The free radical theory of aging was conceived by Denham Harman in the 1950s when prevailing scientific opinion held that free radicals were too unstable to exist in biological systems. This was followed by an outpouring of research from many laboratories that showed accumulation of free radicals during aging.

Studies also demonstrated an association of free radicals with chronic diseases such as arthritis, macular degeneration, and cancer. But, it is important to point out that these studies only showed an association, not causation.


Just what are free radicals and antioxidants anyway?

oxygen free radical
Graphic credit: HonChemistry | CC SA 3.0

Free radicals are molecules that are missing an electron. Oxygen free radicals are oxygen molecules that are missing one electron. They are produced as byproducts of glucose metabolism that takes place in the mitochondria, the energy-producing organelles found in cells of most complex organisms.

Antioxidants are compounds that donate their own electrons to free radicals, thus making them (electronically) whole. The level of free radicals in the body is determined by the amount generated and by the activity of naturally occurring antioxidant enzymes, such as superoxide dismutase and catalase.


What can we learn from evolution?

Oxygen became a significant component of Earth’s atmosphere about 2.4 billion years ago and ancient bacteria containing mitochondria are known to have existed 2.3 billion years ago. So, mitochondria are as ancient as organisms using oxygen for their energy metabolism. And as long as these organelles have existed, they have been producing oxygen free radicals as a metabolic by-product.

Judging by the number of species, ranging from aerobic bacteria to human beings, that have thrived in our oxygenated world, one would have to conclude that oxygen-dependent organisms must have evolved an effective way to deal with free radicals.

Indeed, that is the case. The two naturally occurring antioxidant enzymes that I mentioned earlier, superoxide dismutase and catalase have kept those pesky free radicals under pretty effective control quite nicely for eons.


Are all free radicals bad?

These antioxidant enzymes are powerful enough to do away with any oxygen free radical that comes their way. So why are some spared? Again, natural selection provides a hint. Not all free radicals are bad—some are beneficial, in fact, even indispensable.

For instance, macrophages, those white cells that patrol every nook and cranny of the body in search of foreign invaders, kill their prey with a blast of, you guessed it, free radicals. Without them, we’d have a hard time surviving in the germ-rich environment we live in.


The bad side of free radicals

The fact that we evolved early on enzymes to neutralize oxygen free radicals suggests that left unbridled, they must be detrimental. Indeed, if they somehow escape the clutches of the antioxidant enzymes, they can attack the cell’s membrane lipids, its proteins, and its DNA.

The injury they inflict on these components of the cell is cumulative, and given enough time, can cause the cell to die. Indeed, the free radical theory of aging is based on this process: accumulation of free radicals causes damage to lipids and proteins and structural damage to the DNA that leads to mutations. All these adverse changes eventually result in cellular dysfunction, organ failure, and death.


What we learned from a tiny worm

caenorhbditis elegans
Caenorhbditis elegans | Bob Goldstein, UNC Chapel Hill – Own work. | CC BY-SA 3.0 | via WikiMedia Commons

Wen Yang and Sigfried Hekimi engineered a version of Caenorhbditis elegans, a tiny short-lived worm that is easy to breed in the lab, to overproduce superoxide, an oxygen free radical. As Hekimi relates to Scientific American, he expected this experiment would provide proof of oxygen free radicals as a cause of aging.

Instead, he was astonished to find that the modified worms not only failed to develop high levels of oxidative damage, they actually lived, on average, 32% longer than normal worms. To drive the final nail, he then treated the worms with the antioxidant, vitamin C, and found that it prevented the increase in life span!

In a later publication, Hekimi came to the counter-intuitive conclusion that free radicals actually act as protective agents against the ravages of aging. How so? Hekimi and his colleagues propose that oxygen free radicals are tightly associated with aging because they play a role in mediating a stress response to age-dependent damage.

For instance, free radicals are known to cause the activation of a gene called HIF-1. This gene mediates responses to a variety of tissue injuries caused by trauma or inflammation. One such response is angiogenesis, or formation of new blood vessels, which is central to the healing of wounds of all kinds, including heart attacks. Another example, already mentioned, is when white cells encounter an invading microorganism, they respond with a spike in oxygen free radicals production, which kills the foe.


Does this hold true for more complex organisms?

You might wonder, are the more complex vertebrates, different from worms? Arlan Richardson, currently at the University of Oklahoma, genetically engineered 18 different strains of mice to produce varying amounts of the antioxidant enzyme, superoxide dismutase. Some of the mice produced more, some less.

If oxygen free radicals were responsible for aging, you’d expect the mice with higher levels of antioxidant enzymes to live longer, and the ones with lower levels to have a shorter lifespan. As Richardson colorfully summed up his experiments for Scientific American, “I watched those goddamn lifespan curves, and there was not an inch of difference between them.”


Could antioxidants supplements be bad for you?

vitamins and pills
Photo credit: Photl

For starters, as we said before, physiological levels of free radicals are necessary to activate processes involved in repair of tissue injury and fighting off infection. Taking high doses of antioxidant supplements, such as vitamin C, readily available over the counter, could theoretically interfere with these beneficial processes. Indeed, Michael Ristow and his colleagues showed that athletes who took vitamin C and vitamin E supplements had worse performance than athletes that did not.

Another study, named SELECT, looked at the effect of vitamin E and selenium supplements on the incidence of prostate cancer in 36,000 healthy adult males. Here are its conclusions:

  • Taking vitamin E alone boosted the risk of developing high-grade prostate cancer in men who started the study with low (but within the normal range) selenium levels.
  • In men who started the study with higher selenium levels (presumably from their diet), taking selenium supplementation, either alone or in combination with supplemental vitamin E, increased the risk of high-grade prostate cancer.
  • Among men who didn’t take either vitamin E or selenium, those who started the study with higher selenium levels were no more likely to have developed prostate cancer than men who started it with low selenium levels. (This means the culprit is added selenium from supplements, not selenium from food.)

Prostate cancer expert Dr. Marc Garnick, a clinical professor of medicine at Harvard Medical School, an oncologist at Beth Israel Deaconess Medical Center, and editor in chief of Harvard’s Annual Report on Prostate Diseases says,

“I counsel all of my patients to absolutely avoid any dietary supplements that contain selenium or vitamin E—including multivitamins.”


What’s the takeaway?

This discussion focused on single antioxidants, taken as supplements. The studies presented suggest antioxidant nutritional supplements are not only not beneficial, but they could also have adverse effects.

Our metabolic pathways are extraordinarily stable and effective, having been honed to perfection over billions of years. It really shouldn’t surprise us that simple-minded solutions, like antioxidant pills, do not provide a magic bullet. In fact, we know that nutrients have different effects when taken as food as opposed to vitamin pills. We did, after all, evolve while eating FOOD, not PILLS.

So I say, instead of spending your money on nutritional supplements, spend it on real foods naturally rich in antioxidants, like green leafy vegetables, blueberries, and dark chocolate. And, don’t forget to exercise—it generates oxygen free radicals in the muscle that are good for you.

Featured Image Credit: Designed by Freepik

Dov Michaeli, MD, PhD
Dov Michaeli, MD, PhD loves to write about the brain and human behavior as well as translate complicated basic science concepts into entertainment for the rest of us. He was a professor at the University of California San Francisco before leaving to enter the world of biotech. He served as the Chief Medical Officer of biotech companies, including Aphton Corporation. He also founded and served as the CEO of Madah Medica, an early stage biotech company developing products to improve post-surgical pain control. He is now retired and enjoys working out, following the stock market, travelling the world, and, of course, writing for TDWI.


  1. Thank you for giving light to this subject of supplements and multivitamins. Sometimes I can’t help but speculate that insistence of taking supplements are driven by making money. Why take vit c pills when u can get it bupy eating fruits?… and thereby helping farmers. I heard a lot of ads about food supplements and I think they are misleading in some way. They tell you the benefits but not the risks.

    • In some very specific cases, such as macular degeneration, antioxidant supplements do show a limited, but definite,benefit. But for the most part, they are pretty useless. A recent paper shows that antioxidants actually facilitate the metastatic spread of melanoma.

  2. I am a supplicant at your feet…

    I always knew this stuff was a crock but have never seen all the evidence gathered in one place and explained as coherently as you did.


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