The myth of antioxidants / Melinda Wenner Moyer

The sacred idea that oxidative damage causes aging and that vitamins can preserve youth is now being questioned

David Gems' life was turned upside down in 2006, when a group of worms that were supposed to die insisted on staying alive. James, assistant director of the Institute for Healthy Aging at University College London, used to regularly conduct experiments with a roundworm of a type Caenorhabditis elegans often used to study the biology of aging. In this experiment, he tested the idea that the accumulation of cellular damage caused by oxidation, a chemical reaction of removing electrons from a molecule using particularly active compounds, such as free radicals, is the main mechanism responsible for aging. According to this theory, daily oxidation over time destroys more and more fats, proteins, DNA segments and other essential components in the cells, a destruction that ultimately endangers the tissues and organs and thus the functioning of the entire body.

James genetically engineered the enzymes that neutralize the free radicals in the roundworms, that is, enzymes that function normally as antioxidants. Indeed, in the absence of antioxidants, the level of free radicals in the worms skyrocketed and caused apparently harmful oxidation reactions throughout the worms' bodies.

However, contrary to James's expectations, the engineered worms did not die before their time. Their lifespan was just like that of normal worms. The researcher was amazed. "I said, come on, it can't be,'" he recalled. "'Obviously something went wrong in the experiment.'" He asked another researcher in his lab to check the results and repeat the experiment. Nothing has changed. The genetically engineered worms did not produce the antioxidants; They accumulated free radicals, as expected, yet they did not die before their time even though they suffered from extreme oxidation damage.

Other researchers have found the same puzzling results in different laboratory animals. Arlen Richardson, director of the Barshop Institute for the Study of Longevity and Aging at the University of Texas Health Science Center in San Antonio in the United States, used genetic engineering to develop 18 different strains of mice, some of which produced more antioxidants than normal mice, and others less. If the production of free radicals is what causes the oxidative damage and is responsible for aging, then the mice that contained an excess of antioxidants in their bodies should have lived longer than those with less antioxidants in their bodies. And yet "I looked at the damn life expectancy curves, and there wasn't even an inch of difference between the two groups," Richardson said. He published the modified results in a series of papers between 2001 and 2009.

Meanwhile, a few doors away from Richardson's lab, physiologist Rochelle Bornstein has spent 11 years trying to understand why the longest-lived rodent, the naked mole rat, lives 30-25 years, about eight times as long as any mouse of similar size. Bornstein found in her experiments that the naked mole rat has fewer natural antioxidants than mice, and it accumulates oxidative damage in its tissues at a younger age than other rodents. And on top of that, paradoxically, she lived disease-free until her death in good health.

Adherents of the old theory which holds that oxidative damage is the cause of aging consider these findings to be heretical. But such results of studies are no longer unusual. During the previous decade, many attempts were made to support the idea that free radicals and other active molecules promote aging, but in fact they contradicted it. And what's more, it seems that in certain concentrations and situations, not only are these high-energy molecules harmless, but they can be useful and healthy by stimulating defense mechanisms that are responsible for keeping our bodies in excellent condition. Not only do these ideas have extreme effects on the future intervention in the aging process, but they also raise questions about the widespread habit of flooding our bodies with large amounts of antioxidants. If the oxidative damage theory is wrong, then the aging processes are even more complex than researchers thought, and they must correct their understanding of the molecular level responsible for normal aging.

"The field of aging has progressed on the back of a series of paradigms as a surfer advances on a wave, but ideas about the nature of aging were somewhat groundless," James says. "We have to examine other theories and take into account that we have to look at biology in a completely different way."

The birth of radical theory

The origin of the theory of aging due to oxidation damage or free radicals is attributed to Denham Herman, who found his true calling in life in December 1945 thanks to a women's magazine. His wife Helen brought home a copy of the journal and drew his attention to an article discussing the possible causes of aging. The article fascinated him.

At the time, Herman was a young 29-year-old chemist who worked in the research and development department of the Shell oil company. He did not become free to deal with the subject until the end of nine years, after he finished his medical studies and internship. So he moved to work as a research fellow at the University of California at Berkeley and began to seriously engage in the science of aging. One morning when he was sitting in his office he had an epiphany: "You know, like thunder on a clear day," he recalled in an interview with him in 2003: free radicals are the cause of aging.

Although free radicals had never before been linked to aging, Herman thought they were apt to be the culprits. He relied on the knowledge that ionizing radiation, which comes from X-rays or atomic bombs, encourages the creation of free radicals in the body and can be fatal. Studies from that time revealed that a diet rich in antioxidants weakens the harmful effect of radiation. From this it was clear, and rightly so, that free radicals are the cause of radiation damage. Moreover, free radicals are byproducts of respiration and metabolism, which accumulate over time. Herman thought that since both cellular damage and the amount of free radicals increase with age, it is likely that free radicals are the cause of the damage that is responsible for aging, and antioxidants probably slow down the process.

Herman began to test his hypothesis. In one of the experiments he fed mice antioxidants and showed that they lived longer. (However, in very high concentrations, the antioxidants had a harmful effect.) Following him, other scientists also began to examine the subject. In 1969, researchers at Duke University discovered the first antioxidant enzyme produced in the body, superoxide dismutase, and hypothesized that it evolved during evolution to counteract the harmful effects of free radical accumulation. Upon receiving this data, most scientists accepted the idea. "If you're working on aging, free radical theory is like the air you breathe," James says. "It is found everywhere, in every textbook. Every article deals with her either directly or indirectly."

And yet, over time, scientists found it difficult to repeat Hermann's experimental findings. In the 70s, "there was no solid evidence that feeding animals antioxidants affected longevity," says Richardson. He assumed that the contradictory experiments, conducted by other researchers, were simply not properly controlled. It is possible that the animals could not absorb the antioxidants they received in their food, therefore the level of free radicals in their blood did not change. In the 20s of the 90th century, advances in genetics made it possible to examine the effect of antioxidants in a more precise way: direct genetic modification of the amount of antioxidant enzymes that the animal produces. Richardson's experiments with genetically modified mice repeatedly showed that the level of free radicals in the animals' bloodstream and the oxidative damage caused to the paws had no effect on their lifespan.

Recently Siegfried Hekimi, a biologist from McGill University, created roundworms that produce an excess of a free radical known as superoxide. "I thought the worms would help us prove the theory that conditions of oxidative stress cause aging," says Hekimi, who thought the worms would die at a younger age than usual. But in 2010 he reported in a paper published in PLOS Biology that the engineered worms did not suffer high levels of oxidative damage and swam 32% longer, on average, than normal worms. Moreover, the antioxidant vitamin C prevented the extension of the life span of the transgenic worms. Hekimi hypothesizes that superoxide does not act as a destructive molecule but as a protective signal in the worm's body, which activates genes that help repair cellular damage.

Then, in a follow-up experiment, Hakim tested normal worms after exposing them from birth to low levels of a herbicide that stimulates the formation of free radicals in both animals and plants. In the 2010 article mentioned here, he reported counterintuitive results: the lives of the worms exposed to the insecticide were 58% longer than the lives of untreated worms. And again, feeding the worms with antioxidants canceled out the beneficial effect of the poison. In April 2012, Hekimi and his colleagues showed that disabling all five genes encoding superoxide dismutase enzymes in worms had no effect on lifespan at all.

Do these discoveries mean that the theory of free radicals is fundamentally disproven? Simon Melob, a biochemist at the Buck Institute for the Study of Aging in Novato, California, doesn't think the issue is that simple. Free radicals can be beneficial in some situations and harmful in others. It is indisputably known that a high level of oxidative damage causes cancer and organ damage, and there is also ample evidence that this damage plays a role in the development of some chronic diseases, such as heart disease. On top of that, researchers from the University of Washington have shown that mice that have been genetically engineered to produce high levels of the antioxidant catalase live longer. Hence, there is something in oxidative damage that sometimes contributes to aging, but in any case "it is impossible to say that it causes pathology," Melov points out. Aging is probably not a single cause and curable thing, he claims, and it was wishful thinking to assume that it was.

Changing the point of view

Assuming that free radicals accumulate during the aging period but do not necessarily cause it, what are they Yes do? Until now, this question has led to many hypotheses without solid data.

"They are actually part of the defense mechanism," claims Hekimi. Free radicals can be formed in response to cellular damage, for example as a way to signal the body's repair mechanisms. In this case the free radicals are the result of age-related damage and not the cause of it. However, at high levels, according to Hekimi, free radicals can also cause damage.

The idea that minor injuries can help the body withstand more serious injuries is not new. Indeed, this is how the muscles get stronger in response to a gradual increase in the level of effort exerted on them. On the other hand, many amateur athletes have learned from their painful experience that a sudden increase in the physical demands placed on their bodies after a long week of sitting at their desk in their office is a guarantee of muscle cramps, strained tendons and other injuries.

Researchers at the University of Colorado at Boulder in 2002 exposed worms to heat or chemicals that stimulate the formation of free radicals for a short time and showed that each of the environmental conditions accelerated the worms' ability to survive injury and extended their lives by 20%. It is not clear how these interventions affected the overall level of oxidative damage because the researchers did not measure these changes. In 2010, researchers from the University of California, San Francisco and Pohang University of Science and Technology in South Korea reported in the journal Current Biology that some free radicals activate a gene called HIF-1, which itself is responsible for the activation of several genes involved in cellular repair, including one that helps repair DNA mutations.

Free radicals can partially explain the benefits of exercise. For years, researchers have assumed that physical activity is good despite the free radicals that are created because of them and not because of them. In an article published by nutritionist Michael Ristow and his colleagues from the Friedrich Schiller University in Vienna, Germany in 2009 in the Proceedings of the National Academy of Sciences of the USA, they presented a comparison between the profile of gymnasts who took antioxidants and those who did not. Similar to Richardson's results in his studies in mice, Ristow found that the gymnasts who did not take vitamins were healthier than those who did. For example, they showed fewer signs that they might develop type 2 diabetes. Beth Levin, a microbiologist at Texas Southwestern University Medical Center, showed that exercise increases a biological process called autophagy, in which cells recycle bits of disused proteins and other intracellular debris. The tool used to break down and digest the damaged molecules is free radicals. Just to complicate matters further, Levin's research shows that autophagy also reduces the overall level of free radicals. Hence the type of free radicals and their amount in different parts of the cell have a variety of roles depending on the conditions.

The myth of antioxidants

If free radicals are not always bad, then the substances that contradict them, the antioxidants, are not always good. This figure is somewhat alarming if you consider that 52% of Americans take substantial amounts of antioxidants, such as vitamin E and beta-carotene, as part of multivitamin food supplements every day. In 2007 it was published in the Journal of the American Medical Association (JAMA) סקירה A systematic review of 68 clinical trials shows that the addition of antioxidants does not reduce the risk of dying. When the authors limited the review to trials in which the likelihood of bias in any direction was the least, that is, those in which the selection of participants in the study was completely random and the trial was carried out in a double-blind manner (both the participants and the researchers did not know who received the supplement) - the result was that certain antioxidants increased the risk of dying, sometimes up to 16%.

Several American organizations, including the American Heart Association and the American Dietetic Association, now advise people not to take antioxidant supplements unless they have been diagnosed with a vitamin deficiency. "The literature provides a growing body of evidence that these supplements, especially in high doses, are not as beneficial as we thought," said Demetrius Albans, a senior researcher in the National Cancer Institute's branch of nutritional epidemiology. However, he said, "We are certainly aware of the possible disadvantages inherent in them."

Although it is difficult to imagine that the absence of antioxidants will be completely tolerated, or that most aging researchers will be comfortable with the idea that free radicals are beneficial without much additional evidence, it is slowly becoming clear that aging is a much more complex and complicated process than Herman thought about 60 years ago. James believes that the evidence is converging on a new theory according to which aging results from the overactivity of biological processes involved in growth and development. But no matter what ideas the researchers propose or promote, "scientists' continued crunching of the facts is moving the field to a strange but more real place," James says. "This is a wonderful and refreshing breath of fresh air."

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on the notebook

Melinda Wenner Moyer (Moyer) is a science reporter living in Brooklyn, New York. She is also an associate professor at the City University of New York's School of Journalism

in brief

For decades, researchers have assumed that very active molecules, known as free radicals, cause aging through damage to cells that results in damage to the activity of tissues and organs.

Recent experiments show that there is a correlation between the increase in the amount of certain free radicals in mice and worms and an increase in life expectancy. Indeed, under certain conditions free radicals stimulate the activity of cellular repair mechanisms.

If these results are confirmed, then taking antioxidants, whether as vitamins or as supplements, may cause healthy people more harm than good.

Evidence in humans

When vitamins kill

Epidemiological studies show that people who eat a lot of fruits and vegetables rich in vitamins and antioxidants tend to live longer than those who do not and get less cancer. From here it seems obvious that food supplements containing antioxidants are supposed to improve health. But the results in most carefully designed studies do not support this assumption. And indeed the evidence shows that some of the people who take certain supplements are actually more prone to develop fatal diseases, such as lung cancer and heart disease.

Early signs that antioxidants may cause trouble

In a study conducted in 1996 with the participation of 18,000 men and women, it was found that the rate of lung cancer in the group that took beta-carotene and retinol was 28% higher than the rate among those who did not take antioxidants, and the mortality rate in this group was 17% higher than the rate in the other group. The increase in risk became clear after 18 months, especially among heavy smokers, and was especially noticeable among heavy smokers who were exposed to asbestos, a known cancer-inducing substance (carcinogen).

Evidence in animals

Insight from mutant worms

Not only do free radicals not cause aging (through chemical oxidation reactions that cause cellular damage), but some of them have even been shown to be beneficial. One possibility, supported by the work of the chemist Siegfried Won Young, is that certain free radicals trigger internal repair mechanisms in animals. In an experiment published in 2010, researchers genetically modified a group of worms that caused them to produce higher levels of certain free radicals. Much to their surprise, the mutant worms lived longer than the normal worms. When the researchers fed the worms antioxidants, the advantage in longevity disappeared.

And more on the subject

Is the Oxidative Stress Theory of Aging Dead? Viviana I. Pérez et al. in Biochemica Biophysica Acta, Vol. 1970, no. 10, pages 1005-1014; October 2009.

Biology of Aging: Research Today for a Healthier Tomorrow. National Institute on Aging. National Institutes of Health, November 2011. www.nia.nih.gov/health/publication/biology-aging

Alternative Perspectives on Aging in Caenorhabditis elegans: Reactive Oxygen Species or Hyperfunction? David Gems and Yila de la Guardia in Antioxidants Redox Signaling. Published online September 24, 2012.

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