Monday, January 30, 2012

Malocclusion: Disease of Civilization, Part IX

A Summary

For those who didn't want to wade through the entire nerd safari, I offer a simple summary.

Our ancestors had straight teeth, and their wisdom teeth came in without any problem. The same continues to be true of a few non-industrial cultures today, but it's becoming rare. Wild animals also rarely suffer from orthodontic problems.

Today, the majority of people in the US and other affluent nations have some type of malocclusion, whether it's crooked teeth, overbite, open bite or a number of other possibilities.

There are three main factors that I believe contribute to malocclusion in modern societies:
  1. Maternal nutrition during the first trimester of pregnancy. Vitamin K2, found in organs, pastured dairy and eggs, is particularly important. We may also make small amounts from the K1 found in green vegetables.
  2. Sucking habits from birth to age four. Breast feeding protects against malocclusion. Bottle feeding, pacifiers and finger sucking probably increase the risk of malocclusion. Cup feeding and orthodontic pacifiers are probably acceptable alternatives.
  3. Food toughness. The jaws probably require stress from tough food to develop correctly. This can contribute to the widening of the dental arch until roughly age 17. Beef jerky, raw vegetables, raw fruit, tough cuts of meat and nuts are all good ways to exercise the jaws.
And now, an example from the dental literature to motivate you. In 1976, Dr. H. L. Eirew published an interesting paper in the British Dental Journal. He took two 12-year old identical twins, with identical class I malocclusions (crowded incisors), and gave them two different orthodontic treatments. Here's a picture of both girls before the treatment:

In one, he made more space in her jaws by extracting teeth. In the other, he put in an apparatus that broadened her dental arch, which roughly mimics the natural process of arch growth during childhood and adolescence. This had profound effects on the girls' subsequent occlusion and facial structure:

The girl on the left had teeth extracted, while the girl on the right had her arch broadened. Under ideal circumstances, this is what should happen naturally during development. Notice any differences?

Thanks to the Weston A Price foundation's recent newsletter for the study reference.

Tuesday, January 3, 2012

Butyric Acid: an Ancient Controller of Metabolism, Inflammation and Stress Resistance

An Interesting Finding

Susceptible strains of rodents fed high-fat diets overeat, gain fat and become profoundly insulin resistant. Dr. Jianping Ye's group recently published a paper showing that the harmful metabolic effects of a high-fat diet (lard and soybean oil) on mice can be prevented, and even reversed, using a short-chain saturated fatty acid called butyric acid (hereafter, butyrate). Here's a graph of the percent body fat over time of the two groups:

The butyrate-fed mice remained lean and avoided metabolic problems. Butyrate increased their energy expenditure by increasing body heat production and modestly increasing physical activity. It also massively increased the function of their mitochondria, the tiny power plants of the cell.

Butyrate lowered their blood cholesterol by approximately 25 percent, and their triglycerides by nearly 50 percent. It lowered their fasting insulin by nearly 50 percent, and increased their insulin sensitivity by nearly 300 percent*. The investigators concluded:
Butyrate and its derivatives may have potential application in the prevention and treatment of metabolic syndrome in humans.
There's one caveat, however: the butyrate group at less food. Something about the butyrate treatment caused their food intake to decline after 3 weeks, dropping roughly 20% by 10 weeks. The investigators cleverly tried to hide this by normalizing food intake to body weight, making it look like the food intake of the comparison group was dropping as well (when actually it was staying the same as this group was gaining weight).

I found this study thought-provoking, so I looked into butyrate further.

Butyrate Suppresses Inflammation in the Gut and Other Tissues

In most animals, the highest concentration of butyrate is found in the gut. That's because it's produced by intestinal bacteria from carbohydrate that the host cannot digest, such as cellulose and pectin. Indigestible carbohydrate is the main form of dietary fiber.

It turns out, butyrate has been around in the mammalian gut for so long that the lining of our large intestine has evolved to use it as its primary source of energy. It does more than just feed the bowel, however. It also has potent anti-inflammatory and anti-cancer effects. So much so, that investigators are using oral butyrate supplements and butyrate enemas to treat inflammatory bowel diseases such as Crohn's and ulcerative colitis. Investigators are also suggesting that inflammatory bowel disorders may be caused or exacerbated by a deficiency of butyrate in the first place.

Butyrate, and other short-chain fatty acids produced by gut bacteria**, has a remarkable effect on intestinal permeability. In tissue culture and live rats, short-chain fatty acids cause a large and rapid decrease in intestinal permeability. Butyrate, or dietary fiber, prevents the loss of intestinal premeability in rat models of ulcerative colitis. This shows that short-chain fatty acids, including butyrate, play an important role in the maintenance of gut barrier integrity. Impaired gut barrier integrity is associated with many diseases, including fatty liver, heart failure and autoimmune diseases (thanks to Pedro Bastos for this information-- I'll be covering the topic in more detail later).

Butyrate's role doesn't end in the gut. It's absorbed into the circulation, and may exert effects on the rest of the body as well. In human blood immune cells, butyrate is potently anti-inflammatory***.

Butyrate Increases Resistance to Metabolic and Physical Stress

Certain types of fiber reduce atherosclerosis in animal models, and this effect may be due to butyrate production produced when the fiber is fermented. Fiber intake was associated with lower blood markers of inflammation in the Women's Health Initiative study, and has been repeatedly associated with lower heart attack risk and reduced progression of atherosclerosis in humans. Butyrate also sharply reduces the harmful effects of type 1 diabetes in rats, as does dietary fiber to a lesser extent.

Butyrate increases the function and survival of mice with certain neurodegenerative diseases. Polyglutamine diseases, which are the most common class of genetic neurodegenerative diseases, are delayed in mice treated with butyrate (1, 2, 3). Many of you have probably heard of Huntington's disease, which is the most common of the class. I did my thesis on a polyglutamine disease called SCA7, and this is the first suggestion I've seen that diet may be able to modify its course.

Yet another interesting finding in the first paper I discussed: mice treated with butyrate were more cold-resistant than the comparison group. When they were both placed in a cold room, body temperature dropped quite a bit in the comparison group, while it remained relatively stable in the butyrate group, despite the fact that the butyrate group was leaner****. This was due to increased heat production in the butyrate group.

Due to the potent effect butyrate has on a number of bodily processes, I believe it may be a fundamental controller of metabolism, stress resistance and the immune system in mammals, similar to omega-6:3 balance.

An Ancient Line of Communication Between Symbiotic Organisms

Why does butyrate have so much control over inflammation? Let's think about where it comes from. Bacteria in the gut produce it. It's a source of energy, so our bodies take it up readily. It's one of the main molecules that passes from the symbiotic (helpful) bacteria in the gut to the rest of the body. It's only logical that the body would receive butyrate as a signal that there's a thriving colony of symbiotic bacteria in the gut, and induce a tolerance to them. The body may alter its immune response (inflammation) in order to permit a mutually beneficial relationship between itself and its symbionts.

A Change of Heart

Butyrate has caused me to re-think my position on fiber-- which was formerly that it's irrelevant at best. I felt that fiber came along with nutrient-dense whole plant foods, but was not beneficial per se. I believed that the associations between fiber intake and a lower risk of a number of diseases were probably due to the fact that wealthier, more educated, healthier people tend to buy more whole grains, fruit and vegetables. In other words, I believed that fiber intake was associated with better health, but did not contribute to it. I now feel, based on further reading about fiber and short-chain fatty acids like butyrate, that the associations represent a true cause-and-effect relationship.

I also didn't fully appreciate the caloric contribution of fiber to the human diet. In industrialized countries, fiber may contribute 5 to 10 percent of total calorie intake, due to its conversion to short-chain fatty acids like butyrate in the large intestine (free full text). This figure is probably at least twice as high in cultures consuming high-fiber diets. It's interesting to think that "high-carbohydrate" cultures may be getting easily 15 percent of their calories from short-chain fats. Since that isn't recorded in dietary surveys, they may appear more dependent on carbohydrate than they actually are. The Kitavans may be getting more than 30 percent of their total calories from fat, despite the fact that their food is only 21 percent fat when it passes their lips. Their calorie intake may be underestimated as well.

Sources of Butyrate

There are two main ways to get butyrate and other short-chain fatty acids. The first is to eat fiber and let your intestinal bacteria do the rest. Whole plant foods such as sweet potatoes, properly prepared whole grains, beans, vegetables, fruit and nuts are good sources of fiber. Refined foods such as white flour, white rice and sugar are very low in fiber. Clinical trials have shown that increasing dietary fiber increases butyrate production, and decreasing fiber decreases it (free full text).

Butyrate also occurs in significant amounts in food. What foods contain butyrate? Hmm, I wonder where the name BUTYR-ate came from? Butter perhaps? Butter is 3-4 percent butyrate, the richest known source. But everyone knows butter is bad for you, right?

After thinking about it, I've decided that butyrate must have been a principal component of Dr. Weston Price's legendary butter oil. Price used this oil in conjunction with high-vitamin cod liver oil to heal tooth decay and a number of other ailments in his patients. The method he used to produce it would have concentrated fats with a low melting temperature, including butyrate, in addition to vitamin K2*****. Thus, the combination of high-vitamin cod liver oil and butter oil would have provided a potent cocktail of fat-soluble vitamins (A, D3, K2), omega-3 fatty acids and butyrate. It's no wonder it was so effective in his patients.

* According to insulin tolerance test.

** Acetate (acetic acid, the main acid in vinegar), propionate and butyrate are the primary three fatty acids produced by intestinal fermentation.

*** The lowest concentration used in this study, 30 micromolar, is probably higher than the concentration in peripheral serum under normal circumstances. Human serum butyrate is in the range of 4 micromolar in British adults, and 29 micromolar in the hepatic portal vein which brings fats from the digestive tract to the liver (ref). This would likely be at least two-fold higher in populations eating high-fiber diets.

**** Due to higher mitochondrial density in brown fat and more mitochondrial uncoupling.

***** Slow crystallization, which selectively concentrates triglycerides with a low melting point.

Dr. Rosedale Replies

A few months ago, I posted link to an article by Dr. Ron Rosedale and made a few comments about it. Dr. Rosedale has sent a reply to my comments, which I have agreed to publish as a new post because they may be of interest to readers. In the following exchange, my numbered comments are in quotes and Dr. Rosedale's replies follow them.

Dr. Rosedale's Comments

1. Dr. Rosedale says that insulin's ability to regulate blood sugar is a minor role, and that other hormones do the same thing. Tell that to a type 1 diabetic. Excessive blood glucose is Not Good, and that's what you get if there isn't enough insulin around.
What I have said was that insulin does not control glucose levels in the blood, and that insulin's biological purpose (not ability) plays only a minor role in BS control... and that is a correct statement. Insulin reduces blood glucose by storing it for a rainy day as glycogen and fat, but not for the purpose of regulating blood sugar levels. The control of BS is in an upward direction, not a downward direction. The problem in our evolutionary history was to have enough BS for emergency anaerobic respiration and for those tissues that require it such as red blood cells. Lowering blood sugar was never a priority in our history. For one, it didn't rise much very often. There wasn't much glucose around. Uncooked rice and potatoes, etc., are mostly indigestible. The sugar that was around, such as in fruit, required considerable effort to obtain therefore lowered the sugar prior to obtaining it. Also, the sugar that is in fruit is largely fructose which doesn't convert that much into glucose but rather into fat in the liver. Even if it did raise blood sugar levels, even if it did cause diabetes in evolutionary time, nature would consider that irrelevant as it wouldn't have killed people prior to the reproductive years, only post-reproductively when nature doesn't give a damn.

Furthermore, insulin's major purpose goes way beyond sugar. At the very least, it is a nutrient storage hormone being relevant not only in glucose storage, but also in fat and protein (amino acid) storage. It also plays a significant role in micronutrient storage and conversions. However, overwhelmingly more important, is insulin's role as a nutrient sensor greatly influencing genetic expression and modifying the rate of aging by up or down regulating maintenance and repair.

2. I'm not convinced by the theory that organisms balance reproduction and repair, emphasizing one at the expense of the other. The amount of energy it takes to fuel cellular repair processes is negligible compared to the amount it takes to maintain body temperature, fuel the brain and contract skeletal muscles. Why not just have the organism eat an extra half-teaspoon of mashed potatoes to fuel the heat-shock proteins and make a little extra catalase? I think the true reasons behind lifespan extension upon caloric restriction will turn out to be more complex than a balance between reproduction and repair.
Stephan does not have to be convinced. Almost everybody who studies the biology of aging is convinced that there is a dichotomy between reproduction and maintenance and repair and that biologically a cell can spend the majority of available resources towards one or the other, but not both. This can actually be shown genetically as the up or down regulation of the expression of genes regulating heat shock proteins, intracellular antioxidant systems, DNA repair enzymes, "garbage collection", etc versus the up or down regulation of genes which regulate reproductive behavior. It should also be noted that excessive reproductive behavior is, in individual cells of multicellular organisms, a strong predisposition to cancer. Furthermore, Stephan’s statement that it takes negligible energy for maintenance and repair is very wrong. In fact one could make the argument that almost all of the energy spent by both individual cells and by the cell societies of multi-celled organisms when not reproducing is towards maintenance and repair.

3. I disagree with the idea that carbohydrate itself is behind elevated fasting insulin and leptin. Just look at the Kitavans. They get 69% of their calories from high-glycemic-load carbohydrates, with not much fat (21%) or protein (10%) to slow digestion. Yet, they have low fasting insulin and remarkably low fasting leptin. I believe the fasting levels of these hormones are more responsive to macronutrient quality than quantity. In other words, what matters most is not how much carbohydrate is in the diet, but where the carbohydrate comes from. The modern Western combination of carelessly processed wheat, sugar and linoleic acid-rich vegetable oil seems to be particularly harmful.
It is not where the carbohydrates come from, but where the carbohydrates go. In other words, what carbohydrates are digested into, i.e what the cells are being fed. Feeding them glucose, fructose, galactose and amino acids as energy (as opposed to using the amino acids whole as structural components) is bad.

Stephan himself could answer this one. It's not the percent of calories from carbohydrates that is relevant; it is the absolute amount of non-fiber carbohydrates that is relevant as the glycemic load.

A few further comments on the Kitavans, though I really am not an expert on their diet:

I find that indigenous diets are only partially helpful as there are so many variables that can go unaccounted for. I prefer the more elementary sciences to form opinions. However, it sounds like there really isn't that much non-fiber carbohydrate in the diet and there is considerable fiber, fish and coconut oil, and moderate to low protein, all of which are quite fine for health. If it is known, the total gram quantities of macronutrients would be good to know. Another important point; what is their lifespan? It sounds like it might be long, but it would be nice to know a more accurate figure. It is not weight loss that we should be after, it is health as indicated by a long and youthful lifespan. Another point; though they (the Kitavans) may be doing well if one defines well as better than most human counterparts, it isn't really saying much. The majority of society eats so badly that it really is not difficult to eat a diet that is better. What I am after is not just better, but best. Perhaps one could take the Kitavan diet and improve upon it by reducing the non-fiber carbohydrate content and perhaps adding more beneficial fats and oils. It is quite possible, in fact probable, that there have been no human societies that have eaten an ideal diet. We can only use what modern science is telling us to come up with this.

My Reply to Dr. Rosedale

Thank you for your comments.

1. I agree with you that control of blood sugar is not insulin's only purpose, and that there are other mechanisms of blood glucose control. There were several papers published recently showing that type 1 diabetic rats (lacking insulin) can be restored to a normal blood glucose level and near-normal glucose tolerance by infusing leptin into the lateral or the third cerebral ventricles (1, 2). This was totally independent of insulin, because the rats weren't producing any. And yes, insulin signaling influences lifespan in a number of animal models.

However, insulin is still the primary controller of blood sugar under normal circumstances, as shown in type 1 diabetes where the primary defect is in insulin production. Furthermore, excessively elevated glucose is damaging per se, due to protein glycation, competition with vitamin C, etc. Therefore, the glucose-controlling function of insulin is important.

I do not agree that glucose from starch and fruit played an insignificant role in human evolution. A number of modern hunter-gatherers eat a significant amount of starch, and our ancestors probably did as well, as soon as they could cook. The timeline of cooking is debated, but we've probably been doing it for at least half a million years, or as long as Homo sapiens has existed. Fruit sugar is roughly 50% glucose, as is honey.

2. As someone who spent two years in the field of aging research, I don't see a scientific consensus on the idea that reproduction and aging are in balance with one another. The two correlate with one another in some, but not all models. I was at a seminar just the other day by Dr. Linda Partridge, from the Max Planck institute, and she was talking about her lifespan experiments in fruit flies. She was able to independently modify lifespan and fecundity using amino acid restriction, leading her to the conclusion that there is no link between the two in her model. She published these data recently in the journal Nature (reference).

Regarding the energy required for cellular maintenance, a little math is instructive here.
I eat maybe 3,200 calories a day, which is normal for an active male of my weight. My basal metabolic rate is roughly 1,700 kcal per day. So 1,500 of my calories have already gone to moving my skeletal muscles. Of the basal metabolic rate, the vast majority comes from maintaining body temperature. Thermogenesis is why cold-blooded animals only need to eat a fraction of the calories mammals do. Then there's cardiac function, and smooth muscle activity, which eat up more calories. Then there are the energy-intensive cellular processes of maintaining ionic gradients across cell membranes (which is why the brain eats up 20% of our calories) and protein synthesis.

After you subtract out all those functions, only a small fraction of total caloric intake is left for other cellular processes. So the caloric needs for processes that combat cellular aging (DNA repair, etc.) are quite low, compared to overall energy requirements. This is consistent with the fact that naked mole rats, which live ten times longer than
Rattus norvegicus, have a similar basal metabolic rate to one another. Keeping cells from being damaged is not a particularly energy-intensive process, and so we have to look elsewhere for the reason why it hasn't been prioritized by evolution.

3. The Kitavan diet is high in digestible starch. The foods they eat have been characterized for starch content, glycemic index, and fiber content. Their diet overall has a high glycemic load, is 69% carbohydrate by calories, and is similar in calories to the American diet. They have a low BMI, a low fasting insulin and low fasting glucose. I agree that there are many factors at play here, and the example of the Kitavans doesn't necessarily give carbohydrate a free pass in all situations. But it does show that a high carbohydrate intake, at least under certain circumstances, is compatible with low fasting insulin, high insulin sensitivity, leanness, and apparent good health.

I also agree that the Kitavans are not really a good model of longevity. Although they live a long time relative to other non-industrial cultures, and have individuals exceeding 95 years old, they don't have a longer average lifespan than people in affluent nations. One can guess that it's due to a lack of modern medical care to treat infectious diseases, and I think that's likely to play a role, but ultimately it's speculation. It's an open question whether you could improve their lifespan by reducing the non-fiber carbohydrate content of their diet, but I'm skeptical.

In the end, it's also an open question whether or not you can extend life by restricting carbohydrate. For the typical overweight American who responds well to carbohydrate restriction, it's reasonable to speculate that it might. For an insulin-sensitive, lean American, it's not clear that it would have much benefit, outside of reducing potentially harmful foods such as gluten and sugar. Although insulin signaling is probably tied up with lifespan in humans, as in many other species, no one has shown that post-meal insulin spikes caused by carbohydrate, as opposed to chronically elevated insulin and insulin resistance, is harmful. The story is not as simple as "more serum insulin = shorter lifespan".

Is there any evidence that carbohydrate restriction extends lifespan in a non-carnivorous mammal such as a rodent or monkey? I'm open to the possibility, but I haven't seen any studies. I'll look forward to them.