Polyphenols, Hormesis and Disease: Part II

Thursday, February 24, 2011
In the last post, I explained that the body treats polyphenols as potentially harmful foreign chemicals, or "xenobiotics". How can we reconcile this with the growing evidence that at least a subset of polyphenols have health benefits?

Clues from Ionizing Radiation

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 Case of Resveratrol

Resveratrol is perhaps the most widely known polyphenol, available in supplement stores nationwide. It's seen a lot of hype, being hailed as a "calorie restriction mimetic" and the reason for the "French paradox."* But there is quite a large body of evidence suggesting that resveratrol functions in the same manner as low-dose ionizing radiation and other bioactive polyphenols: by acting as a mild toxin that triggers a hormetic response (7). Just as in the case of radiation, high doses of resveratrol are harmful rather than helpful. This has obvious implications for the supplementation of resveratrol and other polyphenols. A recent review article on polyphenols stated that while dietary polyphenols may be protective, "high-dose fortified foods or dietary supplements are of unproven efficacy and possibly harmful" (8).

The Cellular Response to Oxidants

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.

Nrf2 is one of the main pathways by which polyphenols increase stress resistance and antioxidant defenses, including the key cellular antioxidant glutathione (14). Nrf2 activity is correlated with longevity across species (15). Inducing Nrf2 activity via polyphenols or by other means substantially reduces the risk of common lifestyle disorders in animal models, including cardiovascular disease, diabetes and cancer (16, 17, 18), although Nrf2 isn't necessarily the only mechanism. The human evidence is broadly consistent with the studies in animals, although not as well developed.

One of the most interesting effects of hormesis is that exposure to one stressor can increase resistance to other stressors. For example, long-term consumption of high-polyphenol chocolate increases sunburn resistance in humans, implying that it induces a hormetic response in skin (19). Polyphenol-rich foods such as green tea reduce sunburn and skin cancer development in animals (20, 21).

Chris Masterjohn first introduced me to Nrf2 and the idea that polyphenols act through hormesis. Chris studies the effects of green tea on health, which seem to be mediated by polyphenols.

A Second Mechanism

There is a place in the body where polyphenols are concentrated enough to be direct antioxidants: in the digestive tract after consuming polyphenol-rich foods. Digestion is a chemically harsh process that readily oxidizes ingested substances such as polyunsaturated fats (22). Oxidized fat is neither healthy when it's formed in the deep fryer, nor when it's formed in the digestive tract (23, 24). Eating polyphenol-rich foods effectively prevents these fats from being oxidized during digestion (25). One consequence of this appears to be better absorption and assimilation of the exceptionally fragile omega-3 polyunsaturated fatty acids (26).

What does it all Mean?

I think that overall, the evidence suggests that polyphenol-rich foods are healthy in moderation, and eating them on a regular basis is generally a good idea. Certain other plant chemicals, such as suforaphane found in cruciferous vegetables, and allicin found in garlic, exhibit similar effects and may also act by hormesis (27). Some of the best-studied polyphenol-rich foods are tea (particularly green tea), blueberries, extra-virgin olive oil, red wine, citrus fruits, hibiscus tea, soy, dark chocolate, coffee, turmeric and other herbs and spices, and a number of traditional medicinal herbs. A good rule of thumb is to "eat the rainbow", choosing foods with a variety of colors.

Supplementing with polyphenols and other plant chemicals in amounts that would not be achievable by eating food is probably not a good idea.

* The "paradox" whereby the French eat a diet rich in saturated fat, yet have a low heart attack risk compared to other affluent Western nations.

** Genes containing an antioxidant response element (ARE) in the promoter region. ARE is also sometimes called the electrophile response element (EpRE).

Will the Congress Change the Health Care Law During the Next Two Years?

Tuesday, February 15, 2011
No. But I expect the Patient Protection and Affordability Act to be “relitigated” in 2013, to one degree or another.I recently posted on the controversy over the individual mandate. I suggested a number of alternatives to the mandate—including my own ideas.I was asked if I really thought the Congress would change the individual mandate in the short term.As I have posted before, it will be the

Polyphenols, Hormesis and Disease: Part I

Sunday, February 13, 2011
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.

Alternatives to the Individual Mandate—Some Are A Lot Better Than Others

Saturday, February 12, 2011
With Constitutional challenges to the individual mandate now threatening the very life of the new health care law, Republicans aren’t the only ones that would like to see it jettisoned and replaced with something better.And it isn’t just the Constitutional challenges that are prompting a second look. The mandate doesn't work politically and it doesn't maintain the integrity of the market because

My Gluten-Free January

Thursday, February 10, 2011
I've been avoiding most gluten, particularly wheat, for over a year now. I never had obvious symptoms that I could clearly link to eating wheat, although I had my suspicions. I've made many changes to my diet over the last decade, and I feel much better than I did ten years ago, but it's hard to disentangle all the factors. I don't think I ever went an entire month without eating any gluten at all before this January. After posting Matt Lentzner's challenge to go gluten-free this January, I felt obligated to do it myself, so I signed up!

I succeeded in avoiding all gluten for the month of January, even though it was a pain at times. I felt good before January, and didn't start with any health or body weight problems, so there wasn't much to improve. I also felt good while strictly avoiding gluten this January, perhaps a little better than usual but it's hard to say.

At the end of the month, I did a blinded wheat challenge using the method I described in a previous post, which uses gluten-free bread as the placebo (1). I recorded my blood sugar at 30 minute intervals after eating the bread, and recorded how I felt physically and emotionally for three days after each challenge.

The result? I think the bread gave me gas, but that's about it. I'm not even positive that was due to the wheat. My energy level was good, and I didn't experience any digestive pain or changes in transit time. There was no significant difference in my blood glucose response between the bread and the gluten-free bread.

I decided that I didn't have any symptoms, so I celebrated by having a porter (1) with friends a few nights later. I slept poorly and woke up with mild digestive discomfort and gas. Then I ate wheat later in the week and slept poorly and got gas again. Hmmm...

Some people might say that the body adapts to any food, and wheat is no different. Go without it for a while, and the body has a tough time digesting it. But I can go for weeks without eating a potato, a chicken thigh or broccoli, and all will digest just fine when I eat them again.

I'm pretty sure I don't have a severe reaction to gluten. I think I'm going to stick with my mostly gluten-free habits, and eat it occasionally when I'm offered food in social situations.

Did anyone else do a blinded wheat challenge? Describe it in the comments!

Things Are About to Get Ugly—-Republicans Plan to Defund the Health Bill Next Week

Wednesday, February 9, 2011
Word is that House Republicans will attach an amendment to the latest federal spending bill that will cut-off funding for the health care bill.The last Congress never finalized a budget for the current fiscal year—the feds have been operating under a series of continuing resolutions. The most recent one will expire on March 4th. If another resolution is not agreed to, much of the government has

Gluten-Free January Raffle!

Hi, Gluten-Free January participants. Matt, Janine and I have collected about 200 survey responses at this point. So far, the results are very interesting! But we want to get as many responses as possible, because the more responses we get, the more informative the data will be for all of us. So please fill out the survey Matt sent you by e-mail, no matter what your results were, and no matter whether you stuck with the diet or not! The survey is strictly about your GFJ experience, not investment opportunities, timeshares, ShamWows or anything else. It will take you less than 5 minutes, and it's totally anonymous. The deadline is Feb 15th. Big thanks to everyone who has taken it so far.

To encourage participants to complete the survey, we're organizing a raffle. Matt and I have five Gluten-Free January T-shirts we're ready to give out for free. These shirts were designed by Matt and they're really cool. I have one myself, and the print and fabric quality are top notch. Here's what the logo looks like:
If you've completed the survey and want to be included in the raffle, please e-mail Matt to let him know you've completed it. Anyone who has already e-mailed Matt to let him know they completed the survey will automatically be entered, so no need for a second e-mail. So far, very few people have written Matt, so your probability of winning a shirt is high!

Assorted Thoughts About the 2010 Dietary Guidelines

Saturday, February 5, 2011
In the past week, I've been rooting through the USDA's 2010 Dietary Guidelines (1). Here are a few of my thoughts.


One of the things I've been enjoying recently is watching health authorities shift away from a nutrient-oriented philosophy in favor of a more food-oriented philosophy. For example, I recently read a nice editorial by Drs. Dariush Mozaffarian and David S. Ludwig (not associated with the USDA) that encapsulates this (2). Here's a quote:
Nutritional science has advanced rapidly, and the evidence now demonstrates the major limitations of nutrient-based metrics for prevention of chronic disease. The proportion of total energy from fat appears largely unrelated to risk of cardiovascular disease, cancer, diabetes, or obesity. Saturated fat—targeted by nearly all nutrition-related professional organizations and governmental agencies—has little relation to heart disease within most prevailing dietary patterns. Typical recommendations to consume at least half of total energy as carbohydrate, a nutrient for which humans have no absolute requirement, conflate foods with widely divergent physiologic effects (eg, brown rice, white bread, apples). Foods are grouped based on protein content (chicken, fish, beans, nuts) despite demonstrably different health effects. With few exceptions (eg, omega-3 fats, trans fat, salt), individual compounds in isolation have small effects on chronic diseases. Thus, little of the information found on food labels’ “nutrition facts” panels provides useful guidance for selecting healthier foods to prevent chronic disease.

In contrast with discrete nutrients, specific foods and dietary patterns substantially affect chronic disease risk, as shown by controlled trials of risk factors and prospective cohorts of disease end points

Although this approach may seem radical, it actually represents a return to more traditional, time-tested ways of eating. Healthier food-based dietary patterns have existed for generations among some populations.
Tell it! Although he doesn't use the word nutritionism, that's basically what he's arguing against. Dr. Mozaffarian seems to represent the less reductionist school of nutrition, which is a more informed version of what nutrition pioneers such as Sir Edward Mellanby, Dr. May Mellanby, Dr. Weston Price and Sir Robert McCarrison advocated.

Although the 2010 guidelines are too focused on nutrients for my taste, they do spend some time talking about food groups and eating patterns, for example, recommending an increase in the consumption of vegetables, fruit, whole grains and seafood. They also recommend Mediterranean and plant-focused eating patterns. Although I don't think their recommendations quite hit the mark, they do reflect a shift in thinking.

Another thing I enjoyed about the Guidelines is the table on page 12 of chapter 2, which shows just how messed up the average American diet is. The number one source of calories in all age groups is "grain-based desserts". The next five in adults are yeast breads, chicken dishes, soda/sports drinks, alcohol and pizza. To see typical American food habits presented like this just blows me away. They call this the "obesogenic environment"; the idea that we're surrounded by tasty but unhealthy food and situations that favor the consumption of it. I agree.

The Guidelines also contain a surprisingly accurate one-sentence review of the glycemic index literature:
Strong evidence shows that glycemic index and/or glycemic load are not associated with body weight; thus, it is not necessary to consider these measures when selecting carbohydrate foods and beverages for weight management.

The first problem is the creation of the category "solid fats and added sugars", abbreviated SoFAS. With the creation of this term, they lump pastured butter together with Crisco and Red Hots. If they've been hiding the evidence that pastured butter, virgin coconut oil or red palm oil contribute to heart disease, I'd like to see it so I can stop eating them!

Another problem is their list of recommendations to curb the obesity epidemic. They say:
The current high rates of overweight and obesity among virtually all subgroups of the population in the United States demonstrate that many Americans are in calorie imbalance—that is, they consume more calories than they expend. To curb the obesity epidemic and improve their health, Americans need to make significant efforts to decrease the total number of calories they consume from foods and beverages and increase calorie expenditure through physical activity.
Looks like we have Sherlock Holmes on the case. Now that we have this information, all we have to do is tell overweight people to eat less and they'll be lean again! What's that, they already know and it's not working?? Someone should tell the USDA.

Jokes aside, I do think energy balance is a huge issue, perhaps even the central issue in chronic disease risk in affluent nations. The basic problem is that Americans are eating more calories than is optimal, and they have a very hard time stopping. It's not because they have less willpower than their stoic ancestors, it's because their bodies have decided that overweight/obesity is the new lean, and they defend that higher level of fat mass against changes. Simply telling an overweight person to eat fewer calories, without changing the dietary context, is not very effective in the long term, due to compensatory mechanisms including hunger and increased metabolic efficiency (fewer calories burned for the same muscular exertion).

What does the USDA recommend to lose fat or maintain leanness?
  • Count calories. Doesn't work for most people, although I acknowledge that it is physically possible to lose fat (and lean mass) by restricting calories.
  • Reduce sweetened beverages. Thumbs up.
  • Serve smaller portions. As far as I know, this rests exclusively on very short-term studies that showed that food consumed at a single meal or three is reduced if portion size is smaller. I guess it can't hurt to try it, but I'm not convinced it will have any effect on long-term body fatness. I think restaurant portion sizes have probably increased because people eat more, rather than the other way around, although both could be true.
  • Eat foods that are less calorie dense. I think vegetables are healthy, but is it because they're less calorie-dense? Why is dietary fat intake generally not associated with obesity if it's the most calorie-dense substance? Why do many people lose body fat eating energy-dense low-carbohydrate diets? Not convinced, but I'm feeling open minded about this one.
  • Exercise more and watch less TV. Exercise is good. But don't let it make you hungry, because then you'll eat more!
Overall, I think their recommendations for fat loss are not very satisfying because they don't address the core reasons Americans aren't in energy balance. Eliminating sweetened beverages and exercising are the most solid advice they offered in my opinion. The rest strikes me as wishy-washy advice that's offered because they have to say something.

At one point, they talk about changes in the US diet that have corresponded with the obesity epidemic:
Average daily calories available per person in the marketplace increased approximately 600 calories, with the greatest increases in the availability of added fats and oils, grains, milk and milk products, and caloric sweeteners.
Let me edit that so it's more complete:
Average daily calories available per person in the marketplace increased approximately 600 calories per day, 250 calories of which were actually consumed (USDA and NHANES). Added fats increased, due to a large increase in seed oil intake, but total fat intake remained approximately the same because of a roughly equal decrease in fatty meat and whole milk consumption (USDA and NHANES). Grain intake, predominantly wheat, increased, as did the consumption of refined sweeteners, predominantly high-fructose corn syrup (USDA).
It reads a bit differently once you have a little more information, doesn't it? Animal fat intake declined considerably, and was replaced by seed oils, in parallel with the obesity and diabetes epidemics. Maybe it contributed, maybe it didn't, but why not just be forthright about it? People appreciate honesty.


Although the 2010 USDA Dietary Guidelines show some promising trends, and contain some good information, I hope you can find a better source than the USDA for your nutrition advice.