Polyphenols, Hormesis and Disease: Part I

What are Polyphenols?

Polyphenols are a diverse class of molecules containing multiple phenol rings. They are synthesized in large amounts by plants, certain fungi and a few animals, and serve many purposes, including defense against predators/infections, defense against sunlight damage and chemical oxidation, and coloration. The color of many fruits and vegetables, such as blueberries, eggplants, red potatoes and apples comes from polyphenols. Some familiar classes of polyphenols in the diet-health literature are flavonoids, isoflavonoids, anthocyanidins, and lignins.

The Case Against Polyphenols

Mainstream diet-health authorities seem pretty well convinced that dietary polyphenols are an important part of good health, due to their supposed antioxidant properties. In the past, I've been critical of the hypothesis. There are several reasons for it:

1. Polyphenols are often, but not always, defensive compounds that interfere with digestive processes, which is why they often taste bitter and/or astringent. Plant-eating animals including humans have evolved defensive strategies against polyphenol-rich foods, such as polyphenol-binding proteins in saliva (1).
2. Ingested polyphenols are poorly absorbed (2). The concentration in blood is low, and the concentration inside cells is probably considerably lower*. In contrast, essential antioxidant nutrients such as vitamins E and C are efficiently absorbed rather than excluded from the circulation.
   
3. Polyphenols that manage to cross the gut barrier are rapidly degraded by the liver, just like a variety of other foreign molecules, again suggesting that the body doesn't want them hanging around (2).
4. The most visible hypothesis of how polyphenols influence health is the idea that they are antioxidants, protecting against the ravages of reactive oxygen species. While many polyphenols are effective antioxidants at high concentrations in a test tube, I don't find it very plausible that the low and transient blood concentration of polyphenols achieved by eating polyphenol-rich foods makes a meaningful contribution to that person's overall antioxidant status, when compared to the relatively high concentrations of other antioxidants in blood (uric acid; vitamins C, E; ubiquinone) and particularly inside cells (SOD1/2, catalase, glutathione reductase, thioredoxin reductase, paraoxonase 1, etc.).
   
5. There are a number of studies showing that the antioxidant capacity of the blood increases after eating polyphenol-rich foods. These are often confounded by the fact that fructose (in fruit and some vegetables) and caffeine (in tea and coffee) can increase the blood level of uric acid, the blood's main water-soluble antioxidant. Drinking sugar water has the same effect (2).
6. Rodent studies showing that polyphenols improve health typically use massive doses that exceed what a person could consume eating food, and do not account for the possibility that the rodents may have been calorie restricted because their food tastes horrible.
   

The main point is that the body does not seem to "want" polyphenols in the circulation at any appreciable level, and therefore it gets rid of them pronto. Why? I think it's because the diversity and chemical structure of polyphenols makes them potentially bioactive-- they have a high probability of altering signaling pathways and enzyme activity, in the same manner as pharmaceutical drugs. It would not be a very smart evolutionary strategy to let plants (that often don't want you eating them) take the reins on your enzyme activity and signaling pathways. Also, at high enough concentrations polyphenols can be pro-oxidants, promoting excess production of free radicals, although the biological relevance of that may be questionable due to the concentrations required.

A Reappraisal

After reading more about polyphenols, and coming to understand that the prevailing hypothesis of why they work makes no sense, I decided that the whole thing is probably bunk: at best, specific polyphenols are protective in rodents at unnaturally high doses due to some drug-like effect. But-- I kept my finger on the pulse of the field just in case, and I began to notice that more sophisticated studies were emerging almost weekly that seemed to confirm that realistic amounts of certain polyphenol-rich foods (not just massive quantities of polyphenol extract) have protective effects against a variety of health problems. There are many such studies, and I won't attempt to review them comprehensively, but here are a few I've come across:

• Dr. David Grassi and colleagues showed that polyphenol-rich chocolate lowers blood pressure, improves insulin sensitivity and lowers LDL cholesterol in hypertensive and insulin resistant volunteers when compared with white chocolate (3). Although dark chocolate is also probably richer in magnesium, copper and other nutrients than white chocolate, the study is still intriguing.
• Dr. Christine Morand and colleagues showed that drinking orange juice every day lowers blood pressure and increases vascular reactivity in overweight volunteers, an effect that they were able to specifically attribute to the polyphenol hesperidin (4).
• Dr. F. Natella and colleagues showed that red wine prevents the increase in oxidized blood lipids (fats) that occurs after consuming a meal high in oxidized and potentially oxidizable fats (5).
• Several studies have shown that hibiscus tea lowers blood pressure in people with hypertension when consumed regularly (6, 7, 8). It also happens to be delicious.
  
• Dr. Arpita Basu and colleagues showed that blueberries lower blood pressure and oxidized LDL in men and women with metabolic syndrome (9).
• Animal studies have generally shown similar results. Dr. Xianli Wu and colleagues showed the blueberries potently inhibit atherosclerosis (hardening and thickening of the arteries that can lead to a heart attack) in a susceptible strain of mice (10). This effect was associated with a higher expression level of antioxidant enzymes in the vessel walls and other tissues.

Wait a minute... let's rewind. Eating blueberries caused mice to increase the expression level of their own antioxidant enzymes?? Why would that happen if blueberry polyphenols were themselves having a direct antioxidant effect? One would expect the opposite reaction if they were. What's going on here?

In the face of this accumulating evidence, I've had to reconsider my position on polyphenols. In the process, and through conversations with knowledgeable researchers in the polyphenol field, I encountered a different hypothesis that puts the puzzle pieces together nicely.


* Serum levels briefly enter the mid nM to low uM range, depending on the food (2). Compare that with the main serum antioxidants: ~200 uM for uric acid, ~100 uM for vitamin C, ~30 uM for vitamin E.

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

The diet-heart hypothesis states three things:

1. Dietary saturated fat increases blood cholesterol
   
2. Elevated blood cholesterol increases the risk of having a heart attack
3. Therefore, dietary saturated fat increases the risk of having a heart attack
   

To evaluate the second contention, investigators have examined the relationship between blood cholesterol and heart attack risk. Many studies including MRFIT have shown that the two are related (1):

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

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

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

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

The Studies

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

The earliest and perhaps most interesting study I found was published in the British Medical Journal in 1963 and is titled "Diet and Plasma Cholesterol in 99 Bank Men" (4). Investigators asked volunteers to weigh all food consumed at home for 1-2 weeks, and describe in detail all food consumed away from home. Compliance was good. This dietary accounting method was much more thorough than in most observational studies today**. Animal fat intake ranged from 55 to 173 grams per day, and blood cholesterol ranged from 154 to 324 mg/dL, yet there was no relationship whatsoever between the two. I'm looking at a graph of animal fat intake vs. blood cholesterol as I write this, and it looks like someone shot it with a shotgun at 50 yards. They twisted the data every which way, but were never able to squeeze even a hint of an association out of it:

Making the most out of the data in other ways- for example, by analysis of the men very stable in their diets, or in whom weighing of food intake was maximal, or where blood was taken close to the diet [measurement]- did not increase the correlation. Because the correlation coefficient is almost as often negative as positive, moreover, what is being discussed mostly is the absence of association, not merely association that is unexpectedly small.

The next study to discuss is the 1976 Tecumseh study (5). This was a large cardiovascular observational study conducted in Tecumseh, Michigan, which is often used as the basis for comparison for other cardiovascular studies in the literature. Using the 24 hour dietary recall method, including an analysis of saturated fat, the investigators found that:

Cholesterol and triglyceride levels were unrelated to quality, quantity, or proportions of fat, carbohydrate or protein consumed in the 24-hr recall period.

They also noted that the result was consistent with what had been reported in other previously published studies, including the Evans county study (6), the massive Israel Ischemic Heart Disease Study (7) and the Framingham study. One of the longest-running, most comprehensive and most highly cited observational studies, the Framingham study was organized by Harvard investigators and continues to this day. When investigators analyzed the relationship between saturated fat intake, serum cholesterol and heart attack risk, they were so disappointed that they never formally published the results. We know from multiple sources that they found no significant relationship between saturated fat intake and blood cholesterol or heart attack risk***.

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

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

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

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

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

Conclusion

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

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

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


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

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

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

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

Potato Diet Interpretation

If you read my post on December 16th, you know that Chris Voigt saw remarkable fat loss and improvements in health markers as a result of two months of eating almost nothing but potatoes. This has left many people scratching their heads, because potatoes are not generally viewed as a healthy food. This is partially due to the fact that potatoes are very rich in carbohydrate, which also happens to be a quickly digested type, resulting in a high glycemic index. The glycemic index refers to the degree to which a particular food increases blood glucose when it's eaten, and I've questioned the relevance of this concept to health outcomes in the past (1, 2, 3). I think Mr. Voigt's results once again argue against the importance of the glycemic index as a diet-health concept.

It's often pointed out that potatoes are low in vitamins and minerals compared to vegetables on a per-calorie basis, but I think it's a misleading comparison because potatoes are much more calorie-dense than most vegetables. Potatoes compare favorably to other starchy staples such as bread, rice and taro.

Over the course of two months, Mr. Voigt lost 21 pounds. No one knows exactly how much of that weight came out of fat and how much out of lean mass, but the fact that he reported a decrease in waist and neck circumference indicates that most of it probably came out of fat. Previous long-term potato feeding experiments have indicated that it's possible to maintain an athletic muscle mass on the amount of protein in whole potatoes alone (4). So yes, Mr. Voigt lost fat on a very high-carbohydrate diet (75-80% carbohydrate, up to 440g per day).

On to the most interesting question: why did he lose fat? Losing fat requires that energy leaving the body exceed energy entering the body. But as Gary Taubes would say, that's obvious but it doesn't get us anywhere. In the first three weeks of his diet, Mr. Voigt estimates that he was only eating 1,600 calories per day. Aha! That's why he lost weight! Well, yes. But let's look into this more deeply. Mr. Voigt was not deliberately restricting his calorie intake at all, and he did not intend this as a weight loss diet. In my interview, I asked him if he was hungry during the diet. He said that he was not hungry, and that he ate to appetite during this period, realizing only after three weeks that he was not eating nearly enough calories to maintain his weight*. I also asked him how his energy level was, and he said repeatedly that it was very good, perhaps even better than usual. Those were not idle questions.

Calorie restriction causes a predictable physiological response in humans that includes hunger and decreased energy. It's the starvation response, and it's powerful in both lean and overweight people, as anyone knows who has tried to lose fat by decreasing calorie intake alone. The fact that he didn't experience hunger or fatigue implies that his body did not think it was starving. Why would that be?

I believe Mr. Voigt's diet lowered his fat mass 'setpoint'. In other words, for whatever reason, the diet made his body 'want' to be leaner that it already was. His body began releasing stored fat that it considered excess, and therefore he had to eat less food to complete his energy needs. You see this same phenomenon very clearly in rodent feeding studies. Changes in diet composition/quality can cause dramatic shifts in the fat mass setpoint (5, 6). Mr. Voigt's appetite would eventually have returned to normal once he had stabilized at a lower body fat mass, just as rodents do.

Rodent studies have made it clear that diet composition has a massive effect on the level of fat mass that the body will 'defend' against changes in calorie intake (5, 6). Human studies have shown similar effects from changes in diet composition/quality. For example, in controlled diet trials, low-carbohydrate dieters spontaneously reduce their calorie intake quite significantly and lose body fat, without being asked to restrict calories (7). In Dr. Staffan Lindeberg's Paleolithic diet trials, participants lost a remarkable amount of fat, yet a recent publication from his group shows that the satiety (fullness) level of the Paleolithic group was not different from a non-Paleolithic comparison group despite a considerably lower calorie intake over 12 weeks (8, 9). I'll discuss this important new paper soon. Together, this suggests that diet composition/quality can have a dominant impact on the fat mass setpoint.

One possibility is that cutting the wheat, sugar, most vegetable oil and other processed food out of Mr. Voigt's diet was responsible for the fat loss. I think that's likely to have contributed. Many people find, for example, that they lose fat simply by eliminating wheat from their diet.

Another possibility that I've been exploring recently is that changes in palatability (pleasantness of flavor) influence the fat mass setpoint. There is evidence in rodents that it does, although it's not entirely consistent. For example, rats will become massively obese if you provide them with chocolate flavored Ensure (a meal replacement drink), but not with vanilla or strawberry Ensure (10). They will defend their elevated fat mass against calorie restriction (i.e. they show a physiological starvation response when you try to bring them down to a lower weight by feeding them less chocolate Ensure) while they're eating chocolate Ensure, but as soon as you put them back on unpurified rodent pellets, they will lose fat and defend the lower fat mass. Giving them food in liquid or paste form often causes obesity, while the same food in solid pellet form will not. Eating nothing but potatoes is obviously a diet with a low overall palatability.

So I think that both a change in diet composition/quality and a decrease in palatability probably contributed to a decrease in Mr. Voigt's fat mass setpoint, which allowed him to lose fat mass without triggering a starvation response (hunger, fatigue).

The rest of his improvements in health markers were partially due to the fat loss, including his decreased fasting glucose, decreased triglycerides, and presumably increased insulin sensitivity. They may also have been partially due to a lack of industrial food and increased intake of certain micronutrients such as magnesium.

One of the most striking changes was in his calculated LDL cholesterol ("bad" cholesterol), which decreased by 41%, putting him in a range that's more typical of healthy non-industrial cultures including hunter-gatherers. Yet hunter-gatherers didn't eat nothing but potatoes, often didn't eat much starch, and in some cases had a high intake of fat and saturated fat, so what gives? It's possible that a reduced saturated fat intake had an impact on his LDL, given the relatively short timescale of the diet. But I think there's something mysterious about this setpoint mechanism that has a much broader impact on metabolism than is generally appreciated. For example, calorie restriction in humans has a massive impact on LDL, much larger than the impact of saturated fat (11). And in any case, the latter appears to be a short-term phenomenon (12). It's just beginning to be appreciated that energy balance control systems in the brain influence cholesterol metabolism.

Mr. Voigt's digestion appeared to be just fine on his potato diet, even though he generally ate the skins. This makes me even more skeptical of the idea that potato glycoalkaloids in common potato varieties are a health concern, especially if you were to eliminate most of the glycoalkaloids by peeling.

I asked Mr. Voigt about what foods he was craving during the diet to get an idea of whether he was experiencing any major deficiencies. The fact that Mr. Voigt did not mention craving meat or other high-protein foods reinforces the fact that potatoes are a reasonable source of complete protein. The only thing he craved was crunchy/juicy food, which I'm not sure how to interpret.

He also stopped snoring during the diet, and began again immediately upon resuming his normal diet, perhaps indicating that his potato diet reduced airway inflammation. This could be due to avoiding food allergies and irritants (wheat anyone?) and also fat loss.

Overall, a very informative experiment! Enjoy your potatoes.


*Until the last 5.5 weeks, when he deliberately stuffed himself beyond his appetite because his rapid weight loss worried him. Yet, even with deliberate overfeeding up to his estimated calorie requirement of 2,200 calories per day, he continued to lose weight. He probably was not quite reaching his calorie goal, or his requirement is higher than he thought.

Diet-Heart Controlled Trials: a New Literature Review

Many controlled studies have measured the cardiovascular effects of replacing animal ("saturated") fats with seed oils (predominantly the omega-6 polyunsaturated fat linoleic acid) in humans. A number of these studies recorded heart attacks and total mortality during the following 1-8 years. Several investigators have done meta-analyses (literature reviews) to try to tease out overall conclusions from these studies.

I'm pleased to point out a new meta-analysis of these controlled trials by Dr. Christopher Ramsden and colleagues (1). This paper finally cleans up the mess that previous meta-analyses have made of the diet-heart literature. One recent paper in particular by Dr. Dariush Mozaffarian and colleagues concluded that overall, the controlled trials show that replacing animal fat with linoleic acid (LA)-rich seed oils reduces heart attack risk (2). I disagreed strongly with their conclusion because I felt their methods were faulty (3).

Dr. Ramsden and colleagues pointed out several fundamental flaws in the review paper by Dr. Mozaffarian and colleagues, as well as in the prevailing interpretation of these studies in the scientific literature in general. These overlap with the concerns that I voiced in my post (4):

1. Omission of unfavorable studies, including the Rose corn oil trial and the Sydney diet-heart trial.
2. Inclusion of weak trials with major confounding variables, such as the Finnish mental hospital trial.
3. Failure to distinguish between omega-6 and omega-3 fatty acids.
4. Failure to acknowledge that seed oils often replaced large quantities of industrial trans fats in addition to animal fat in these trials.
   

Dr. Ramsden and colleagues accounted for all of these factors in their analysis, which has never been done before. They chose inclusion criteria* that made sense, and stuck with them. In addition, they did an impressive amount of historical work, digging up old unpublished data from these trials to determine the exact composition of the control and experimental diets. The paper is published in the British Journal of Nutrition, an excellent journal, and overall is written in a scientific and professional manner.

What did they find?

• Interventions that replaced animal and trans fat with seed oils that were rich in LA but low in omega-3 caused a non-significant trend toward increased heart attacks (13% increase) and overall mortality.
  
• Interventions that replaced animal and trans fat with a combination of LA and omega-3 fats significantly reduced heart attacks (by 22%). The numbers for total mortality followed a similar trend.

In other words, LA-rich seed oils do not prevent heart attacks (and may actually promote them), but correcting an omega-3 deficiency and reducing industrial trans fat intake may be protective. This is similar to what I've been saying for a while now, based on my own interpretation of the same studies and others. However, Dr. Ramsden and colleagues have taken the idea to a new level by their thorough and sophisticated detective work and analysis. For example, I didn't realize that in virtually all of these controlled trials, the intervention group reduced its trans fat intake substantially in addition to reducing animal fat. From the paper:

...experimental diets replaced common ‘hard’ margarines, industrial shortenings and other sources of [trans fat] in all seven of the [controlled trials] included in the meta-analysis by Mozaffarian et al. The mean estimated [trans fat] content of the seven control diets was 3·0 [% of calories] (range 1·5–9·6 [%]).
...the displacement of [trans fat], rather than the substitution of mixed n-3/n-6 [polyunsaturated fat] for [saturated fat], may account for some or all of the 22% reduction in non-fatal [heart attacks and heart attack] death in our meta-analysis. By contrast, the increased [heart attack] risks from n-6 specific [polyunsaturated fat] diets in our meta-analysis may be underestimated as n-6 [polyunsaturated fat] also replaced substantial quantities of [trans fat] (Table 3). The consistent trends towards increased [heart attack] risk of n-6 specific [polyunsaturated fat] diets may have become significant if the n-6 [polyunsaturated fat] replaced only [saturated fat], instead of a combination of [saturated fat] and [trans fat].

In other words, it looks like trans fat is probably the issue, not animal fat, but these trials replaced both simultaneously so we can't know for sure. I will note here that trans fat does not generally promote atherosclerosis (thickening and hardening of arteries) in animal models, so if it does truly increase heart attack risk as many studies suggest, it's probably through a mechanism that is independent of atherosclerosis.

The article also contains an excellent discussion of the Finnish mental hospital trial (5, 6) and why it was excluded from the meta-analysis, in which Dr. Ramsden and colleagues point out major design flaws, some of which I was not aware of. For example, trans fat intake was on average 13 times higher in the control groups than in the experimental groups. In addition, one of the control groups received more than twice as much of the antipsychotic drug thioridazine, which is known to be highly toxic to the heart, as any other group. Ouch. I'm glad to see this study finally discussed in an open and honest manner. I discussed my own problems with the Finnish trial in an earlier post (7).

I was also glad to see an open discussion of the Oslo Diet-heart study (8), in which diet changes led to a reduction in heart attack risk over five years. Dr. Mozaffarian and colleagues included it in their analysis as if it were a controlled trial in which animal fat was replaced by seed oils only. In reality, the investigators changed many variables at once, which I had also pointed out in my critique of Dr. Mozaffarian's meta-analysis (9). Here's what Dr. Ramsden and colleagues had to say about it:

First, experimental dieters were instructed to substitute fish, shellfish and ‘whale beef’ for meats and eggs, and were actually supplied with ‘considerable quantities of Norwegian sardines canned in cod liver oil, which proved to be popular as a bread spread’(32)... Second, the experimental group consumed massive amounts of soybean oil, which provided large quantities of both LA (15·6 en %) and ALA (2·7 en %). ALA consumption was about 4·5 times average US intake(42), or about twelve typical flax oil pills (1 g pill ¼ 560 mg ALA) per d. In addition, the fish and cod liver oil consumption provided Oslo (598N latitude) dieters with 610 IU (15·25 mg) of daily vitamin D3, recently linked to lower blood pressure, plaque stabilisation, and reduced [heart attack risk] (64). Furthermore, experimental dieters were encouraged to eat more nuts, fruits, and vegetables; to limit animal fats; and to restrict their intake of refined grains and sugar.

trans fat intake was also reduced substantially by excluding margarine in the experimental group. Other review papers have used this trial as a justification to replace animal fat with seed oils. Hmm... The only reason they get away with this is because the trial was published in 1966 and almost no one today has actually read it.

One criticism I have of Dr. Ramsden's paper is that they used the Oslo trial in their analysis, despite the major limitation described above. However, they were extremely open about it and discussed the problem in detail. Furthermore, the overall result would have been essentially the same even if they had excluded the Oslo trial from the analysis.

Overall, the paper is an excellent addition to the literature, and I hope it will bring a new level of sophistication to the dialogue on dietary prevention of cardiovascular disease. In the meantime, brace yourselves for an avalanche of criticism from the seed oil brigade.


* Guidelines that determine which studies to include in the analysis. For example, you want to exclude any study that wasn't randomized, because it will not be interpretable from a statistical standpoint. You also want to exclude trials where major variables differ between groups besides the specific variable you're trying to test. The Finnish mental hospital trial fails by both criteria.

The China Study on Wheat

Denise Minger has just put up another great China Study post that's worth reading if you haven't already. Denise has been busy applying her statistics skills to the mountain of data the study collected. She noted in a previous post that wheat intake was strongly associated with coronary heart disease (CHD), the quintessential modern cardiovascular disease. I, and several other people, requested that she work her mathmagic to see if the association could be due to some other factor. For example, wheat is eaten mostly in the Northern regions of China, and CHD rates are generally higher at higher latitudes (vitamin D insufficiency?). This is true in Europe as well, and may be partly responsible for the purported benefits of the Mediterranean diet. You can mathematically determine if the association between wheat and CHD is simply due to the fact that wheat eaters live further North.

To make a long story short, nothing could explain the association except wheat itself, even latitude. Furthermore, she found a strong association between wheat intake and body mass index, typically a predictor of fat mass although we can't say that for sure. That finding echos a previous study in China where wheat eaters were more likely to be overweight than rice eaters (1, 2). Head over to Denise's post for the full story.

The China Study has major limitations built into its basic design, due to the fact that it was observational and pooled the blood samples of many individuals. Therefore, its findings can never prove anything, they can only suggest or be consistent with hypotheses. However, the study also has some unique advantages, such as a diversity of diets and regions, and the fact that people had presumably been eating a similar diet for a long time. I feel that Denise's efforts are really teasing out some useful information from the study that have been de-emphasized by other investigators.

There has been so little serious investigation into the health effects of wheat in the general population that I have to rely mostly on indirect evidence, such as the observation that the diseases of civilization tend to closely follow the introduction of white flour around the globe. Researchers studying celiac disease and other forms of gluten allergy, and the efforts of the paleolithic diet community in spreading that information (for example, Loren Cordain and Pedro Bastos), have been major contributors to understanding the health effects of wheat. Denise's analysis is one of the strongest pieces of evidence I've come by so far. One of these days, I'll post all of my references incriminating wheat. There are quite a few, although none of them is the smoking gun. I think there's enough indirect evidence that investigators should begin taking the idea seriously that wheat, particularly in the form of industrial flour products, may contribute to chronic disease in more than just a small subset of the population.

Tropical Plant Fats: Coconut Oil, Part I

Traditional Uses for Coconut

Coconut palms are used for a variety of purposes throughout the tropics. Here are a few quotes from the book Polynesia in Early Historic Times:

Most palms begin to produce nuts about five years after germination and continue to yield them for forty to sixty years at a continuous (i.e., nonseasonal) rate, producing about fifty nuts a year. The immature nut contains a tangy liquid that in time transforms into a layer of hard, white flesh on the inner surface of the shell and, somewhat later, a spongy mass of embryo in the nut's cavity. The liquid of the immature nut was often drunk, and the spongy embryo of the mature nut often eaten, raw or cooked, but most nuts used for food were harvested after the meat had been deposited and before the embryo had begun to form...

After the nut had been split, the most common method of extracting its hardened flesh was by scraping it out of the shell with a saw-toothed tool of wood, shell, or stone, usually lashed to a three-footed stand. The shredded meat was then eaten either raw or mixed with some starchy food and then cooked, or had its oily cream extracted, by some form of squeezing, for cooking with other foods or for cosmetic or medical uses...

Those Polynesians fortunate enough to have coconut palms utilized their components not only for drink and food-- in some places the most important, indeed life-supporting food-- but also for building-frames, thatch, screens, caulking material, containers, matting, cordage, weapons, armor, cosmetics, medicine, etc.

Mainstream Ire

Coconut fat is roughly 90 percent saturated, making it one of the most highly saturated fats on the planet. For this reason, it has been the subject of grave pronouncements by health authorities over the course of the last half century, resulting in its near elimination from the industrial food system. If the hypothesis that saturated fat causes heart disease and other health problems is correct, eating coconut oil regularly should tuck us in for a very long nap.

Coconut Eaters

As the Polynesians spread throughout the Eastern Pacific islands, they encountered shallow coral atolls that were not able to sustain their traditional starchy staples, taro, yams and breadfruit. Due to its extreme tolerance for poor, salty soils, the coconut palm was nearly the only food crop that would grow on these islands*. Therefore, their inhabitants lived almost exclusively on coconut and seafood for hundreds of years.

One group of islands that falls into this category is Tokelau, which fortunately for us was the subject of a major epidemiological study that spanned the years 1968 to 1982: the Tokelau Island Migrant Study (1). By this time, Tokelauans had managed to grow some starchy foods such as taro and breadfruit (introduced in the 20th century by Europeans), as well as obtaining some white flour and sugar, but their calories still came predominantly from coconut.

Over the time period in question, Tokelauans obtained roughly half their calories from coconut, placing them among the most extreme consumers of saturated fat in the world. Not only was their blood cholesterol lower than the average Westerner, but their hypertension rate was low, and physicians found no trace of previous heart attacks by ECG (age-adjusted rates: 0.0% in Tokelau vs 3.5% in Tecumseh USA). Migrating to New Zealand and cutting saturated fat intake in half was associated with a rise in ECG signs of heart attack (1.0% age-adjusted) (2, 3).

Diabetes was low in men and average in women by modern Western standards, but increased significantly upon migration to New Zealand and reduction of coconut intake (4). Non-migrant Tokelauans gained body fat at a slower rate than migrants, despite higher physical activity in the latter (5). Together, this evidence seriously challenges the idea that coconut is unhealthy.

The Kitavans also eat an amount of coconut fat that would make Dr. Ancel Keys blush. Dr. Staffan Lindeberg found that they got 21% of their 2,200 calories per day from fat, nearly all of which came from coconut. They were getting 17% of their calories from saturated fat; 55% more than the average American. Dr. Lindeberg's detailed series of studies found no trace of coronary heart disease or stroke, nor any obesity, diabetes or senile dementia even in the very old (6, 7).

Of course, the Tokelauans, Kitavans and other traditional cultures were not eating coconut in the form of refined, hydrogenated coconut oil cake icing. That distinction will be important when I discuss what the biomedical literature has to say in the next post.


* Most also had pandanus palms, which are also tolerant of poor soils and whose fruit provided a small amount of starch and sugar.

Can a Statin Neutralize the Cardiovascular Risk of Unhealthy Dietary Choices?

The title of this post is the exact title of a recent editorial in the American Journal of Cardiology (1). Investigators calculated the "risk for cardiovascular disease associated with the total fat and trans fat content of fast foods", and compared it to the "risk decrease provided by daily statin consumption". Here's what they found:

The risk reduction associated with the daily consumption of most statins, with the exception of pravastatin, is more powerful than the risk increase caused by the daily extra fat intake associated with a 7-oz hamburger (Quarter Pounder®) with cheese and a small milkshake. In conclusion, statin therapy can neutralize the cardiovascular risk caused by harmful diet choices.

Routine accessibility of statins in establishments providing unhealthy food might be a rational modern means to offset the cardiovascular risk. Fast food outlets already offer free condiments to supplement meals. A free statin-containing accompaniment would offer cardiovascular benefits, opposite to the effects of equally available salt, sugar, and high-fat condiments. Although no substitute for systematic lifestyle improvements, including healthy diet, regular exercise, weight loss, and smoking cessation, complimentary statin packets would add, at little cost, 1 positive choice to a panoply of negative ones.

Wow. Later in the editorial, they recommend "a new and protective packet, “MacStatin,” which could be sprinkled onto a Quarter Pounder or into a milkshake." I'm not making this up!

I can't be sure, but I think there's a pretty good chance the authors were being facetious in this editorial, in which case I think a) it's hilarious, b) most people aren't going to get the joke. If they are joking, the editorial is designed to shine a light on the sad state of mainstream preventive healthcare. Rather than trying to educate people and change the deadly industrial food system, which is at the root of a constellation of health problems, many people think it's acceptable to partially correct one health risk by tinkering with the human metabolism using drugs. To be fair, most people aren't willing to change their diet and lifestyle habits (and perhaps for some it's even too late), so frustrated physicians prescribe drugs to mitigate the risk. I accept that. But if our society is really committed to its own health and well-being, we'll remove the artificial incentives that favor industrial food, and educate children from a young age on how to eat well.

I think one of the main challenges we face is that our current system is immensely lucrative for powerful financial interests. Industrial agriculture lines the pockets of a few large farmers and executives (while smaller farmers go broke and get bought out), industrial food processing concentrates profit among a handful of mega-manufacturers, and then people who are made ill by the resulting food spend an exorbitant amount of money on increasingly sophisticated (and expensive) healthcare. It's a system that effectively milks US citizens for a huge amount of money, and keeps the economy rolling at the expense of the average person's well-being. All of these groups have powerful lobbies that ensure the continuity of the current system. Litigation isn't the main reason our healthcare is so expensive in the US; high levels of chronic disease, expensive new technology, a "kitchen sink" treatment approach, and inefficient private companies are the real reasons.

If the editorial is serious, there are so many things wrong with it I don't even know where to begin. Here are a few problems:

1. They assume the risk of heart attack conveyed by eating fast food is due to its total and trans fat content, which is simplistic. To support that supposition, they cite one study: the Health Professionals Follow-up Study (2). This is one of the best diet-health observational studies conducted to date. The authors of the editorial appear not to have read the study carefully, because it found no association between total or saturated fat intake and heart attack risk, when adjusted for confounding variables. The number they quoted (relative risk = 1.23) was before adjustment for fiber intake (relative risk = 1.02 after adjustment), and in any case, it was not statistically significant even before adjustment. How did that get past peer review? Answer: reviewers aren't critical of hypotheses they like.
   
2. Statins mostly work in middle-aged men, and reduce the risk of heart attack by about one quarter. The authors excluded several recent unsupportive trials from their analysis. Dr. Michel de Lorgeril reviewed these trials recently (3). For these reasons, adding a statin to fast food would probably have a negligible effect on the heart attack risk of the general population.
   
3. "Statins rarely cause negative side effects." BS. Of the half dozen people I know who have gone on statins, all of them have had some kind of negative side effect, two of them unpleasant enough that they discontinued treatment against their doctor's wishes. Several of them who remained on statins are unlikely to benefit because of their demographic, yet they remain on statins on their doctors' advice.
   
4. Industrial food is probably the main contributor to heart attack risk. Cultures that don't eat industrial food are almost totally free of heart attacks, as demonstrated by a variety of high-quality studies (4, 5, 6, 7, 8, 9). No drug can replicate that, not even close.
   

I have an alternative proposal. Rather than giving people statins along with their Big Mac, why don't we change the incentive structure that artificially favors the Big Mac, french fries and soft drink? If it weren't for corn, soybean and wheat subsidies, fast food wouldn't be so cheap. Neither would any other processed food. Fresh, whole food would be price competitive with industrial food, particularly if we applied the grain subsidies to more wholesome foods. Grass-fed beef and dairy would cost the same as grain-fed. I'm no economist, so I don't know how realistic this really is. However, my central point still stands: we can change the incentive structure so that it no longer artificially favors industrial food. That will require that the American public get fed up and finally butt heads with special interest groups.

Saturated Fat Consumption Still isn't Associated with Cardiovascular Disease

The American Journal of Clinical Nutrition just published the results of a major Japanese study on saturated fat intake and cardiovascular disease (1). Investigators measured dietary habits, then followed 58,453 men and women for 14.1 years. They found that people who ate the most saturated fat had the same heart attack risk as those who ate the least*. Furthermore, people who ate the most saturated fat had a lower risk of stroke than those who ate the least. It's notable that stroke is a larger public health threat in Japan than heart attacks.

This is broadly consistent with the rest of the observational studies examining saturated fat intake and cardiovascular disease risk. A recent review paper by Dr. Ronald Krauss's group summed up what is obvious to any unbiased person who is familiar with the literature, that saturated fat consumption doesn't associate with heart attack risk (2). In a series of editorials, some of his colleagues attempted to discredit and intimidate him after its publication (3, 4). No meta-analysis is perfect, but their criticisms were largely unfounded (5, 6).


*Actually, people who ate the most saturated fat had a lower risk but it wasn't statistically significant.

Interview with Jimmy Moore

About two months ago, I did an interview with Jimmy Moore of the Livin' la Vida Low Carb internet empire. I hardly remember what we talked about, but I think it went well. I enjoyed Jimmy's pleasant and open-minded attitude. Head over to Jimmy's website and listen to the interview here.

I do recall making at least one mistake. When discussing heart attacks,I said "atrial fibrillation" when I meant "ventricular fibrillation".

Nitrate: a Protective Factor in Leafy Greens

Cancer Link and Food Sources

Nitrate (NO3) is a molecule that has received a lot of bad press over the years. It was initially thought to promote digestive cancers, in part due to its ability to form carcinogens in the digestive tract. As it's used as a preservative in processed meats, and there is a link between processed meats and gastric cancer (1), nitrate was viewed with suspicion and a number of countries imposed strict limits on its use as a food additive.

But what if I told you that by far the greatest source of nitrate in the modern diet isn't processed meat-- but vegetables, particularly leafy greens (2)? And that the evidence specifically linking nitrate consumption to gastric cancer has largely failed to materialize? For example, one study found no difference in the incidence of gastric cancer between nitrate fertilizer plant workers and the general population (3). Most other studies in animals and humans have not supported the hypothesis that nitrate itself is carcinogenic (4, 5, 6). This, combined with recent findings on nitrate biology, has the experts singing a different tune in the last few years.

A New Example of Human Symbiosis

In 2003, Dr. K. Cosby and colleagues showed that nitrite (NO2; not the same as nitrate) dilates blood vessels in humans when infused into the blood (7). Investigators subsequently uncovered an amazing new example of human-bacteria symbiosis: dietary nitrate (NO3) is absorbed from the gut into the bloodstream and picked up by the salivary glands. It's then secreted into saliva, where oral bacteria use it as an energy source, converting it to nitrite (NO2). After swallowing, the nitrite is reabsorbed into the bloodstream (8). Humans and oral bacteria may have co-evolved to take advantage of this process. Antibacterial mouthwash prevents it.

Nitrate Protects the Cardiovascular System

In 2008, Dr. Andrew J. Webb and colleagues showed that nitrate in the form of 1/2 liter of beet juice (equivalent in volume to about 1.5 soda cans) substantially lowers blood pressure in healthy volunteers for over 24 hours. It also preserved blood vessel performance after brief oxygen deprivation, and reduced the tendency of the blood to clot (9). These are all changes that one would expect to protect against cardiovascular disease. Another group showed that in monkeys, the ability of nitrite to lower blood pressure did not diminish after two weeks, showing that the animals did not develop a tolerance to it on this timescale (10).

Subsequent studies showed that dietary nitrite reduces blood vessel dysfunction and inflammation (CRP) in cholesterol-fed mice (11). Low doses of nitrite also dramatically reduce tissue death in the hearts of mice exposed to conditions mimicking a heart attack, as well as protecting other tissues against oxygen deprivation damage (12). The doses used in this study were the equivalent of a human eating a large serving (100 g; roughly 1/4 lb) of lettuce or spinach.

Mechanism

Nitrite is thought to protect the cardiovascular system by serving as a precursor for nitric oxide (NO), one of the most potent anti-inflammatory and blood vessel-dilating compounds in the body (13). A decrease in blood vessel nitric oxide is probably one of the mechanisms of diet-induced atherosclerosis and increased clotting tendency, and it is likely an early consequence of eating a poor diet (14).

The Long View

Leafy greens were one of the "protective foods" emphasized by the nutrition giant Sir Edward Mellanby (15), along with eggs and high-quality full-fat dairy. There are many reasons to believe greens are an excellent contribution to the human diet, and what researchers have recently learned about nitrate biology certainly reinforces that notion. Leafy greens may be particularly useful for the prevention and reversal of cardiovascular disease, but are likely to have positive effects on other organ systems both in health and disease. It's ironic that a molecule suspected to be the harmful factor in processed meats is turning out to be one of the major protective factors in vegetables.

Saturated Fat and Health: a Brief Literature Review, Part II

I'm aware of twelve major controlled trials designed to evaluate the relationship between saturated fat and risk of death, without changing other variables at the same time (e.g., increased vegetable intake, omega-3 fats, exercise, etc.). Here is a summary of the results:

• Two trials found that replacing saturated animal fat with polyunsaturated vegetable fat decreased total mortality.
• Two trials found that replacing saturated animal fat with polyunsaturated vegetable fat increased total mortality.
• Eight trials found that reducing saturated fat had no effect on total mortality.

Of the two trials that found a benefit of saturated fat reduction, neither was properly controlled. The first was conducted in Sweden and published in 1965. The intervention group reduced saturated animal fat and increased polyunsaturated vegetable fat. The control group was significantly older than the intervention group, confounding the results. In addition, physicians regularly monitored the intervention group while the control group went off their radar, thus the intervention group was getting better care. This is the definition of an improperly controlled trial.

The second study to "support" the idea that saturated fat increases total mortality was the Finnish mental hospitals trial. In this trial, two mental hospitals in different towns fed their patients different diets and monitored their health. One diet was low in animal fat and high in polyunsaturated vegetable fat, while the other was higher in saturated fat. Patients eating the polyunsaturated diet had a greatly reduced death rate, mostly due to a reduction in heart attacks. The study design was pitiful. They included all patients in their analysis, even those who stayed at the hospital for only one month or who checked in and out repeatedly. Furthermore, they used a "crossover" design where the hospitals switched diets halfway through the study. This was designed to control for location, but it means we don't know whether the increase in deaths after switching to the control diet was due to the saturated fat or the vegetable oil diet that preceded it for 6 years! The only reason I included this poor study in my list is that it's commonly cited as evidence against saturated fat.

The first study to show an increase in deaths from replacing saturated animal fat with polyunsaturated vegetable fat was the tragically named Anti-Coronary Club study. After four years, despite lowering their cholesterol substantially, the intervention group saw more than twice the number of deaths as the control group. Amazingly, rather than emphasizing the increased mortality, the study authors instead focused on the cholesterol reduction. This study was not properly controlled, but if anything, that should have biased it in favor of the intervention group.

The second study to show an increase in deaths from replacing saturated animal fats with polyunsaturated vegetable fats was the Sydney Diet-Heart study. This was one of the larger, longer, better-conducted trials. After five years, the intervention group saw about 50% more deaths than the control group.

I should also mention that one of the studies in the "no effect" category actually saw more than a four-fold increase in deaths after replacing saturated fat with corn oil, but somehow the result didn't achieve statistical significance (the paper states that p= 0.05-0.1, whatever that means). It may have simply been due to the small size of the study.

Overall, the data from controlled trials are clear: replacing animal fat with vegetable oil does not reduce your risk of dying! The same is true of reducing total fat. The main counterpoint to this conclusion is that the trials may have been too short to pick up the effect of saturated fat. However, two years was enough time to detect the effect of fish oil on death in the DART trial, and the trials I'm writing about lasted up to 8 years (not including the Finnish mental hospital trial or the Swedish one). There's also the fact that the greatest consumers of saturated fat in the world eat it for their entire lives and don't seem to suffer from it. Proponents of the theory that saturated fat is unhealthy have the burden of proof on their shoulders, and the data have failed to deliver.

Most trials of this nature are designed with cardiovascular outcomes in mind. Out of the twelve studies mentioned above, nine measured coronary heart disease mortality.

• Two found it was reduced when saturated fat was replaced with polyunsaturated vegetable fat.
• One found that is was increased when saturated fat was replaced with polyunsaturated vegetable fat.
• Six found no effect.

Of the two that found an effect, the first was the Finnish mental hospital study. See above. The second was the L.A. Veterans Administration study, which was actually a good, eight-year study. However, it's worth noting three things about it: first, there were significantly more heavy smokers in the control group; second, overall mortality was the same in both groups, partly because of an increased cancer risk in the diet group; and third, it's the only well-conducted study of its kind to find such a result.

The study to find an increase in cardiovascular deaths was again the unfortunately-named Anti-Coronary Club trial. The Sydney Diet-Heart trial did not report cardiovascular mortality, which was almost certainly increased. Also, the study mentioned above that saw a "non-significant" four-fold increase in deaths on corn oil also saw a similar increase in cardiovascular deaths. I included it in the "no effect" category.

So not only do the best data not support the idea that saturated fat increases the overall risk of death, they don't even support the idea that it causes heart disease! In fact, the body seems to prefer saturated fat to unsaturated fats in the bloodstream. Guess what your liver does with carbohydrate when you eat a low-fat diet? It turns it into saturated fat (palmitic acid) and then pumps it into your bloodstream. We have the enzymes necessary to desaturate palmitic acid, so why does the liver choose to secrete it into the blood in its saturated form? Kitavan lipoproteins contain a lot of palmitic acid, which is not found in their diet. Are their livers trying to kill them? Apparently they aren't succeeding.

Eat the fat on your steaks folks. Just like your great-grandparents did, and everyone who came before.

Saturated Fat and Health: a Brief Literature Review, Part I

Even years ago, when I watched my saturated fat intake, I always had a certain level of cognitive dissonance about it. I knew that healthy non-industrial cultures often consumed large amounts of saturated fat. For example, the Masai of East Africa, who traditionally subsist on extremely fatty milk, blood and meat, do not appear to experience heart attacks. Their electrocardiogram readings are excellent and they have the lowest level of arterial plaque during the time of their lives when they are restricted (for cultural reasons) to their three traditional foods. They get an estimated 33% of their calories from saturated animal fat.

Then there are the Pacific islanders, who often eat large amounts of highly saturated coconut. Kitavans get 17% of their calories from saturated fat (Americans get about 10% on average), yet show no trace of heart disease, stroke or overweight. The inhabitants of the island of Tokelau, who I learned about recently, eat more saturated fat than any other culture I'm aware of. They get a whopping 55% of their calories from saturated fat! Are they keeling over from heart attacks or any of the other diseases that kill people in modern societies? Apparently not. So from the very beginning, the theory faces the problem that the cultures consuming the most saturated fat on Earth have an undetectable frequency of heart attacks and other modern non-communicable diseases.

Humans have eaten saturated animal fat since our species first evolved, and historical hunter-gatherers subsisted mostly on animal foods. Our closest recent relatives, neanderthals, were practically carnivores. Thus, the burden of proof is on proponents of the theory that saturated fat is unhealthy.

There have been countless studies on the relationship between saturated fat and health. The first studies were epidemiological. Epidemiological studies involve collecting data from one or more populations and seeing if any specific factors associate with the disease in question. For example, the Framingham Heart study collected data on diet, lifestyle and mortality from various diseases and attempted to connect diseases to lifestyle factors. This type of study is useful for creating hypotheses, but it can only determine associations. For example, it can establish that smokers tend to die more often from heart disease than non-smokers, but it can't determine that smoking is actually the cause of heart disease. This is because multiple factors often travel together. For example, maybe smokers also tend to take care of themselves less in other ways, sleeping less, eating more sugar, etc.

Epidemiological data are often incorrectly used to demonstrate causality. This is a big problem, and it irritates me to no end. There's only one way to show conclusively that a diet or lifestyle factor actually causes something else: a controlled trial. In a controlled trial, researchers break participants into two groups: an intervention group and a control group. If they want to know the effect of saturated fat on health, they will advise the participants in each group to eat different amounts of saturated fat, and keep everything else the same. At the end of the trial, they can determine the effect of saturated fat on health because it was the only factor that differed between groups. In practice, reducing saturated fat also involves either increasing unsaturated fat or decreasing total fat intake, so it's not perfect.

I'm not going to review the epidemiological data because they are contradictory and they are "lesser evidence" compared to the controlled trials that have been conducted. However, I will note that Dr. Ancel Keys' major epidemiological study linking saturated fat consumption to heart disease, the "Seven Countries" study, has been thoroughly discredited due to the omission of contradictory data (read: the other 15 countries where data were available). This was the study that sparked the anti-saturated fat movement. Older epidemiological studies and those conducted internationally tend to find nonexistent or weak links between saturated fat and health problems, while more recent American studies, such as the Nurses' Health study, have sometimes found strong associations. I'll address this phenomenon in another post.

In the next post, I'll get into the meaty data: the controlled trails evaluating the effect of saturated fat on health.

Thanks to Rockies for the CC photo.

DART: Many Lessons Learned

The Diet and Reinfarction Trial (DART), published in 1989, is one of the most interesting clinical trials I've had the pleasure to read about recently. It included 2,033 British men who had already suffered from an acute myocardial infarction (MI; heart attack), and tested three different strategies to prevent further MIs. Subjects were divided into six groups:

• One group was instructed to reduce total fat to 30% of calories (from about 35%) and replace saturated fat (SFA) with polyunsaturated fat (PUFA).
• The second group was told to double grain fiber intake.
• The third group was instructed to eat more fatty fish or take fish oil if they didn't like fish.
• The remaining three were control groups that were not advised to change diet; one for each of the first three.
  

Researchers followed the six groups for two years, recording deaths and MIs. The fat group reduced their total fat intake from 35.0 to 32.3% of calories, while doubling the ratio of PUFA to SFA (to 0.78). After two years, there was no change in all-cause or cardiac mortality. This is totally consistent with the numerous other controlled trials that have been done on the subject. Here's the mortality curve:

Here's what the authors have to say about it:

Five randomised trials have been published in which a diet low in fat or with a high P/S [polyunsaturated/saturated fat] ratio was given to subjects who had recovered from MI. All these trials contained less than 500 subjects and none showed any reduction in deaths; indeed, one showed an increase in total mortality in the subjects who took the diet.

So... why do we keep banging our heads against the wall if clinical trials have already shown repeatedly that total fat and saturated fat consumption are irrelevant to heart disease and overall risk of dying? Are we going to keep doing these trials until we get a statistical fluke that confirms our favorite theory? This DART paper was published in 1989, and we have not stopped banging our heads against the wall since. The fact is, there has never been a properly controlled clinical trial that has shown an all-cause mortality benefit for reducing total or saturated fat in the diet (without changing other variables at the same time). More than a dozen have been conducted to date.

On to fish. The fish group tripled their omega-3 intake, going from 0.6 grams per week of EPA to 2.4 g (EPA was their proxy for fish intake). This group saw a significant reduction in MI and all-cause deaths, 9.3% vs 12.8% total deaths over two years (a 27% relative risk reduction). Here's the survival chart:

Balancing omega-6 intake with omega-3 has consistently improved cardiac risk in clinical trials. I've discussed that here.

The thing that makes the DART trial really unique is it's the only controlled trial I'm aware of that examined the effect of grain fiber on mortality (without simultaneously changing other factors). The fiber group doubled their grain fiber intake, going from 9 to 17 grams by eating more whole grains. This group saw a non-significant trend toward increased mortality and MI compared to its control group. Deaths went up from 9.9% to 12.1%, a relative risk increase of 18%. I suspect this result was right on the cusp of statistical significance, judging by the numbers and the look of the survival curve:

You can see that the effect is consistent and increases over time. At this rate, it probably would have been statistically significant at 2.5 years. This result is consistent with short term trials I've found showing that wheat bran causes insulin resistance. In one, feeding five healthy subjects wheat bran for 7 weeks in addition to a controlled diet initially reduced blood glucose levels but resulted in insulin resistance, insulin hypersecretion and reactive hypoglycemia by the end of the seven weeks. Other trials show a non-significant trend toward insulin resistance on a whole-grain rich diet. The longer the trial, the stronger the effect.

I think the problem with whole grains is that the bran and germ contain a disproportionate amount of toxins, among which are the lectins. I've speculated before that grain lectins could contribute to leptin and insulin resistance. The bran and germ also contain a disproportionate amount of nutrients. To have your cake and eat it too, soak, sprout or ferment grains. This reduces the toxin load but preserves or enhances nutritional value. Wheat may be a problem whether it's treated this way or not.

Subjects in the studies above were eating grain fiber that was not treated properly, and so they were increasing their intake of some pretty nasty toxins while decreasing their nutrient absorption. Healthy non-industrial cultures would never have made this mistake. Grains must be treated with respect, and whole grains in particular.

Kitava: Wrapping it Up

There's a lot to be learned from the Kitava study. Kitavans eat a diet of root vegetables, coconut, fruit, vegetables and fish and have undetectable levels of cardiovascular disease (CVD), stroke and overweight. Despite smoking like chimneys. 69% of their calories come from carbohydrate, 21% from fat and 10% from protein. This is essentially a carbohydrate-heavy version of what our paleolithic ancestors ate. They also get lots of sunshine and have a moderately high activity level.

The first thing we can say is that a high intake of carbohydrate is not enough, by itself, to cause overweight or the diseases of civilization. It's also not enough to cause insulin resistance. I sent an e-mail to Dr. Lindeberg asking if his group had measured Kitavans' glucose tolerance. He told me they had not. However, I can only guess they had good glucose control since they suffered from none of the complications of unmanaged diabetes.

The Kitavan diet is low in fat, but most of the fat they eat is saturated because it comes from coconuts. Compared to Americans and Swedes, they have a high intake of saturated fat. So much for the theory that saturated fat causes CVD... They also have a relatively high intake of fish fat, at 4g per day. This gives them a high ratio of omega-3 to omega-6 fatty acids, with plenty of DHA and EPA.

Their blood lipid profile is not what a mainstream cardiologist would expect. In fact, it's "worse" than the Swedish profile in many ways, despite the fact that Swedes are highly prone to CVD. This suggests that blood lipids are not causing CVD, but are simply markers of diet and lifestyle factors. That's very easy for me to swallow because it never made sense to me that our livers would try to kill us by secreting triglycerides and witholding HDL. The blood lipid profile that associates best with CVD and metabolic syndrome in the West (but has no relation to them on Kitava) is one that's consistent with a high carbohydrate intake. Where does carbohydrate come from in the West? Grains and sugar maybe?

Kitavans also have very low serum leptin. This may be a keystone to their leanness and health. It suggests that their diet is not interfering with the body's metabolic feedback loops that maintain leanness.

The Kitavan diet is one path to vibrant health. Like many other non-industrial groups, Kitavans eat whole, natural foods that are broadly consistent with what our hunter-gatherer ancestors would have eaten. It amazes me that as humans, we can live well on diets that range from complete carnivory to plant-rich omnivory. We are possibly the most adaptable species on the planet.

The ideal diet for humans includes a lot of possibilities. I believe the focus on macronutrients is misguided. There are examples of cultures that were/are healthy eating high-fat diets, high-carbohydrate diets and everything in between. What they do not eat is processed grains, particularly wheat, refined sugar, industrially processed vegetable oils and other modern foods. I believe these are unhealthy, and this is visible in the trail of destruction they have left around the globe. Its traces can be found in the Pacific islands, where close genetic relatives of the Kitavans have become morbidly obese and unhealthy on a processed-food diet.

One last caveat. I do still believe in the efficacy of low-carbohydrate diets for weight loss and health. The Western diet and lifestyle can damage the metabolism severely, particularly glucose metabolism. It seems to be somewhat reversible, but it depends on the extent of the damage and the individual. People with a history of overweight or poor glucose control should be careful with carbohydrate. It's possible that some people will not be able to handle normal amounts of carbohydrate in any form. Be aware of what your body is telling you.

Cardiovascular Risk Factors on Kitava, Part III: Insulin

The Kitava study continues to get more and more interesting in later publications. Dr. Lindeberg and his colleagues continued exploring disease markers in the Kitavans, perhaps because their blood lipid findings were not consistent with what one would expect to find in a modern Western population with a low prevalence of CVD.

In their next study, the researchers examined Kitavans' insulin levels compared to Swedish controls. This paper is short but very sweet. Young Kitavan men and women have a fasting serum insulin level considerably lower than their Swedish counterparts (KM 3.9 IU/mL; SM 5.7; KW 3.5; SW 6.2). Kitavan insulin is relatively stable with age, whereas Swedish insulin increases. In the 60-74 year old group, Kitavans have approximately half the fasting serum insulin of Swedes. One thing to keep in mind is that these are average numbers. There is some overlap between the Kitavan and Swedish numbers, with a few Kitavans above the Swedish mean.

In figure 2, they address the possibility that exercise is the reason for Kitavans' low insulin levels. Kitavans have an activity level comparable to a moderately active Swedish person. They divided the Swedes into three categories: low, medium, and high amounts of physical activity at work. The people in the "low" category had the highest insulin, followed by the "high" group and then the "medium" group. The differences were small, however, and Kitavans had far lower serum insulin, on average, than any of the three Swedish groups. These data show that exercise can not explain Kitavans' low insulin levels.

The researchers also found that they could accurately predict average Swedish and Kitavan insulin levels using an equation that factored in age, BMI and waist circumference. This shows that there is a strong correlation between body composition and insulin levels, which applies across cultures.

Now it's time to take a step back and do some interpreting. First of all, this paper is consistent with the idea (but does not prove) that elevated insulin is a central element of overweight, vascular disease and possibly the other diseases of civilization. While we saw previously that mainstream blood lipid markers do not correlate well with CVD or stroke on Kitava, insulin has withstood the cross-cultural test.

In my opinion, the most important finding in this paper is that a high-carbohydrate diet does not necessarily lead to elevated fasting insulin. This is why I think the statement "carbohydrate drives insulin drives fat" is an oversimplification. What drives fat accumulation is chronically high insulin (hyperinsulinemia), which the Kitavans do not have. With a properly-functioning pancreas and insulin-sensitive tissues (which many people in industrial societies do not have), a healthy person can eat a high-carbohydrate meal and keep blood glucose under control. Insulin definitely spikes, but it's temporary. The rest of the day, insulin is at basal levels. The Kitavans show that insulin spikes per se do not cause hyperinsulinemia.

So this leads to the Big Question: what causes hyperinsulinemia?? The best I can give you is informed speculation. Who has hyperinsulinemia? Industrial populations, especially the U.S. and native populations that have adopted Western foods. Who doesn't? Non-industrial populations that have not been affected by Western food habits, including the traditional Inuit, the Kuna, the traditional Masai and the Kitavans.

We can safely rule out that total fat, saturated fat and carbohydrate cause hyperinsulinemia, based on data from the Inuit, the Masai and the Kitavans, respectively. We can also safely rule out that there's some specific food that protects these populations, since they eat completely different things. Exercise is also not a compelling explanation, based on the data above and others. What does that leave us with? Western food habits. In my opinion, the trail of metabolic destruction that has followed Westerners throughout the world is probably due in large part to wheat and refined sugar.

I'm not the first person to come up with this idea, far from it. The idea that specific types of carbohydrate foods, rather than carbohydrate in general, are responsible for the diseases of civilization, has been around for at least a century. It was an inescapable conclusion in the time of Weston Price, when anthropologists and field physicians could observe the transitions of native people to Western diets all over the world. This information has gradually faded from our collective consciousness as native cultures have become increasingly rare. The Kitava study is a helpful modern-day reminder.