Paleolithic Diet Clinical Trials Part IV

Dr. Staffan Lindeberg has published a new study using the "paleolithic diet" to treat type II diabetics (free full text). Type II diabetes, formerly known as late-onset diabetes until it began appearing in children, is typically thought to develop as a result of insulin resistance (a lowered tissue response to the glucose-clearing function of insulin). This is often followed by a decrease in insulin secretion due to degeneration of the insulin-secreting pancreatic beta cells.

After Dr. Lindeberg's wild success treating patients with type II diabetes or glucose intolerance, in which he normalized the glucose tolerance of all 14 of his volunteers in 12 weeks, he set out to replicate the experiment. This time, he began with 13 men and women who had been diagnosed with type II diabetes for an average of 9 years.

Patients were put on two different diets for 3 months each. The first was a "conventional diabetes diet". I read a previous draft of the paper in which I believe they stated it was based on American Diabetes Association guidelines, but I can't find that statement in the final draft. In any case, here are the guidelines from the methods section:

The information on the Diabetes diet stated that it should aim at evenly distributed meals with increased intake of vegetables, root vegetables, dietary fiber, whole-grain bread and other whole-grain cereal products, fruits and berries, and decreased intake of total fat with more unsaturated fat. The majority of dietary energy should come from carbohydrates from foods naturally rich in carbohydrate and dietary fiber. The concepts of glycemic index and varied meals through meal planning by the Plate Model were explained [18]. Salt intake was recommended to be kept below 6 g per day.

The investigators gave the paleolithic group the following advice:

The information on the Paleolithic diet stated that it should be based on lean meat, fish, fruit, leafy and cruciferous vegetables, root vegetables, eggs and nuts, while excluding dairy products, cereal grains, beans, refined fats, sugar, candy, soft drinks, beer and extra addition of salt. The following items were recommended in limited amounts for the Paleolithic diet: eggs (≤2 per day), nuts (preferentially walnuts), dried fruit, potatoes (≤1 medium-sized per day), rapeseed or olive oil (≤1 tablespoon per day), wine (≤1 glass per day). The intake of other foods was not restricted and no advice was given with regard to proportions of food categories (e.g. animal versus plant foods). The evolutionary rationale for a Paleolithic diet and potential benefits were explained.

Neither diet was restricted in calories. After comparing the effects of the two diets for 3 months, the investigators concluded that the paleolithic diet:

• Reduced HbA1c more than the diabetes diet (a measure of average blood glucose)
• Reduced weight, BMI and waist circumference more than the diabetes diet
• Lowered blood pressure more than the diabetes diet
  
• Reduced triglycerides more than the diabetes diet
• Increased HDL more than the diabetes diet

However, the paleolithic diet was not a cure-all. At the end of the trial, 8 out of 13 patents still had diabetic blood glucose after an oral glucose tolerance test (OGTT). This is compared to 9 out of 13 for the diabetes diet. Still, 5 out of 13 with "normal" OGTT after the paleolithic diet isn't bad. The paleolithic diet also significantly reduced insulin resistance and increased glucose tolerance, although it didn't do so more than the diabetes diet.

As has been reported in other studies, paleolithic dieters ate fewer total calories than the comparison group. This is part of the reason why I believe that something in the modern diet causes hyperphagia, or excessive eating. According to the paleolithic diet studies, this food or combination of foods is neolithic, and probably resides in grains, refined sugar and/or dairy. I have my money on wheat and sugar, with a probable long-term contribution from industrial vegetable oils as well.

Were the improvements on the paleolithic diet simply due to calorie restriction? Maybe, but keep in mind that neither group was told to restrict its caloric intake. The reduction in caloric intake occurred naturally, despite the participants presumably eating to fullness. I suspect that the paleolithic diet reset the dieters' body fat set-point, after which fat began pouring out of their fat tissue. They were supplementing their diets with body fat-- 13 pounds (6 kg) of it over 3 months.

The other notable difference between the two diets, besides food types, was carbohydrate intake. The diabetes diet group ate 56% more carbohydrate than the paleo diet group, with 42% of their calories coming from it. The paleolithic group ate 32% carbohydrate. Could this have been the reason for the better outcome of the paleolithic group? I'd be surprised if it wasn't a factor. Advising a diabetic to eat a high-carbohydrate diet is like asking someone who's allergic to bee stings to fetch you some honey from your bee hive. Diabetes is a disorder of glucose intolerance. Starch is a glucose polymer.

Although to be fair, participants on the diabetes diet did improve in a number of ways. There's something to be said for eating whole foods.

This trial was actually a bit of a disappointment for me. I was hoping for a slam dunk, similar to Lindeberg's previous study that "cured" all 14 patients of glucose intolerance in 3 months. In the current study, the paleolithic diet left 8 out of 13 patients diabetic after 3 months. What was the difference? For one thing, the patients in this study had well-established diabetes with an average duration of 9 years. As Jenny Ruhl explains in her book Blood Sugar 101, type II diabetes often progresses to beta cell loss, after which the pancreas can no longer secrete an adequate amount of insulin.

This may be the critical finding of Dr. Lindeberg's two studies: type II diabetes can be prevented when it's caught at an early stage, such as pre-diabetes, whereas prolonged diabetes may cause damage that cannot be completely reversed though diet. I think this is consistent with the experience of many diabetics who have seen an improvement but not a cure from changes in diet. Please add any relevant experiences to the comments.

Collectively, the evidence from clinical trials on the "paleolithic diet" indicate that it's a very effective treatment for modern metabolic dysfunction, including excess body fat, insulin resistance and glucose intolerance. Another way of saying this is that the modern industrial diet causes metabolic dysfunction.

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

Veganism as Intersectional Social Justice (part 1)

Introduction
Would any sane person think dumpster diving would have stopped Hitler, or that composting would have ended slavery or brought about the eight-hour workday...Then why now, with all the world at stake, do so many people retreat into these entirely personal “solutions”?--Derrick Jensen[*]

[Oppressions are ideologies—]“a set of socially shared beliefs that legitmates an existing or desired social order. Prejudice, on the other hand, is an individual predisposition to devalue a group of others… speciesism is also an ideology—that is, a set of widely held, socially inherited beliefs… When the psychological and moral (or immoral) bases of oppression are accentuated, social structural forces are downplayed or overlooked entirely… they tend to stifle any realization of the need for social change.” –David Nibert[*]

The discourse of vegetarian and vegan advocates is saturated with personal choice. Perhaps more persistently than any other social justice movement in America today other than the pro-choice movement, animal defenders emphasize the individual: the individual animal who suffers, the individual person who chooses three times a day to choose compassion over cruelty, the individuality of the movement, etc.

It is the individual who is responsible for the suffering of each individual animal because of some irrational prejudice. If only these people were just more enlightened about animal sentience, about nutrition, they would leave cruelty-free lives. It is also the individual who is responsible for world hunger because they selfishly feed the world’s grain to livestock. If only each individual chose a vegetarian lifestyle, there would be enough food for everyone.

When the individual person is not totally responsible for the suffering of each individual animal, it is because vegetarianism is too inconvenient and the law is too permissive of cruelty. If only restaurants and grocery stores offered more vegetarian foods (especially faux-meats), people would stop eating meat. If only there were stricter penalties for animal cruelty, less people would harm animals and there would be more justice. Thus the irony of the dominant discourse is that animal liberation is possible so long as humans become more rational and less self-interested; but, so long as people are self-interested, we ought to make vegetarianism as convenient and non-threatening as possible and make animal cruelty as inconvenient and punishable as possible.

In this post I will lay-out the myriad of ways the most popular forms of animal advocacy (at least in the USA) privileges a white, middle-class audience at the expense of including people of color and people of low-income. Drawing on the vast, original works over at The Vegan Ideal [TVI], I wish to demonstrate 1) how focusing on punishing, shaming, and dehumanizing individual animal exploiters a) draws attention away from the institutional oppression (i.e. speciesism) in favor of vice (i.e. cruelty) as well as b) how such punishment is often part of ethnocentric and nationalist projects, and finally, c) how such projects merely seek to substitute human cages for animal cages.

Further, I would like to point out 2) how focus on individual action and lifestyle changes often centers around "voting" with one's dollar, which a) privileges the middle-class at the expense of marginalizing low- and no-income classes, b) privileges non-profit dissemination of literature at the expense of real social organizing and mobilization that empowers people and communities, and c) encourages conservative discourse by said non-profits that target "mainstream" audiences with money that can be used to support said kind of campaigns.
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Animal Models of Atherosclerosis: LDL

Researchers have developed a number of animal models of atherosclerosis (fatty/fibrous lesions in the arteries that influence heart attack risk) to study the factors that affect its development. In the next two posts, I will argue that these models rely on a massive increase in LDL, up to 10-fold, due to overloading the cholesterol metabolism of herbivorous species with excessive dietary cholesterol. This also greatly increases oxidized LDL, leading to atherosclerosis. I will discuss the role of saturated fat, which often receives the blame, in this process.

A reader recently sent me a reference to an interesting paper titled "Dietary Fat Saturation Effects on Low-density-lipoprotein Concentrations and Metabolism in Various Animal Models". It's a review of animal studies that have looked at the effect of different fats on LDL concentration as of 1997. 

When an investigator wants to study diet-induced atherosclerosis, first he selects a species that's susceptible to it. These are generally herbivorous or nearly herbivorous species such as rabbits, guinea pigs, hamsters, and several species of monkey. Then, he feeds it an "atherogenic diet". This is typically a combination of 0.1 to 1% cholesterol by weight, plus 20-40% of calories as fat. The fat can come from a variety of sources, but animal fats or saturated vegetable fats are typical. The remainder of the diet is processed grains, vitamin and mineral supplements, and often casein for protein.

Let's put that amount of cholesterol into human context. Assuming the average person eats about 2 pounds dry weight of food per day, 0.5% cholesterol would be 4.5 grams. That's the equivalent of:

• 17.5 pounds of beef steak, or
• 3.8 pounds of beef liver, or
• 22.5 eggs

Per day. Now feed that to an herbivore that's not adapted to clearing cholesterol. You can imagine it doesn't do their blood lipids any favors. For example, in one study, compared to a low-fat, low-cholesterol "control diet", a diet of 20% hydrogenated coconut oil plus 0.12% cholesterol caused hamsters' LDL to increase by more than 7-fold. A polyunsaturated fat (PUFA) rich diet caused LDL to increase less. This study is typical, and the interpretation is typical as well: SFA raises LDL. But there's another possible explanation: in the absence of unnatural amounts of dietary cholesterol, PUFA reduces LDL in some species, and SFA has very little effect on it in most.

It's important to remember that the relevance of this hamster experiment to humans is unclear. No one is claiming that reducing saturated fat and cholesterol will reduce a human's LDL by 7-fold.  

But let's get back to the animal models. The hypothesis the paper addresses is that saturated fat raises LDL in animal models. If that is true, it should be able to raise LDL even in the absence of added cholesterol. So let's consider only the studies that didn't add extra cholesterol to the diets. And if saturated fat raises LDL, it should also do it relative to monounsaturated fat (MUFA- like olive oil), rather than only in comparison to PUFA, which has a known cholesterol-lowering effect. So let's narrow the studies further to those that compared SFA-rich fats, MUFA-rich fats and PUFA-rich fats. In Fernandez et al. (1989), investigators fed guinea pigs 35% of calories from corn oil (PUFA), olive oil (MUFA) or lard (MUFA-SFA). Here's what their LDL looked like:
The same investigators published two more studies showing similar results over the next five years. The next study was published by Khosla et al. in 1992. They fed cebus and rhesus monkeys cholesterol-free diets containing 40% of calories from safflower oil (PUFA), high-oleic safflower oil (MUFA) or palm oil (SFA-MUFA). How was their LDL?
None of the differences were statistically significant. Khosla and colleagues published another study with the same result in 1993. This is hardly supportive of the idea that saturated fat raises LDL in animal models. The most you can say is that PUFA lowers LDL in some, but not all, species. There is no indication from these studies that SFA raises LDL in the absence of excessive dietary cholesterol. I didn't cherry pick studies here; this is every study in the review paper that met my two criteria of no added cholesterol and a MUFA comparison group.

The bottom line is that experimental models of atherosclerosis appear to rely on overloading herbivorous species with dietary cholesterol that they are not equipped to clear. SFA does exacerbate the increase in LDL caused by cholesterol overload. But in the absence of excess cholesterol, it does not necessarily raise LDL even in species ill-equipped to digest these types of fats. Dietary cholesterol has a modest effect on LDL cholesterol in humans, and it has even less effect on LDL particle number, a more important measure. So there may not be a cholesterol overload for saturated fat to exacerbate in humans. 

PUFA vegetable oils do lower LDL in humans, and the effect appears to persist for at least a few years (probably indefinitely). But the evidence is not conclusive that lowering cholesterol in this way actually prevents heart attacks.

Dr. Stephan

After a very challenging summer, I've finally turned in my written thesis, so it's official: I have my Ph.D. I'm publishing the abstract below. These findings should all be published in peer-reviewed journals in the next 6 months.


Ataxin-7 Conserved Motifs Determine the Severity of the Neurodegenerative Disorder Spinocerebellar Ataxia Type 7 in Transgenic Mice and Influence Lifespan in Yeast

Spinocerebellar ataxia type 7 (SCA7) is an autosomal dominant, progressive neurodegenerative disorder whose characteristic features are cerebellar ataxia, dysarthria, and retinal cone-rod dystrophy culminating in blindness. SCA7 is caused by an abnormally long glutamine-coding CAG repeat in the SCA7 gene, which encodes the protein Ataxin-7.

Ataxin-7 contains several conserved motifs that may influence the toxicity of the glutamine tract. Among these are three conserved regions (conserved block I – III), two caspase-7 cleavage sites, a nuclear export signal and two monopartite nuclear localization signals (NLS). Previous investigations have shown that the caspase-7 cleavage site D266 is required for the full toxicity of the Ataxin-7 protein in cell culture. We generated SCA7 transgenic mice expressing a 92 CAG version of the human SCA7 cDNA, with and without a D266N mutation. Mice carrying the D266N mutation were protected from SCA7-like neurodegeneration, behavioral signs and shortened lifespan.

To further characterize the role of conserved motifs in SCA7 pathology, we generated SCA7 transgenic mice carrying point mutations in both C-terminal NLSs (KKRK -> KAAK). Previous work has shown that nuclear localization is an important step in the pathology of CAG repeat disorders. We observed that mice lacking C-terminal NLS activity were substantially protected from degeneration of the retina and cerebellum, SCA7-like behavioral signs and shortened lifespan.

Age is the primary risk factor for neurodegenerative disease. Even in the absence of overt disease, the aging brain shows histopathological and molecular changes reminiscent of neurodegeneration. To explore the link between neurodegenerative disease and aging, we have examined the replicative lifespan of Saccharomyces cerevisiae missing the SCA7 ortholog, SGF73. This strain exhibits an unusually long lifespan, which is dependent on the function of the NAD+-dependent deacetylase SIR2. We present evidence that the extended lifespan of the SGF73 null strain is due to the influence of Sgf73 on the activity of Sir2 and the histone deubiquitinase Ubp8. Furthermore, we show that the level of ubiquitinated H2B is elevated in an SCA7 transgenic mouse line, indicating that an alteration in Ubp8 activity may play a role in SCA7 pathology and that aging and neurodegeneration may share a common mechanism.

FiveFingers in the Alpine Lakes Wilderness

I recently bought a pair of Vibram FiveFingers Sprint (pictured). They're minimal, lightweight shoes with "toes". They're designed to mimic barefoot walking as closely as possible, while protecting the feet from punctures and abrasion. The soles are thin, flexible and offer no padding whatsoever.

I've always been a barefoot walker, because I enjoy it and our feet evolved to be nude (or close to it). Besides feeling amazing, walking barefoot may allow the body to express better biomechanics. My feet have become tougher over time, but I still can't handle a rough trail barefoot.

When I first put the FiveFingers on, my initial thought was "these don't feel as much like being barefoot as I wish they did". Simply having something between your skin and the ground makes your feet much less sensitive. But I got used to them quickly, eventually using them for my parkour training.

I had a few converstions with my parkour instructor Rafe Kelley, during which I realized I had to re-teach myself how to walk and run correctly. Rafe is well-versed in natural human movement due to his background in MovNat, gymnastics, martial arts, strength training, parkour and anthropology. Modern shoes allow us to walk and run in a way that our bodies did not evolve to tolerate. The padding in shoes allows us to take large steps, in which we overshoot our center of gravity and contact the ground in a jarring manner. It also allows us to strike with our heels when we run, which is not comfortable when you're barefoot.

I took the FiveFingers on a 13-mile hike in the Alpine Lakes wilderness with a few friends last weekend. The Pacific Northwest has to be one of the most beautiful places in the world. I was expecting to use the shoes for a few miles and then swap them for my lightweight hiking shoes (Inov8 Flyroc trail runners). The beginning of the trail was really rocky and I thought I was going to have to take them off in the first few hundred yards. Surprisingly, my feet adapted, and although the trail stayed rocky, it became fairly comfortable by the time we had walked a mile.

I found myself thinking about Rafe's advice, and taking smaller steps that strike closer to my center of gravity. Although my strides were shorter, I had no trouble keeping up, and in fact going up the hills was remarkably easy. We gained 3,000 feet of elevation but I never got winded. I had to pay close attention to foot placement, which kept me from looking around much but was actually kind of fun.

After a few miles, I switched to my hiking shoes, with the idea that I should switch before my feet really started to hurt, rather than after. I immediately noticed that going up hills was harder, especially on my calves. My feet felt more cumbersome as well.

Here's me foraging for mushrooms on the trail. This is Laetiporus sulphureus, also known as "chicken of the woods". It's widely eaten in this area. However, my mushroom guide All That the Rain Primises, and More, had this to say about it:

"If you eat and enjoy this moushroom, always cook it thoroughly and do not serve it to lawyers, landlords, employers, policemen, pit bull owners, or others whose good will you cherish!"

I didn't take my chances. If you're going to pick wild mushrooms, make sure you know what you're doing and carry a regional identification guide. "I recognize them from China/Russia/Europe" kills several people a year in the Pacific Northwest. If you're experienced, this area is a mushroom bonanza. I can't set foot outside without stepping on a king bolete (porcini, cep) in the fall.

I ended up switching back to the FiveFingers for the majority of the hike, about 9 miles of it. The soles of my feet were a bit sore by the end (due to stepping on sharp rocks for miles), but my joints and muscles felt remarkably good! I had no joint pain or muscle tightness. I also felt pretty energetic. This was a big surprise, since I haven't done much hiking this year. The next day, my calves were sore, but that was it.

All in all, I really like the FiveFingers. I can wear them in places that require shoes, yet remain nearly barefoot. One potential drawback is the price-to-durability ratio. They cost me $80 and I don't expect them to last a year [Update 2013-- they are surprisingly durable]. That being said, I'm putting a beating on them. Parkour training destroys shoes. The rubber seems to be excellent quality (which you'd expect from Vibram), but it's thin and it has cuts in it for flexibility and grip, which will lower its lifespan. The upper is simply a piece of stretchy fabric that tears easily. I'm willing to deal with the durability issues because the advantages outweigh them [update- several FiveFingers wearers have commented that they actually last a surprisingly long time. See comments].

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.

The Diet-Heart Hypothesis: Oxidized LDL, Part I

In my reading about lipoprotein particles (LDL, HDL, etc.) and how they associate with cardiac risk, I've come across three LDL-related markers that associate with risk: LDL cholesterol, LDL particle number, and LDL size/density. Is this a coincidence, or is there a reason for it?

The first marker, LDL cholesterol, is probably nothing more than a crude approximation of particle number. But LDL particle number and size/density are related to something else, that probably actually causes atherosclerosis rather than simply being associated with it: oxidized LDL (oxLDL).

oxLDL is formed when the lipids in LDL particles react with oxygen and break down. This happens specifically to the unsaturated fats in LDL, because saturated fats, by their chemical nature, are very resistant to oxidative damage. Polyunsaturated fats are much more susceptible to oxidative damage than saturated or monounsaturated fats. Linoleic acid (the omega-6 fatty acid found abundantly in industrial seed oils) is the main polyunsaturated fatty acid in LDL.

LDL is packaged with antioxidants in the liver, primarily vitamin E and coenzyme Q10 (CoQ10), to prevent its oxidation. However, the more time it spends in the blood, the more likely it is to exhaust its antioxidant store and become oxidized. Also, the smaller the LDL particle, the more likely it is to become trapped in the vessel wall and become oxidized there.

Oxidized LDL Correlates Tightly with Cardiac Risk

oxLDL has turned out to be a very sensitive marker of cardiac risk, surpassing traditional markers like LDL, HDL, and triglycerides in most studies to date. Since the discovery of sensitive assays that detect oxidized LDL drawn directly from patient blood, a number of studies have been published supporting its ability to detect atherosclerosis (plaque buildup in the arteries), heart attack risk and even the metabolic syndrome.

Holovet and colleagues published a study comparing the ability of oxLDL and a traditional risk factor assessment to detect coronary artery disease. The traditional method is called the Global Risk Factor Assessment Score (GRAS), and includes age, total cholesterol, HDL, blood pressure, diabetes and smoking status. It's similar to the commonly used Framingham risk score (which, interestingly enough, doesn't include LDL).

GRAS was able to correctly differentiate a healthy person from a person with coronary artery disease 49% of the time, while oxLDL was correct 82% of the time. Thus, oxLDL by itself was far more accurate than a whole battery of traditional cholesterol and cardiac markers. Coronary patients had more than twice the level of circulating oxLDL than the healthy comparison group.

In a large prospective study by Meisinger and colleagues, participants with high oxLDL had a 4.25 higher risk of heart attack than patients with lower oxLDL. oxLDL blew away all other blood lipid markers by nearly a factor of two. From the abstract:

Plasma oxLDL was the strongest predictor of CHD events compared with a conventional lipoprotein profile and other traditional risk factors for CHD.

Oxidized LDL Makes Sense

 Regular, non-oxidized LDL has few properties that would make it a suspect in atherosclerosis. It's just a little particle carrying cholesterol and fats from the liver to other organs. As soon as it oxidizes, however, it becomes pro-inflammatory, immunogenic, damaging to the vessel wall, and most importantly, capable of transforming immune cells called macrophages into foam cells, a major constituent of arterial plaque.

Researchers have been interested in the plaque-generating properties of oxLDL for over three decades, and quite a bit of data have accumulated. They've identified cellular receptors that allow macrophages to ingest oxLDL (CD36 and SR-A). These receptors are specific for oxLDL and do not recognize normal LDL to a significant degree. Mice whose macrophages lack either of these two receptors have the same amount of circulating LDL as normal mice, yet have 60 to 70 percent less atherosclerosis when fed a plaque-forming diet (1, 2). Shorter-term studies have not always been consistent however, suggesting that there are alternative mechanisms. I'll expand on this more later.

Another line of evidence comes from the ability of LDL-borne antioxidants to prevent atherosclerosis in animal models. The powerful synthetic antioxidant probucol greatly reduces atherosclerosis in a number of animal models. It also reduces the extremely high cholesterol rodents and herbivorous animals get when they eat a high-cholesterol "atherogenic diet", but several studies have concluded that the majority of probucol's effect is due to its antioxidant ability rather than its ability to reduce cholesterol (ref).

Vitamin E and CoQ10 are two other LDL-borne antioxidants that can reduce atherosclerosis in animal models, particularly in combination with one another. Vitamin E alone is not as effective, and in some studies totally ineffective, which is one possible explanation for the equivocal results of vitamin E cardiovascular trials in humans. The most effective combination of antioxidants is probably the one provided by a nutrient-dense diet.

In Summary

Multiple lines of evidence suggest that oxidized LDL plays a dominant role in atherosclerosis. Not only is it associated with cardiovascular risk, there's also a large body of evidence suggesting it actually directly contributes to it.