A lot of people still try to understand aging as a kind of accumulated damage, or wear-and-tear. Theories of oxidative damage are one poular version, and anti-oxidants have been promoted as a remedy for aging by people who should know better. One trouble with the damage theories is the of things that increase damage, but that lengthen life span. Exercise is the best example, but there are many others.
For twenty years and more, it has been clear that anti-oxidants don’t lead to longer life. More recently, there is evidence that anti-oxidants can actually take away the benefits of exercise. The latest such study was reported just last week.
Writing in her NYTimes column this week, Gretchen Reynolds reported on a Norwegian study* combining vitamin C and E supplements with a vigorous exercise program. The study recruited people who were already exercising, and intensified their aerobic program for 11 weeks, with both endurance exercise and interval training. The outcome that they highlighted was in the mitochondrial metabolism. Mitochondria are tiny “organelles”, hundreds of them in each cell, burning sugar to supply the cell with energy. One of the things that happens to increase strength and endurance in response to exercise is that the cells grow new mitochondria, and the existing mitochondria become more efficient. In the Norwegian study, this seemed to be happening on schedule in the test subjects who exercised without vitamin supplements, but not in the group taking vitamins. Nevertheless, endurance capacity of both groups was imroved by the exercise program.
The first result of this type (that I am aware of) was reported from a German study in 2009 **. In this study, non-exercisers were given an exercise program for just 4 weeks, and their insulin sensitivity and glutathione both improved; but supplementation with vitamins E and C blocked these benefits. I think both these are pretty good markers for aging – more basic and more closely-related to aging than mitochondrial markers. Of course, what we really would like to see would be long-term effects on mortality and longevity.
In between, there have been a number of studies confirming the effect. Here’s one that found that generation of new mitochondria is blocked by alpha lipoic acid. Another one related glutathione and mitochondrial markers to vitamin C. There are studies of old and young people, people who did no exercise prior to the experiment, and people who had exercised regularly, and were challenged with more. There were also some studies that failed to find an effect [ref for rats; ref for humans]
In one study of mice, very large doses of resveratrol seemed to give the mice great strength and endurance. However, in a human study last year (from this same Norwegian group), resveratrol diminished the benefits of exercise.
The theory is that temporary elevation of ROS (= free radicals, sources of oxidative damage) is a signal that tells the body to build new muscle, to proliferate mitochondria, and to improve the sensitivity to insulin. All these changes are plausibly related to better strength and health, and perhaps youthfulness. The fact that the effects appear when measuring a variety of outcomes from a variety of anti-oxidants (vitamins A, C, E, CoQ10 and resveratrol) lends to the credibility of this idea. Vitamin C, in particular, is intimately related to the energy metabolism of the mitochondria, lending plausibility to results for vitamin C in particular.
The bottom line, for me, is that results are still quite sketchy, that we don’t know the full story, that some physiological benefits of exercise seem to be blunted for some people, if certain anti-oxiadants are taken in combination with the exercise program. But the broader context is clear: Anti-oxidant vitamins have never been shown to increase life span in rodents, or to reduce mortality in humans. But exercise robustly increases life span in animal studies, and reduces mortality in humans. For me, the evidence is clear enough to advise against vitamin E and C supplements for people who exercise. For resveratrol and CoQ10, I remain uncertain.
* I get error messages when I try to pull up the original study in the Journal of Physiology. If I get a good web reference to the study, I’ll link it above and erase this footnote.
** There are precursors that go back to 1971, when competitive swimmers were given vitamin E, and it was reported to slow them down. Here’s a 1997 study that reported CoQ10 supplementation dragged down performance improvements from high-intensity sprint training.
Statin drugs, too, can erase the benefit of exercise.
They also can create muscle problems that make exercise painful or difficult. There are other down sides to statins as well. http://articles.mercola.com/sites/articles/archive/2013/10/09/statin-cholesterol-lowering-drugs.aspx
Most cardiologists find that it’s hard to motivate their patients to exercise, so the choice between statins and exercise is easy for them. However, someone should be thinking about the patients who are willing to exercise. Can changes in diet and exercise be a more effective alternative than statins for some heart patients?
Very interesting post, Josh. This certainly agrees with what we know about the ability of antioxidants to interfere with mitochondrial-driven homeostasis in terms of apoptosis. To me, the increased risk of cancer from taking antioxidants far outweighs any effect on exercise, since it shortens life. I’m sure you’re well aware of the large vitamin E and retinol studies done in the U.S. (Google search: CARET Study) and in Finland (see my post at http://bigthink.com/devil-in-the-data/the-dark-side-of-antioxidants), which took many years and involved tens of thousands of adults. Both studies showed that smokers who take vitamin E or retinol experience more cancer and more mortality. In fact, the U.S. study (which was terminated early, because of the finding of higher death rates) verified a dose-response relationship. The Cochrane Collaboration has also looked at this. There is no reasonable scientific doubt whatsoever that vitamin E and retinol interfere with normal apoptosis, and in so doing, they increase one’s cancer risks.
I have found your posts consistently informative, interesting, and well-researched. I’ve modified my diet as a result of some of your posts, and warned my friends of the possible risks to health of taking methionine, for example. I wonder if you’ve done any investigating of folic acid’s potentially harmful effects? Folate stimulates DNA methylation in mammals, which (it’s thought by some) can in turn complicate or even encourage tumorigenesis.
Good diet plan. My only reservation is that I’m dubious about short-term methionine restriction. It has been theorized that the way methionine restriction works is to limit protein synthesis, since methionine is the “start codon” that initiates all protein synthesis. I think that the body stores proteins for a good long time, and that one day without methionine won’t be missed.
“Writing in her NYTimes column this week, Gretchen Reynolds reported on a Norwegian study* combining vitamin C and E supplements with a vigorous exercise program. ”
The body rapidly absorbs ever greater amounts of vitamin C up to around 400mg, suggesting this is the optimal level doubling C blood levels further is said to require 10x increase in ingestion, iirc. Other animals produce quite a bit of vitamin C and don’t seem to have problems related to such production.
Regards vitamin E it’s been suggested that all tocopherols should be included for optimal nutrition. Simple alpha tocopherol megadose, is said to possibly not be as helpful and may even be detrimental. It is known that a diet rich in nuts on its own provides almost as much lifespan benefit as that gotten from exercise, and that the benefit of nut consumption is cummulative with exercise.
The benefit from nuts seems to be most probably from a complex lipid soluble antioxidant complex of substances including the tocopherols(unless nuts happen to share some compound that tweaks gene expression).
Vitamin C and Vitamin E can turn pro-oxidant at some doses, regards E as stated if supplemented with just alpha tocopherol it is said the result may not be as good as varied tocopherol intake. I could see vitamin C interfering if megadosed because it is water soluble, as for vitamin E it could affect via pro-oxidant status at high dose. But membrane pacemaker is a very strong hypothesis, and antioxidants, particularly those residing in membranes are extremely promising imho.
IT is said that there’s an age dependent decrease in Methionine sulfoxide reductases(which repair oxidative damage to methionine whose restriction has been linked to CR), also it is said that there’s a decrease in glutathione, and that there is an increase in membrane peroxidation index(membranes become more damage prone and can spread the damage far from the source.). All this points to an ever increasing damage load, guided one might say(the production of enzymes is controlled by gene expression and the membrane composition is tightly regulated), that may exceed homeostatic maintenance mechanisms accelerating the failure of the organism.
“However, in a human study last year (from this same Norwegian group), resveratrol diminished the benefits of exercise.”
That study was challenged by some individuals, which said it turned out the findings where not statistically significant.
” Anti-oxidant vitamins have never been shown to increase life span in rodents, or to reduce mortality in humans. But exercise robustly increases life span in animal studies, and reduces mortality in humans. For me, the evidence is clear enough to advise against vitamin E and C supplements for people who exercise.”
Resveratrol has increased the lifespan of yeast, worms, fruit flies, fish, mice fed a high-calorie diet, genetically induced mitochondrially dysfunctional mice, and in senescence accelerated SAMP8 and SAMR1 mice. Regards the studies that failed with normal lifespan mice, I’m prone to believe either strains not amenable to Calorie Restriction were used(would have to look at the studies) or errors in the procedures could’ve taken place.
Mitochondrially targetted antioxidants have been quite promising
“You might recall that researchers have in recent years demonstrated that antioxidants targeted to the mitochondria in your cells can boost life span in mice by around 20-30% or so.”https://www.fightaging.org/archives/2010/05/an-update-on-mitochondrially-targeted-antioxidants.php
And interventions that increase longevity can ramp up endogenous antioxidants or reduce production of ROS, such as with reduced membrane peroxidation index or even affect both.
Regards vitamin C and vitamin E. Vitamin C intake can easily surpass RDA in a high fruits and vegetable diet(other primates get high doses from their diet.), that required to prevent illness from disease is not the same as that required for optimal function of the body. Regards vitamin E a handful of nuts a day is recommended to get about 60% of the benefits on lifespan from exercise, and these benefits are about linearly cummulative with exercise(nuts will provide varied tocopherols as well as plenty of other antioxidants).