Dr. Mellanby's Tooth Decay Reversal Diet

I have a lot of admiration for Drs. Edward and May Mellanby. A husband-and-wife team, they discovered vitamin D, and determined that rickets is caused by poor calcium (or phosphorus) status, typically due to vitamin D deficiency. They believed that an ideal diet is omnivorous, based on whole foods, and offers an adequate supply of fat-soluble vitamins and easily absorbed minerals. They also felt that grain intake should be modest, as their research showed that unsoaked whole grains antagonize the effect of vitamins D and A.

Not only did the Mellanbys discover vitamin D and end the rickets epidemic that was devastating Western cities at the time, they also discovered a cure for early-stage tooth decay that has been gathering dust in medical libraries throughout the world since 1924.

It was in that year that Dr. May Mellanby published a summary of the results of the Mellanby tooth decay reversal studies in the British Medical Journal, titled "Remarks on the Influence of a Cereal-free Diet Rich in Vitamin D and Calcium on Dental Caries in Children". Last year, I had to specially request this article from the basement of the University of Washington medical library (1). Thanks to the magic of the internet, the full version of the paper is now freely available online (2).

You don't need my help to read the study, but in this post I offer a little background, a summary and my interpretation.

In previous studies, the Mellanbys used dogs to define the dietary factors that influence tooth development and repair. They identified three, which together made the difference between excellent and poor dental health (from Nutrition and Disease):

1. The diet's mineral content, particularly calcium and phosphorus
2. The diet's fat-soluble vitamin content, chiefly vitamin D
3. The diet's content of inhibitors of mineral absorption, primarily phytic acid

Once they had defined these factors, they set about testing their hypotheses in humans. They performed eight trials, each one in children in an institutionalized setting where diet could be completely controlled. The number of cavities in each child's mouth was noted at the beginning and end of the period. I'll only discuss the three most informative, and only the most successful in detail. First, the results:

I'll start with diet 1. Children on this diet ate the typical fare, plus extra oatmeal. Oatmeal is typically eaten as an unsoaked whole grain (and soaking it isn't very effective in any case), and so it is high in phytic acid, which effectively inhibits the absorption of a number of minerals including calcium. These children formed 5.8 cavities each and healed virtually none-- not good!

Diet number 2 was similar to diet 1, except there was no extra oatmeal and the children received a large supplemental dose of vitamin D. Over 28 weeks, only 1 cavity per child developed or worsened, while 3.9 healed. Thus, simply adding vitamin D to a reasonable diet allowed most of their cavities to heal.

Diet number 3 was the most effective. This was a grain-free diet plus supplemental vitamin D. Over 26 weeks, children in this group saw an average of only 0.4 cavities form or worsen, while 4.7 healed. The Mellanbys considered that they had essentially found a cure for this disorder in its early stages.

What exactly was this diet? Here's how it was described in the paper (note: cereals = grains):

...instead of cereals- for example, bread, oatmeal, rice, and tapioca- an increased allowance of potatoes and other vegetables, milk, fat, meat, and eggs was given. The total sugar, jam, and syrup intake was the same as before. Vitamin D was present in abundance in either cod-liver oil or irradiated ergosterol, and in egg yolk, butter, milk, etc. The diet of these children was thus rich in those factors, especially vitamin D and calcium, which experimental evidence has shown to assist calcification, and was devoid of those factors- namely, cereals- which interfere with the process.

Carbohydrate intake was reduced by almost half. Bread and oatmeal were replaced by potatoes, milk, meat, fish, eggs, butter and vegetables. The diet is reminiscent of what Dr. Weston Price used to reverse tooth decay in his dental clinic in Cleveland, although Price's diet did include rolls made from freshly ground whole wheat. Price also identified the fat-soluble vitamin K2 MK-4 as another important factor in tooth decay reversal, which would have been abundant in Mellanby's studies due to the dairy. The Mellanbys and Price were contemporaries and had parallel and complementary findings. The Mellanbys did not understand the role of vitamin K2 in mineral metabolism, and Price did not seem to appreciate the role of phytic acid from unsoaked whole grains in preventing mineral absorption.

Here are two sample meals provided in Dr. Mellanby's paper. I believe the word "dinner" refers to the noon meal, and "supper" refers to the evening meal:

Breakfast- Omelette, cocoa, with milk.
Lunch- Milk.
Dinner- Potatoes, steamed minced meat, carrots, stewed fruit, milk.
Tea- Fresh fruit salad, cocoa made with milk.
Supper- Fish and potatoes fried in dripping, milk.

Breakfast- Scrambled egg, milk, fresh salad.
Dinner- Irish stew, potatoes, cabbage, stewed fruit, milk.
Tea- Minced meat warmed with bovril, green salad, milk.
Supper- Thick potato soup made with milk.

In addition, children received vitamin D daily. Here's Dr. Mellanby's summary of their findings:

The tests do not indicate that in order to prevent dental caries children must live on a cereal-free diet, but in association with the results of the other investigations on animals and children they do indicate that the amount of cereal eaten should be reduced, particularly during infancy and in the earlier years of life, and should be replaced by an increased consumption of milk, eggs, butter, potatoes, and other vegetables. They also indicate that a sufficiency of vitamin D and calcium should be given from birth, and before birth, by supplying a suitable diet to the pregnant mother. The teeth of the children would be well formed and more resistant to dental caries instead of being hypoplastic and badly calcified, as were those in this investigation.

If I could add something to this program, I would recommend daily tooth brushing and flossing, avoiding sugar, and rinsing the mouth with water after each meal.

This diet is capable of reversing early stage tooth decay. It will not reverse advanced decay, which requires professional dental treatment as soon as possible. It is not a substitute for dental care in general, and if you try using diet to reverse your own tooth decay, please do it under the supervision of a dentist. And while you're there, tell her about Edward and May Mellanby!

Preventing Tooth Decay
Reversing Tooth Decay
Images of Tooth Decay Healing due to an Improved Diet
Dental Anecdotes

Tropical Plant Fats: Palm Oil

A Fatal Case of Nutritionism

The concept of 'nutritionism' was developed by Dr. Gyorgy Scrinis and popularized by the food writer Michael Pollan. It states that the health value of a food can be guessed by the sum of the nutrients it contains. Pollan argues, I think rightfully, that nutritionism is a reductionist philosophy that assumes we know more about food composition and the human body than we actually do. You can find varying degrees of this philosophy in most mainstream discussions of diet and health*.

One conspicuous way nutritionism manifests is in the idea that saturated fat is harmful. Any fat rich in saturated fatty acids is typically assumed to be unhealthy, regardless of its other constituents. There is also apparently no need to directly test that assumption, or even to look through the literature to see if the assumption has already been tested. In this manner, 'saturated' tropical plant fats such as palm oil and coconut oil have been labeled unhealthy, despite essentially no direct evidence that they're harmful. As we'll see, there is actually quite a bit of evidence, both indirect and direct, that their unrefined forms are not harmful and perhaps even beneficial.

Palm Oil and Heart Disease

Long-time readers may recall a post I wrote a while back titled Ischemic Heart Attacks: Disease of Civilization (1). I described a study from 1964 in which investigators looked for signs of heart attacks in thousands of consecutive autopsies in the US and Africa, among other places. They found virtually none in hearts from Nigeria and Uganda (3 non-fatal among more than 4,500 hearts), while Americans of the same age had very high rates (up to 1/3 of hearts).

What do they eat in Nigeria? Typical Nigerian food involves home-processed grains, starchy root vegetables, beans, fruit, vegetables, peanuts, red palm oil, and a bit of dairy, fish and meat**. The oil palm Elaeis guineensis originated in West Africa and remains one of the main dietary fats throughout the region.

To extract the oil, palm fruit are steamed, and the oily flesh is removed and pressed. It's similar to olive oil in that it is extracted gently from an oil-rich fruit, rather than harshly from an oil-poor seed (e.g., corn or soy oil). The oil that results is deep red and is perhaps the most nutrient-rich fat on the planet. The red color comes from carotenes, but red palm oil also contains a large amount of vitamin E (mostly tocotrienols), vitamin K1, coenzyme Q10 and assorted other fat-soluble constituents. This adds up to a very high concentration of fat-soluble antioxidants, which are needed to protect the fat from rancidity in hot and sunny West Africa. Some of these make it into the body when it's ingested, where they appear to protect the body's own fats from oxidation.

Mainstream nutrition authorities state that palm oil should be avoided due to the fact that it's approximately half saturated. This is actually one of the main reasons palm oil was replaced by hydrogenated seed oils in the processed food industry. Saturated fat raises blood cholesterol, which increases the risk of heart disease. Doesn't it? Let's see what the studies have to say.

Most of the studies were done using refined palm oil, unfortunately. Besides only being relevant to processed foods, this method also introduces a new variable because palm oil can be refined and oxidized to varying degrees. However, a few studies were done with red palm oil, and one even compared it to refined palm oil. Dr. Suzanna Scholtz and colleagues put 59 volunteers on diets predominating in sunflower oil, refined palm oil or red palm oil for 4 weeks. LDL cholesterol was not different between the sunflower oil and red palm oil groups, however the red palm oil group saw a significant increase in HDL. LDL and HDL both increased in the refined palm oil group relative to the sunflower oil group (2).

Although the evidence is conflicting, most studies have not been able to replicate the finding that refined palm oil increases LDL relative to less saturated oils (3, 4). This is consistent with studies in a variety of species showing that saturated fat generally doesn't raise LDL compared to monounsaturated fat in the long term, unless a large amount of purified cholesterol is added to the diet (5).

Investigators have also explored the ability of palm oil to promote atherosclerosis, or hardening and thickening of the arteries, in animals. Not only does palm oil not promote atherosclerosis relative to monounsaturated fats (e.g., olive oil), but in its unrefined state it actually protects against atherosclerosis (6, 7). A study in humans hinted at a possible explanation: compared to a monounsaturated oil***, palm oil greatly reduced oxidized LDL (8). As a matter of fact, I've never seen a dietary intervention reduce oxLDL to that degree (69%). oxLDL is a major risk factor for cardiovascular disease, and a much better predictor of risk than the typically measured LDL cholesterol (9). The paper didn't state whether or not the palm oil was refined. I suspect it was lightly refined, but still rich in vitamin E and CoQ10.

As I discussed in my recent interview with Jimmy Moore, atherosclerosis is only one factor in heart attack risk (10). Several other factors are also major determinants of risk: clotting tendency, plaque stability, and susceptibility to arrhythmia. Another factor that I haven't discussed is how resistant the heart muscle is to hypoxia, or loss of oxygen. If the coronary arteries are temporarily blocked-- a frequent occurrence in modern people-- the heart muscle can be damaged. Dietary factors determine the degree of damage that results. For example, in rodents, nitrites derived from green vegetables protect the heart from hypoxia damage (11). It turns out that red palm oil is also protective (12, 13). Red palm oil also protects against high blood pressure in rats, an effect attributed to its ability to reduce oxidative stress (14, 15).

Together, the evidence suggests that red palm oil does not contribute to heart disease risk, and in fact is likely to be protective. The benefits of red palm oil probably come mostly from its minor constituents, i.e. the substances besides its fatty acids. Several studies have shown that a red palm oil extract called palmvitee lowers serum lipids in humans (16, 17). The minor constituents are precisely what are removed during the refining process.

Palm Oil and the Immune System

Red palm oil also has beneficial effects on the immune system in rodents. It protects against bacterial infection when compared with soybean oil (18). It also protects against certain cancers, compared to other oils (19, 20). This may be in part due to its lower content of omega-6 linoleic acid (roughly 10%), and minor constituents.

The Verdict

Yet again, nutritionism has gotten itself into trouble by underestimating the biological complexity of a whole food. Rather than being harmful to human health, red palm oil, an ancient and delicious food, is likely to be protective. It's also one of the cheapest oils available worldwide, due to the oil palm's high productivity. It has a good shelf life and does not require refrigeration. Its strong, savory flavor goes well in stews, particularly meat stews. It isn't available in most grocery stores, but you can find it on the internet. Make sure not to confuse it with refined palm oil or palm kernel oil.


* The approach that Pollan and I favor is a simpler, more empirical one: eat foods that have successfully sustained healthy cultures.

** Some Nigerians are also pastoralists that subsist primarily on dairy.

*** High oleic sunflower oil, from a type of sunflower bred to be high in monounsaturated fat and low in linoleic acid. I think it's probably among the least harmful refined oils. I use it sometimes to make mayonnaise. It's often available in grocery stores, just check the label.

Pastured Dairy may Prevent Heart Attacks

Not all dairy is created equal. Dairy from grain-fed and pasture-fed cows differs in a number of ways. Pastured dairy contains more fat-soluble nutrients such as vitamin K2, vitamin A, vitamin E, carotenes and omega-3 fatty acids. It also contains more conjugated linoleic acid, a fat-soluble molecule that has been under intense study due to its ability to inhibit obesity and cancer in animals. The findings in human supplementation trials have been mixed, some confirming the animal studies and others not. In feeding experiments in cows, Dr. T. R. Dhiman and colleagues found the following (1):

Cows grazing pasture and receiving no supplemental feed had 500% more conjugated linoleic acid in milk fat than cows fed typical dairy diets.

Fat from ruminants such as cows, sheep and goats is the main source of CLA in the human diet. CLA is fat-soluble. Therefore, skim milk doesn't contain any. It's also present in human body fat in proportion to dietary intake. This can come from dairy or flesh.

In a recent article from the AJCN, Dr. Liesbeth Smit and colleagues examined the level of CLA in the body fat of Costa Rican adults who had suffered a heart attack, and compared it to another group who had not (a case-control study, for the aficionados). People with the highest level of CLA in their body fat were 49% less likely to have had a heart attack, compared to those with the lowest level (2).

Since dairy was the main source of CLA in this population, the association between CLA and heart attack risk is inextricable from the other components in pastured dairy fat. In other words, CLA is simply a marker of pastured dairy fat intake in this population, and the (possible) benefit could just as easily have come from vitamin K2 or something else in the fat.

This study isn't the first one to suggest that pastured dairy fat may be uniquely protective. The Rotterdam and EPIC studies found that a higher vitamin K2 intake is associated with a lower risk of heart attack, cancer and overall mortality (3, 4, 5). In the 1940s, Dr. Weston Price estimated that pastured dairy contains up to 50 times more vitamin K2 than grain-fed dairy. He summarized his findings in the classic book Nutrition and Physical Degeneration. This finding has not been repeated in recent times, but I have a little hunch that may change soon...

Vitamin K2
Cardiovascular Disease and Vitamin K2
Can Vitamin K2 Reverse Arterial Calcification?

Full-fat Dairy for Cardiovascular Health

I just saw a paper in the AJCN titled "Dairy consumption and patterns of mortality of
Australian adults". It's a prospective study with a 15-year follow-up period. Here's a quote from the abstract:

There was no consistent and significant association between total dairy intake and total or cause-specific mortality. However, compared with those with the lowest intake of full-fat dairy, participants with the highest intake (median intake 339 g/day) had reduced death due to CVD (HR: 0.31; 95% confidence interval (CI): 0.12–0.79; P for trend = 0.04) after adjustment for calcium intake and other confounders. Intakes of low-fat dairy, specific dairy foods, calcium and vitamin D showed no consistent associations.

People who ate the most full-fat dairy had a 69% lower risk of cardiovascular death than those who ate the least. Otherwise stated, people who mostly avoided dairy or consumed low-fat dairy had more than three times the risk of dying of coronary heart disease or stroke than people who ate the most full-fat diary.

Contrary to popular belief, full-fat dairy, including milk, butter and cheese, has never been convincingly linked to cardiovascular disease. In fact, it has rather consistently been linked to a lower risk, particularly for stroke. What has been linked to cardiovascular disease is milk fat's replacement, margarine. In the Rotterdam study, high vitamin K2 intake was linked to a lower risk of fatal heart attack, aortic calcification and all-cause mortality. Most of the K2 came from full-fat cheese. In my opinion, artisanal cheese and butter made from pasture-fed milk are the ultimate dairy foods.

From a 2005 literature review on milk and cardiovascular disease in the EJCN:

In total, 10 studies were identified. Their results show a high degree of consistency in the reported risk for heart disease and stroke, all but one study suggesting a relative risk of less than one in subjects with the highest intakes of milk.

...the studies, taken together, suggest that milk drinking may be associated with a small but worthwhile reduction in heart disease and stroke risk.

...All the cohort studies in the present review had, however, been set up at times when reduced-fat milks were unavailable, or scarce.

The fat is where the vitamins A, K2, E and D are. The fat is where the medium-chain triglycerides, butyric acid and omega-3 fatty acids are. The fat is where the conjugated linoleic acid is. So the next time someone admonishes you to reduce your dairy fat intake, what are you going to tell them??

Magnesium and Vitamin D Metabolism

Ted Hutchinson posted a link in the comments section of my last post, pointing to a page on the Vitamin D Council's website where Dr. John Cannell discusses cofactors required for proper vitamin D metabolism. It's actually the site's home page, highlighting how important he feels this matter is. In this case, 'cofactor' simply means another nutrient that's required for the efficient production and use of vitamin D. They include:

• Magnesium
• Zinc
• Vitamin K2
• Vitamin A
• Boron

And probably others we aren't yet aware of. On another page, Dr. Cannell links to two papers that review the critical interaction between magnesium status and vitamin D metabolism (1, 2). Here's a quote from the abstract of the second paper:

Magnesium... is essential for the normal function of the parathyroid glands, metabolism of vitamin D and adequate sensitivity of target tissues to [parathyroid hormone] and active vitamin D metabolites. Magnesium deficit is usually associated with hypoparathyroidism, low production of active vitamin D metabolites, in particular 1,25(OH)2 vitamin D3 and resistance to PTH and vitamin D. On the contrary, magnesium excess, similar to calcium, inhibits PTH secretion. Bone metabolism is impaired under positive as well as under negative magnesium balance.

Magnesium status is critical for normal vitamin D metabolism, insulin sensitivity, and overall health. Supplemental magnesium blocks atherosclerosis in multiple animal models (3, 4). Most Americans don't get enough magnesium (5).

The bottom line is that no nutrient acts in a vacuum. The effect of every part of one's diet and lifestyle is dependent on every other part. I often talk about single nutrients on this blog, but my core philosophy is that a proper diet focuses on Real Food, not nutrients. Tinkering with nutritional status using supplements is potentially problematic. Despite what some people might tell you, our understanding of nutrition and human health is currently rather crude-- so it's best to respect the accumulated wisdom of cultures that don't get the diseases we're trying to avoid.

Low Vitamin D: Cause or Result of Disease?

Don Matesz at Primal Wisdom put up a post a few days ago that I think is worth reading. It follows an e-mail discussion between us concerning a paper on magnesium restriction in rats (executive summary: moderate Mg restriction reduces the hormone form of vitamin D by half and promotes osteoporosis). In his post, Don cites several papers showing that vitamin D metabolism is influenced by more than just vitamin D intake from the diet and synthesis in the skin.

Celiac disease patients have low 25(OH)D3, the circulating storage form of vitamin D, which spontaneously corrects on a gluten-free diet. There are numerous suggestions in the medical literature that overweight and sickness cause low vitamin D, potentially confounding the interpretation of studies that find lower levels of illness among people with low vitamin D levels.

Don't get me wrong, I still think vitamin D is important in preventing disease. But it does lead me to question the idea that we should force down huge doses of supplemental vitamin D to get our 25(OH)D3 up to 60, 70 or even 80 ng/mL. When the dosage of supplemental D goes beyond what a tan Caucasian could conceivably make on a day at the beach (4,000 IU?), that's when I start becoming skeptical. Check out Don's post for more.

Vitamin D May Prevent Flu and Asthma

The AJCN just published a new controlled trial evaluating the effectiveness of vitamin D supplements on flu and asthma (1). Dr. Hiroyuki Ida's group gave Japanese schoolchildren (10 years average age) 1,200 IU of vitamin D3 or placebo per day from December through March. They found that children taking vitamin D had a significantly lower incidence of influenza A but not influenza B. These are two strains of flu that each accounted for roughly half the flu incidence in this population. Sadly, if you add the total flu incidence for A and B together (which the authors don't do in their tables), vitamin D supplementation didn't reduce total flu incidence significantly.

They also found that in the subset of children not already taking vitamin D supplements, the effect was greater, with unsupplemented children contracting nearly three times as many influenza A infections as children receiving vitamin D. They didn't analyze the influenza B or total influenza incidence in that way, so we don't know if prior supplementation makes a difference there.

The most striking finding of the paper is that the vitamin D group suffered from 6 times fewer asthma attacks than the placebo group. This needs to be repeated but it's consistent with other data and I find it very encouraging.

The paper did have some limitations. They didn't measure vitamin D status so they have no way to know exactly how effective their pill-based supplements were.

Another problem is that they began collecting data immediately after beginning supplementation. Vitamin D is a fat-soluble vitamin that can take 3 months to reach maximum concentration in the body following supplementation. By the time the children were reaching their maximum serum concentration of vitamin D, the trial was over. It would be nice to see the next trial begin supplementation in the fall and look at flu incidence in the winter.

This paper comes on the heels of another showing that vitamin D is necessary for the activation of an immune cell called the killer T cell (2). These are important for resistance to infections and cancer. Overall, these papers add to the accumulating evidence that vitamin D is important for the proper functioning of the human immune system. However, mice may not be the best model for use in studying vitamin D biology. From the first paper:

The evolution of different mechanisms for the regulation of PLC-γ1 activity in human and mouse T cells parallels the development of divergent VDR-dependent and VDR-independent antimicrobial pathways in human and mouse macrophages31, respectively, and may reflect the fact that mice are nocturnal animals with fur and humans are daytime creatures that synthesize vitamin D in the skin after exposure to ultraviolet light.

In other words, mice don't use vitamin D in the same way as humans because they have a different evolutionary relationship to it.

The Body Fat Setpoint, Part IV: Changing the Setpoint

Prevention is Easier than Cure

Experiments in animals have confirmed what common sense suggests: it's easier to prevent health problems than to reverse them. Still, many health conditions can be improved, and in some cases reversed, through lifestyle interventions. It's important to have realistic expectations and to be kind to oneself. Cultivating a drill sergeant mentality will not improve quality of life, and isn't likely to be sustainable.

Fat Loss: a New Approach

If there's one thing that's consistent in the medical literature, it's that telling people to eat fewer calories does not help them lose weight in the long term. Gary Taubes has written about this at length in his book Good Calories, Bad Calories, and in his upcoming book on body fat. Many people who use this strategy see transient fat loss, followed by fat regain and a feeling of defeat. There's a simple reason for it: the body doesn't want to lose weight. It's extremely difficult to fight the fat mass setpoint, and the body will use every tool it has to maintain its preferred level of fat: hunger, reduced body temperature, higher muscle efficiency (i.e., less energy is expended for the same movement), lethargy, lowered immune function, et cetera.

Therefore, what we need for sustainable fat loss is not starvation; we need a treatment that lowers the fat mass setpoint. There are several criteria that this treatment will have to meet to qualify:

1. It must cause fat loss
2. It must not involve deliberate calorie restriction
3. It must maintain fat loss over a long period of time
4. It must not be harmful to overall health
   

I also prefer strategies that make sense from the perspective of human evolution.

Strategies: Diet Pattern

The most obvious treatment that fits all of my criteria is low-carbohydrate dieting. Overweight people eating low-carbohydrate diets generally lose fat and spontaneously reduce their calorie intake. In fact, in several diet studies, investigators compared an all-you-can-eat low-carbohydrate diet with a calorie-restricted low-fat diet. The low-carbohydrate dieters generally reduced their calorie intake and body fat to a similar or greater degree than the low-fat dieters, despite the fact that they ate all the calories they wanted (1). This suggest that their fat mass setpoint had changed. At this point, I think moderate carbohydrate restriction may be preferable to strict carbohydrate restriction for some people, due to the increasing number of reports I've read of people doing poorly in the long run on extremely low-carbohydrate diets (2).

Another strategy that appears effective is the "paleolithic" diet. In Dr. Staffan Lindeberg's 2007 diet study, overweight volunteers with heart disease lost fat and reduced their calorie intake to a remarkable degree while eating a diet consistent with our hunter-gatherer heritage (3). This result is consistent with another diet trial of the paleolithic diet in diabetics (4). In post hoc analysis, Dr. Lindeberg's group showed that the reduction in weight was apparently independent of changes in carbohydrate intake*. This suggests that the paleolithic diet has health benefits that are independent of carbohydrate intake.

Strategies: Gastrointestinal Health

Since the gastrointestinal (GI) tract is so intimately involved in body fat metabolism and overall health (see the former post), the next strategy is to improve GI health. There are a number of ways to do this, but they all center around four things:

1. Don't eat food that encourages the growth of harmful bacteria
2. Eat food that encourages the growth of good bacteria
3. Don't eat food that impairs gut barrier function
4. Eat food that promotes gut barrier health

The first one is pretty easy: avoid refined sugar, refined carbohydrate in general, and lactose if you're lactose intolerant. For the second and fourth points, make sure to eat fermentable fiber. In one trial, oligofructose supplements led to sustained fat loss, without any other changes in diet (5). This is consistent with experiments in rodents showing improvements in gut bacteria profile, gut barrier health, glucose tolerance and body fat mass with oligofructose supplementation (6, 7, 8).

Oligofructose is similar to inulin, a fiber that occurs naturally in a wide variety of plants. Good sources are jerusalem artichokes, jicama, artichokes, onions, leeks, burdock and chicory root. Certain non-industrial cultures had a high intake of inulin. There are some caveats to inulin, however: inulin and oligofructose can cause gas, and can also exacerbate gastroesophageal reflux disorder (9). So don't eat a big plate of jerusalem artichokes before that important date.

The colon is packed with symbiotic bacteria, and is the site of most intestinal fermentation. The small intestine contains fewer bacteria, but gut barrier function there is critical as well. The small intestine is where the GI doctor will take a biopsy to look for celiac disease. Celiac disease is a degeneration of the small intestinal lining due to an autoimmune reaction caused by gluten (in wheat, barley and rye). This brings us to one of the most important elements of maintaining gut barrier health: avoiding food sensitivities. Gluten and casein (in dairy protein) are the two most common offenders. Gluten sensitivity is widespread and typically undiagnosed (10).

Eating raw fermented foods such as sauerkraut, kimchi, yogurt and half-sour pickles also helps maintain the integrity of the upper GI tract. I doubt these have any effect on the colon, given the huge number of bacteria already present. Other important factors in gut barrier health are keeping the ratio of omega-6 to omega-3 fats in balance, eating nutrient-dense food, and avoiding the questionable chemical additives in processed food. If triglycerides are important for leptin sensitivity, then avoiding sugar and ensuring a regular source of omega-3 should aid weight loss as well.

Strategies: Micronutrients

As I discussed in the last post, micronutrient deficiency probably plays a role in obesity, both in ways that we understand and ways that we (or I) don't. Eating a diet that has a high nutrient density and ensuring a good vitamin D status will help any sustainable fat loss strategy. The easiest way to do this is to eliminate industrially processed foods such as white flour, sugar and seed oils. These constitute more than 50% of calories for the average Westerner.

After that, you can further increase your diet's nutrient density by learning to properly prepare grains and legumes to maximize their nutritional value and digestibility (11, 12; or by avoiding grains and legumes altogether if you wish), selecting organic and/or pasture-raised foods if possible, and eating seafood including seaweed. One of the problems with extremely low-carbohydrate diets is that they may be low in water-soluble micronutrients, although this isn't necessarily the case.

Strategies: Miscellaneous

In general, exercise isn't necessarily helpful for fat loss. However, there is one type of exercise that clearly is: high-intensity intermittent training (HIIT). It's basically a fancy name for sprints. They can be done on a track, on a stationary bicycle, using weight training circuits, or any other way that allows sufficient intensity. The key is to achieve maximal exertion for several brief periods, separated by rest. This type of exercise is not about burning calories through exertion: it's about increasing hormone sensitivity using an intense, brief stressor (hormesis). Even a ridiculously short period of time spent training HIIT each week can result in significant fat loss, despite no change in diet or calorie intake (13).

Anecdotally, many people have had success using intermittent fasting (IF) for fat loss. There's some evidence in the scientific literature that IF and related approaches may be helpful (14). There are different approaches to IF, but a common and effective method is to do two complete 24-hour fasts per week. It's important to note that IF isn't about restricting calories, it's about resetting the fat mass setpoint. After a fast, allow yourself to eat quality food until you're no longer hungry.

Insufficient sleep has been strongly and repeatedly linked to obesity. Whether it's a cause or consequence of obesity I can't say for sure, but in any case it's important for health to sleep until you feel rested. If your sleep quality is poor due to psychological stress, meditating before bedtime may help. I find that meditation has a remarkable effect on my sleep quality. Due to the poor development of oral and nasal structures in industrial nations, many people do not breathe effectively and may suffer from conditions such as sleep apnea that reduce sleep quality. Overweight also contributes to these problems.

I'm sure there are other useful strategies, but that's all I have for now. If you have something to add, please put it in the comments.


* Since reducing carbohydrate intake wasn't part of the intervention, this result is observational.

The Body Fat Setpoint, Part III: Dietary Causes of Obesity

What Caused the Setpoint to Change?

We have two criteria to narrow our search for the cause of modern fat gain:

1. It has to be new to the human environment
   
2. It has to cause leptin resistance or otherwise disturb the setpoint
   

Although I believe that exercise is part of a healthy lifestyle, it probably can't explain the increase in fat mass in modern nations. I've written about that here and here. There are various other possible explanations, such as industrial pollutants, a lack of sleep and psychological stress, which may play a role. But I feel that diet is likely to be the primary cause. When you're drinking 20 oz Cokes, bisphenol-A contamination is the least of your worries.

In the last post, I described two mechanisms that may contribute to elevating the body fat set point by causing leptin resistance: inflammation in the hypothalamus, and impaired leptin transport into the brain due to elevated triglycerides. After more reading and discussing it with my mentor, I've decided that the triglyceride hypothesis is on shaky ground*. Nevertheless, it is consistent with certain observations:

• Fibrate drugs that lower triglycerides can lower fat mass in rodents and humans
  
• Low-carbohydrate diets are effective for fat loss and lower triglycerides
• Fructose can cause leptin resistance in rodents and it elevates triglycerides (1)
• Fish oil reduces triglycerides. Some but not all studies have shown that fish oil aids fat loss (2)
  

Inflammation in the hypothalamus, with accompanying resistance to leptin signaling, has been reported in a number of animal studies of diet-induced obesity. I feel it's likely to occur in humans as well, although the dietary causes are probably different for humans. The hypothalamus is the primary site where leptin acts to regulate fat mass (3). Importantly, preventing inflammation in the brain prevents leptin resistance and obesity in diet-induced obese mice (3.1). The hypothalamus is likely to be the most important site of action. Research is underway on this.

The Role of Digestive Health

What causes inflammation in the hypothalamus? One of the most interesting hypotheses is that increased intestinal permeability allows inflammatory substances to cross into the circulation from the gut, irritating a number of tissues including the hypothalamus.

Dr. Remy Burcelin and his group have spearheaded this research. They've shown that high-fat diets cause obesity in mice, and that they also increase the level of an inflammatory substance called lipopolysaccharide (LPS) in the blood. LPS is produced by gram-negative bacteria in the gut and is one of the main factors that activates the immune system during an infection. Antibiotics that kill gram-negative bacteria in the gut prevent the negative consequences of high-fat feeding in mice.

Burcelin's group showed that infusing LPS into mice on a low-fat chow diet causes them to become obese and insulin resistant just like high-fat fed mice (4). Furthermore, adding 10% of the soluble fiber oligofructose to the high-fat diet prevented the increase in intestinal permeability and also largely prevented the body fat gain and insulin resistance from high-fat feeding (5). Oligofructose is food for friendly gut bacteria and ends up being converted to butyrate and other short-chain fatty acids in the colon. This results in lower intestinal permeability to toxins such as LPS. This is particularly interesting because oligofructose supplements cause fat loss in humans (6).

A recent study showed that blood LPS levels are correlated with body fat, elevated cholesterol and triglycerides, and insulin resistance in humans (7). However, a separate study didn't come to the same conclusion (8). The discrepancy may be due to the fact that LPS isn't the only inflammatory substance to cross the gut lining-- other substances may also be involved. Anything in the blood that shouldn't be there is potentially inflammatory.

Overall, I think gut dysfunction probably plays a major role in obesity and other modern metabolic problems. Insufficient dietary fiber, micronutrient deficiencies, excessive gut irritating substances such as gluten, abnormal bacterial growth due to refined carbohydrates (particularly sugar), and omega-6:3 imbalance may all contribute to abnormal gut bacteria and increased gut permeability.

The Role of Fatty Acids and Micronutrients

Any time a disease involves inflammation, the first thing that comes to my mind is the balance between omega-6 and omega-3 fats. The modern Western diet is heavily weighted toward omega-6, which are the precursors to some very inflammatory substances (as well as a few that are anti-inflammatory). These substances are essential for health in the correct amounts, but they need to be balanced with omega-3 to prevent excessive and uncontrolled inflammatory responses. Animal models have repeatedly shown that omega-3 deficiency contributes to the fat gain and insulin resistance they develop when fed high-fat diets (9, 10, 11).

As a matter of fact, most of the papers claiming "saturated fat causes this or that in rodents" are actually studying omega-3 deficiency. The "saturated fats" that are typically used in high-fat rodent diets are refined fats from conventionally raised animals, which are very low in omega-3. If you add a bit of omega-3 to these diets, suddenly they don't cause the same metabolic problems, and are generally superior to refined seed oils, even in rodents (12, 13).

I believe that micronutrient deficiency also plays a role. Inadequate vitamin and mineral status can contribute to inflammation and weight gain. Obese people typically show deficiencies in several vitamins and minerals. The problem is that we don't know whether the deficiencies caused the obesity or vice versa. Refined carbohydrates and refined oils are the worst offenders because they're almost completely devoid of micronutrients.

Vitamin D in particular plays an important role in immune responses (including inflammation), and also appears to influence body fat mass. Vitamin D status is associated with body fat and insulin sensitivity in humans (14, 15, 16). More convincingly, genetic differences in the vitamin D receptor gene are also associated with body fat mass (17, 18), and vitamin D intake predicts future fat gain (19).

Exiting the Niche

I believe that we have strayed too far from our species' ecological niche, and our health is suffering. One manifestation of that is body fat gain. Many factors probably contribute, but I believe that diet is the most important. A diet heavy in nutrient-poor refined carbohydrates and industrial omega-6 oils, high in gut irritating substances such as gluten and sugar, and a lack of direct sunlight, have caused us to lose the robust digestion and good micronutrient status that characterized our distant ancestors. I believe that one consequence has been the dysregulation of the system that maintains the fat mass "setpoint". This has resulted in an increase in body fat in 20th century affluent nations, and other cultures eating our industrial food products.

In the next post, I'll discuss my thoughts on how to reset the body fat setpoint.


* The ratio of leptin in the serum to leptin in the brain is diminished in obesity, but given that serum leptin is very high in the obese, the absolute level of leptin in the brain is typically not lower than a lean person. Leptin is transported into the brain by a transport mechanism that saturates when serum leptin is not that much higher than the normal level for a lean person. Therefore, the fact that the ratio of serum to brain leptin is higher in the obese does not necessarily reflect a defect in transport, but rather the fact that the mechanism that transports leptin is already at full capacity.

Malocclusion: Disease of Civilization, Part V

Prenatal Development of the Face and Jaws

The structures of the face and jaws take shape during the first trimester of pregnancy. The 5th to 11th weeks of pregnancy are particularly crucial for occlusion, because this is when the jaws, nasal septum and other cranial structures form. The nasal septum is the piece of cartilage that forms the structure of the nose and separates the two air passages as they enter the nostrils.

Maternal Nutritional Status Affects Fetal Development

Abnormal nutrient status can lead to several types of birth defects. Vitamin A is an essential signaling molecule during development. Both deficiency and excess can cause birth defects, with the effects predominantly targeting the cranium and nervous system, respectively. Folic acid deficiency causes birth defects of the brain and spine. Other nutrients such as vitamin B12 may influence the risk of birth defects as well*.

The Role of Vitamin K

As early as the 1970s, physicians began noting characteristic developmental abnormalities in infants whose mothers took the blood-thinning drug warfarin (coumadin) during the first trimester of pregnancy. These infants showed an underdevelopment of the nasal septum, the maxilla (upper jaw), small or absent sinuses, and a characteristic "dished" face. This eventually resulted in narrow dental arches, severe malocclusion and tooth crowding**. The whole spectrum was called Binder's syndrome, or warfarin embryopathy.

Warfarin works by inhibiting vitamin K recycling, thus depleting a nutrient necessary for normal blood clotting. It's now clear that Binder's syndrome can result from anything that interferes with vitamin K status during the first trimester of pregnancy. This includes warfarin, certain anti-epilepsy drugs, certain antibiotics, genetic mutations that interfere with vitamin K status, and celiac disease (intestinal damage due to gluten).

Why is vitamin K important for the development of the jaws and face of the fetus? Vitamin K is required to activate a protein called matrix gla protein (MGP), which prevents unwanted calcification of the nasal septum in the developing fetus (among other things). If this protein isn't activated by vitamin K during the critical developmental window, calcium deposits form in the nasal septum, stunting its growth and also stunting the growth of the maxilla and sinuses. Low activity of MGP appears to be largely responsible for Binder's syndrome, since the syndrome can be caused by genetic mutations in MGP in humans. Small or absent sinuses are common in the general population.

One of the interesting things about MGP is its apparent preference for vitamin K2 over vitamin K1. Vitamin K1 is found predominantly in green vegetables, and is sufficient to activate blood clotting factors and probably some other vitamin K-dependent proteins. "Vitamin K2" refers to a collection of molecules known as menaquinones. These are denoted as "MK", followed by a number indicating the length of the side chain attached to the quinone ring.

Biologically important menaquinones are MK-4 through MK-12 or so. MK-4 is the form that animals synthesize from vitamin K1 for their own use. Certain organs (brain, pancreas, salivary gland, arteries) preferentially accumulate K2 MK-4, and certain cellular processes are also selective for K2 MK-4 (MGP activation, PKA-dependent transcriptional effects). Vitamin K2 MK-4 is found almost exclusively in animal foods, particularly pastured butter, organs and eggs. It is always found in foods designed to nourish growing animals, such as eggs and milk.

Humans have the ability to convert K1 to K2 when K1 is ingested in artificially large amounts. However, due to the limited absorption of normal dietary sources of K1 and the unknown conversion efficiency, it's unclear how much green vegetables contribute to K2 status. Serum vitamin K1 reaches a plateau at about 200 micrograms per day of dietary K1 intake, the equivalent of 1/4 cup of cooked spinach (see figure 1 of this paper). Still, I think eating green vegetables regularly is a good idea, and may contribute to K2 status. Other menaquinones such as MK-7 (found in natto) may contribute to K2 status as well, but this question has not been resolved.

Severe vitamin K deficiency clearly impacts occlusion. Could more subtle deficiency lead to a less pronounced form of the same developmental syndrome? Here are a few facts about vitamin K relevant to this question:

• In industrial societies, newborns are typically vitamin K deficient. This is reflected by the fact that in the US, nearly all newborns are given vitamin K1 at birth to prevent potentially fatal hemorrhage. In Japan, infants are given vitamin K2 MK-4, which is equally effective at preventing hemmorhage.
• Fetuses generally have low vitamin K status, as measured by the activity of their clotting factors.
  
• The human placenta transports vitamin K across the placental barrier and accumulates it. This transport mechanism is highly selective for vitamin K2 MK-4 over K1.
• The concentration of K1 in maternal blood is much higher than its concentration in umbilical cord blood, whereas the concentration of K2 in maternal blood is similar to the concentration in cord blood. Vitamin K2 MK-7 is undetectable in cord blood, even when supplemented, suggesting that MK-7 is not an adequate substitute for MK-4 during pregnancy.
  
• In rat experiments, arterial calcification due to warfarin was inhibited by vitamin K2 MK-4, but not vitamin K1. This is probably due to K2's ability to activate MGP, the same protein required for the normal development of the human face and jaws.
  
• The human mammary gland appears to be the most capable organ at converting vitamin K1 to K2 MK-4.
  

Together, this suggests that in industrial societies, fetuses and infants are vitamin K deficient, to the point of being susceptible to fatal hemorrhage. It also suggests that vitamin K2 MK-4 plays a critical role in fetal and early postnatal development. Could subclinical vitamin K2 deficiency be contributing to the high prevalence of malocclusion in modern societies?

An Ounce of Prevention

Vitamin A, folic acid, vitamin D and vitamin K2 are all nutrients with a long turnover time. Body stores of these nutrients depend on long-term intake. Thus, the nutritional status of the fetus during the first trimester reflects what the mother has been eating for several months before conception.

Dr. Weston Price noted that a number of the traditional societies he visited prepared women of childbearing age for healthy pregnancies by giving them special foods rich in fat-soluble vitamins. This allowed them to gestate and rear healthy, well-formed children. Nutrient-dense animal foods and green vegetables are a good idea before, during and after pregnancy.


* Liver is the richest source of vitamin A, folic acid and B12.

** Affected individuals may show class I, II, or III malocclusion.

The Diet-Heart Hypothesis: Oxidized LDL, Part II

In the last post, I presented the evidence that oxidized LDL (oxLDL) is a dominant factor in the arterial disease known as atherosclerosis, although probably not the only factor. In this post, I'll describe some of the major contributors to oxLDL.

Polyunsaturated Fats Increase LDL Oxidation

The serum concentration of oxLDL is strongly influcenced by diet. One dietary determinant of oxLDL is dietary polyunsaturated fat (PUFA). PUFA are inherently susceptible to oxidative damage, compared to monounsaturated and saturated fats. The predominant PUFA in the modern diet is linoleic acid, found excessively in industrial seed oils like corn oil, sunflower oil, safflower oil, cottonseed oil and soy oil. LDL is naturally rich in linoleic acid, even in cultures such as the Kitavans who have a very low dietary intake of it. However, LDL content of linoleic acid does correlate with dietary intake, and the Kitavans have a comparatively small amount of linoleic acid in their LDL, relative to industrial cultures.

There have been a number of media reports in the last few years proclaiming that monounsaturated fat reduces LDL oxidation compared to saturated and polyunsaturated fat. This is rather implausible on the surface, so let's take a closer look. There are two ways to measure oxLDL:

1. Measure it directly from the blood
   
2. Take normal LDL from the blood, expose it to copper in a test tube, and see how fast it oxidizes

The first reflects actual oxLDL in the blood, whereas the second reflects "susceptibility to oxidation" and has a dubious relationship with actual oxidized LDL in the bloodstream. This results in statements like the following (ref):

LDL resistance to copper-induced oxidation, expressed as lag time, was highest during the MUFA-rich diet (55.1±7.3 minutes) and lowest during the PUFA(n-3)– (45.3±7 minutes) and SFA- (45.3±6.4 minutes) rich diets.

This was published in a paper by P. Mata and colleagues in 1996. They fed 42 volunteers one of four different diets for 5 weeks each: one rich in saturated fat, one rich in monounsaturated fat, one rich in linoleic acid PUFA, and one rich in linoleic acid plus omega-3 PUFA. They emphasized the finding quoted above, as did the media. But there's an embarrassing piece of data buried in the paper that the authors, and the media, ignored (thanks to Chris Masterjohn for pointing this out). Here's what they saw when they looked directly at LDL oxidation in their volunteers:

Oops! LDL oxidation in the two PUFA groups was increased by more than 31%. The difference between the leftmost two groups and the rightmost two was statistically significant. As one would expect, oxidized LDL is proportional to the amount of PUFA in LDL, which is proportional to dietary PUFA. This somehow got left out of the abstract and media reports. The same investigators published a similar report a year later.

In another diet trial, participants were placed on one of two diets for 5 weeks: a low-fat, high PUFA diet low in vegetables; or a low-fat, high PUFA diet high in vegetables. The authors were forthright about their findings, so I'll let them summarize:

The median plasma OxLDL-EO6 increased by 27% (P less than 0.01) in response to the low-fat, low-vegetable diet and 19% (P less than 0.01) in response to the low-fat, high-vegetable diet. Also, the Lp(a) concentration was increased by 7% (P less than 0.01) and 9% (P=0.01), respectively.

This is the diet mainstream cardiologists have been prescribing to heart attack patients for 40 years. The trials I mentioned above are the only three I'm aware of in which fat quality was manipulated and oxLDL was directly measured (the first two were based on subsets of the same data). They all suggest that replacing saturated fat with PUFA increases oxLDL.

I suspect that the effect has less to do with the decrease in saturated fat and more to do with the increase in PUFA, although there's no way to know for sure. In the Lyon Diet-Heart trial, which I believe was the most successful diet trial of all time, linoleic acid was reduced to 3.6% of calories, but saturated fat was also reduced. Another reason is that there are numerous low-fat, low PUFA, high-carbohydrate cultures that have low levels of atherosclerosis and heart attacks. The Kitavans, for example, don't seem to have heart attacks or strokes (although no autopsies have been done so we don't know how much atherosclerosis they have).

They get 69% of their calories from high-glycemic starchy tubers, and their 21% fat comes mostly from coconut so it's highly saturated. Their blood lipids are low in omega-6 linoleic acid and very saturated. But there's a little surprise in the data: their lipids are full of palmitic acid (saturated), despite the fact that their diet contains very little of it. The reason is that their livers are turning all that carbohydrate into saturated fat, which is what happens when you eat more carbohydrate than you can burn immediately or store as glycogen. The moral of the story is that you don't need to eat saturated fat to have saturated LDL: a high-carbohydrate diet can accomplish the same thing, especially if it has a high glycemic index.

Fat-Soluble Antioxidants Decrease LDL Oxidation

LDL carries fat-soluble antioxidants, predominantly vitamin E and coenzyme Q10 (CoQ10). One form of vitamin E, alpha-tocopherol, slows atherosclerosis in most animal models but has shown equivocal results in human trials. There is even the suggestion that it may increase LDL oxidation under some circumstances. I don't recommend supplementing with vitamin E. However, the first line of antioxidant defense in LDL is provided by CoQ10. CoQ10 unequivocally reduces LDL oxidation in human subjects, and potently reduces atherosclerosis in animal models.

CoQ10 has a special relationship with cardiovascular health. Levels are reduced in individuals with cardiovascular disease and high oxLDL. Whether this is cause or effect, it's difficult to say. However, supplementing with CoQ10 has been repeatedly shown to be effective for high blood pressure and congestive heart failure. There has been one controlled trial of CoQ10 (120 mg/day) supplementation for the prevention of heart attacks, which reduced cardiac events including deaths by 45%, compared to a group receiving B vitamins. The CoQ10 group showed a large reduction in plasma lipid oxidation. This is a promising result and the experiment should be repeated.

CoQ10 is not an essential nutrient, although food does contribute a small portion of our total CoQ10 use. The large majority of CoQ10 is synthesized by the body itself, and this is dependent on a number of essential nutrients, including vitamin B2, B3, B5, B6, B12, vitamin C and folic acid. Thus, the body's synthesis of CoQ10 is dependent on overall nutritional status. Sub-clinical deficiency of any of these vitamins can hypothetically contribute to reduced CoQ10 production and thus oxLDL. This is potentially a big problem since modern Americans get more than half their calories from nutrient-poor refined foods. Liver is the single best source of many of these vitamins, and also holds the title of Most Nutritious Food on the Planet. It's also rich in CoQ10.

CoQ10 synthesis declines with age and is reduced in people with disorders involving oxidative stress, like cardiovascular disease. It's also greatly reduced by the cholesterol-lowering drugs statins. I'm not generally in favor of supplements, but CoQ10 seems to have a lot of promise and nothing but positive side effects that I'm aware of. CoQ10 deficiency may be a common theme in a number of modern disorders.

Excess Blood Sugar and Fructose Increase LDL Oxidation

Both type I and type II diabetes are associated with higher levels of oxLDL, therefore, prolonged high blood glucose may contribute to LDL oxidation due to glycosylation of the LDL protein ApoB. Fructose consumption increases oxLDL relative to glucose. Fructose is a very powerful glycosylating agent (binds non-specifically to other molecules, causing damage). Although it isn't present at high levels in the general circulation, it does interact with blood lipids in the hepatic portal vein as it moves from the digestive tract to the liver to be turned into fat (palmitic acid). Peter at Hyperlipid has written extensively about the role of glycosylation in LDL oxidation.

The Diet-Heart Hypothesis: The Verdict

The diet-heart hypothesis, the idea that dietary saturated fat and cholesterol raise blood cholesterol and thus increase heart attack risk, is a half-century embarrassment to the international scientific community. It requires willful ignorance of the fact that saturated fat does not increase total cholesterol or LDL in humans, in the long term. It requires a simplistic view of blood lipids that ignores the potentially harmful effects of replacing animal fats with carbohydrate or industrial seed oils. Worst of all, it requires selective citation of the literature on diet modification trials.

I have to conclude that if dietary saturated fat and cholesterol play any role whatsoever in cardiovascular disease, it's a minor one that's trumped by other factors. Industrial seed oils and sugar are likely to play an important role in cardiovascular disease.

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

It's time to cross the threshold from markers of heart attack risk to causes of atherosclerosis. 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. In the next post, I'll describe how you can modify your level of oxidized LDL using diet.

* People often think of colorful fruits and vegetables when they think of antioxidants, but vitamin E and CoQ10 are found in both plant and animal foods. Fruits and vegetables are generally not good sources of these fat-soluble antioxidants. Good sources include organ meats, nuts, pastured butter, avocados and red palm oil. The body also manufactures CoQ10 itself.

Dihydro-Vitamin K1

Step right up ladies and gents; I have a new miracle vitamin for you. Totally unknown to our ignorant pre-industrial ancestors, it's called dihydro-vitamin K1. It's formed during the oil hydrogenation process, so the richest sources are hydrogenated fats like margarine, shortening and commercial deep fry oil. Some of its benefits may include:

• Inhibiting vitamin K2 metabolism
• Reducing bone mineral density
  
• Causing organ damage and inhibiting platelet formation in animal models
• Dramatically increasing the death rate of spontaneously hypertensive rats

Dihydro-vitamin K1 accounts for roughly 30% of the vitamin K intake of American children, and a substantial portion of adult intake as well. Over 99 percent of Americans have it in their diet. Research on dihydro-vitamin K1 is in its infancy at this point, so no one has a very solid idea of its effects on the body beyond some preliminary and disturbing suggestions from animal experiments and brief human trials.

This could be another mechanism by which industrially processed vegetable oils degrade health. It's also another example of why it's not a good idea to chemically alter food. We don't understand food, or our bodies, well enough to know the long-term consequences of foods that have been recently introduced to the human diet. I believe these foods should be avoided on principle.

Pastured Eggs

Eggs are an exceptionally nutritious food. It's not surprising, considering they contain everything necessary to build a chick! But all eggs are not created equal. Anyone who has seen the tall, orange yolk, viscous white, and tough shell of a true pastured egg knows they're profoundly different. So has anyone who's tasted one. This has been vigorously denied by the American Egg Board and the Egg Nutrition Council, primarily representing conventional egg farmers, which assert that eggs from giant smelly barns are nutritionally equal to their pastured counterparts.

In 2007, the magazine Mother Earth News decided to test that claim. They sent for pastured eggs from 14 farms around the U.S., tested them for a number of nutrients, and compared them to the figures listed in the USDA Nutrient Database for conventional eggs. Here are the results per 100 grams for conventional eggs, the average of all the pastured eggs, and eggs from Skagit River Ranch, which sells at my farmer's market:

Vitamin A:

• Conventional: 487 IU
• Pastured avg: 792 IU
• Skagit Ranch: 1013 IU
  

Vitamin D:

• Conventional: 34 IU
  
• Pastured avg: 136 - 204 IU
  
• Skagit Ranch: not determined
  

Vitamin E:

• Conventional: 0.97 mg
• Pastured avg: 3.73 mg
  
• Skagit Ranch: 4.02 mg

Beta-carotene:

• Conventional: 10 mcg
  
• Pastured avg: 79 mcg
  
• Skagit Ranch: 100 mcg
  

Omega-3 fatty acids:

• Conventional: 0.22 g
  
• Pastured avg: 0.66 g
  
• Skagit Ranch: 0.74 g
  

Looks like the American Egg Board and the Egg Nutrition Council have some egg on their faces...

Eggs also contain vitamin K2, with the amount varying substantially according to the hen's diet. Guess where the A, D, K2, beta-carotene and omega-3 fatty acids are? In the yolk of course. Throwing the yolk away turns this powerhouse into a bland, nutritionally unimpressive food.

It's important to note that "free range" supermarket eggs are nutritionally similar to conventional eggs. The reason pastured eggs are so nutritious is that the chickens get to supplement their diets with abundant fresh plants and insects. Having little doors on the side of a giant smelly barn just doesn't replicate that.

Vitamin A, Vitamin D and Osteoporosis Reprise

Chris Masterjohn just pointed out a new study that examined the relationship of vitamin A to osteoporosis in the context of vitamin D intake. The study is part of the massive Women's Health Initiative, which involved over 75,000 women. The conclusion:

No association between vitamin A or retinol intake and the risk of hip or total fractures was observed in postmenopausal women. Only a modest increase in total fracture risk with high vitamin A and retinol intakes was observed in the low vitamin D-intake group.

In other words, only women with a low vitamin D intake (less than 440 IU per day) had an increased likelihood of fracture at high vitamin A intakes (more than 8,000 IU per day). This is consistent with the hypothesis that an above-average intake of vitamin A only increases the risk of osteoporosis in the presence of low vitamin D, and that vitamin D deficiency, not vitamin A excess, is the true problem. Hop over to Chris's post for more details.

Vitamin A on Trial: Does Vitamin A Cause Osteoporosis?
Is Vitamin A Toxicity a Concern?

Nutrition and Infectious Disease

Dr. Edward Mellanby's book Nutrition and Disease contains a chapter titled "Nutrition and Infection". It begins:

There is general agreement among medical men that the susceptibility of mankind to many types of infection is closely related to the state of nutrition. The difficulty arises, when closer examination is given to this general proposition, as to what constitutes good and bad nutrition, and the problem is not rendered easier by recent advances in nutritional science.

Dr. Mellanby was primarily concerned with the effect of fat-soluble vitamins on infectious disease, particularly vitamins A and D. One of his earliest observations was that butter protected against pneumonia in his laboratory dogs. He eventually identified vitamin A as the primary protective factor. He found that by placing rats on a diet deficient in vitamin A, they developed numerous infectious lesions, most often in the urogenital tract, the eyes, the intestine, the middle ear and the lungs. This was prevented by adding vitamin A or cabbage (a source of beta-carotene, which the rats converted to vitamin A) to the diet. Mellanby and his colleagues subsequently dubbed vitamin A the "anti-infective vitamin".

Dr. Mellanby was unsure whether the animal results would apply to humans, due to "the difficulty in believing that diets even of poor people were as deficient in vitamin A and carotene as the experimental diets." However, their colleagues had previously noted marked differences in the infection rate of largely vegetarian African tribes versus their carnivorous counterparts. The following quote from Nutrition and Disease refers to two tribes which, by coincidence, Dr. Weston Price also described in Nutrition and Physical Degeneration:

The high incidence of bronchitis, pneumonia, tropical ulcers and phthisis among the Kikuyu tribe who live on a diet mainly of cereals as compared with the low incidence of these diseases among their neighbours the Masai who live on meat, milk and raw blood (Orr and Gilks), probably has a similar or related nutritional explanation. The differences in distribution of infective disease found by these workers in the two tribes are most impressive. Thus in the cereal-eating tribe, bronchitis and pneumonia accounted for 31 per cent of all cases of sickness, tropical ulcers for 33 per cent, and phthisis for 6 per cent. The corresponding figures for the meat, milk and raw blood tribe were 4 per cent, 3 per cent and 1 per cent.

So they set out to test the theory under controlled conditions. Their first target: puerperal sepsis. This is an infection of the uterus that occurs after childbirth. They divided 550 women into two groups: one received vitamins A and D during the last month of pregnancy, and the other received nothing. Neither group was given instructions to change diet, and neither group was given vitamins during their hospital stay. The result, quoted from Nutrition and Disease:

The morbidity rate in the puerperium using the [British Medical Association] standard was 1.1 per cent in the vitamin group and 4.7 in the control group, a difference of 3.6 per cent which is twice the standard error (1.4), and therefore statistically significant.

This experiment didn't differentiate between the effects of vitamin A and D, but it did establish that fat-soluble vitamins are important for resistance to bacterial infection. The next experiment Dr. Mellanby undertook was a more difficult one. This time, he targeted puerperal septicemia. This is a more advanced stage of puerperal sepsis, in which the infection spreads into the bloodstream. In this experiment, he treated women who had already contracted the infection. This trial was not as tightly controlled as the previous one. Here's a description of the intervention, from Nutrition and Disease:

...all patients received when possible a diet rich not only in vitamin A but also of high biological quality. This diet included much milk, eggs, green vegetables, etc., as well as the vitamin A supplement. For controls we had to use the cases treated in previous years by the same obstetricians and gynecologists as the test cases.

In the two years prior to this investigation, the mortality rate for puerperal septicemia in 18 patients was 92%. In 1929, Dr. Mellanby fed 18 patients in the same hospital his special diet, and the mortality rate was 22%. This is a remarkable treatment for an infection that was almost invariably fatal at the time.

Dr. Mellanby was a man with a lot of perspective. He was not a reductionist; he knew that a good diet is more than the sum of its parts. Here's another quote from Nutrition and Disease:

It is probable that, as in the case of vitamin D and rickets, the question is not simple and that it will ultimately be found that vitamin A works in harmony with some dietetic factors, such as milk proteins and other proteins of high biological value, to promote resistance of mucous membranes and epithelial cells to invasion by micro-organisms, while other factors such as cereals, antagonise its influence. The effect of increasing the green vegetable and reducing the cereal intake on the resistance of herbivorous animals to infection is undoubted (Glenny and Allen, Boock and Trevan) and may well indicate a reaction in which the increased carotene of the vegetable plays only a part, but an important part.

And finally, let's not forget the effect of vitamin D on infection resistance. Low vitamin D is consistently associated with a higher frequency of respiratory infections, and a controlled trial showed that vitamin D supplements significantly reduce the occurrence of flu symptoms in wintertime. Vitamins A and D are best taken together. Did someone say high-vitamin cod liver oil??

P.S.- I have to apologize, I forgot to copy down the primary literature references for this post before returning the book to the library. So for the skeptics out there, you'll either have to take my word for it, or find a copy of the book yourself.