Fight Aging!

I was slowly planning to write something about a recent study that shows antioxidant supplements blocking (one part of) the mechanism by which exercise produces (some of its) health benefits. Here I am instead reaping the benefits of procrastination. If you leave a blog post percolating for long enough, someone else will do part of your job for you:

So, what actually causes [the beneficial effects of exercise on metabolism]? There has to be a signal (or set of signals) down at the molecular level that tells your cells what’s happening, and initiates changes in their metabolism. One good candidate is the formation of reactive oxygen species (ROS) in the mitochondria. Exercise most certainly increases a person’s use of oxygen, and increases the work load on the mitochondria (since that’s where all the biochemical energy is coming from, anyway). Increased mitochondrial formation of ROS has been well documented, and they have a lot of physiological effects.

...

as it turns out, antioxidant supplements appear to cancel out many of the beneficial effects of exercise. Soaking up those transient bursts of reactive oxygen species keeps them from signaling. Looked at the other way, oxidative stress could be a key to preventing type II diabetes.

By way of a reminder, you should recall that mitochondria produce ROS as a side effect of their normal operation as the cell's power plants. When they do more work, you get more ROS. It's a sort of pollution, and like other forms of pollution it can also be interpreted as a call to action.

This study is very interesting - given the importance of exercise to health and longevity, this could be the mechanism by which some studies of rodents found a negative effect on healthy life span through antioxidant supplements, one item that immediately springs to mind. However, as for all such studies, beware of ascribing all the benefits to the one new mechanism that has come to light. I think it's a fair bet, for example, that some percentage of the long-term metabolic benefits of exercise arise from shedding visceral fat:

We have previously demonstrated that surgical removal of visceral fat (VF) in rats improves insulin action, thus, we set out to determine if VF removal affects longevity. ... these observations provide the most direct evidence to date that a reduction in fat mass, and specifically VF, may be one of the possible underlying mechanisms of the anti-aging effect of [calorie restriction].

Though that said, this study was conducted over a period of a few weeks; hardly long enough to shed a significant amount of weight. Here's a link to the original paper if you'd like to follow up at your own pace - it's open access so the full PDF is available.

Consistent with the concept of mitohormesis, exercise-induced oxidative stress ameliorates insulin resistance and causes an adaptive response promoting endogenous antioxidant defense capacity. Supplementation with antioxidants may preclude these health-promoting effects of exercise in humans.

For the layperson, probably quite confused by the conflicting messages (and propaganda in some cases) about antioxidants, some important things to recognize about our biochemistry are:

• A chemical compound can be good, indifferent, or bad for health and the operation of your cells and tissues depending on both a) how much of it there is and b) exactly where it is in your cells.
• This is because evolution in complex systems - such as mammalian biochemistry - leads to a promiscuous reuse of components. Any given common biochemical might be important in tens of different mechanisms in different amounts, at different times, or under different circumstances. This is one of the reasons that manipulating our metabolism is so hard: the only levers that are easy to pull are each connected to a dozen different parts of the machinery and will each accomplish a dozen different (and probably undesirable) results when moved. I exaggerate for effect, but not by much.
• Hormesis in particular is one characteristic of this sort of evolved system with a lot of overlapping machinery - a small amount of a particular chemical can be much better for you than either none at all or a large amount.

So it is with reactive oxgen species (or free radicals) and the many mechanisms in the body that either generate or make use of them. Thus all of the following are well-supported by science:

• Free radicals generated by your mitochondria are damaging you so badly that they are a major contribution to aging. Differences in mitochondria between species appear to determine a large fraction of differences in longevity.
• Taking antioxidant supplements doesn't do anything for longevity, since those compounds don't end up near the mitochondria where the problem lies.
• Unless you have cleverly engineered an antioxidant that does end up in the mitochondria, of course, in which case you can boost mouse life spans by 30% or so. Not that we humans can buy that in a store yet.
• A temporary boost in the level of free radicals generated by your mitochondria (you know, the ones that are killing you slowly though various forms of biochemical damage) through exercise or other methods does a lot of good by telling the body to better defend itself.
• Unless you're taking antioxidant supplements, in which case the message never gets through, since the free radicals are consumed along the way.

Don't expect any of this to daunt the magical thinkers who are out there selling and consuming vast quantities of antioxidants based on the science of 20 years ago, of course. Large industries change slowly, buoyed to the end by their own inertia.

Ristow, M., Zarse, K., Oberbach, A., Kloting, N., Birringer, M., Kiehntopf, M., Stumvoll, M., Kahn, C., & Bluher, M. (2009). Antioxidants prevent health-promoting effects of physical exercise in humans Proceedings of the National Academy of Sciences DOI: 10.1073/pnas.0903485106