even those administering the treatment.
Known as a double-blind control trial, this is the gold standard of pharmaceutical research. Since the 1970s, there have been many trials like this trying to figure out what antioxidant supplementation does for our health and survival. The results are far from heartening.
In 1994, for example, one trial followed the lives of 29,133 Finish people in their 50s. All smoked, but only some were given beta-carotene supplements. Within this group, the incidence of lung cancer increased by 16%.
A similar result was found in postmenopausal women in the U.S. After 10 years of taking folic acid (a variety of B vitamin) every day their risk of breast cancer increased by 20% relative to those women who didn’t take the supplement.
It gets worse. One study of more than 1,000 heavy smokers published in 1996 had to be terminated nearly two years early. After just four years of beta-carotene and vitamin A supplementation, there was a 28% increase in lung cancer rates and a 17% increase in those who died.
These aren’t trivial numbers. Compared to placebo, 20 more people were dying every year when taking these two supplements. Over the four years of the trial, that equates to 80 more deaths. As the authors wrote at the time, “The present findings provide ample grounds to discourage use of supplemental beta-carotene and the combination of beta-carotene and vitamin A.”
Of course, these notable studies don’t tell the full story. There are some studies that do show benefits of taking antioxidants, especially when the population sampled doesn’t have access to a healthy diet.
But, according a review from 2012 that noted the conclusions of 27 clinical trials assessing the efficacy of a variety of antioxidants, the weight of evidence does not fall in its favour.
Just seven studies reported that supplementation led to some sort of health benefit from antioxidant supplements, including reduced risk of coronary heart disease and pancreatic cancer. Ten studies didn’t see any benefit at all – it was as if all patients were given the sugar pill also (but, of course, they weren’t). That left another 10 studies that found many patients to be in a measurably worse state after being administered antioxidants than before, including an increased incidence of diseases such as lung and breast cancer.
“The idea that antioxidant [supplementation] is a miracle cure is completely redundant,” says Enriquez. Linus Pauling was largely unaware of the fact that his own ideas could be fatal. In 1994, before the publication of many of the large-scale clinical trials, he died of prostate cancer. Vitamin C certainly wasn’t the cure-all that he cantankerously claimed it was up until his last breath. But did it contribute to a heightened risk?
We’ll never know for sure. But given that multiple studies have linked excess antioxidants to cancer, it certainly isn’t out of the question. A study published in 2007 from the US National Cancer Institute, for instance, found that men that took multivitamins were twice as likely to die from prostate cancer compared to those who didn’t. And in 2011, a similar study on 35,533 healthy men found that vitamin E and selenium supplementation increased prostate cancer by 17%.
Ever since Harman proposed his great theory of free radicals and ageing, the neat separation of antioxidants and free radicals (oxidants) has been deteriorating. It has aged.
Antioxidant is only a name, not a fixed definition of nature. Take vitamin C, Pauling’s preferred supplement. At the correct dose, vitamin C neutralises highly charged free radicals by accepting their free electron. It’s a molecular martyr, taking the hit upon itself to protect the cellular neighbourhood.
But by accepting an electron, the vitamin C becomes a free radical itself, able to damage cell membranes, proteins and DNA. As the food chemist William Porter wrote in 1993, “[vitamin C] is truly a two-headed Janus, a Dr Jekyll-Mr Hyde, an oxymoron of antioxidants.”
Thankfully, in normal circumstances, the enzyme vitamin C reductase can return vitamin C’s antioxidant persona. But what if there’s so much vitamin C that it simply can’t keep up with supply? Although such simplifying of complex biochemistry is in itself problematic, the clinical trials above provide some possible outcomes.
Divide and conquer
Antioxidants have a dark side. And, with increasing evidence that free radicals themselves are essential for our health, even their good side isn’t always helpful
We now know that free radicals are often used as molecular messengers that send signals from one region of the cell to another. In this role, they have been shown to modulate when a cell grows, when it divides in two, and when it dies. At every stage of a cell’s life, free radicals are vital.
Without them, cells would continue to grow and divide uncontrollably. There’s a word for this: cancer.
We would also be more prone to infections from outside. When under stress from an unwanted bacterium or virus, free radicals are naturally produced in higher numbers, acting as silent klaxons to our immune system. In response, those cells at the vanguard of our immune defense – macrophages and lymphocytes – start to divide and scout out the problem. If it is a bacterium, they will engulf it like Pac-Man eating a blue ghost.
It is trapped, but it is not yet dead. To change that, free radicals are once again called into action. Inside the immune cell, they are used for what they are infamous for: to damage and to kill. The intruder is torn apart.
From start to finish, a healthy immune response depends on free radicals being there for us, within us. As geneticists Joao Pedro Magalhaes and George Church wrote in 2006: “In the same way that fire is dangerous and nonetheless humans learned how to use it, it now appears that cells evolved mechanisms to control and use [free radicals].”
Put another way, freeing ourselves of free radicals with antioxidants is not a good idea. “You would leave the body helpless against some infections,” says Enriquez.
Thankfully, your body has systems in place to keep a your inner biochemistry as stable as possible. For antioxidants, this generally involves filtering any excess out of the bloodstream into urine for disposal. “They go in the toilet,” says Cleva Villanueva from Instituto Politécnico Nacional, Mexico City, in an email.
“We’re very good at balancing things out so that the affect [of supplementation] is moderate whatever you do, which we should be grateful for,” says Lane. Our bodies have been selected to balance the risk of oxygen ever since the first microbes started to breathe this toxic gas. We can’t change billions of years of evolution with a simple pill.
No one would deny that vitamin C is vital to a healthy lifestyle, as are all antioxidants, but unless you are following doctor’s orders, these supplements are rarely going to be the answer for a longer life when a healthy diet is also an option. “Administration of antioxidants is justified only when it is evident that there is a real deficiency of a specific antioxidant,” says Villanueva. “The best option is to get antioxidants from food because it contains a mixture of antioxidants that work together.”
“Diets rich in fruits and vegetables have been shown generally to be good for you,” says Lane. “Not invariably, but generally that’s agreed to be the case.” Although often attributed to antioxidants, the benefits of such a diet, he says, might also hail from a healthy balance of pro-oxidants and other compounds whose roles aren’t yet fully understood.
After decades of unlocking the baroque biochemistry of free radicals and antioxidants, hundreds of thousands of volunteers, and millions of pounds spent on clinical trials, the best conclusion that 21st Century science has to offer is also found within a child’s classroom – eat your five-a-day.