A New Understanding of an Old "Obesity Gene"

As you know if you've been following this blog for a while, obesity risk has a strong genetic component.  Genome-wide association studies (GWAS) attempt to identify the specific locations of genetic differences (single-nucleotide polymorphisms or SNPs) that are associated with a particular trait.  In the case of obesity, GWAS studies have had limited success in identifying obesity-associated genes.  However, one cluster of SNPs consistently show up at the top of the list in these studies: those that are near the gene FTO.

As with many of the genes in our genome, different people carry different versions of FTO.  People with two copies of the "fat" version of the FTO SNPs average about 7 pounds (3 kg) heavier than people with two copies of the "thin" version, and they also tend to eat more calories (1, 2).  

Despite being the most consistent hit in these genetic studies, FTO has remained a mystery.  As with most obesity-associated genes, it's expressed in the brain and it seems to respond somewhat to nutritional status.  Yet its function is difficult to reconcile with a role in weight regulation: 

• It's an enzyme that removes methyl groups from RNA, which doesn't immediately suggest a weight-specific function.
• It's not primarily expressed in the brain or in body fat, but in all tissues.
• Most importantly, as far as we know, the different versions of the gene do not result in different tissue levels of FTO, or different activity of the FTO enzyme, so it's hard to understand how they would impact anything at all.  

An important thing to keep in mind is that GWAS studies don't usually pinpoint specific genes.  Typically, they tell us that obesity risk is associated with variability in a particular region of the genome.  If the region corresponds to the location of a single gene, it's a pretty good guess that the gene is the culprit.  However, that's not always the case...

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The Genetics of Obesity, Part III

Genetics Loads the Gun, Environment Pulls the Trigger

Thanks to a WHS reader* for reminding me of the above quote by Dr. Francis Collins, director of the US National Institutes of Health**.  This is a concept that helps reconcile the following two seemingly contradictory observations:

1. Roughly 70 percent of obesity risk is genetically inherited, leaving only 30 percent of risk to environmental factors such as diet and lifestyle.
2. Diet and lifestyle have a large impact on obesity risk.  The prevalence of obesity has tripled in the last 30 years, and the prevalence of extreme obesity has increased by almost 10-fold.  This is presumably not enough time for genetic changes to account for it.

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The Genetics of Obesity, Part II

Rodents Lead the Way

The study of obesity genetics dates back more than half a century.  In 1949, researchers at the Jackson Laboratories identified a remarkably fat mouse, which they determined carried a spontaneous mutation in an unidentified gene.  They named this the "obese" (ob/ob) mouse.  Over the next few decades, researchers identified several other genetically obese mice with spontaneous mutations, including diabetic (db/db) mice, "agouti" (Avy) mice, and "Zucker" (fa/fa) rats.

At the time of discovery, no one knew where the mutations resided in the genome.  All they knew is that the mutations were in single genes, and they resulted in extreme obesity.  Researchers recognized this as a huge opportunity to learn something important about the regulation of body fatness in an unbiased way.  Unbiased because these mutations could be identified with no prior knowledge about their function, therefore the investigators' pre-existing beliefs about the mechanisms of body fat regulation could have no impact on what they learned.  Many different research groups tried to pin down the underlying source of dysfunction: some thought it was elevated insulin and changes in adipose tissue metabolism, others thought it was elevated cortisol, and a variety of other hypotheses.

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The Genetics of Obesity, Part I

Choosing the Right Parents: the Best Way to Stay Lean?

In 1990, Dr. Claude Bouchard and colleagues published a simple but fascinating study demonstrating the importance of genetics in body fatness (1).  They took advantage of one of the most useful tools in human genetics: identical twins.  This is what happens when a single fertilized egg generates two embryos in utero and two genetically identical humans are born from the same womb.   By comparing identical twins to other people who are not genetically identical (e.g., non-identical twins), we can quantify the impact of genes vs. environment on individual characteristics (2).

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Beyond Ötzi: European Evolutionary History and its Relevance to Diet. Part III

In previous posts, I reviewed some of the evidence suggesting that human evolution has accelerated rapidly since the development of agriculture (and to some degree, before it).  Europeans (and other lineages with a long history of agriculture)  carry known genetic adaptations to the Neolithic diet, and there are probably many adaptations that have not yet been identified.  In my final post in this series, I'll argue that although we've adapted, the adaptation is probably not complete, and we're left in a sort of genetic limbo between the Paleolithic and Neolithic state. 

Recent Genetic Adaptations are Often Crude

It may at first seem strange, but many genes responsible for common genetic disorders show evidence of positive selection.  In other words, the genes that cause these disorders were favored by evolution at some point because they presumably provided a survival advantage.  For example, the sickle cell anemia gene protects against malaria, but if you inherit two copies of it, you end up with a serious and life-threatening disorder (1).  The cystic fibrosis gene may have been selected to protect against one or more infectious diseases, but again if you get two copies of it, quality of life and lifespan are greatly curtailed (2, 3).  Familial Mediterranean fever is a very common disorder in Mediterranean populations, involving painful inflammatory attacks of the digestive tract, and sometimes a deadly condition called amyloidosis.  It shows evidence of positive selection and probably protected against intestinal disease due to the heightened inflammatory state it confers to the digestive tract (4, 5).  Celiac disease, a severe autoimmune reaction to gluten found in some grains, may be a by-product of selection for protection against bacterial infection (6).  Phenylketonuria also shows evidence of positive selection (7), and the list goes on.  It's clear that a lot of our recent evolution was in response to new disease pressures, likely from increased population density, sendentism, and contact with domestic animals.

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Beyond Ötzi: European Evolutionary History and its Relevance to Diet. Part I

In the previous post, I explained that Otzi descended in large part from early adopters of agriculture in the Middle East or nearby.  What I'll explain in further posts is that Otzi was not a genetic anomaly: he was part of a wave of agricultural migrants that washed over Europe thousands of years ago, spreading their genes throughout.  Not only that, Otzi represents a halfway point in the evolutionary process that transformed Paleolithic humans into modern humans.

Did Agriculture in Europe Spread by Cultural Transmission or by Population Replacement?

There's a long-standing debate in the anthropology community over how agriculture spread throughout Europe.  One camp proposes that agriculture spread by a cultural route, and that European hunter-gatherers simply settled down and began planting grains.  The other camp suggests that European hunter-gatherers were replaced (totally or partially) by waves of agriculturalist immigrants from the Middle East that were culturally and genetically better adapted to the agricultural diet and lifestyle.  These are two extreme positions, and I think almost everyone would agree at this point that the truth lies somewhere in between: modern Europeans are a mix of genetic lineages, some of which originate from the earliest Middle Eastern agriculturalists who expanded into Europe, and some of which originate from indigenous hunter-gatherer groups including a small contribution from neanderthals.  We know that modern-day Europeans are not simply Paleolithic mammoth eaters who reluctantly settled down and began farming. 

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Lessons From Ötzi, the Tyrolean Ice Man. Part I

This is Otzi, or at least a reconstruction of what he might have looked like.  5,300 years ago, he laid down on a glacier near the border between modern-day Italy and Austria, under unpleasant circumstances.  He was quickly frozen into the glacier.  In 1991, his slumber was rudely interrupted by two German tourists, which eventually landed him in the South Tyrol Museum of Archaeology in Italy. 

Otzi is Europe's oldest natural human mummy, and as such, he's an important window into the history of the human species in Europe.  His genome has been sequenced, and it offers us clues about the genetic history of modern Europeans.

Otzi's Story

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Eocene Diet Follow-up

Now that WHS readers around the globe have adopted the Eocene Diet and are losing weight at an alarming rate, it's time to explain the post a little more.  First, credit where credit is due: Melissa McEwen made a similar argument in her 2011 AHS talk, where she rolled out the "Cambrian Explosion Diet", which beats the Eocene Diet by about 470 million years.  It was probably in the back of my head somewhere when I came up with the idea.

April Fools day is good for a laugh, but humor often has a grain of truth in it.  In this case, the post was a jumping off point for discussing human evolution and what it has to say about the "optimal" human diet, if such a thing exists.  Here's a preview: evolution is a continuous process that has shaped our ancestors' genomes for every generation since the beginning of life.  It didn't end with the Paleolithic, in fact it accelerated, and most of us today carry meaningful adaptations to the Neolithic diet and lifestyle. 

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New Obesity Review Paper by Yours Truly

The Journal of Clinical Endocrinology and Metabolism just published a clinical review paper written by myself and my mentor Dr. Mike Schwartz, titled "Regulation of Food Intake, Energy Balance, and Body Fat Mass: Implications for the Pathogenesis and Treatment of Obesity" (1).  JCEM is one of the most cited peer-reviewed journals in the fields of endocrinology, obesity and diabetes, and I'm very pleased that it spans the gap between scientists and physicians.  Our paper takes a fresh and up-to-date look at the mechanisms by which food intake and body fat mass are regulated by the body, and how these mechanisms are altered in obesity.  We explain the obesity epidemic in terms of the mismatch between our genes and our current environment, a theme that is frequently invoked in ancestral health circles.

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What Causes Insulin Resistance? Part IV

So far, we've explored three interlinked causes of insulin resistance: cellular energy excess, inflammation, and insulin resistance in the brain.  In this post, I'll explore the effects on micronutrient status on insulin sensitivity.

Micronutrient Status

There is a large body of literature on the effects of nutrient intake/status on insulin action, and it's not my field, so I don't intend this to be a comprehensive post.  My intention is simply to demonstrate that it's important, and highlight a few major factors I'm aware of.

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What Causes Insulin Resistance? Part I

Insulin is an ancient hormone that influences many processes in the body.  Its main role is to manage circulating concentrations of nutrients (principally glucose and fatty acids, the body's two main fuels), keeping them within a fairly narrow range*.  It does this by encouraging the transport of nutrients into cells from the circulation, and discouraging the export of nutrients out of storage sites, in response to an increase in circulating nutrients (glucose or fatty acids). It therefore operates a negative feedback loop that constrains circulating nutrient concentrations.  It also has many other functions that are tissue-specific.

Insulin resistance is a state in which cells lose sensitivity to the effects of insulin, eventually leading to a diminished ability to control circulating nutrients (glucose and fatty acids).  It is a major contributor to diabetes risk, and probably a contributor to the risk of cardiovascular disease, certain cancers and a number of other disorders. 

Why is it important to manage the concentration of circulating nutrients to keep them within a narrow range?  The answer to that question is the crux of this post. 

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Does High Circulating Insulin Drive Body Fat Accumulation? Answers from Genetically Modified Mice

The house mouse Mus musculus is an incredible research tool in the biomedical sciences, due to its ease of care and its ability to be genetically manipulated.  Although mice aren't humans, they resemble us closely in many ways, including how insulin signaling works.  Genetic manipulation of mice allows researchers to identify biological mechanisms and cause-effect relationships in a very precise manner.  One way of doing this is to create "knockout" mice that lack a specific gene, in an attempt to determine that gene's importance in a particular process.  Another way is to create transgenic mice that express a gene of interest, often modified in some way.  A third method is to use an extraordinary (but now common) tool called "Cre-lox" recombination (1), which allows us to delete or add a single gene in a specific tissue or cell type. 

Studying the relationship between obesity and insulin resistance is challenging, because the two typically travel together, confounding efforts to determine which is the cause and which is the effect of the other (or neither).  Some have proposed the hypothesis that high levels of circulating insulin promote body fat accumulation*.  To truly address this question, we need to consider targeted experiments that increase circulating insulin over long periods of time without altering a number of other factors throughout the body.  This is where mice come in.  Scientists are able to perform precise genetic interventions in mice that increase circulating insulin over a long period of time.  These mice should gain fat mass if the hypothesis is correct. 

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The Case for the Food Reward Hypothesis of Obesity, Part II

In this post, I'll explore whether or not the scientific evidence is consistent with the predictions of the food reward hypothesis, as outlined in the last post.

Before diving in, I'd like to address the critique that the food reward concept is a tautology or relies on circular reasoning (or is not testable/falsifiable).  This critique has no logical basis.  The reward and palatability value of a food is not defined by its effect on energy intake or body fatness.  In the research setting, food reward is measured by the ability of food or food-related stimuli to reinforce or motivate behavior (e.g., 1).  In humans, palatability is measured by having a person taste a food and rate its pleasantness in a standardized, quantifiable manner, or sometimes by looking at brain activity by fMRI or related techniques (2).  In rodents, it is measured by observing stereotyped facial responses to palatable and unpalatable foods, which are similar to those seen in human infants.  It is not a tautology or circular reasoning to say that the reinforcing value or pleasantness of food influences food intake and body fatness. These are quantifiable concepts and as I will explain, their relationship with food intake and body fatness can be, and already has been, tested in a controlled manner. 

1.   Increasing the reward/palatability value of the diet should cause fat gain in animals and humans

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A Roadmap to Obesity

In this post, I'll explain my current understanding of the factors that promote obesity in humans.  

Heritability

To a large degree, obesity is a heritable condition.  Various studies indicate that roughly two-thirds of the differences in body fatness between individuals is explained by heredity*, although estimates vary greatly (1).  However, we also know that obesity is not genetically determined, because in the US, the obesity rate has more than doubled in the last 30 years, consistent with what has happened to many other cultures (2).  How do we reconcile these two facts?  By understanding that genetic variability determines the degree of susceptibility to obesity-promoting factors.  In other words, in a natural environment with a natural diet, nearly everyone would be relatively lean, but when obesity-promoting factors are introduced, genetic makeup determines how resistant each person will be to fat gain.  As with the diseases of civilization, obesity is caused by a mismatch between our genetic heritage and our current environment.  This idea received experimental support from an interesting recent study (3).

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Obesity and the Brain

Nature Genetics just published a paper that caught my interest (1). Investigators reviewed the studies that have attempted to determine associations between genetic variants and common obesity (as judged by body mass index or BMI). In other words, they looked for "genes" that are suspected to make people fat.

There are a number of gene variants that associate with an increased or decreased risk of obesity. These fall into two categories: rare single-gene mutations that cause dramatic obesity, and common variants that are estimated to have a very small impact on body fatness. The former category cannot account for common obesity because it is far too rare, and the latter probably cannot account for it either because it has too little impact*. Genetics can't explain the fact that there were half as many obese people in the US 40 years ago. Here's a wise quote from the obesity researcher Dr. David L. Katz, quoted from an interview about the study (2):

Let us by all means study our genes, and their associations with our various shapes and sizes... But let's not let it distract us from the fact that our genes have not changed to account for the modern advent of epidemic obesity -- our environments and lifestyles have.

Exactly. So I don't usually pay much attention to "obesity genes", although I do think genetics contributes to how a body reacts to an unnatural diet/lifestyle. However, the first part of his statement is important too. Studying these types of associations can give us insights into the biological mechanisms of obesity when we ask the question "what do these genes do?" The processes these genes participate in should be the same processes that are most important in regulating fat mass.

So, what do the genes do? Of those that have a known function, nearly all of them act in the brain, and most act in known body fat regulation circuits in the hypothalamus (a brain region). The brain is the master regulator of body fat mass. It's also the master regulator of nearly all large-scale homeostatic systems in the body, including the endocrine (hormone) system. Now you know why I study the neurobiology of obesity.


* The authors estimated that "together, the 32 confirmed BMI loci explained 1.45% of the inter-individual variation in BMI." In other words, even if you were unlucky enough to inherit the 'fat' version of all 32 genes, which is exceedingly unlikely, you would only have a slightly higher risk of obesity than the general population.

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Malocclusion: Disease of Civilization

In his epic work Nutrition and Physical Degeneration, Dr. Weston Price documented the abnormal dental development and susceptibility to tooth decay that accompanied the adoption of modern foods in a number of different cultures throughout the world. Although he quantified changes in cavity prevalence (sometimes finding increases as large as 1,000-fold), all we have are Price's anecdotes describing the crooked teeth, narrow arches and "dished" faces these cultures developed as they modernized.

Price published the first edition of his book in 1939. Fortunately, Nutrition and Physical Degeneration wasn't the last word on the matter. Anthropologists and archaeologists have been extending Price's findings throughout the 20th century. My favorite is Dr. Robert S. Corruccini, currently a professor of anthropology at Southern Illinois University. He published a landmark paper in 1984 titled "An Epidemiologic Transition in Dental Occlusion in World Populations" that will be our starting point for a discussion of how diet and lifestyle factors affect the development of the teeth, skull and jaw (Am J. Orthod. 86(5):419)*.

First, some background. The word occlusion refers to the manner in which the top and bottom sets of teeth come together, determined in part by the alignment between the upper jaw (maxilla) and lower jaw (mandible). There are three general categories:

• Class I occlusion: considered "ideal". The bottom incisors (front teeth) fit just behind the top incisors.
• Class II occlusion: "overbite." The bottom incisors are too far behind the top incisors. The mandible may appear small.
  
• Class III occlusion: "underbite." The bottom incisors are beyond the top incisors. The mandible protrudes.
  

Malocclusion means the teeth do not come together in a way that's considered ideal. The term "class I malocclusion" is sometimes used to describe crowded incisors when the jaws are aligning properly.

Over the course of the next several posts, I'll give an overview of the extensive literature showing that hunter-gatherers past and present have excellent occlusion, subsistence agriculturalists generally have good occlusion, and the adoption of modern foodways directly causes the crooked teeth, narrow arches and/or crowded third molars (wisdom teeth) that affect the majority of people in industrialized nations. I believe this process also affects the development of the rest of the skull, including the face and sinuses.

In his 1984 paper, Dr. Corruccini reviewed data from a number of cultures whose occlusion has been studied in detail. Most of these cultures were observed by Dr. Corruccini personally. He compared two sets of cultures: those that adhere to a traditional style of life and those that have adopted industrial foodways. For several of the cultures he studied, he compared it to another that was genetically similar. For example, the older generation of Pima indians vs. the younger generation, and rural vs. urban Punjabis. He also included data from archaeological sites and nonhuman primates. Wild animals, including nonhuman primates, almost invariably show perfect occlusion.

The last graph in the paper is the most telling. He compiled all the occlusion data into a single number called the "treatment priority index" (TPI). This is a number that represents the overall need for orthodontic treatment. A TPI of 4 or greater indicates malocclusion (the cutoff point is subjective and depends somewhat on aesthetic considerations). Here's the graph: Every single urban/industrial culture has an average TPI of greater than 4, while all the non-industrial or less industrial cultures have an average TPI below 4. This means that in industrial cultures, the average person requires orthodontic treatment to achieve good occlusion, whereas most people in more traditionally-living cultures naturally have good occlusion.

The best occlusion was in the New Britain sample, a precontact Melanesian hunter-gatherer group studied from archaeological remains. The next best occlusion was in the Libben and Dickson groups, who were early Native American agriculturalists. The Pima represent the older generation of Native Americans that was raised on a somewhat traditional agricultural diet, vs. the younger generation raised on processed reservation foods. The Chinese samples are immigrants and their descendants in Liverpool. The Punjabis represent urban vs. rural youths in Northern India. The Kentucky samples represent a traditionally-living Appalachian community, older generation vs. processed food-eating offspring. The "early black" and "black youths" samples represent older and younger generations of African-Americans in the Cleveland and St. Louis area. The "white parents/youths" sample represents different generations of American Caucasians.

The point is clear: there's something about industrialization that causes malocclusion. It's not genetic; it's a result of changes in diet and/or lifestyle. A "disease of civilization". I use that phrase loosely, because malocclusion isn't really a disease, and some cultures that qualify as civilizations retain traditional foodways and relatively good teeth. Nevertheless, it's a time-honored phrase that encompasses the wide array of health problems that occur when humans stray too far from their ecological niche. I'm going to let Dr. Corruccini wrap this post up for me:

I assert that these results serve to modify two widespread generalizations: that imperfect occlusion is not necessarily abnormal, and that prevalence of malocclusion is genetically controlled so that preventive therapy in the strict sense is not possible. Cross-cultural data dispel the notion that considerable occlusal variation [malocclusion] is inevitable or normal. Rather, it is an aberrancy of modern urbanized populations. Furthermore, the transition from predominantly good to predominantly bad occlusion repeatedly occurs within one or two generations' time in these (and other) populations, weakening arguments that explain high malocclusion prevalence genetically.

* This paper is worth reading if you get the chance. It should have been a seminal paper in the field of preventive orthodontics, which could have largely replaced conventional orthodontics by now. Dr. Corruccini is the clearest thinker on this subject I've encountered so far.

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Ischemic Heart Attacks: Disease of Civilization

Or, more precisely, disease of industrial civilization.

The scientific literature contains examples of cultures that don't suffer from the chronic non-communicable diseases that are so common in modern societies. Much of what I've read indicates that heart attacks are practically unique to cultures that have adopted industrial foodways and a modern lifestyle, being infrequent or entirely absent in those that have not.

I recently came across an incredible paper from 1964 in the American Journal of Cardiology, titled "Geographic Pathology of Myocardial Infarction", by lead author Dr. Kyu Taik Lee (Am. J. Cardiol. 13:30. 1964). This was published during a period of intense research into the cardiovascular health of non-industrial cultures, including Dr. George V. Mann's famous study of the Masai.

The first thing Lee and his colleagues did was collect autopsy statistics from San Francisco and Los Angeles hospitals. They analyzed the data by race, including categories for Caucasian-Americans (white), Japanese-Americans, Chinese-Americans, and Filipino-Americans. All races had a similar incidence of autopsy-proven myocardial infarction (MI = heart attack), including both silent (healed) and fatal MI. For comparison, they included a table with autopsy data from hospitals in Tokyo, South Japan and North Japan. I'm including the data from Tokyo in the graph because it's also an urban environment, but the finding was the same in all three regions. Here's what they found, by age group: The Japanese had a very low rate of MI compared to both Caucasian-Americans and Japanese-Americans. The rate of MI in Caucasian-Americans and Japanese-Americans did not differ significantly. Thus, location but not race determined the susceptibility to MI.

Next, the investigators collected autopsy data from hospitals in New Orleans, again divided by race. This time they exained Caucasian-Americans and African-Americans. Both groups had a very high rate of MI, as expected, although the African-Americans had a lower rate than Caucasian-Americans. They also collected data from autopsies in Nigeria and Uganda for comparison. Here are the data for men: And for women: Again, location but not race largely determined the incidence of MI. MI was extremely rare in the African autopsies. Here's what they had to say:

There was only 1 case of healed myocardial infarction among over 4,000 adult autopsies in the Uganda series, and only 2 cases of healed myocardial infarction among over 500 adult autopsies in the Nigerian series. In the New Orleans Negro series the occurrence rate was far greater in every sex and age group than in either one of the Negro series in East and West Africa.

Over 4,500 autopsies and not a single fatal MI. If this isn't worth studying, what is? These data should be part of first-year training in medicine and health programs.

To satisfy the skeptics, Lee and colleagues imported hundreds of hearts from consecutive autopsies in Albany (USA), Africa, Korea and Japan. They had an American pathologist analyze them side-by side to eliminate any diagnostic bias. Here's what they found:

In the African Negro series no infarct was found in any age group [out of 244 hearts, 39 over 60 years old]. In the Korean series there were only 2 cases of myocardial infarction [out of 106 hearts] and they were both women... In the Japanese series there were 8 cases of myocardial infarction in 259 hearts. All were men...

In the American sample, nearly 40% of the hearts of men and women over 60 showed signs of MI. The findings of the American pathologist confirmed the international autopsy data, showing that diagnostic bias did not contribute to the results significantly. They also took measurements of the thickness of the coronary artery wall, an index of atherosclerosis. They found that the Americans had the most atherosclerosis, but all cultures had some degree of it and there was overlap in the amount of atherosclerosis between samples. This led the investigators to state:

Myocardial infarction and coronary thrombosis are almost nonexistent in Uganda and Nigeria, and the amount of coronary arteriosclerosis is significantly less in Africans than in whites. However, in the two groups there was some overlapping in the degree of arteriosclerosis. No Africans had infarcts, but some had the same or a greater degree of coronary arteriosclerosis as a few whites who had myocardial infarctions. One explanation for this may be that some difference in clotting or clot-lysis mechanisms is present in the two groups. In a previous study, we showed that the incidence of thromboembolic phenomena in the pulmonary circulation [blood clots in the lungs] was low in East Africans as compared with Americans.

Now, the authors' conclusions:

These data strongly suggest that among the Orientals the environmental factor is playing a major role in the etiology of myocardial infarction and coronary thrombosis. If the genetic factor is an important one, those Orientals who moved to this country many years ago or who were born in this country should still maintain their low occurrence rate of myocardial infarction at least to some extent, and one would not expect to see similar occurrence rates of myocardial infarction in Orientals and whites as old as 50 to 59 years... As with the Orientals, this suggests that for Negroes in the United States environmental factors are more important than genetic factors in the etiology of myocardial infarction.

Africans in Africa and Japanese in Japan = low incidence of MI. Africans, Japanese and Caucasians in the US = high and similar incidence of MI. Genes only influence a person's susceptibility to MI when they live in an environment that promotes MI. Otherwise, genes are basically irrelevant.

What do the traditional diets and lifestyles of Japan and Africa have in common? Not much. Even within Nigeria, the diet varies from heavily starch-based (root vegetables, soaked/fermented non-gluten grains, beans, plantains) to mostly reliant on high-fat dairy and meat, though the former is much more common and I'm not sure how much the latter is represented in the data. In fact, I believe it's the wrong question to ask. A better question is "what do we eat/do in the US that traditional Japanese, Koreans, Chinese, Polynesians, Melanesians and Africans don't"? For starters, none of them rely on industrially processed foods. Their food is generally prepared at home using wholesome ingredients and traditional methods.

There are a number of lifestyle factors that probably play a role here.  They probably get more exercise than Americans, even if it's only walking in Tokyo or domestic tasks for women in parts of Africa. Traditional Africans surely get more sunlight and thus more vitamin D. I can't imagine life is less stressful in Tokyo than in San Francisco or Los Angeles.  Cigarettes are probably much less prevalent in parts of Africa than in the modern US.

I really like this study, and I think these graphs should be disseminated as much as possible. I've prepared high-resolution versions in JPEG, Powerpoint and PDF formats. E-mail me (click on my profile for the link) if you would like a copy. Let me know which format(s) you want.

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Paleolithic Diet Clinical Trials Part III

I'm happy to say, it's time for a new installment of the "Paleolithic Diet Clinical Trials" series. The latest study was recently published in the European Journal of Clinical Nutrition by Dr. Anthony Sebastian's group. Dr. Sebastian has collaborated with Drs. Loren Cordain and Boyd Eaton in the past.

This new trial has some major problems, but I believe it nevertheless adds to the weight of the evidence on "paleolithic"-type diets. The first problem is the lack of a control group. Participants were compared to themselves, before eating a paleolithic diet and after having eaten it for 10 days. Ideally, the paleolithic group would be compared to another group eating their typical diet during the same time period. This would control for effects due to getting poked and prodded in the hospital, weather, etc. The second major problem is the small sample size, only 9 participants. I suspect the investigators had a hard time finding enough funding to conduct a larger study, since the paleolithic approach is still on the fringe of nutrition science.

I think this study is best viewed as something intermediate between a clinical trial and 9 individual anecdotes.

Here's the study design: they recruited 9 sedentary, non-obese people with no known health problems. They were 6 males and 3 females, and they represented people of African, European and Asian descent. Participants ate their typical diets for three days while investigators collected baseline data. Then, they were put on a seven-day "ramp-up" diet higher in potassium and fiber, to prepare their digestive systems for the final phase. In the "paleolithic" phase, participants ate a diet of:

Meat, fish, poultry, eggs, fruits, vegetables, tree nuts, canola oil, mayonnaise, and honey... We excluded dairy products, legumes, cereals, grains, potatoes and products containing potassium chloride...

Mmm yes, canola oil and mayo were universally relished by hunter-gatherers. They liked to feed their animal fat and organs to the vultures, and slather mayo onto their lean muscle meats. Anyway, the paleo diet was higher in calories, protein and polyunsaturated fat (I assume with a better n-6 : n-3 ratio) than the participants' normal diet. It contained about the same amount of carbohydrate and less saturated fat.

There are a couple of twists to this study that make it more interesting. One is that the diets were completely controlled. The only food participants ate came from the experimental kitchen, so investigators knew the exact calorie intake and nutrient composition of what everyone was eating.

The other twist is that the investigators wanted to take weight loss out of the picture. They wanted to know if a paleolithic-style diet is capable of improving health independent of weight loss. So they adjusted participants' calorie intake to make sure they didn't lose weight. This is an interesting point. Investigators had to increase the participants' calorie intake by an average of 329 calories a day just to get them to maintain their weight on the paleo diet. Their bodies naturally wanted to shed fat on the new diet, so they had to be overfed to maintain weight.

On to the results. Participants, on average, saw large improvements in nearly every meaningful measure of health in just 10 days on the "paleolithic" diet. Remember, these people were supposedly healthy to begin with. Total cholesterol and LDL dropped. Triglycerides decreased by 35%. Fasting insulin plummeted by 68%. HOMA-IR, a measure of insulin resistance, decreased by 72%. Blood pressure decreased and blood vessel distensibility (a measure of vessel elasticity) increased. It's interesting to note that measures of glucose metabolism improved dramatically despite no change in carbohydrate intake. Some of these results were statistically significant, but not all of them. However, the authors note that:

In all these measured variables, either eight or all nine participants had identical directional responses when switched to paleolithic type diet, that is, near consistently improved status of circulatory, carbohydrate and lipid metabolism/physiology.

Translation: everyone improved. That's a very meaningful point, because even if the average improves, in many studies a certain percentage of people get worse. This study adds to the evidence that no matter what your gender or genetic background, a diet roughly consistent with our evolutionary past can bring major health benefits. Here's another way to say it: ditching certain modern foods can be immensely beneficial to health, even in people who already appear healthy. This is true regardless of whether or not one loses weight.

There's one last critical point I'll make about this study. In figure 2, the investigators graphed baseline insulin resistance vs. the change in insulin resistance during the course of the study for each participant. Participants who started with the most insulin resistance saw the largest improvements, while those with little insulin resistance to begin with changed less. There was a linear relationship between baseline IR and the change in IR, with a correlation of R=0.98, p less than 0.0001. In other words, to a highly significant degree, participants who needed the most improvement, saw the most improvement. Every participant with insulin resistance at the beginning of the study ended up with basically normal insulin sensitivity after 10 days. At the end of the study, all participants had a similar degree of insulin sensitivity. This is best illustrated by the standard deviation of the fasting insulin measurement, which decreased 9-fold over the course of the experiment.

Here's what this suggests: different people have different degrees of susceptibility to the damaging effects of the modern Western diet. This depends on genetic background, age, activity level and many other factors. When you remove damaging foods, peoples' metabolisms normalize, and most of the differences in health that were apparent under adverse conditions disappear. I believe our genetic differences apply more to how we react to adverse conditions than how we function optimally. The fundamental workings of our metabolisms are very similar, having been forged mostly in hunter-gatherer times. We're all the same species after all.

This study adds to the evidence that modern industrial food is behind our poor health, and that a return to time-honored foodways can have immense benefits for nearly anyone. A paleolithic-style diet may be an effective way to claim your genetic birthright to good health. 

Paleolithic Diet Clinical Trials
Paleolithic Diet Clinical Trials Part II
One Last Thought

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Masai and Atherosclerosis

I've been digging deeper into the health of the Masai lately. A commenter on Chris's blog pointed me to a 1972 paper showing that the Masai have atherosclerosis, or hardening of the arteries. This interested me so I got my hands on the full text, along with a few others from the same time period. What I found is nothing short of fascinating.

First, some background. Traditional Masai in Kenya and Tanzania are pastoralists, subsisting on fermented cow's milk, meat and blood, as well as traded food in modern times. They rarely eat fresh vegetables. Contrary to popular belief, they are a genetically diverse population, due to the custom of abducting women from neighboring tribes. Many of these tribes are agriculturalists. From Mann et al: "The genetic argument is worthless". This will be important to keep in mind as we interpret the data.

At approximately 14 years old, Masai men are inducted into the warrior class, and are called Muran. For the next 15-20 years, tradition dictates that they eat a diet composed exclusively of cow's milk, meat and blood. Milk is the primary food. Masai cows are not like wimpy American cows, however. Their milk contains almost twice the fat of American cows, more protein, more cholesterol and less lactose. Thus, Muran eat an estimated 3,000 calories per day, 2/3 of which comes from fat. Here is the reference for all this. Milk fat is about 50% saturated. That means the Muran gets 33% of his calories from saturated fat. This population eats more saturated fat than any other I'm aware of.

How's their cholesterol? Remarkably low. Their total serum cholesterol is about half the average American's. I haven't found any studies that broke it down further than total cholesterol. Their blood pressure is also low, and hypertension is rare. Overweight is practically nonexistent. Their electrocardiogram readings show no signs of heart disease. They have exceptionally good endurance, but their grip strength is significantly weaker than Americans of African descent. Two groups undertook autopsies of male Masai to look for artery disease.

The first study, published in 1970, examined 10 males, 7 of which were over 40 years old. They found very little evidence of atherosclerosis, even in individuals over 60. The second study, which is often used as evidence against a high-fat diet, was much more thorough and far more interesting. Mann et al. autopsied 50 Masai men, aged 10 to 65. The single most represented age group was 50-59 years old, at 13 individuals. They found no evidence of myocardial infarction (heart attack) in any of the 50 hearts. What they did find, however, was coronary artery disease. Here's a figure showing the prevalence of "aortic fibrosis", a type of atherosclerotic lesion:


It looks almost binary, doesn't it? What could be causing the dramatic jump in atherosclerosis at age 40? Here's another figure, of total cholesterol (top) and "sudanophilia" (fatty streaks in the arteries, bottom). Note that the Muran period is superimposed (top).


There appears to be a pattern here. Either the Masai men are eating nothing but milk, meat and blood and they're nearly free from atherosclerosis, or they're eating however they please and they have as much atherosclerosis as the average American. There doesn't seem to be much in between.

Here's a quote from the paper that I found interesting:

We believe... that the Muran escapes some noxious dietary agent for a time. Obviously, this is neither animal fat nor cholesterol. The old and the young Masai do have access to such processed staples as flour, sugar, confections and shortenings through the Indian dukas scattered about Masailand. These foods could carry the hypothetical agent."

This may suggest that you can eat a wide variety of foods and be healthy, except industrial grain products (particularly white flour), sugar, industrial vegetable oil and other processed food. The Masai are just one more example of a group that's healthy when eating a traditional diet.

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Genetics and Disease

There is a lot of confusion surrounding the role of genetics in health. It seems like every day the media have a new story about gene X or Y 'causing' obesity, diabetes or heart disease. There are some diseases that are strongly and clearly linked to a gene, such as the disease I study: spinocerebellar ataxia type 7. I do not believe that genetics are the cause of more than a slim minority of health problems however. Part of this is a semantic issue. How do you define the word 'cause'? It's a difficult question, but I'll give you an example of my reasoning and then we'll come back to it.

A classic and thoroughly studied example of genetic factors in disease can be found in the Pima indians of Arizona. Currently, this population eats a version of the American diet, high in refined and processed foods. It also has the highest prevalence of type II diabetes of any population on earth (much higher than the US average), and a very high rate of obesity. One viewpoint is that these people are genetically susceptible to obesity and diabetes, and thus their genes are the cause of their health problems.

However, if you walk across the national border to Mexico, you'll find another group of Pima indians. This population is genetically very similar to the Arizona Pima except they have low rates of obesity and diabetes. They eat a healthier, whole-foods, agriculture-based diet. Furthermore, 200 years ago, the Arizona Pima were healthy as well. So what's the cause of disease here? Strictly speaking, it's both genetics and lifestyle. Both of these factors are necessary for the health problems of the Arizona Pima. However, I think it's more helpful to think of lifestyle as the cause of disease, since that's the factor that changed.

The Pima are a useful analogy for the world in general. They are an extreme example of what has happened to many if not all modern societies. Thus, when we talk about the 'obesity gene' or the 'heart disease gene', it's misleading. It's only the 'obesity gene' in the context of a lifestyle to which we are not genetically adapted.

I do not believe that over half of paleolithic humans were overweight, or that 20% had serious blood glucose imbalances. In fact, studies of remaining populations living naturally and traditionally have shown that they are typically much healthier than industrialized humans. Yet here we are in the US, carrying the very same genes as our ancestors, sick as dogs. That's not all though: we're actually getting sicker. Obesity, diabetes, allergies and many other problems are on the rise, despite the fact that our genes haven't changed.

I conclude that genetics are only rarely the cause of disease, and that the vast majority of health problems in the US are lifestyle-related. Studies into the genetic factors that predispose us to common health problems are interesting, but they're a distraction from the real problems and the real solutions that are staring us in the face. These solutions are to promote a healthy diet, exercise, and effective stress management.

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