Food Reward: a Dominant Factor in Obesity, Part I

A Curious Finding

It all started with one little sentence buried in a paper about obese rats. I was reading about how rats become obese when they're given chocolate Ensure, the "meal replacement drink", when I came across this:
...neither [obesity-prone] nor [obesity-resistant] rats will overeat on either vanilla- or strawberry-flavored Ensure.
The only meaningful difference between chocolate, vanilla and strawberry Ensure is the flavor, yet rats eating the chocolate variety overate, rapidly gained fat and became metabolically ill, while rats eating the other flavors didn't (1). Furthermore, the study suggested that the food's flavor determined, in part, what amount of fatness the rats' bodies "defended."

As I explained in previous posts, the human (and rodent) brain regulates the amount of fat the body carries, in a manner similar to how the brain regulates blood pressure, body temperature, blood oxygenation and blood pH (2). That fact, in addition to several other lines of evidence, suggests that obesity probably results from a change in this regulatory system. I refer to the amount of body fat that the brain defends as the "body fat setpoint", however it's clear that the setpoint is dependent on diet and lifestyle factors. The implication of this paper that I could not escape is that a food's flavor influences body fatness and probably the body fat setpoint.

An Introduction to Food Reward

The brain contains a sophisticated system that assigns a value judgment to everything we experience, integrating a vast amount of information into a one-dimensional rating system that labels things from awesome to terrible. This is the system that decides whether we should seek out a particular experience, or avoid it. For example, if you burn yourself each time you touch the burner on your stove, your brain will label that action as bad and it will discourage you from touching it again. On the other hand, if you feel good every time you're cold and put on a sweater, your brain will encourage that behavior. In the psychology literature, this phenomenon is called "reward," and it's critical to survival.

The brain assigns reward to, and seeks out, experiences that it perceives as positive, and discourages behaviors that it views as threatening. Drugs of abuse plug directly into reward pathways, bypassing the external routes that would typically trigger reward. Although this system has been studied most in the context of drug addiction, it evolved to deal with natural environmental stimuli, not drugs.

As food is one of the most important elements of survival, the brain's reward system is highly attuned to food's rewarding properties. The brain uses input from smell, taste, touch, social cues, and numerous signals from the digestive tract* to assign a reward value to foods. Experiments in rats and humans have outlined some of the qualities of food that are inherently rewarding:
  • Fat
  • Starch
  • Sugar
  • Salt
  • Meatiness (glutamate)
  • The absence of bitterness
  • Certain textures (e.g., soft or liquid calories, crunchy foods)
  • Certain aromas (e.g., esters found in many fruits)
  • Calorie density ("heavy" food)
We are generally born liking the qualities listed above. In addition, aromas and flavors that are associated with these qualities can become rewarding over time. For example, beer tastes terrible the first time you drink it because it's bitter, but after you drink it a few times and your brain catches wind that there are calories and a drug in there, it often begins tasting good. The same applies to many vegetables. Children are generally not fond of vegetables, but if you serve them spinach smothered in butter enough times, they'll learn to like it by the time they're adults.

The human brain evolved to deal with a certain range of rewarding experiences. It didn't evolve to constructively manage strong drugs of abuse such as heroin and crack cocaine, which overstimulate reward pathways, leading to the pathological drug seeking behaviors that characterize addiction. These drugs are "superstimuli" that exceed our reward system's normal operating parameters. Over the next few posts, I'll try to convince you that in a similar manner, industrially processed food, which has been professionally crafted to maximize its rewarding properties, is a superstimulus that exceeds the brain's normal operating parameters, leading to an increase in body fatness and other negative consequences.


* Nerves measure stomach distension. A number of of gut-derived paracrine and endocrine signals, including CCK, PYY, ghrelin, GLP-1 and many others potentially participate in food reward sensing, some by acting directly on the brain via the circulation, and others by signaling indirectly via the vagus nerve. More on this later.

Upcoming Talks

I'll be giving at least two talks at conferences this year:

Ancestral Health Symposium; "The Human Ecological Niche and Modern Health"; August 5-6 in Los Angeles. This is going to be a great conference. Many of my favorite health/nutrition writers will be presenting. Organizer Brent Pottenger and I collaborated on designing the symposium's name so I hope you like it.

My talk will be titled "Obesity; Old Solutions to a New Problem." I'll be presenting some of my emerging thoughts on obesity. I expect to ruffle some feathers!

Tickets are going fast so reserve one today! I doubt there will be any left two weeks from now.


TEDx Harvard Law; "Food Policy and Public Health"; Oct 21 at Harvard. My talk is tentatively titled "The American Diet: a Historical Perspective." This topic interests me because it helps us frame the discussion on why chronic disease is so prevalent today, and what are the appropriate public health measures to combat it. This should also be a great conference.

Obesity and the Fluid-in, Fluid-out Therapy for Edema

I recently attended a lecture by Dr. Arya M. Sharma here at the University of Washington. Dr. Sharma is a Canadian clinician who specializes in the treatment of obesity. He gave the UW Science in Medicine lecture, which is a prestigious invited lecture.

He spent a little bit of time pointing out the fallacy behind conventional obesity treatment. He used the analogy of edema, which is an abnormal accumulation of fluid in the body.

Since we know that the amount of fluid contained in the body depends on the amount of fluid entering the body and the amount of fluid leaving the body, the treatment for edema is obvious: drink less, pee more.

Of course, this makes no sense. It doesn't address the underlying cause of edema and it will not help the patient. Yet we apply that exact same logic to fat loss. Since the amount of energy contained in the body (in the form of fat) depends on the amount entering and the amount leaving, the solution is easy: eat less, move more. Well, yes, if you can stick to that program it will cause fat loss. But that's equivalent to telling someone with edema to drink less water. It will cause a loss of fluid, but it won't correct the underlying problem that caused excessive fluid retention in the first place.

For example, if you have edema because your heart isn't pumping effectively (cardiac insufficiency), the heart is the problem that must be addressed. Any other treatment is purely symptomatic and is not a cure.

The same applies to obesity. If you don't correct the alteration in the system that causes an obese person to 'defend' his elevated fat mass against changes*, anything you do is symptomatic treatment and is unlikely to be very effective in the long term. My goal is to develop a method that goes beyond symptomatic treatment and allows the body to naturally return to a lower fat mass. I've been doing a lot of reading and I have a simple new idea that I feel confident in. It also neatly explains the results of a variety of weight loss diets. I've dropped a few hints here and there, but I'll be formally unveiling it in the next couple of months. Stay tuned.


* The body fat homeostasis system. The core element appears to be a negative feedback loop between body fat (via leptin, and insulin to a lesser degree) and the brain (primarily the hypothalamus, but other regions are involved). There are many other elements in the system, but that one seems to set the 'gain' on all the others and guides long-term fat mass homeostasis. The brain is the gatekeeper of both energy intake and energy expenditure, and unconscious processes strongly suggest appropriate levels for both factors according to the brain's perceived homeostatic needs. Those suggestions can be overridden consciously, but it requires a perpetual high degree of discipline, whereas someone who has been lean all her life doesn't require discipline to remain lean because her brain is suggesting behaviors that naturally defend leanness. I know what I'm saying here may seem controversial to some people reading this, because it's contrary to what they've read on the internet or in the popular press, but it's not particularly controversial in my field. In fact, you'll find most of this stuff in general neuroscience textbooks dating back more than 10 years (e.g., Eric Kandel and colleagues, Principles of Neuroscience).

US Omega-6 and Omega-3 Fat Consumption over the Last Century

Omega-6 and omega-3 polyunsaturated fats (PUFA) are essential nutrients that play many important roles in the body. They are highly bioactive, and so any deviation from ancestral intake norms should probably be viewed with suspicion. I've expressed my opinion many times on this blog that omega-6 consumption is currently too high due to our high intake of refined seed oils (corn, soybean, sunflower, etc.) in industrial nations. Although it's clear that the quantity of omega-6 and omega-3 polyunsaturated fat have changed over the last century, no one had ever published a paper that attempted to systematically quantify it until last month (1).

Drs. Chris Ramsden and Joseph Hibbeln worked on this paper (the first author was Dr. Tanya Blasbalg and the senior author was Dr. Robert Rawlings)-- they were the first and second authors of a different review article I reviewed recently (2). Their new paper is a great reference that I'm sure I'll cite many times. I'm going to briefly review it and highlight a few key points.

1. The intake of omega-6 linoleic acid has increased quite a bit since 1909. It would have been roughly 2.3% of calories in 1909, while in 1999 it was 7.2%. That represents an increase of 213%. Linoleic acid is the form of omega-6 that predominates in seed oils.

2. The intake of omega-3 alpha-linolenic acid has also increased, for reasons that I'll explain below. It changed from 0.35% of calories to 0.72%, an increase of 109%.

3. The intake of long-chain omega-6 and omega-3 fats have decreased. These are the highly bioactive fats for which linoleic acid and alpha-linolenic acid are precursors. Arachidonic acid, DHA, DPA and EPA intakes have declined. This mostly has to do with changing husbandry practices and the replacement of animal fats with seed oils in the diet.

4. The ratio of omega-6 to omega-3 fats has increased. There is still quite a bit of debate over whether the ratios matter, or simply the absolute amount of each. I maintain that there is enough evidence from highly controlled animal studies and the basic biochemistry of PUFAs to tentatively conclude that the ratio is important. At a minimum, we know that excess linoleic acid inhibits omega-3 metabolism (3, 4, 5, 6). The omega-6:3 ratio increased from 5.4:1 to 9.6:1 between 1909 and 2009, a 78% increase.

5. The biggest factor in both linoleic acid and alpha-linolenic acid intake changes was the astonishing rise in soybean oil consumption. Soybean oil consumption increased from virtually nothing to 7.4% of total calories, eclipsing all sources of calories besides sugar, dairy and grains! That's because processed food is stuffed with it. It's essentially a byproduct of defatted soybean meal-- the second most important animal feed after corn. Check out this graph from the paper:

I think this paper is an important piece of the puzzle as we try to figure out what happened to nutrition and health in the US over the last century.

Fat-ten-u

I recently bought the book Food in the United States, 1820s-1890. I came across an ad for an interesting product that was sold in the late 1800s called Fat-ten-u. Check your calendars, it's not April fools day anymore; this is for real. Fat-ten-u was a dietary supplement guaranteed to "make the thin plump and rosy with honest fleshiness of form." I found several more ads for it online, and they feature drawings of despondent, lean women and drawings of happy overweight women accompanied by enthusiastic testimonials such as this:
"FAT-TEN-U FOODS increased my weight 39 pounds, gave me new womanly vigor and developed me finely. My two sisters also use FAT-TEN-U and because of our newly found vigor we have taken up Grecian dancing and have roles in all local productions."
I'm dying to know what was in this stuff, but I can't find the ingredients anywhere.

I find this rather extraordinary, for two reasons:
  • Social norms have clearly changed since the late 1800s. Today, leanness is typically considered more attractive than plumpness.
  • Women had to make an effort to become overweight in the late 1800s. In 2011, roughly two-thirds of US women are considered overweight or obese, despite the fact that most of them would rather be lean.
A rhetorical question: did everyone count calories in the 1800s, or did their diet and lifestyle naturally promote leanness? The existence of Fat-ten-u is consistent with the idea that our bodies naturally "defended" a lean body composition more effectively in the late 1800s, when our diets were less industrialized. This is supported by the only reliable data on obesity prevalence in the 1890s I'm aware of: body height and weight measurements from over 35,000 Union civil war veterans aged 40-69 years old (1). In that group of Caucasian men, obesity was about 10% of what it is today in the same age group. Whether or not you believe that this sample was representative of the population at large, I can't imagine any demographic in the modern US with an obesity prevalence of 3 percent (certainly not 60 year old war veterans).

Here are two more ads for Fat-ten-u and "Corpula foods" for your viewing pleasure:

Dr. Kevin Patterson on Western Diets and Health

A few readers have pointed me to an interesting NPR interview with the Canadian physician Kevin Patterson (link). He describes his medical work in Afghanistan and the Canadian arctic treating cultures with various degrees of industrialization. He discusses the "epidemiological transition", the idea that cultures experience predictable changes in their health as they go from hunter-gatherer, to agricultural, to industrial. I think he has an uncommonly good perspective on the effects of industrialization on human health, which tends to be true of people who have witnessed the effects of the industrial diet and lifestyle on diverse cultures.

A central concept behind my thinking is that it's possible to benefit simultaneously from both:

  • The sanitation, medical technology, safety technology, law enforcement and lower warfare-related mortality that have increased our life expectancy dramatically relative to our distant ancestors.

  • The very low incidence of obesity, diabetes, coronary heart disease and other non-infectious chronic diseases afforded by a diet and lifestyle roughly consistent with our non-industrial heritage.

But it requires discipline, because going with the flow means becoming unhealthy.


Randy Tobler Show: Welcome

This morning, I had a conversation with Dr. Randy Tobler on his radio show "Vital Signs", on 97.1 FM News Talk in St Louis. Dr. Tobler is an obstetrician-gynecologist with an interest in nutrition, fitness and reproductive endocrinology from a holistic perspective. He asked me to appear on his show after he discovered my blog and found that we have some things in common, including an interest in evolutionary/ancestral health. We talked about the history of the American diet, the health of non-industrial cultures, what fats are healthiest, and the difference between pastured and conventional meat/dairy-- we took a few questions from listeners-- it was fun.

The show is available as a podcast here (3/26 show), although as far as I can tell, you need iTunes to listen to it. My section of the show starts around 8:20.

To everyone who arrived here after hearing me on the air this morning: welcome! Here are a few posts to give you a feel for what I do here at Whole Health Source:

The Coronary Heart Disease Epidemic

US Weight, Lifestyle and Diet Trends, 1970-2007
Butter vs. Margarine Showdown
Preventing and Reversing Tooth Decay
The Kitavans: Wisdom from the Pacific Islands
Potatoes and Human Health, Part I, Part II and Part III
Traditional Preparation Methods Improve Grains' Nutritional Value
Real Food XI: Sourdough Buckwheat Crepes
Glucose Tolerance in Non-industrial Cultures
Tropical Plant Fats: Palm Oil

It's Time to Let Go of the Glycemic Index

Safflower Oil Study

A few people have sent me a new study claiming to demonstrate that half a tablespoon of safflower oil a day improves insulin sensitivity, increases HDL and decreases inflammation in diabetics (1). Let me explain why this study does not show what it claims.

It all comes down to a little thing called a control group, which is the basis for comparison that you use to determine if your intervention had an effect. This study didn't have one for the safflower group. What it had was two intervention groups, one given 6.4g conjugated linoleic acid (CLA; 50% c9t11 and 50% t10c12-CLA) per day, and one given 8g safflower oil. I have to guess that this study was originally designed to test the effects of the CLA, with the safflower oil group as the control group, and that the interpretation of the data changed after the results came in. Otherwise, I don't understand why they would conduct a study like this without a control group.

Anyway, they found that the safflower oil group did better than the CLA group over 16 weeks, showing a higher insulin sensitivity, higher HDL, lower HbA1c (a marker of average blood glucose levels) and lower CRP (a marker of inflammation). But they also found that the safflower group improved slightly compared to baseline, therefore they decided to attribute the difference to a beneficial effect of safflower oil. The problem is that without a control (placebo) group for comparison, there's no way to know if the improvement would have occurred regardless of treatment, due to the season changing, more regular check-ups at the doctor's office due to participating in a study, or countless other unforeseen factors. A control group is essential for the accurate interpretation of results, which is why drug studies always have placebo groups.

What we can say is that the safflower oil group fared better than the CLA group, because there was a difference between the two. However, what I think really happened is that the CLA supplement was harmful and the small dose of safflower oil had no effect. Why? Because the t10c12 isomer of CLA, which was half their pill, has already been shown by previous well-controlled studies to reduce insulin sensitivity, decrease HDL and increase inflammatory markers at a similar dose and for a similar duration (2, 3). The safflower oil group only looked good by comparison. We can add this study to the "research bloopers" file.

It's worth noting that naturally occurring CLA mixtures, similar to those found in pastured dairy and ruminant fat, have not been shown to cause metabolic problems such as those caused by isolated t10c12 CLA.

New Ancestral Diet Review Paper

Pedro Carrera-Bastos and his colleagues Maelan Fontes-Villalba, James H. O'Keefe, Staffan Lindeberg and Loren Cordain have published an excellent new review article titled "The Western Diet and Lifestyle and Diseases of Civilization" (1). The paper reviews the health consequences of transitioning from a traditional to a modern Western diet and lifestyle. Pedro is a knowledgeable and tireless advocate of ancestral, primarily paleolithic-style nutrition, and it has been my privilege to correspond with him regularly. His new paper is the best review of the underlying causes of the "diseases of civilization" that I've encountered. Here's the abstract:
It is increasingly recognized that certain fundamental changes in diet and lifestyle that occurred after the Neolithic Revolution, and especially after the Industrial Revolution and the Modern Age, are too recent, on an evolutionary time scale, for the human genome to have completely adapted. This mismatch between our ancient physiology and the western diet and lifestyle underlies many so-called diseases of civilization, including coronary heart disease, obesity, hypertension, type 2 diabetes, epithelial cell cancers, autoimmune disease, and osteoporosis, which are rare or virtually absent in hunter–gatherers and other non-westernized populations. It is therefore proposed that the adoption of diet and lifestyle that mimic the beneficial characteristics of the preagricultural environment is an effective strategy to reduce the risk of chronic degenerative diseases.
At 343 references, the paper is an excellent resource for anyone with an academic interest in ancestral health, and in that sense it reminds me of Staffan Lindeberg's book Food and Western Disease. One of the things I like most about the paper is that it acknowledges the significant genetic adaptation to agriculture and pastoralism that has occurred in populations that have been practicing it for thousands of years. It hypothesizes that the main detrimental change was not the adoption of agriculture, but the more recent industrialization of the food system. I agree.

I gave Pedro my comments on the manuscript as he was editing it, and he was kind enough to include me in the acknowledgments.

Gluten-Free January Survey Data, Part II: Health Effects of a Gluten-Free Diet

GFJ participants chose between three diet styles: a simple gluten-free diet; a "paleo light" diet diet that eliminated sugar and industrial seed (vegetable) oils in addition to gluten; and a "paleo full monty" diet that only included categories of food that would have been available to our pre-agricultural ancestors. The data in this post represent the simple gluten-free diet group, and do not represent the other two, which I'll analyze separately.

To get the data I'll be presenting below, first I excluded participants who stated on the survey that they did not adhere to the diet. Next, I excluded participants who were gluten-free before January, because they would presumably not have experienced a change from continuing to avoid gluten. That left us with 53 participants.

For each of these graphs, the vertical axis represents the number of participants in each category. They won't necessarily add up to 53, for several reasons. The most common reason is that for the questions asking about changes in health conditions, I didn't include responses from people who didn't have the condition in question at baseline because there was nothing to change.

Question #1: What is your overall opinion of the effect of gluten free January on you?

Participants had a very positive experience with the gluten-free diet. Not one person reported a negative overall experience.

Question #2: Did you note a weight change at the end of gluten free January?

And here are the data for people who described themselves as overweight at baseline:

Two-thirds of people who were overweight at baseline lost weight, and only one person out of 37 gained weight. That is striking. A number of people didn't weigh themselves, which is why the numbers only add up to 37.

Question #3: Before January 2011, did you have a problem with intestinal transit (frequent constipation or diarrhea)? If so, did your symptoms change during the month of January?


Responses are heavily weighted toward improvement, although there were a few instances where transit worsened. Transit problems are one of the most common manifestations of gluten sensitivity.

Question #4: Before January 2011, did you have frequent digestive discomfort (pain, bloating, etc.)? If so, did your symptoms change during the month of January?


Digestive discomfort was common, and the gluten-free diet improved it in nearly everyone who had it at baseline. I find this really impressive.

Question #5: Before January 2011, did you have acid reflux? If so, did your symptoms change during the month of January?

Acid reflux responded well to a gluten-free diet.

Question #6: Before January 2011, did you have a problem with tiredness/lethargy? If so, did your symptoms change during the month of January?
Lethargy was common and generally improved in people who avoided gluten. This doesn't surprise me at all. The recent controlled gluten study in irritable bowel syndrome patients found that lethargy was the most reliable consequence of eating gluten that they measured (1, 2). That has also been my personal experience.

Question #7: Before January 2011, did you have a problem with anxiety? If so, did your symptoms change during the month of January?

Anxiety tended to improve in most participants who started with it.

Question #8: Before January 2011, did you have a problem with an autoimmune or inflammatory condition? If so, did your symptoms change during the month of January?

Autoimmune and inflammatory conditions tended to improve in the gluten-free group, although one person experienced a worsening of symptoms.

Question #9: If you ate gluten again or did a gluten challenge after gluten free January, what was the effect?

Just under half of participants experienced moderate or significant negative symptoms when they re-introduced gluten at the end of the month. Two people felt better after re-introducing gluten.


Conclusion

I find these results striking. Participants overwhelmingly improved in every health category we measured. Although the data may have been somewhat biased due to the 53% response rate, it's indisputable that a large number of participants, probably the majority, benefited from avoiding gluten for a month. At some point, we're going to compile some of the comments people left in the survey, which were overwhelmingly positive. Here's a typical comment in response to the question " In your own words, how would you describe your January 2011 experience" (used with permission):
Amazing! I would recommend the experiment to anyone. I felt completely more alert, and less bloated. When I ate some gluten at the close of the experiment, I felt gross, bloated, and lethargic.
I think it's worth mentioning that some participants also eliminated other starches, particularly refined starches. Judging by the comments, the diet was probably lower in carbohydrate for a number of participants. We may try to assess that next year.

Gluten-Free January Survey Data, Part I: Demographics and Limitations

Thanks to Matt Lentzner for organizing Gluten-Free January, and everyone who participated and completed the survey, we have a nice data set illustrating what happens when a group of people stop eating gluten for a month. Janine Jagger, Matt and I have been busy analyzing the data, and I'm ready to begin sharing our findings.

GFJ had over 500 participants, 527 of which received the survey and 279 of which completed the survey at the end of the month. Of those who received the survey, 53 percent completed it. I think these are respectable numbers for a survey of this nature, and it reflects the conscientious nature of the people who participated in GFJ.

Demographics

Although respondents were primarily from the United States, I'm happy to say that the data represent 18 different nationalities:

Respondents represented a diversity of ages, the largest group being 30-39 years old, with similar numbers in the 20-29 and 40-49 year groups.
Respondents were just under 2/3 women.

Respondents represented a variety of weights, but the sample was biased toward lean people, in comparison with the general population. There were not many obese participants.
Overall, I was pleased to see that the demographics were quite diverse, particularly in the age and gender categories.

Limitations

There are a few caveats to keep in mind when interpreting the survey results:
  1. GFJ participants do not represent a random cross-section of the population at large. They represent primarily health-conscious individuals who were motivated enough to make a substantial dietary change. In addition, many of the people who participated probably did so because they already suspected they had a problem with gluten.
  2. The survey response rate was 53%. Although I think that's a reasonable number considering the circumstances, it leaves open the possibility that survey responders differ from non-responders. It's conceivable that participants with better adherence and better outcomes were more likely to complete the survey than those who did not adhere to the diet or had neutral or unfavorable outcomes, despite our efforts to encourage everyone to complete the survey regardless of adherence or outcome. So the results could be biased toward positive outcomes, meaning that we will need to see a strong effect for it to be believable.
  3. This was a non-blinded diet trial without a control group. There's no way to know how much of the effect was due to avoiding gluten per se, how much was due to overall changes in diet patterns, and how much was a placebo effect.
With that in mind, what can we take from the survey data? I feel that we can use it to answer the following question: "what is likely to happen when a motivated, health-conscious person decides to avoid gluten for a month?" And I think we can also use it to generate (but not test) hypotheses about the effects of eating gluten on the general population.

Flu Season is Here

I've noticed everyone around me getting sick lately (I seem to have become mostly immune to colds and the flu in the last couple of years), so I took a look at Google Flu Trends. Lo and behold, the United States is currently near peak flu incidence for the 2010-2011 season. Here's a graph from Flu Trends. This year's trend is in dark blue:


Flu Trends also has data for individual US states and a number of other countries.

It's time to tighten up your diet and lifestyle if you want to avoid the flu this year. Personally, I feel that eating well, managing stress effectively, and taking 2,000 IU of vitamin D3 per day in winter have helped me avoid colds and the flu.

Gluten-Free January Raffle Winners Selected!

Raffle winners have been selected and shirts are on their way. You know who you are. Thanks to everyone who participated and filled out the survey! For those who didn't, there's always next year.

Janine Jagger, Matt Lentzner and I are busy crunching the mountain of data we collected from the GFJ survey. We got 279 responses, which is remarkable for a survey of this nature.

Stay tuned for data!

Oltipraz

Oltipraz is a drug that was originally used to treat intestinal worms. It was later found to prevent a broad variety of cancers (1). This was attributed to its ability to upregulate cellular detoxification and repair mechanisms.

Researchers eventually discovered that oltipraz acts by activating Nrf2, the same transcription factor activated by ionizing radiation and polyphenols (2, 3, 4). Nrf2 activation mounts a broad cellular protective response that appears to reduce the risk of multiple health problems.

A recent paper in Diabetologia illustrates this (5). Investigators put mice on a long-term refined high-fat diet, with or without oltipraz. These carefully crafted diets are very unhealthy indeed, and when fed to rodents they rapidly induce fat gain and something that looks similar to human metabolic syndrome (insulin resistance, abdominal adiposity, blood lipid disturbances). Adding oltipraz to the diet prevented the fat gain, insulin resistance and inflammatory changes that occurred in the refined high-fat diet group.

The difference in fasting insulin was remarkable. The mice taking oltipraz had 1/7 the fasting insulin of the refined high-fat diet comparison group, and 1/3 the fasting insulin of the low-fat comparison group! Yet their glucose tolerance was normal, indicating that they were not low on insulin due to pancreatic damage. The low-fat diet they used in this study was also refined, which is why the two control groups (high-fat and low-fat) didn't diverge more in body fatness and other parameters. If they had used a group fed unrefined rodent chow as the comparator, the differences between groups would have been larger.

This shows that in addition to preventing cancer, Nrf2 activation can attenuate the metabolic damage caused by an unhealthy diet in rodents. Oltipraz illustrates the power of the cellular hormesis response. We can exploit this pathway naturally using polyphenols and other chemicals found in whole plant foods.

Polyphenols, Hormesis and Disease: Part II

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).

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


Mainstream 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 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 horrible.
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 enzyme activity and signaling pathways. 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 the 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 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?

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.


* Serum levels 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.

My Gluten-Free January

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!

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

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

Positive

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.
Negative

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.

Conclusion

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.

Gluten-free January Participants: Take the Survey!

Matt Lentzner, Janine Jagger and I have designed a survey for participants of Gluten-free January, using the online application StatCrunch. Janine is an epidemiologist who studies healthcare worker safety at the University of Virginia; she has experience designing surveys for data collection so we're glad to have her on board. The survey will allow us to systematically gather and analyze data on the results of Gluten-free January. It will be 100 percent anonymous-- none of your answers will be connected to your identity in any way.

This survey has the potential to be really informative, but it will only work if you respond! The more people who take the survey, the more informative it will be, even if you didn't avoid gluten for a single day. If not very many people respond, it will be highly susceptible to "selection bias", where perhaps the only people who responded are people who improved the most, skewing the results.

Matt will be sending the survey out to everyone on his mailing list. Please complete it, even if you didn't end up avoiding gluten at all! There's no shame in it. The survey has responses built in for people who didn't avoid gluten. Your survey will still be useful!

We have potential data from over 500 people. After we crunch the numbers, I'll share them on the blog.

The Diabetes Epidemic

The CDC just released its latest estimate of diabetes prevalence in the US (1):
Diabetes affects 8.3 percent of Americans of all ages, and 11.3 percent of adults aged 20 and older, according to the National Diabetes Fact Sheet for 2011. About 27 percent of those with diabetes—7 million Americans—do not know they have the disease. Prediabetes affects 35 percent of adults aged 20 and older.
Wow-- this is a massive problem. The prevalence of diabetes has been increasing over time, due to more people developing the disorder, improvements in diabetes care leading to longer survival time, and changes in the way diabetes is diagnosed. Here's a graph I put together based on CDC data, showing the trend of diabetes prevalence (percent) from 1980 to 2008 in different age categories (2):


These data are self-reported, and do not correct for differences in diagnosis methods, so they should be viewed with caution-- but they still serve to illustrate the trend. There was an increase in diabetes incidence that began in the early 1990s. More than 90 percent of cases are type 2 diabetics. Disturbingly, the trend does not show any signs of slowing.

The diabetes epidemic has followed on the heels of the obesity epidemic with 10-20 years of lag time. Excess body fat is the number one risk factor for diabetes*. As far as I can tell, type 2 diabetes is caused by insulin resistance, which is probably due to energy intake exceeding energy needs (overnutrition), causing a state of cellular insulin resistance as a defense mechanism to protect against the damaging effects of too much glucose and fatty acids (3). In addition, type 2 diabetes requires a predisposition that prevents the pancreatic beta cells from keeping up with the greatly increased insulin needs of an insulin resistant person**. Both factors are required, and not all insulin resistant people will develop diabetes as some people's beta cells are able to compensate by hypersecreting insulin.

Why does energy intake exceed energy needs in modern America and in most affluent countries? Why has the typical person's calorie intake increased by 250 calories per day since 1970 (4)? I believe it's because the fat mass "setpoint" has been increased, typically but not always by industrial food. I've been developing some new thoughts on this lately, and potentially new solutions, which I'll reveal when they're ready.


* In other words, it's the best predictor of future diabetes risk.

** Most of the common gene variants (of known function) linked with type 2 diabetes are thought to impact beta cell function (5).

Two Wheat Challenge Ideas from Commenters

Some people have remarked that the blinded challenge method I posted is cumbersome.

Reader "Me" suggested:
You can buy wheat gluten in a grocery store. Why not simply have your friend add some wheat gluten to your normal protein shake.
Reader David suggested:
They sell empty gelatin capsules with carob content to opacify them. Why not fill a few capsules with whole wheat flour, and then a whole bunch with rice starch or other placebo. For two weeks take a set of, say, three capsules every day, with the set of wheat capsules in line to be taken on a random day selected by your friend. This would further reduce the chances that you would see through the blind, and it prevent the risk of not being able to choke the "smoothie" down. It would also keep it to wheat and nothing but wheat (except for the placebo starch).
The reason I chose the method in the last post is that it directly tests wheat in a form that a person would be likely to eat: bread. The limitation of the gluten shake method is that it would miss a sensitivity to components in wheat other than gluten. The limitation of the pill method is that raw flour is difficult to digest, so it would be difficult to extrapolate a sensitivity to cooked flour foods. You might be able to get around that by filling the pills with powdered bread crumbs. Those are two alternative ideas to consider if the one I posted seems too involved.

Blinded Wheat Challenge

Self-experimentation can be an effective way to improve one's health*. One of the problems with diet self-experimentation is that it's difficult to know which changes are the direct result of eating a food, and which are the result of preconceived ideas about a food. For example, are you more likely to notice the fact that you're grumpy after drinking milk if you think milk makes people grumpy? Maybe you're grumpy every other day regardless of diet? Placebo effects and conscious/unconscious bias can lead us to erroneous conclusions.

The beauty of the scientific method is that it offers us effective tools to minimize this kind of bias. This is probably its main advantage over more subjective forms of inquiry**. One of the most effective tools in the scientific method's toolbox is a control. This is a measurement that's used to establish a baseline for comparison with the intervention, which is what you're interested in. Without a control measurement, the intervention measurement is typically meaningless. For example, if we give 100 people pills that cure belly button lint, we have to give a different group placebo (sugar) pills. Only the comparison between drug and placebo groups can tell us if the drug worked, because maybe the changing seasons, regular doctor's visits, or having your belly button examined once a week affects the likelihood of lint.

Another tool is called blinding. This is where the patient, and often the doctor and investigators, don't know which pills are placebo and which are drug. This minimizes bias on the part of the patient, and sometimes the doctor and investigators. If the patient knew he were receiving drug rather than placebo, that could influence the outcome. Likewise, investigators who aren't blinded while they're collecting data can unconsciously (or consciously) influence it.

Back to diet. I want to know if I react to wheat. I've been gluten-free for about a month. But if I eat a slice of bread, how can I be sure I'm not experiencing symptoms because I think I should? How about blinding and a non-gluten control?

Procedure for a Blinded Wheat Challenge

1. Find a friend who can help you.

2. Buy a loaf of wheat bread and a loaf of gluten-free bread.

3. Have your friend choose one of the loaves without telling you which he/she chose.

4. Have your friend take 1-3 slices, blend them with water in a blender until smooth. This is to eliminate differences in consistency that could allow you to determine what you're eating. Don't watch your friend do this-- you might recognize the loaf.

5. Pinch your nose and drink the "bread smoothie" (yum!). This is so that you can't identify the bread by taste. Rinse your mouth with water before releasing your nose. Record how you feel in the next few hours and days.

6. Wait a week. This is called a "washout period". Repeat the experiment with the second loaf, attempting to keep everything else about the experiment as similar as possible.

7. Compare how you felt each time. Have your friend "unblind" you by telling you which bread you ate on each day. If you experienced symptoms during the wheat challenge but not the control challenge, you may be sensitive to wheat.

If you want to take this to the next level of scientific rigor, repeat the procedure several times to see if the result is consistent. The larger the effect, the fewer times you need to repeat it to be confident in the result.


* Although it can also be disastrous. People who get into the most trouble are "extreme thinkers" who have a tendency to take an idea too far, e.g., avoid all animal foods, avoid all carbohydrate, avoid all fat, run two marathons a week, etc.

** More subjective forms of inquiry have their own advantages.

Eating Wheat Gluten Causes Symptoms in Some People Who Don't Have Celiac Disease

Irritable bowel syndrome (IBS) is a condition characterized by the frequent occurrence of abdominal pain, diarrhea, constipation, bloating and/or gas. If that sounds like an extremely broad description, that's because it is. The word "syndrome" is medicalese for "we don't know what causes it." IBS seems to be a catch-all for various persistent digestive problems that aren't defined as separate disorders, and it has a very high prevalence: as high as 14 percent of people in the US, although the estimates depend on what diagnostic criteria are used (1). It can be brought on or exacerbated by several different types of stressors, including emotional stress and infection.

Maelán Fontes Villalba at Lund University recently forwarded me an interesting new paper in the American Journal of Gastroenterology (2). Dr. Jessica R. Biesiekierski and colleagues recruited 34 IBS patients who did not have celiac disease, but who felt they had benefited from going gluten-free in their daily lives*. All patients continued on their pre-study gluten-free diet, however, all participants were provided with two slices of gluten-free bread and one gluten-free muffin per day. The investigators added isolated wheat gluten to the bread and muffins of half the study group.

During the six weeks of the intervention, patients receiving the gluten-free food fared considerably better on nearly every symptom of IBS measured. The most striking difference was in tiredness-- the gluten-free group was much less tired on average than the gluten group. Interestingly, they found that a negative reaction to gluten was not necessarily accompanied by the presence of anti-gluten antibodies in the blood, which is a test often used to diagnose gluten sensitivity.

Here's what I take away from this study:
  1. Wheat gluten can cause symptoms in susceptible people who do not have celiac disease.
  2. A lack of circulating antibodies against gluten does not necessarily indicate a lack of gluten sensitivity.
  3. People with mysterious digestive problems may want to try avoiding gluten for a while to see if it improves their symptoms**.
  4. People with mysterious fatigue may want to try avoiding gluten.
A previous study in 1981 showed that feeding volunteers a large dose of gluten every day for 6 weeks caused adverse gastrointestinal effects, including inflammatory changes, in relatives of people with celiac disease, who did not themselves have celiac (3). Together, these two studies are the most solid evidence that gluten can be damaging in people without celiac disease, a topic that has not received much interest in the biomedical research community.

I don't expect everyone to benefit from avoiding gluten. But for those who are really sensitive, it can make a huge difference. Digestive, autoimmune and neurological disorders associate most strongly with gluten sensitivity. Avoiding gluten can be a fruitful thing to try in cases of mysterious chronic illness. We're two-thirds of the way through Gluten-Free January. I've been fastidiously avoiding gluten, as annoying as it's been at times***. Has anyone noticed a change in their health?


* 56% of volunteers carried HLA-DQ2 or DQ8 alleles, which is slightly higher than the general population. Nearly all people with celiac disease carry one of these two alleles. 28% of volunteers were positive for anti-gliadin IgA, which is higher than the general population.

** Some people feel they are reacting to the fructans in wheat, rather than the gluten. If a modest amount of onion causes the same symptoms as eating wheat, then that may be true. If not, then it's probably the gluten.

*** I'm usually about 95% gluten-free anyway. But when I want a real beer, I want one brewed with barley. And when I want Thai food or sushi, I don't worry about a little bit of wheat in the soy sauce. If a friend makes me food with gluten in it, I'll eat it and enjoy it. This month I'm 100% gluten-free though, because I can't in good conscience encourage my blog readership to try it if I'm not doing it myself. At the end of the month, I'm going to do a blinded gluten challenge (with a gluten-free control challenge) to see once and for all if I react to it. Stay tuned for more on that.

Does Dietary Saturated Fat Increase Blood Cholesterol? An Informal Review of Observational Studies

The diet-heart hypothesis states three things:
  1. Dietary saturated fat increases blood cholesterol
  2. Elevated blood cholesterol increases the risk of having a heart attack
  3. Therefore, dietary saturated fat increases the risk of having a heart attack
To evaluate the second contention, investigators have examined the relationship between blood cholesterol and heart attack risk. Many studies including MRFIT have shown that the two are related (1):

The relationship becomes much more complex when you consider lipoprotein subtypes, density and oxidation level, among other factors, but at the very least there is an association between habitual blood cholesterol level and heart attack risk. This is what you would want to see if your hypothesis states that high blood cholesterol causes heart attacks.

Now let's turn to the first contention, the hypothesis that dietary saturated fat increases serum cholesterol. This idea is so deeply ingrained in the scientific literature that many authors don't even bother providing references for it anymore. When references are provided, they nearly always point to the same type of study: short-term controlled diet trials, in which volunteers are fed different fats for 2-13 weeks and their blood cholesterol measured (2)*. These are the studies on which the diet-heart hypothesis was built.

But now we have a problem. Nearly every high-quality (prospective) observational study ever conducted found that saturated fat intake is not associated with heart attack risk (3). So if saturated fat increases blood cholesterol, and higher blood cholesterol is associated with an increased risk of having a heart attack, then why don't people who eat more saturated fat have more heart attacks?

I'll begin to answer that question with another question: why do researchers almost never cite observational studies to support the idea that dietary saturated fat increases blood cholesterol? Surely if the hypothesis is correct, then people who habitually eat a lot of saturated fat should have high cholesterol, right? One reason may be that in most instances, when researchers have looked for a relationship between saturated fat intake and blood cholesterol, they haven't found one. Those findings have essentially been ignored, but let's have a look...

The Studies

It's difficult to do a complete accounting of these studies, but I've done my best to round them up. I can't claim this post is comprehensive, but I doubt I missed very many, and I certainly didn't exclude any that I came across. If you know of any I missed, please add them to the comments.

The earliest and perhaps most interesting study I found was published in the British Medical Journal in 1963 and is titled "Diet and Plasma Cholesterol in 99 Bank Men" (4). Investigators asked volunteers to weigh all food consumed at home for 1-2 weeks, and describe in detail all food consumed away from home. Compliance was good. This dietary accounting method was much more thorough than in most observational studies today**. Animal fat intake ranged from 55 to 173 grams per day, and blood cholesterol ranged from 154 to 324 mg/dL, yet there was no relationship whatsoever between the two. I'm looking at a graph of animal fat intake vs. blood cholesterol as I write this, and it looks like someone shot it with a shotgun at 50 yards. They twisted the data every which way, but were never able to squeeze even a hint of an association out of it:
Making the most out of the data in other ways- for example, by analysis of the men very stable in their diets, or in whom weighing of food intake was maximal, or where blood was taken close to the diet [measurement]- did not increase the correlation. Because the correlation coefficient is almost as often negative as positive, moreover, what is being discussed mostly is the absence of association, not merely association that is unexpectedly small.
The next study to discuss is the 1976 Tecumseh study (5). This was a large cardiovascular observational study conducted in Tecumseh, Michigan, which is often used as the basis for comparison for other cardiovascular studies in the literature. Using the 24 hour dietary recall method, including an analysis of saturated fat, the investigators found that:
Cholesterol and triglyceride levels were unrelated to quality, quantity, or proportions of fat, carbohydrate or protein consumed in the 24-hr recall period.
They also noted that the result was consistent with what had been reported in other previously published studies, including the Evans county study (6), the massive Israel Ischemic Heart Disease Study (7) and the Framingham study. One of the longest-running, most comprehensive and most highly cited observational studies, the Framingham study was organized by Harvard investigators and continues to this day. When investigators analyzed the relationship between saturated fat intake, serum cholesterol and heart attack risk, they were so disappointed that they never formally published the results. We know from multiple sources that they found no significant relationship between saturated fat intake and blood cholesterol or heart attack risk***.

The next study is the Bogalusa Heart Study, published in 1978, which studied the diet and health of 10 year old American children (8). This study found an association by one statistical method, and none by a second method****. They found that the dietary factors they analyzed explained no more than 4% of the variation in blood cholesterol. Overall, I think this study lends little or no support to the hypothesis.

Next is the Western Electric study, published in 1981 (9). This study found an association between saturated fat intake and blood cholesterol in middle-aged men in Chicago. However, the correlation was small, and there was no association between saturated fat intake and heart attack deaths. They cited two other studies that found an association between dietary saturated fat and blood cholesterol (and did not cite any of the numerous studies that found no association). One was a very small study conducted in young men doing research in Antarctica, which did not measure saturated fat but found an association between total fat intake and blood cholesterol (10). The other studied Japanese (Nagasaki and Hiroshima) and Japanese Americans in Japan, Hawai'i and California respectively (11).

This study requires some discussion. Published in 1973, it found a correlation between saturated fat intake and blood cholesterol in Japan, Hawai'i but not in California. The strongest association was in Japan, where going from 5 to 75 g/day of saturated fat (a 15-fold change!) was associated with an increase in blood cholesterol from about 175 to 200 mg/dL. However, I don't think this study offers much support to the hypothesis upon closer examination. Food intake in Japan was collected by 24-hour recall in 1965-1967, when the diet was mostly white rice in some areas. The lower limit of saturated fat intake in Japan was 5g/day, 1/12th what was typically eaten in Hawai'i and California, and the Japanese average was 16g, with most people falling below 10g. That is an extraordinarily low saturated fat intake. I think a significant portion of the Japanese in this study, living in the war-ravaged cities of Nagasaki and Hiroshima, were over-reliant on white rice and perhaps bordering on malnourishment.

In Japanese-Americans living in Hawai'i, over a range of saturated fat intakes between 5 and 110 g/day, cholesterol went from 210 to 220 mg/dL. That was statistically significant but it's not exactly knocking my socks off, considering it's a 22-fold change in saturated fat intake. In California, going from 15 to 110 g/day of saturated fat (7.3-fold change) was not associated with a change in blood cholesterol. Blood cholesterol was 20-30 mg/dL lower in Japan than in Hawai'i or California at any given level of saturated fat intake (e.g., Japanese eating 30g per day vs. Hawai'ians eating 30g per day). I think it's probable that saturated fat is not the relevant factor here, or at least it's being trumped by other factors. An equally plausible explanation is that people in the very low range of saturated fat intake are the rural poor who eat an impoverished diet that differs in many ways from the diets at the upper end of the range.

The most recent study was the Health Professional Follow-up study, published in 1996 (12). This was a massive, well funded study that found no hint of a relationship between saturated fat intake and blood cholesterol.

Conclusion

Of all the studies I came across, only the Western Electric study found a clear association between habitual saturated fat intake and blood cholesterol, and even that association was weak. The Bogalusa Heart study and the Japanese study provided inconsistent evidence for a weak association. The other studies I cited, including the bank workers' study, the Tecumseh study, the Evans county study, the Israel Ischemic Heart study, the Framingham study and the Health Professionals Follow-up study, found no association between the two factors.

Overall, the literature does not offer much support for the idea that long term saturated fat intake has a significant effect on the concentration of blood cholesterol. If it's a factor at all, it must be rather weak, which is consistent with what has been observed in multiple non-human species (13). I think it's likely that the diet-heart hypothesis rests in part on an over-interpretation of short-term controlled feeding studies. I'd like to see a more open discussion of this in the scientific literature. In any case, these controlled studies have typically shown that saturated fat increases both LDL and HDL, so even if saturated fat did have a small long-term effect on blood cholesterol, as hinted at by some of the observational studies, its effect on heart attack risk would still be difficult to predict.

The Diet-heart Hypothesis: Stuck at the Starting Gate
Animal Models of Atherosclerosis: LDL


* As a side note, many of these studies were of poor quality, and were designed in ways that artificially inflated the effects of saturated fat on blood lipids. For example, using a run-in period high in linoleic acid, or comparing a saturated fat-rich diet to a linoleic acid-rich diet, and attributing the differences in blood cholesterol to the saturated fat. Some of them used hydrogenated seed oils as the saturated fat. Although not always consistent, I do think that overall these studies support the idea that saturated fat does have a modest ability to increase blood cholesterol in the short term.

** Although I would love to hear comments from anyone who has done controlled diet trials. I'm sure this method had flaws, as it was applied in the 1960s.

*** Reference cited in the Tecumseh paper: Kannel, W et al. The Framingham Study. An epidemiological Investigation of Cardiovascular Diseases. Section 24: The Framingham Diet Study: Diet and the Regulation of Serum Cholesterol. US Government Printing Office, 1970.

**** Table 5 shows that the Pearson correlation coefficient for saturated fat intake vs. blood cholesterol is not significant; table 6 shows that children in the two highest tertiles of blood cholesterol have a significantly higher intake of saturated fat, unsaturated fat, total fat and sodium than the lowest tertile. The relationship between saturated fat and blood cholesterol shows no evidence of dose-dependence (cholesterol tertiles= 15.6g, 18.4g, 18.5g saturated fat). The investigators made no effort to adjust for confounding variables.