February 27, 2011
Polyphenols Protect As Mild Stressors

Stephan Guyenet recently did 2 posts explaining that antioxidant properties do not explain the (quite real) health benefits of polyphenols in the diet and therefore another mechanism must be at work.

After reading more about polyphenols, and coming to understand that the prevailing hypothesis of why they work makes no sense, I decided that the whole thing is probably bunk: at best, specific polyphenols are protective in rodents at unnaturally high doses due to some drug-like effect. But-- I kept my finger on the pulse of the field just in case, and I began to notice that more sophisticated studies were emerging almost weekly that seemed to confirm that realistic amounts of certain polyphenol-rich foods (not just massive quantities of polyphenol extract) have protective effects against a variety of health problems.

Stephan then proceeds to list a sampling of recent studies showing health benefits from polyphenols. Click thru to read the details. Though if you are regular reader here you've seen similar reports such as berries cutting Parkinson's risk, red wine polyphenols to slow blood vessel aging, black raspberries to cut colon cancer risk, blueberries to also cut colon cancer risk, many posts about the glories of chocolate, and of course benefits of cherries.

Aside: I accidentally discovered some years back that eating Montmorency cherries shifted my body clock to wake up earlier. I can even tell you why: high melatonin. So foods are drugs. Cherries even attracted the (unwanted as far as I am concerned) attention of the US Food and Drug Administration.

Okay, back on point: The thrust of Stephan's first post above was that the main theory advanced for the benefits of polyphenols (antioxidant effect) does not stand up to scrutiny. Yet much to his surprise the foods that contain polyphenols really do benefit health for reasons related to their polyphenol concentrations. Why? He gives a clue in the first post:

Wait a minute... let's rewind. Eating blueberries caused mice to increase the expression level of their own antioxidant enzymes?? Why would that happen if blueberry polyphenols were themselves having a direct antioxidant effect? One would expect the opposite reaction if they were. What's going on here?

For some more biologically knowledgeable readers that clue is enough. Anyone see it? Stephan likes to set up his ideas in one post, leave his regular readers (including me btw) hanging, and then provide the answers one or two posts later. To save my own readers the agony of suspense I waited until he came out with his second post. He starts out with the observation that other known mild stressors can improve long term health by up-regulating the body's repair and protection mechanisms.

One of the more curious things that has been reported in the scientific literature is that although high-dose ionizing radiation (such as X-rays) is clearly harmful, leading to cancer, premature aging and other problems, under some conditions low-dose ionizing radiation can actually decrease cancer risk and increase resistance to other stressors (1, 2, 3, 4, 5). It does so by triggering a protective cellular response, increasing cellular defenses out of proportion to the minor threat posed by the radiation itself. The ability of mild stressors to increase stress resistance is called "hormesis." Exercise is a common example. I've written about this phenomenon in the past (6).

The ideal stressor probably would have a very low level of toxicity while eliciting a large repair and defense response. Finding out which polyphenols are best from that standpoint is not trivial though. Whatever damage they cause must be measured as well as the level of each protective response (e.g. up-regulation of each of the enzymes that break down free radicals and other toxins).

Stephan says the body's responses to polyphenols overlap with the body's responses to low level radiation.

Although it may not be obvious, radiation and polyphenols activate a cellular response that is similar in many ways. Both activate the transcription factor Nrf2, which activates genes that are involved in detoxification of chemicals and antioxidant defense**(9, 10, 11, 12). This is thought to be due to the fact that polyphenols, just like radiation, may temporarily increase the level of oxidative stress inside cells. Here's a quote from the polyphenol review article quoted above (13):

We have found that [polyphenols] are potentially far more than 'just antioxidants', but that they are probably insignificant players as 'conventional' antioxidants. They appear, under most circumstances, to be just the opposite, i.e. prooxidants, that nevertheless appear to contribute strongly to protection from oxidative stress by inducing cellular endogenous enzymic protective mechanisms. They appear to be able to regulate not only antioxidant gene transcription but also numerous aspects of intracellular signaling cascades involved in the regulation of cell growth, inflammation and many other processes.
It's worth noting that this is essentially the opposite of what you'll hear on the evening news, that polyphenols are direct antioxidants. The scientific cutting edge has largely discarded that hypothesis, but the mainstream has not yet caught on.

Stephan is on the scientific cutting edge. His own diet and blood lipids are unusual. Since that post is a few years old and he's made adjustments since then I'd be very curious to know exactly how he's eating today. Probably eating more polyphenol-rich food for one.

Share |      Randall Parker, 2011 February 27 01:38 PM  Aging Diet Metabolism

jmanon said at February 28, 2011 8:22 AM:

I spent the last few years building up an immunity to iocane powder

Lou Pagnucco said at March 2, 2011 8:29 PM:

There a quite a few online papers demonstrating that many polyphenols reduce formation of cell cluttering protein aggregates - which also appear to be good biomarkers of aging. It would be interesting to know whether high-polyphenol/flavonoid diets have this effect in humans, and in what cell types.

In said at March 3, 2011 12:03 PM:



Ford Denison said at March 17, 2011 12:04 PM:

" mild stressors can improve long term health by up-regulating the body's repair and protection mechanisms"

So why aren't those "repair and protection" mechanisms turned on all the time, if they're universally beneficial? There must be some tradeoff. The most likely one is the well-known tradeoff between fertility and longevity. Levels of testosterone, etc., that are optimal for reproduction aren't optimal for longevity. So our hypothesis is that these stressors are beneficial because they move our bodies' reproduction-versus-longevity switch towards greater longevity. Why would stressors as different as polyphenols and radiation all have the same effect? See my recent paper in Evolutionary Applications!

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