In my last email, I reviewed the history of B vitamin research. The reductionist models and observational studies initially fooled us that B vitamins were good. The clinical trials, however, revealed that B vitamins don't work, and when they do, there are trade-offs. We were fooled by the reductionist models because they oversimplified our biology, and the observational studies because they cannot distinguish association from causation.
Antioxidants, it turns out, share a very similar history, and a very similar fate. It is a fascinating story that is connected to the grandest health hypothesis of the twentieth century. And it was all wrong.
Reductionist models of antioxidants
A reductionist model tries to explain a complex system, like the human body, by identifying a critical pathway in that system. In the 1950's, a scientist named Denham Harman (pictured below) created one of the most important reductionist models of the century, a reductionist model to explain aging. He claimed to have found not only the pathway for aging, but also the cure, vitamins A,C and E. (Click here for his classic 1956 paper. It has been cited by over 11,000 other papers.)
The inspiration for his model initially came from his interest in radiobiology, the study of radiation's effect on living organisms. Radiobiology began around 1900 with the discovery of radioactivity and radioactive elements, like radium and uranium. What made radioactivity different from other forms of radiation, like microwaves, radio waves, and visible light, was that it was "ionizing". It packed so much energy, it was able to break molecules into highly reactive, unstable particles. Particles such as: ions (charged particles), free radicals (particles needing to take on electrons), and oxidants (particles needing to donate oxygen).
Simple experiments, from as early as 1906, were able to demonstrate this ionizing property. For instance, when radium is added to water, the radiation breaks the molecules of H2O into hydrogen ions (H+), and hydroxide ions (OH-). This is called "water radiolysis". The ions further react to produce hydrogen gas (H2) and hydrogen peroxide (H2O2). Hydrogen peroxide is the quintessential "oxidant". It is a water molecule with an extra oxygen (O) that it wants to get rid of.
Since water is the most abundant molecule in our cells, it is reasonable to infer that the free radicals and oxidants generated by water radiolysis must play a key role in radiobiology. However, we still didn't know at the time, whether this was a good thing, or a bad thing. In fact, radium water (pictured below) was sold to the rich and famous in the 1920's as an energy booster and elixir of life. The NAD+ of its day.
It wasn't until the nuclear age, when victims from Hiroshima and Nagasaki started to die from premature aging and cancer, that we finally figured out ionizing radiation was bad. The free radicals and oxidants from water radiolysis were actually overwhelming the cell. They were binding to the fats, proteins, and DNA of the nearest cell structures, and causing inflammation, damage, and mutation. It was "Oxidative stress" that was damaging the cell, and ultimately responsible for the cancer and premature death seen in the radiation victims.
Around that time, scientists had also figured out the chemistry of cellular respiration; how we convert oxygen and sugar into energy. To our surprise, oxidative stress was a by-product of cellular respiration. This meant that every animal that takes in oxygen produces a slow and steady stream of "oxidative stress", just by being alive.
With this understanding, and how oxidative stress was harmful, Dr Harman was able to formulate his theory of aging. He believed that aging, and the diseases of aging, were caused by the background oxidative stress of cellular respiration. Just a slower, in-born version of the oxidative stress that killed the victims of Hiroshima and Nagasaki. This is the, "Free radical theory of aging". It is possibly the most popular and well known health hypothesis of the twentieth century.
Harman believed that aging, and the diseases of aging, were caused by the background oxidative stress of cellular respiration.
The therapeutic corollary to the "free radical theory of aging", is the "antioxidant theory of aging". It speculates that taking antioxidants will prevent aging. What are antioxidants? They are the chemical opposite of oxidants. Instead of wanting to give oxygen or accept electrons, they want to accept oxygen and donate evlectrons. (See diagram below). They can neutralize oxidants. What are the most potent and prevalent antioxidants found in our foods? Vitamins A,C, and E.
Observational studies of antioxidants
The antioxidant theory of aging was further supported by observational studies. Dozens were launched from the 1960's to the 1990's. They observed the health effects of vitamins A, C and E on different populations. The results were unanimous. Whether you consumed foods with high levels, took supplements, or had high levels in your blood, the more vitamins A,C, or E, the better your health outcomes seemed to be.
Clinical trials of antioxidants
By the 1990's, we began to realize the importance of clinical trials to confirm our reductionist models and observational studies. However, as mentioned in my prior emial, we could not rely on private industry to fund them. Instead, government agencies needed to step in with billions of tax-payer dollars. Dozens of large, well-designed vitamin supplementation trials were completed. Some recruiting tens of thousands of subjects, and lasting up to a decade.
All trials consistently showed that supplementation of the antioxidant vitamins, A,C and E, failed to prevent heart disease and cancer. Surprisingly, there was even a trend to suggest the opposite. Vitamin A seemed to increase heart disease and lung cancer, while vitamin E seemed to increase prostate cancer. There were side effects as well; vitamin A increased hip fractures, and vitamin C was linked to kidney stones.
Why the reductionist models misled us
From the results of the clinical trials, we were obviously misled by reductionist models, and it was for the same reason we were misled by B vitamin reductionist models. Reductionist models underestimate and oversimplify the human body. It turns out that we make our own antioxidants. Not surprising, given that our cells had 3 billion years of evolution to figure this out. Our cells seem to live in a delicate balance of oxidative stress and endogenous antioxidants. Therefore, when we consume exogenous antioxidants as supplements, we only suppress our own internal production. Similar to what happens to testicles when testosterone is given exogenously.
Our cells seem to live in a delicate balance of oxidative stress and endogenous antioxidants.
Furthermore, new models suggest that we shouldn’t be buffering oxidative stress in the first place. Oxidative stress may be a good thing. It seems to play an important role in “cell-signaling”; telling our cells to get stronger and protect themselves for the future. This process is called hormesis - what doesn't kill us, makes us stronger. Some animals, like the naked mole rat (pictured below) have the highest recorded cellular oxidative stress, yet they are the longest living rodents on the planet (28 years).
Oxidative stress may be a good thing.
Finally, it appears that our immune cells are able to weaponize oxidative stress. For example, macrophages can generate and release free radicals to kill cancer cells and infections. Neutralizing immune cells with antioxidant supplements may theoretically disable the immune response. This could explain why supplements were observed to increase cancer in some of the clinical trials.
Why the observational studies misled us
We were also misled by the observational studies, and it was for the same reason we were misled by B vitamin observational studies. Observational studies are unable to determine causation, only association. People observed to have higher levels of antioxidants, are likely to eat more fruits and vegetables and take expensive supplements. It follows that this group is also more likely to: smoke less, take better care of themselves, exercise more, have a higher income, etc. They are healthier because of all these associated traits, not necessarily the antioxidants.
Conclusion
Like B vitamins, antioxidant vitamins don't seem to work, and may even increase the risk of heart disease and cancer. Once again, we were fooled by reductionist models and observational studies. It took 70 years, and hundreds of billions of dollars of research, to show that the most highly celebrated health hypothesis of the 20th century was wrong.
Why is this so important? If our grandest ideas in medicine fall apart when challenged with clinical trials, what can be said of our lesser ideas? They are most likely wrong. Yet, everyone selling healthcare, from acupuncturists, to functional medicine specialists, to spine surgeons, will try to convince you that their idea is right. As a consumer of healthcare, realizing this truth may be a hard pill to swallow, but essential for your health. Please protect yourself. When you are being sold a treatment, ask for strong evidence, ask for clinical trials. If there are none, it's ok. Just be aware of the speculative nature of the treatment.