In the first installment, we reviewed what free radicals are, how antioxidants work, and why they often fail to deliver health benefits. Many brilliant people, including Linus Pauling, thought they had discovered the fountain of youth in antioxidants. When scientists hold beliefs that are contradicted by observation, it’s call for further investigation — even if those people have been awarded a Nobel prize.
Stress Makes Us Strong
Free radicals can go off like a bottle rocket inside your cells and wreak havoc. But that’s not the whole story. Reactive oxygen species (ROS, a type of free radical) are also a byproduct of energy metabolism. They’re inescapable, and evolution has turned these lemons into lemonade. ROS are used by the body as a signal to indicate a stressed state. When this signal is received, the body increases production of endogenous antioxidants, such as glutathione and a variety of enzymes. Our natural defense systems are highly effective at operating within our cells and preventing damage to DNA and cell membranes. In fact, our immune system uses ROS to destroy pathogens.
Rather than trying to shield ourselves from free radicals, science is now indicating stress is vital to our health. The key is in the dose.
What’s Bad Is Good (But Not Too Much)
In toxicology, there is a saying that “the dose makes the poison.” Many things that are toxic in large doses are harmless or even beneficial in small or intermittent doses. A famous example is exposure to low doses of nuclear radiation. Everywhere on Earth, you find varying amounts of naturally occurring radiation. Scientists studying this phenomenon mapped out areas with high levels of background radiation, expecting to find cancer clusters. Instead, they found the opposite. Cancer rates were lower. The hypothesis is that low doses of radiation trigger our body’s defense mechanisms and are actually protective.
A similar dose-response phenomenon called hormesis has been observed in other contexts. A hormetic stressor follows a biphasic dose-response curve, whereby either too high or too low a dose is harmful. The beneficial dose is found in the middle. With a linear dose-response curve, any increase in dose is harmful. Nuclear energy regulators use a linear no-threshold model to create safety guidelines, which often stokes an irrational fear of nuclear energy, leading to fewer nuclear power plants. It has been argued that more people died in the evacuation from Fukushima after their nuclear power plant was hit by a tsunami than died from the radiation.
Exposure to the cold is another hormetic stressor. In response, our body activates our stress response systems. We begin to shiver to raise our core temperature. This causes an elevation in ROS and simultaneous increase in endogenous antioxidants. Interestingly, exogenous antioxidant supplementation blunted this response in rats. Too much cold exposure can lead to hypothermia, which is deadly. However, moderate exposure is believed to be healthy.
Survival of the Fittest Mitochondria
Mitochondria are the power-generating organelles within our cells. They are similar to bacteria and have coevolved with nearly all complex forms of life on Earth. They convert oxygen and energy substrates such as glucose and fatty acids into energy. There can be hundreds or even thousands of them inside of a single cell, depending on the type. Muscle and liver cells are densely packed with mitochondria, and exercise can increase this density, making them more energetically potent.
Oxidative energy production in our mitochondria is responsible for around 90% of ROS production within our bodies. Peak physical exertion elevates our ATP production by several orders of magnitude and consequently our ROS production, too.
Mitochondria are especially vulnerable to damage by free radicals, including the ones they generate. Compared to healthy mitochondria, damaged ones produce greater levels of ROS, leading to further damage. Out-of-control ROS production eventually damages other cells and the entire body. This downward spiral is the basis of the mitochondrial free radical theory of aging, whereby damaged mitochondria accumulate as we age.
Animals with longer life spans tend to have slower metabolic rates and therefore may also suffer less damage from ROS production. Those who practice calorie restriction as a means of improving longevity may be doing so with this theory in mind: Slow your metabolism and live longer — like a sloth.
It was long believed that the life span of animal species generally trended upward from the smallest to the largest animals. Nick Lane, an evolutionary biochemist, challenged that idea, noting an “almost U-shaped curve of longevity versus metabolic rate.” Animals with very slow metabolism, like tortoises, live for a very long time because they are under very little oxidative stress, according to Lane. On the other end of the spectrum, birds have a fast metabolic rate and long life spans. He suspects they have evolved to select for higher-quality mitochondria.
Lane suggests the best way to improve the quality of your mitochondria is to induce selective stress at the cellular level. Exercise, diet, and fasting are hormetic stressors that cause weak cells to die off. This process is called apoptosis — programmed cell death — and it’s vital to the health of an organism. A healthy body is constantly being broken down and rebuilt, one cell at a time. This cycle of death and renewal is essential to life. In fact, a cancer cell is one that has broken free of this cycle, unable to shed the damaged cells. They grow aggressively, but their kill switch (apoptosis) is shut off.
Exercise Without Benefits?
Dr. Michael Ristow of the University of Jena in Germany has proposed an alternative to the free radical theory of aging. This theory, called “mitohormesis,” posits that stress imposed by exercise follows a hormetic dose-response curve. General physical activity and intense intermittent exercise are extremely healthy, whereas inactivity and ultramarathons are not. Exercise has been associated with reductions in heart disease, Type 2 diabetes, cancer, neurodegenerative diseases, obesity, and more. Exercise results in a temporary but dramatic increase in oxidative stress. This stimulates the body’s natural antioxidant defense mechanisms and cellular repair pathways. In Ristow’s words, adaptation to exercise “works like a vaccination — repeated low doses of free radicals will increase stress resistance.”
Ristow made waves in the fields of exercise and nutrition in 2009 when he and eight colleagues published “Antioxidants Prevent Health-Promoting Effects of Physical Exercise in Humans,” which provided evidence that moderate doses of vitamins C and E blunted adaptations to exercise. In the study, 40 healthy young men trained five consecutive days per week for four weeks. The training sessions are described as “20 min of biking or running, 45 min of circuit training, and 20 min periods for warming up and cooling down.” The study authors then split the men into two groups. Both groups followed the same exercise routine, but one group took supplementary antioxidants (1,000 mg/day of vitamin C and 400 IU/day of vitamin E). Members of the control group improved their insulin sensitivity as expected, but this effect was not seen in the antioxidant group. According to Ristow et al., “Physical exercise has been shown to be effective in preventing type 2 diabetes in high risk individuals and may be even more effective than the most widely used anti-diabetic drug, metformin.” The antioxidant group also did not upregulate their bodies’ endogenous antioxidant production (superoxide dismutases 1 and 2; glutathione peroxidase).
In 2016, Ristow published a follow-up with co-author Troy Merry: “Do Antioxidant Supplements Interfere With Skeletal Muscle Adaptation to Exercise Training?” Most prior work on this topic had focused on aerobic exercise. Ristow and Merry’s paper instead presents evidence that antioxidants might interfere to a greater degree with high-intensity training. They posit ROS signaling mediates strength training adaptations in a nonlinear hormetic dose-response.
The paper summarizes the results of several studies:
- Antioxidant supplementation attenuated improvements in mean and peak power output during repeated bouts of 10s of cycling.
- Vitamin C/E supplementation attenuated upper-body strength gains following 10 weeks of resistance training. (Ristow and Merry note other studies have not shown this effect.)
- Vitamin C supplementation decreased muscle hypertrophy in older participants following 12 weeks of resistance training in one study but not after six months in a separate study.
- Vitamin C/E supplementation reduced hypertrophy signaling post-workout. Hypertrophy was not impacted after 10 weeks of resistance training, but measures of strength decreased.
- Several studies of antioxidant supplementation reported participants experienced increases in creatine kinase, a sign of muscle damage. One showed no decrease in participants’ perception of soreness, but vitamin C supplementation did prolong the recovery process following downhill running. Another study that focused on kayakers found elevated markers of muscle damage in the antioxidant group, indicating a blunted recovery process.
Ristow and Merry admit the total body of evidence against antioxidant supplementation is not conclusive but argue there is a growing body of evidence to suggest it “may hamper or prevent the signalling of important adaptations such as muscle mitochondrial biogenesis, insulin sensitivity and hypertrophy.” Antioxidants might have short-term use in situations where ROS will be abnormally elevated, such as a multi-day contest. However, based on the current evidence, they advise against supplementing antioxidants beyond what is provided by a healthy diet.
A hypothetical model of the effects of exercise, aging, and chronic disease on reactive oxygen species production
There are two key takeaways from Ristow’s research: 1. ROS act as chemical messengers to trigger a cascade of events that improve our health over the long term, and 2. antioxidant supplements may have the unintended consequence of neutralizing these ROS signals. The transient two-fold increase in ROS during exercise is nothing to worry about. They signal our body to upregulate our endogenous antioxidants and cellular repair pathways, thus improving our long-term oxidative stress resistance. The health benefits of exercise greatly outweigh the dubious benefits of antioxidant supplements. In a very real sense, exercise is an antioxidant.
Additional Reading
Comments on Why Antioxidant Supplements Don't Work, Part 2
Exercise May Protect Against Deadly Covid-19 Complication, Research Suggests
This article states what might be obvious to many readers here. It proposes that exercise is an antioxidant. A single bout of exercise can elevate levels of a potent endogenous antioxidant- superoxide dismutase. The academic paper is below, which covers cardiovascular, pulmonary, and renal diseases. Covid-19 is mentioned briefly, but seems to be the headline generator.
Extracellular superoxide dismutase, a molecular transducer of health benefits of exercise
Have you guys heard of NRF2 Pathways?
To Greg Glassman, I wasn't referring to CrossFit HQ, I was talking about Sports and Fitness industry in general, as well as those that ride on your coattails on the sport of Crossfit. Just this morning, in Morning Chalk-up there is an advertisement for Hemp CBD recovery drink. This is a supplement intended to aid "recovery". Where is the evidence it does this, and what is the primary endpoint that defines "recovery". That's what I meant.
I generally agree with this article on the role of antioxidants, but in this time of C19, I just wanted to point out that flavonoids protect ACE2 receptors from coronavirus S-protein spikes. Flavonoids are also considered to be antioxidants, but this is a viral-blocking function not related to whether it is also an antioxidant. So I would continue to eat flavonoid-rich vegetables (and some fruit).
Absolutely love these articles and discussion! Hormetic stress and cumulative dose considerations are something I have been researching a lot about over the last few years. This issue comes up routinely with both athletes I coach and patients I see in the clinic - basically every time there is new YouTube video touting the benefits of any one of many hormetic stressors (fasting, cold, heat, antioxidants, hypoxia). Next thing I know I've got a 30 year old Type A CF athlete in the gym doing bike sprints while wearing a gag ball mask during a 3 day fast after sitting in ice water - plus or minus electrified nipple clamps for added adrenaline! I jest - but only barely.
Interestingly enough it seems that moderate level CF athletes and very sick patients seem to be well primed for the kind of masochism needed to embrace the pain usually associated with hormetic stressors, while those in the middle of the road don't seem to give two shits. The moderate level athletes think this is going to be the "thing" to put them in the elite category and the really sick are willing to try anything to get better. Overall, I think these articles highlight two general principles of hormesis.
1. Dose matters - particularly cumulative and additive dose. The cell, organ or organism must be able to mount an appropriate response to the stressor applied. We should not assume that hormetic stressors can be "layered" on one another and still result in positive adaptations - as the studies with antioxidants and exercise point out.
2. An evolutionary context is very important in evaluating hormetic stressors. Nearly every compound/chemical functions as a hormetic stressor but clearly our bodies do not respond in a positive manner to many man made (and the occasional natural) chemicals. For instance there is strong hormetic response of yeast cells and cultured human tissue to DDT, similar in magnitude to the chemical ECGC (green tea antioxidant). So why aren't I telling my patients to make sure and get a dose of DDT with their morning green tea? The answer is that the hormetic dose range of DDT is fairly tight and the mechanisms to reduce free DDT in the system prior to it entering cells have not evolved. In contrast ECGC is ingested as a liquid with hundreds of other phytochemicals, is then subject to multiple actions (intestinal cell excretion, first pass hepatic metabolism) prior to it ever reaching the cellular level. In essence - we are old buddies and playmates from an evolutionary perspective. Our bodies know what to do with it and how to handle it to keep it in the hormetic response dose range. The idea that we can extract a chemical from real food - mass produce it in a laboratory and ingest it and then expect it to act the same way is fundamentally flawed. We are trying to bypass the delicate biochemical dance that we developed with this substance as we co-evolved over the last hundred of thousands of years and it probably won't work well in most situations. This is the main reason why I think the data so far does not show (and probably won't show) any strong benefit to supplementation (in the absence of malnutrition) over food or other natural sources of hormetic stressors.
Take home point for me is that after all the geek out and discussion - the CF prescription for diet and exercise still remain unchallenged. All the other crap that everyone wants to buy, consume or torture themselves with on top of this adds little to the sum total.
For tons more geek out material on this - read or watch material of Edward Calabrese from Umass on the subject of hormesis. Great stuff. I would love to see him speak at a future DDC (if that ever happens again!)
Over
Jeremy,
Thanks for adding your clinical experience and evolutionary perspective to the discussion. Hilarious and insightful! Here is a section out of a Calabrese paper that might interest you (though I'm guessing you've read it):
These quantitative features of the hormetic dose response have important medical implications since constraint is imposed upon the magnitude of a drug to induce a desired effect. For example, if a drug increased cognitive performance in an elderly patient by approximately 25–30%, the hormetic model suggests that no further increase in this level could be obtained by using a new drug combination. Numerous studies on hormesis and drug interaction have corroborated this concept. Flood [173], [174], [175], [176]demonstrated that the hormetic response for memory was limited to the 30–60% increase even when several drugs were used in combination to maximize memory outcome. Similar response magnitude constraint has also been reported for immune stimulation, bacterial growth, increases in hair growth, plant growth, decrease in anxiety, decreases in tumor incidence and many other endpoints [177].
This would suggest you're correct about stacking hormetic stressors. Once you've taken care of the big stuff (training and diet), the ice baths and nipple clamps will have less impact. With that said, hard driving folks will go to great lengths for that final 1 or 2% optimization.
You've gotten me thinking that antioxidants might better be described as "anti-hormetics".
Bravo.
It's a pleasure to read a well thought-out, evidence-based opinion piece that stresses quality evidence.
Which brings us back to standard science-based nutritional advice, of eating a broad-based, diverse healthy diet.
CrossFit HQ has done a good job of pointing out the conflicts of interest that over the past half-century have contaminated governmental advice on macronutrient intake. They have been right to do so.
At the same time, there are plenty of conflicts of interest in Sports and CrossFit and the Fitness Industry, recommending supplements and other potions without hardly a shred of any evidence to back claims of improved health, or its subcomponents. Certainly not high quality evidence. I applaud this objective piece and hope many others are to follow.
Where did we (CrossFit) recommend a supplement or other potion? I would have characterized CrossFit differently. Maybe I am too close.
Please elaborate on "standard science-based nutritional advice". I nearly choke on reading that.
How about EAT-Lancet? Is that "standard science-based nutritional advice". I track chronic disease to "standard science-based nutritional advice".
All right Tyler, I gotta defend myself a little. My comment on part 1 was only a very small spoiler alert! This is a far more eloquent and expansive summary. Thank you. But also, sorry about that ;)
I especially appreciate the theoretical model presented here. It's entirely consistent with what I teach in my university classes on exercise-induced inflammation and oxidative stress. I pose the topic to students as: If ROS are bad, and exercise increases ROS, how can exercise be good? (I let them sit there for a while.. in panic, questioning everything they thought they knew.. if it sounds evil and fun, it is).
The answer lies in whether or not the stressor is resolved. Chronic disease is a problem of unresolved stress, including chronically elevated ROS and inflammatory factors. Exercise, on the other hand, stimulates large but transient increases in the same inflammatory signals and ROS that trigger adaptive processes rendering the cell (and, by extension, the entire body) resilient to future stressors (e.g., novel viruses of zoonotic origin...). The stressor signals these beneficial adaptations (documented in depth in the Ristow papers) but are largely resolved upon cessation of exercise.
With that perspective, then, it makes total sense that oral antioxidants, and any other agents with antioxidant effects underpinning at least part of their putative therapeutic benefit (e.g. statins, metformin), would inhibit the beneficial effects of exercise training. It's like turning the air conditioning on in your house but placing a large piece of furniture squarely in front of the vent and wondering why the house isn't cooling off. Of course it doesn't work. You've messed up the feedback loop.
I wanted to comment on one statement: "Ristow and Merry admit the total body of evidence against antioxidant supplementation is not conclusive but argue there is a growing body of evidence to suggest it 'may hamper or prevent the signalling of important adaptations such as muscle mitochondrial biogenesis, insulin sensitivity and hypertrophy.'" I'd suggest that Ristow and Merry are a bit modest here. The research evidence they and others have produced is pretty compelling. That the data do not necessarily comport with mainstream consensus on the 'benefits' of antioxidant doesn't do much for me. Haven't we learned about the shortcomings, fallacies, and dangers of consensus science elsewhere on this website? More evidence is not better. Convincing evidence is better.
No apologies necessary! The idea that exercise is an antioxidant completely defies conventional wisdom. I agree with you that Ristow and Merry understate their case. My guess is that it's just standard academic hedging. In interviews, Dr. Ristow is more definitive.
The nutritional establishment has been wrong on just about everything. I would say they have egg on their face, but given their fear of cholesterol...it would have to be something else. Micronutrients seemed to be their most defensible territory. They were dead wrong on the macronutrients, but at least they could point to vitamins. It looks like they were wrong on that, too.
I really appreciate your in-depth comment. Lots to digest here, especially with regards to statins and metformin. Did you ever see these images showing the effect of statins on muscle tissue? https://medicalxpress.com/news/2020-02-statins-uncover-cholesterol-lowering-drugs-muscle.html
It's quite striking, isn't it?
I had not seen that particular data yet, Tyler, thanks for the link. It's been my understanding for some that statins cause a host of muscle related side effects, including muscle pain, mitochondrial dysfunction, and attenuated adaptations in muscle mitochondrial capacity. The mechanism(s) for these effects, last I looked into the studies (and it's been a while), have been elusive. Personally, I've always thought that since other literature supported antioxidant & anti-inflammatory mechanisms underlying at least some of their therapeutic benefits (for example, stains can improve endothelial function independent of effects on cholesterol), then maybe those same mechanisms are working against the patient when statin therapy is combined with exercise. Since the mechanism identified in the new paper supports an anti-inflammatory effect (statin-induced activation of the GILZ protein), I think the descriptor "anti-hormetic" that you proposed earlier in this thread is absolutely spot on. Captures the concept perfectly.
Is there a Part 3 to this series? I have no idea what to expect next, and no spoilers. But I hope to see this content continue!
Why Antioxidant Supplements Don't Work, Part 2
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