Sunday, February 13, 2011

Polyphenols, Hormesis and Disease: Part I

What are Polyphenols?
Polyphenols are a diverse class of molecules containing multiple phenol rings. They are synthesized in large amounts by plants, certain fungi and a few animals, and serve many purposes, including defense against predators/infections, defense against sunlight damage and chemical oxidation, and coloration. The color of many fruits and vegetables, such as blueberries, eggplants, red potatoes and apples comes from polyphenols. Some familiar classes of polyphenols in the diet-health literature are flavonoids, isoflavonoids, anthocyanidins, and lignins.

The Case Against Polyphenols

Many diet-health authorities seem pretty well convinced that dietary polyphenols are an important part of good health, due to their supposed antioxidant properties. In the past, I've been critical of the hypothesis. There are several reasons for it:
  1. Polyphenols are often, but not always, defensive compounds that interfere with digestive processes, which is why they often taste bitter and/or astringent. Plant-eating animals including humans have evolved defensive strategies against polyphenol-rich foods, such as polyphenol-binding proteins in saliva (1).
  2. Ingested polyphenols are poorly absorbed (2). The concentration in blood is low, and the concentration inside cells is probably considerably lower*. In contrast, essential antioxidant nutrients such as vitamins E and C are efficiently absorbed and retained rather than excluded from the circulation.
  3. Polyphenols that manage to cross the gut barrier are rapidly degraded by the liver, just like a variety of other foreign molecules, again suggesting that the body doesn't want them hanging around (2).
  4. The most visible hypothesis of how polyphenols influence health is the idea that they are antioxidants, protecting against the ravages of reactive oxygen species. While many polyphenols are effective antioxidants at high concentrations in a test tube, I don't find it very plausible that the low and transient blood concentration of polyphenols achieved by eating polyphenol-rich foods makes a meaningful contribution to that person's overall antioxidant status, when compared to the relatively high concentrations of other antioxidants in blood* (uric acid; vitamins C, E; ubiquinone) and particularly inside cells (SOD1/2, catalase, glutathione reductase, thioredoxin reductase, paraoxonase 1, etc.).
  5. There are a number of studies showing that the antioxidant capacity of the blood increases after eating polyphenol-rich foods. These are often confounded by the fact that fructose (in fruit and some vegetables) and caffeine (in tea and coffee) can increase the blood level of uric acid, the blood's main water-soluble antioxidant. Drinking sugar water has the same effect (2).
  6. Rodent studies showing that polyphenols improve health typically use massive doses that exceed what a person could consume eating food, and do not account for the possibility that the rodents may have been calorie restricted because their food tastes awful.
The main point is that the body does not seem to "want" polyphenols in the circulation at any appreciable level, and therefore it gets rid of them pronto. Why? I think it's because the diversity and chemical structure of polyphenols makes them potentially bioactive-- they have a high probability of altering signaling pathways and enzyme activity, in the same manner as pharmaceutical drugs. It would not be a very smart evolutionary strategy to let plants (that often don't want you eating them) take the reins on your biochemistry. Also, at high enough concentrations polyphenols can be pro-oxidants, promoting excess production of free radicals, although the biological relevance of that may be questionable due to the concentrations required.

A Reappraisal

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. There are many such studies, and I won't attempt to review them comprehensively, but here are a few I've come across:
  • Dr. David Grassi and colleagues showed that polyphenol-rich chocolate lowers blood pressure, improves insulin sensitivity and lowers LDL cholesterol in hypertensive and insulin resistant volunteers when compared with white chocolate (3). Although dark chocolate is also probably richer in magnesium, copper and other nutrients than white chocolate, the study is still intriguing.
  • Dr. Christine Morand and colleagues showed that drinking orange juice every day lowers blood pressure and increases vascular reactivity in overweight volunteers, an effect that they were able to specifically attribute to the polyphenol hesperidin (4).
  • Dr. F. Natella and colleagues showed that red wine prevents the increase in oxidized blood lipids (fats) that occurs after consuming a meal high in oxidized and potentially oxidizable fats (5).
  • Several studies have shown that hibiscus tea lowers blood pressure in people with hypertension when consumed regularly (6, 7, 8). It also happens to be delicious.
  • Dr. Arpita Basu and colleagues showed that blueberries lower blood pressure and oxidized LDL in men and women with metabolic syndrome (9).
  • Animal studies have generally shown similar results. Dr. Xianli Wu and colleagues showed that whole blueberries potently inhibit atherosclerosis (hardening and thickening of the arteries that can lead to a heart attack) in a susceptible strain of mice (10). This effect was associated with a higher expression level of antioxidant enzymes in the vessel walls and other tissues.
Wait a minute... let's rewind. Eating blueberries causes mice to increase the expression level of their own antioxidant enzymes?? Why would that happen if blueberry polyphenols were protecting against oxidative stress? One would expect the opposite reaction if they were. What's going on here?

In the face of this accumulating evidence, I've had to reconsider my position on polyphenols. In the process, and through conversations with knowledgeable researchers in the polyphenol field, I encountered a different hypothesis that puts the puzzle pieces together nicely.  I'll discuss that in the next post.

* Serum levels of polyphenols briefly enter the mid nM to low uM range, depending on the food (2). Compare that with the main serum antioxidants: ~200 uM for uric acid, ~100 uM for vitamin C, ~30 uM for vitamin E.


Helen said...

I think hormesis is a good theory of one way in which polyphenols work. I also think some could have a pharmacological effect, mimicking substances in our own bodies and/or up/downregulating gene replication or expression. for instance, a Chinese herbal remedy (FAFH-2) being studied for anaphylaxis seems to downshift the part of the immune system that becomes overactive in an allergic reaction to food.

It makes sense that we have adapted to various substances in plants, some of which might be toxic at some level, as a lot of polyphenols are. Some might be used by the body environmental cues, indicating seasons, food availability, and so on, helping us adapt to the current state of affairs (evolutionarily, of course - not the 24-hour all-season supermarket). I suspect some may also help one process other substance found in the plant - like fructose in fruits or perhaps an influx of carbs. For instance, phytic acid (I know, I know) upregulates the enzyme glucokinase, which stimulates insulin response. Handy when you've just eaten a lot of grain.

Anonymous said...

A cliff-hanger! I'm a little skeptical of hormesis altogether, where can we see it at work in humans?

Markus said...

Over the last couple of weeks I´ve been reading through all of your posts. I Have to say it's the absolute best health and nutrition blog I´ve ever come across. Keep it up!

Anonymous said...

Antioxidants whether inborn or from food may be a mixed blessing.
Have you read Aubrey de Grey's Ending Aging?
Rather than what the title promise it's a devastating account of the incredible mess of human metabolism.

Anonymous said...


You might find the following article by Ray Peat on caffeine of interest:

Might-o'chondri-AL said...
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Anonymous said...

PDM, Jack C,

Testing at 23andme revealed that I have a SNP that codes for slow metabolism of caffeine. There is a paper from JAMA in 2006 showing increased rates of non-fatal MI for coffee drinkers with slow caffeine metabolism. Other than that, it seems like the rest of the data on coffee is positive. Sadly, I'm cutting back on my intake...

David Pier said...

Very pleased to see the beginning of this series of posts. As I have let you know, this seems to me the most important aspect of nutrition that you haven't covered in detail. It didn't take much for you to bring me around to the hormetic basis of the benefit of polyphenols, as I already had a longstanding understanding of the hormetic mechanism of action of glucosinolates from cruciferae. Please don't neglect to mention, somewhere in this series of posts, the similar mechanism of action of glucosinolates and other non-polyphenol beneficial plant chemicals.

gibby1979 said...

I look at a lot of polyphenols and my first question is "do they interact with the Aryl hydrocarbon receptor". Lots of em do and I'm not a big fan of the response you see from that interaction.

David L said...


When you get to tea, I will be most interested. Is there are good theory as to why green is better than black -- how about white? What about (greem) tea extracts? I know you generally are for whole foods, but I take them because, despite the fact that I drink a fair amount of tea, I just don't compare to the Japanese in volume.

I am a bit more skeptical about resveratrol. I definitely believe in the value of alcohol on well-being, but find most studies seem to be neutral in terms of the specific means of delivery. I think that it's just too convenient for the "French paradox," which I find to be a very mushy and hard to quantify hypothesis. But I will certainly drink to it if Resveratrol is found to be of great value -- but if so, can we get the advantage by taking supplements?

I really think we can't wander too far away from the issue of fat-soluble vitamins. There seems to be so much strong evidence regarding omega-3s, cod liver oil, vitamin butter oil, whole milk and the rest. One of your readers made the comment that our dietary habits have left us with the same amount of calories from fat, but that we have replaced half of the animal fat with industrial seed oils. I remember the study which you cited which showed that taking margarine was more deadly than cigarettes and tobacco combined (or so I seem to recall)

Checking in for the night after having approximately 16 ounces of (black) iced tea.

benn686 said...

This article takes more twists and turns than I have no idea what direction I'm looking at!

Is eating a lot of polyphenol rich foods a good thing?

What about pytochemicals related to polyphenols, like anthocyanin?

Usually black/purple are supposed to indicate healthy (black rice, purple potatoes, etc)

Reijo said...

This is going to be intresting series! I don't know what are the rest of the series to contain but hopefully you will cover the ability of polyphenols to increase nitric oxide production as well. It's not only arginine and nitrates that augment our arteries. See for example:
I just wonder how powerful is this phenomenon is in comparison to arginine/nitrate effects.

Scott Pierce said...

For some reason, I just always thought of hormesis as an odd little quirk shown with concentric circles surrounding devastating human events like Nagasaki or the Dupont dioxin spill. Don't know why I didn't think of it in more common, everyday biology level.

Unknown said...

Another possibility (not excluding hormesis) may be that polyphenols are closely associated with other beneficial substances, for example mineral nutrients that are generally short in the modern diet, as in the example given of dark chocolate rich not only in polyphenols but also Mg and Cu.

donny said...

I think a problem with phytonutrients is that any lifeform contains a myriad of organic substances. The odds that there is something in just about any whole food that will improve some measure of metabolism, by some mechanism, if you just look hard enough and find the right dose, becomes exceedingly high. Probably around 100 percent, given enough time and the right technology. (I'm not saying there's never an advantage to dietary polyphenols, just that studies using therapeutic levels of these substances can be kind of of silly when used to suggest that intake of particular foods should be increased).

Pasi said...

Interesting topic, Stephan. Let's see where you lead us...

Mt-AL talked about energy sparing effect and Gibby mentioned aryl hydrocarbon receptor. Important stuff in my opinion.

I have to remind that majority of in vitro polyphenol studies could have zero value since they've usually been looking at wrong compounds.

Gut microbes do metabolize fiber bound plant polyphenols and that will result small fat soluble biologically active compounds like urolithins. I think that these microbe derived metabolites could explain a lot. This is also why I find information from resveratrol studies extremely important.

Chris Masterjohn said...

Great intro Stephan. Our lab uses green tea to positive effect at doses achievable in humans drinking amounts used in Asia, with evidence for upregulating antioxidant enzymes.


John said...


About the Grassi et al. chocolate study: I also thought that the dark chocolate would have higher magnesium. But according to the online supplement (table 1) [1], 100 grams of dark chocolate had 9.8 mg vs. 25 mg in the white chocolate... The white chocolate also had higher calcium. The dark chocolate was much higher in potassium, 1142 mg vs. 287.5 mg, and slightly higher sodium. So the potassium could also be a reason for the blood pressure reduction.
Also nice to note: the dark chocolate had almost twice the amount of fat of the white chocolate. So much for the idea that low fat is heart-friendly ;-)



Jeremy said...

This is a fantastic review... I've been wondering whether there was any evidence for benefit aside from the (implausible) antioxidant hypothesis. The studies you cite are very interesting, although I'm concerned that at least some of the evidence for benefit could be influenced by publication bias. Polyphenol "antioxidants" are so popular these days that I imagine there must be hundreds of studies being done, especially since they're relatively easy and inexpensive to do. That means there could be a lot of unpublished small studies showing no effect. Some of the effects in the studies you list, for example, are weak enough to be suspect, given the number of studies that are presumably done on polyphenols. On the other hand, I think the overall picture is reasonably clear: there's almost certainly some effect from some polyphenols. My question, which I'm not sure you can answer, is whether we should expect all or a large class of polyphenols to exhibit similar effects. Should all these "antioxidants" activate the same pathways and provide the same hormetic benefits? Or should we expect polyphenols to exhibit effects that we can't really predict yet, with some of them improving health, others having no effect, and maybe some causing damage?

David Isaak said...

This is promising to be a fascinating series. As to the whole "antioxidant" concept of plant chemicals, well... antioxidants are the flavor of the week. Or rather decade.

On Hormesis, a fellow named Todd Becker has an amazing blog about the benefits of stress of all sorts. (He calls his philosophy "Hormetism.") You can find it at: .

Might-o'chondri-AL said...
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Might-o'chondri-AL said...
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joetheplumber said...

Polyphenols are a double-whammy. You get the beneficial gene expression derived from certain polyphenols (even if they do only reach low serum concentrations, chronic ingestion will alter genetic expression). But secondly, your body thinks these compounds are harmful so it ups its own antioxidant defenses. You can't lose.

Unknown said...

Hibiscus tea is quite nice, but IMO needs more sweetening than other teas. It also stains.

Now I'm going to brew some hibiscus tea with green tea, and liquidize some frozen blueberries to put in also (maybe I won't have to put in so much stevia with the natural sweetness of the blueberries).

Red, green, blue tea (RGB Tea haha).

douglis said...

So...polyphenols are good or bad???

Jack said...


stephan left us with a cliffhanger... to be continued. basically he gave several reasons to suspect some issues with polyphenols, but then in his due diligence he found some strong evidence that supports the concept that polyphenols may have some note worthy health benefits. this is part 1 of a series...

douglis said...

Oh...he's a big teaser.Can't wait for part 2.

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Morris said...

Your posts are puzzles to me and perhaps to others; they could be brilliant insights or gibberish. It would help if you simplified the explanations, suitable to the apparent understanding of the readers and also indicated how your comments relate to the subject at hand. By all mean keep it coming and thanks for making the effort.

Carlos Monteiro said...

Hi Stephan,
Regarding the anti-oxidant hypothesis there are some recent studies suggesting that cacau, vitamin C, vitamin E, and folic acid improve baroreflex sensitivity (1, 2, 3, 4, 5, 6). The result of this baroreceptor improvement is the inhibition of the sympathetic nervous system and activation of the parasympathetic nervous system. The confirmation by new researches of this property in the cited anti-oxidants shall strength our acidity theory of atherosclerosis. In the acidity theory of atherosclerosis point of view sympathetic predominance is the primary factor in the cascade of events leading to the atherogenic spiraling.
Carlos Monteiro
Blog: http://www.acidity

1. Kevin D. Monahan et al, Ascorbic acid increases cardiovagal baroreflex sensitivity
in healthy older men. Am J Physiol Heart Circ Physiol 286: H2113–H2117, 2004.
2. Gianfranco Piccirillo et al., Influence of Vitamin C on Baroreflex Sensitivity in
Chronic Heart Failure. Hypertension. 2003; 41:1240-1245.
3. Peter Studinger et al., Effect of vitamin E on carotid artery elasticity and baroreflex gain in young, health adults. Autonomic Neuroscience, V 113, I1, Pages 63-70; 2004
4. Akita M et al., Effects of cacao liquor polyphenols on cardiovascular and autonomic nervous functions in hypercholesterolaemic rabbits. Basic Clin Pharmacol Toxicol. 2008 Dec;103(6):581-7.
5. Markus B├ęchir et al., Folic Acid Improves Baroreceptor Sensitivity in Hypertension. J Cardiovasc Pharmacol;45:44–48), 2005
6. Xiu-juan MA et al, Clonidine, moxonidine, folic acid, and mecobalamin improve baroreflex function in stroke-prone, spontaneously hypertensive rats. Acta Pharmacol Sin 2007 Oct; 28 (10): 1550–1558
7. Carlos ETB Monteiro, Acidic environment evoked by chronic stress: A novel mechanism to explain atherogenesis. Available from Infarct Combat Project, January 28, 2008 at

douglis said...

Hey...I think this is relevant:
"The hormetic role of dietary antioxidants in free radical-related diseases.

Dietary polyphenols present strong cytoprotective effects, however under uncontrolled nutritional supplementation gene induction effects and the interaction with detoxification responses can have negative consequences through the generation of more reactive and harmful intermediates."

Carlos Monteiro said...

Just in time, there is a paper from 2007 telling that resveratrol inhibits carotid baroreceptor activity (1)
Carlos Monteiro

1. Xue Hm et al. Effect of resveratrol on baroreceptor activity of carotid sinus in anesthetized male rats.Yao Xue Xue Bao . 2007 Jun;42(6):601-6.

Mindscaper said...

These two posts are fascinating (narigin/PPAR/Mtor). I've been doing a Paleo diet (modified PaNu)still include raw dairy but no grains or beans or PUFAs (except CLO, and what can't be avoided in some foods)no seeds or seed oils, very limited fruit. A few Veggies are included-mostly greens. Good fats and eggs.
I was skinny most of my life until right before menopause--gradually gained 40 lbs over next 10 years despite exercise and what I was convinced was mostly a "healthy diet" (turns out it was the low fat BS and PUFAs through the roof!) With full blown metabolic syndrome I have been unable to lose weight easily and although a struggle over the past two years I have lost 20 lbs. The last 10 pounds actually did come off quickly finally but only during a month of ADF (alternate day fasting).
My natural (comfortable) eating schedule after being Paleo for about 6 months became about once/day-rarely twice, so I actually do IMF nearly every day. After doing this (IMF) for nearly 6 months, I still could not lose a pound--so I tried ADF and it worked. My fBG is getting better and postprandial is not as high so my glucose tolerance is gradually improving. Now to my questions to you:
1. I do not graze BUT I have not been able to completely eliminate the stevia/dextrose sweetner (1/2 packet) in my coffee with heavy cream that I drink 3-4 times a day (closer to 4 on fast days). The coffee/stevia/cream temporarily raises my blood sugar sometimes 10, sometimes 20 pts. I should eliminate it, I guess, but it enables me to keep up the ADFasting once I psych myself into doing that again. Do you know of any other drink that I could use as a crutch like caffeinated coffee that would not interfere with ADF and keep my blood sugar low. I've tried roobios tea w honey and that raised it just as much. What about yerba mate?

The only other thing I have on fast days is lemon juice w/water or some days 4 oz of pomegranite juice.

2. Is narigin available as a supplement or is it just as good/better to zest a grapefruit. Would it help with metabolic syndrome?

3. Do you know of anything that lowers overexpression of PP1?
Maybe you are not the one to ask about these things but your posts indicate that you might be.

Might-o'chondri-AL said...
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JohnN said...

Love your stream of consciousness.
Please keep it coming.

MaLo said...

Two additional theories to throw into the ring.

Polyphenols are active as antioxidants in the GI tracts, potentially preventing GI cancers...

Polyphenols effect epigentic changes, generally preventing promoter hypermehtylation. In a fortified world where people get too much folic acid, which causes promoter hypermethylation, a thumb on the other side of the scale may help...

joetheplumber said...

Polyphenols do effect epigentic changes, but the effect is not only to modulate methylation, as the vast amount of data in mice shows. Polyphenols can, for instance, stimulate the production of nitric oxide (cacao flavonols), speed fat metabolism in the liver (naringenin), strongly inhibit the formation of glycation end products (rutin), or even promote the elasticity of blood vessels (hesperidin).

microkat said...

To add to your list of documented benefits of polyphenols, here is a study that shows the effects of tannic acid on beta amyloid plaques of Alzheimer's. Apparently it prevents formation and extension of the plaques, and destabilizes them once formed in vitro.

[M] said...

So I suppose taking supplemental quercetin for allergies and other inflammatory conditions is really bad? I read a study in which quercetin was shown to quell peanut induced anaphylaxis in rats and have since given it to my peanut allergic son (with bromelain for increased absorption).

I have also read the work of Dr. Theoharides, who uses quercetin (among other things) to treat inflammatory conditions including autism. Quercetin supposedly inhibits the production of mast cells and can be used to treat several conditions related to mast cell production.

joetheplumber said...

Quercetin is an awesome nutrient likely responsible for the anti-carcinogenic effects of onions. The thing to keep in mind is that when these polyphenols are isolated, if they are dosed too strongly, then they can cause damage. For example, .1% dietary quercetin was found to reduce the lifespan of male mice. On the other hand, a blackcurrant juice extract, containing a mixture of flavonoids in addition to quercetin, prolonged significantly the life span of the 'older dying' female mice. (PMID: 7140862)

Neonomide said...

Thanks a lot for the hibiscus hint, Stephan!

I personally experienced a whopping drop in BP last year, concurrently when I took pretty wild doses of Vit D. I of course attributed the drop to D3, yet now I really have to reconsider it a combo effect. My BP was around 115/60, a lot lower than ever.

I must try hibiscus without changing anything else right now!

I had milder hypertension since being a child, not fun stuff.

Might-o'chondri-AL said...
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Dr. Curmudgeon Gee said...

the plot thickens....

i'd be interested in the studies about tea too.



Might-o'chondri-AL said...
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douglis said...

Polyohenols are phytoestrogens.Does anyone know their effect in testosterone levels?

benn686 said...

polyphenols and anthocyanin are in so much good stuff (coffee, cinnamon, chocolate, black rice/potatoes, etc) that I tend to think they must be good!

However, if you can get too much antioxidants, then I suppose you can get too much polyphenols/anthocyanins

gibby1979 said...

So I've read both good and bad things about the bioavailability of compounds like quercetin. It inhibits SGLT translporters, and I believe some GLUT transporters, but I don't believe it is taken up by them.
I think this extends to a lot of polyphenols, great results in celulo (culture dish etc.), poor uptake when you look at a model animal or even a Caco 2 layer. Resveratrol is a great example, great in the dish, but to get effective levels in the blood to even give a bilogical response you're looking at a ridiculous daily dose.
I started in food science and moved to pharmaceutical sciences. there are so many "nutraceuticals" that just don't cross biological barriers. Never forget the pharmakokinetics.

joetheplumber said...
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joetheplumber said...

"(Resveratrol) great in the dish, but to get effective levels in the blood to even give a bilogical response you're looking at a ridiculous daily dose. "

Where are you getting this from? I've followed hundreds of resveratrol (in vivo) studies. While serum levels from oral dosing are indeed very low, it is still biologically active. Mice studies, for instance, see huge changes in gene expression resembling that of CR by utilizing ONLY 1-4mg/kg/day. With metabolic scaling, the human dose equivalent is only a couple hundred milligrams or less.

Anonymous said...

I am not sure about the whole facts related to Polyphenols. However, I learned somewhere that it helps slowing down the process of aging which is commonly associated with the damage caused by free radicals but in contrast, here I read that high concentration of Polyphenols do this: "promoting excess production of free radicals"! Which is true? Did I assume in a wrong way!?

Ulla said...

This was interesting.

A link:

I like people that think themselves.

Gatersaw said...

There are plenty of people supplementing for decades on herbs, vitamins, extracts, etc and in my experience they are much more healthy, happy and long lived.