Wednesday, January 12, 2011

Widely Publicized Studies Show Purified Diets Hurt Rodents But Blame It On "Fat" -- Another Response to Bix Weber

by Chris Masterjohn

A reader named "blob" asked me to respond to a recent post by the Fanatic Cook Bix Weber, "Two Studies That Link Dietary Fat to Cancer."

Both of these studies were conducted by the same group led by Philippe G. Frank, Ph.D., Assistant Professor in the Department of Stem Cell Biology and Regenerative Medicine at Thomas Jefferson University in Philadelphia.  This group had a rather clever way to blame the ravages of refined, purified diets on "fat."

A recent article  that several others had forwarded to me explained Dr. Frank's reasoning for turning to animal models:
Dietary fat and cholesterol have been shown to be important risk factors in the development and progression of a number of tumor types, but diet-based studies in humans have reached contradictory conclusions. This has led Dr. Frank to turn to animal models of human cancer to examine links between cholesterol, diet, and cancer.
This statement would have made a lot of sense if a few words were switched around.  For example, if the journalist had written that Dr. Frank turned to experimental research because the observational research was conflicting, this would have sounded a bit like the scientific method, which states that we test our hypotheses, which we have generated in an attempt to explain our observations.

As stated, however, it sounds rather silly.  If human studies conflict, what on earth can we learn from mice, as if it were easier to generalize from mice to humans than from some humans to others?

Indeed, this little bit of silliness emphasizes the point that these authors used mice that were genetically engineered to develop spontaneous prostate cancers in one study and mice genetically engineered to develop spontaneous breast cancers in the other study, but never did anything specific to make these mice respond to dietary factors like humans do.  As such, studies like these might be interesting for the light they shed on certain mechanisms of the development of the disease, but not for extrapolating dietary effects from rodents to humans.

Nevertheless, let's give this research group the benefit of the doubt on this point and assume that the journalist had very little training or even casual interest in science.

Still, these authors clearly claimed in their own words that their "data suggest that dietary fat and
cholesterol play an important role in the development of prostate cancer."

Really?  The authors did, in fact, find that a so-called "Western diet" that was rich in fat and cholesterol increased the number and weight of tumors in both models.

But can we blame this on "fat" or "cholesterol"?  Let's take a look at their diets.

Here are the ingredients in the high-fat, high-cholesterol "Western" diet:
Sucrose, milk fat, casein, maltodextrin, powdered cellulose, dextrin, RP Mineral Mix #10 (adds 1.29% fiber), RP Vitamin Mix (adds 1.94% sucrose), DL-methionine, choline chloride, cholesterol, ethoxyquin (a preservative).
Sorry to use the same joke twice, but can you spot the food?

Picture from here.

Of course not, because there is none.  There's just a series of purified ingredients.

According to the manufacturer's web site, that diet corresponds to Basal Diet 5755, which is made of similarly purified ingredients but is lower in sucrose and contains more dextrin instead of milk fat or cholesterol.

Ah, well if we wanted to control our variables that would be a perfect diet to use!

But such a diet, marketed for the very purpose of being a control for the Western diet they were using, did not satisfy Dr. Frank's group.  Instead they used a "chow diet."

Let's take a look at the ingredients:
Ground corn, dehulled soybean meal, wheat middlings, fish meal, ground wheat, wheat germ, brewers dried yeast, ground oats, dehydrated alfalfa meal, calcium carbonate, porcine animal fat preserved with BHA, ground soybean hulls, soybean oil, salt, dried beet pulp, [vitamin and mineral supplements].
Well whaddyaknow, it has food!

As I pointed out in my previous post, "The Did the Same Thing to the Lab Rats That They Did to Us," rats started developing all kinds of problems like fatty liver and excessive bleeding when the American Institute of Nutrition first started encouraging the use of chemically defined, purified diets.  They resolved some of these problems by decreasing the sucrose content and increasing the content of certain vitamins, but some of the problems never resolved.  Consider this reason the AIN gave in 1993 for adding certain "ultratrace elements" that were not known to be essential:

Many of the ultratrace elements are found in plentiful quantities in the natural ingredients that make up cereal-based diets, but their concentrations in purified diets are often very low, and in chemically defined diets, they may be completely absent.  Purified diets without added ultratrace elements suport growth and reproduction, but investigators have noted that animals exposed to stress, toxins, carcinogens or diet imbalances display more negative effects when fed purified diets than when fed cereal-based diets (Bounous 1987, Boyd 1972 and 1983, Evers 1982, Gans 1982, Hafez and Kratzer 1976, Longnecker 1981).  This suggests that detrimental effects may occur with the omission of some substances found in the more natural, cereal-based diets; some of these substances may be the ultratrace elements.

I'm afraid all these studies might be showing is what has already been known for decades
— that chemically defined, purified diets are much worse for rodents than natural food-based diets.

And perhaps they hint at what many people including myself today believe — that humans should also be eating foodThe fat included.

Read more about the author, Chris Masterjohn, PhD, here.


  1. Thanks for responding, Chris! I see this one was not too difficult. I'm dumbstruck to see what passes for scientific research these days.

    As far as I know Bix Weber is working with diabetic patients and sees often that they respond well to low-fat diets. This is probably where his enthusiasm for low-fat comes from. Since lots of other authors like McDougall, Esselstyn etc. write about a similar phenomenon, I do believe this works for some people. However I think this might have to do more with their bodies not properly metabolizing fat (or some other metabolic issue) than with fat being inherently bad for humans. What is your opinion on that?

  2. Hey blob,

    I think there are a few things. First, these practitioners are not attracting a random sample of the public. When you preach this extreme low-fat approach for everyone, you're going to tend to attract people that perceive that diet as possibly right for them. The second thing is that, as Stephan Guyenet has pointed out a few times, when people make dramatic dietary restrictions, they often spontaneously reduce their caloric intake. Perhaps that is happening in these cases. They might, as you said, develop a particular problem metabolizing fats perhaps.

    But I think a major overriding theme here is that the fat most Americans are eating is complete junk. Getting rid of the hydrogenated soybean oil does a body good.


  3. Puh!
    I'm so sure that if you are unable to picture the ingredient as a plant or an animal in your head - then the chances are that you should avoid eating it.
    It's not fool-proof, but it certainly help me avoid a lot of "food makeup" and uneccessary ingredients.
    I believe this to be the main reason for the healt benifits of "low carb", paelo and raw diets mor than anything else.

  4. I note the presence of (horrors!) "porcine animal fat" in the second, real food, rat diet. Is this supposed to be the fatty control for the milk fat and cholesterol in the first? Hmmm.

    Chris M: "The second thing is that, as Stephan Guyenet has pointed out a few times, when people make dramatic dietary restrictions, they often spontaneously reduce their caloric intake." ...and as Gary Taubes has pointed out a few times, they often spontaneously reduce their CARB intake, as well.

  5. Might-o'chondri-ALJanuary 13, 2011 at 5:46 PM

    3rd try posting...

    Doth ye, o cholesterolholics, protest too much? The deduction may be imperfect; but, looks like there might be some "there" there.

  6. Scotyln, no that diet was not intended as the control. The company had a matching control diet and the authors did not use it. I suppose some people decrease their carb intake when they try to reduce fat, but that's kind of a stretch. Most people who deliberately eat low-fat at least reduce their fat much more than their carbohydrate. If there are contrary data I'd be interested.

    ...AL I'm not sure who you're responding to or what you're trying to say, but of course there is something there. Namely what has been recognized for decades, that purified lab diets promote cancer in comparison to cereal-based diets. If they wanted to show something else, they should have used the matching control diet that the company made specifically for the Western diet, instead of a cereal-based chow.


  7. Might-o'chondri-ALJanuary 13, 2011 at 8:11 PM

    still posting problem ...

    "Tumorgenesis and Prostate Neoplastic Progression" was the study. Solid tumors have elevated cholesterol in their tissue, as cancer is developing measureable HDL drops and when angiogenesis underway plasma cholesterols rise are all worth examining.

    The study's conclusion may be questioned, yet the role of cholesterol in prostate neoplasty is worth further investigation. Dismissing any pathological implications for cholesterol here is premature.

  8. ...AL, I did not dimiss any pathological implications for cholesterol, nor did I question their conclusion about serum cholesterol. I questioned their conclusion about the diet, and I stated that the model could be used to provide interesting information about disease mechanisms but not about diet. Of course, given that one diet was a purified diet and one was a cereal-based diet, any conclusions about disease mechanism that rely on intergroup comparisons need to be immediately thrown in the trash, but any other data could be useful.

  9. Might-o'chondri-ALJanuary 14, 2011 at 2:01 AM

    Tumorigenesis and cholesterol:

    Hepatocyte Growth Factor (HGF) plays a role in tissue proliferation. It's fibro-blast's Transforming (a.k.a. "Tumor") Growth Factor beta Type II receptors push prostate epithelial cells to malignancy. (HGF in the healthy people's liver cells and blood serum can work differently - cancer plays by it's own rules.)

    HGF inhibits the enzyme cholesterol 7 alpha hydroxylase (a.k.a. CYP7A1). Less cholesterol is cleaved for healthy clearance and patient can't build it into bile (bile is a far reaching player).

    In addition HGF stimulates LDL cholesterol receptors in the tumor cell. Oxy-sterol Binding Protein (ORP1L) are cholesterol sensors that goes awry in tumors and don't put a limit to regulate uptake.

    Then the cholesterol goes from just being a component in prostate cell membranes and infiltrates into the prostate cells lysosome. The lysosome inside the cell is, for it's part,involved in the degree of neo-plasty invasiveness.

    HDL lipoprotein in circulation, which is supposed to go back to the liver full of cholesterol for recycling, is reduced in prostate cancer. It is not doing much because the tumor is snatching up all the cholesterol it can and growing wants more.

    When we eat fat/cholesterol the "sterol" is normally taken by a protein in our intestine's baso-lateral membrane called ATP Binding Cassette A1 and passed to the lipid Apopoliprotein A1 for HDL syntesis.
    Humans absorb +/- 90-95% of ingested fat.

    Normally other gut proteins, Sterol 1 & 2, actually send excess sterols back out from intestine's enterocyte. We can push some into the gut lumen, where the protein "Niemann-Pick C 1 like 1" works with a scavenger to excrete our sterol overload.

    In prostate cancer's cholesterol gluttony the natural homeostasis feedback mechanism is useless. The growing tumor is taking cholesterol into itself and co-opted our system to get it even more. With the low HDL dynamic the lipid Apopoliprotein A1 just adds to the party of unchecked LDL cruising the bloodstream.

    One last thing: that study's fat diets should have included a high fat but zero cholesterol control. This combination in humans drops, within weeks, the activity of our cholesterol transporters. The result is lowered LDL and an even more lowering of HDL.

    Will try to post this unedited for chance it'll go through. Pardon any errors.

  10. Chris,
    I was looking at the calculations Gary Taubes did on his post here - - to arrive at this conclusion: "Put simply, low-fat diets that also cut significant calories will cut carbohydrates significantly as well, and often by more than they cut fat."

    His sums on this point are eye-opening.

  11. Chris, it also strikes me that it would be more accurate to call the Ratty RealFOOD (TM) chow a "cereal and animal based chow" rather than a "cereal based chow," since its ingredients include both fish meal and porcine fat. Dried yeast could also be argued to fall more in the animal than the cereal category.

    Not calling things what they are is part of the problem in trying to work out what the data from all these studies actually means - and part of the argument your OP is making, if I read it correctly.

  12. Congratulations for your article and your blog overall. I will definitely be a regular here. There is a long way until this type of information gets acceptance from the general public.

  13. Very instructive article and blog indeed, congratulations and thanks, me too. This post makes me wonder again about nuts and seeds.Assuming that more than a little PUFA is harmful but antioxidants, polyphenols are typically often good (eg. Ellagic acid protects endothelial cells from oxidized low-density lipoprotein... PMID: 20691200)the real question might be where the joint optimum area of the two curves is located. Is this reasonable? If so, could it be that optimal intake of nuts and seeds would result in a PUFA intake level that is quite a bit higher than what is generally recommended here and under related approaches?

  14. I really enjoyed this post! I've always believed that you can eat just about anything, as long as you eat it in moderation and try to choose the healthier option whenever you can. So yes, I do eat fat. I don't think it will kill me or the rats.

  15. I'm an ignoramus, no degree or anything, barely any *college*, but I like to read about this stuff and in my ignorance I tend to take pieces of random things I read and start to see patterns in them. So here goes, with the cholesterol and cancer thing.

    I read a while back about a study going underway at a university in either Iowa or Idaho, some state starting with I anyway, about cancer cells and sugar. The working hypothesis, as I recall, was that cancer cells are more susceptible to oxidative damage and therefore had to eat scads and scads of sugar just to stave off that damage and live for a little while longer. I never did go back and find mention of the study again to see if they learned anything from it; life sort of got in the way. But since then I've heard from other sources that many (though not all) types of cancer cell shut off their mitochondria or develop with none at all and therefore have to ferment sugar--there, a related piece of the puzzle. Then you've got insulin being a growth factor and possibly contributing to tumor development, so there's that one-two punch of how high-sugar diets can contribute to cancer growth.

    Then, keeping in mind the bit I'd read about cancer using glucose as a sort of antioxidant, the lightbulb went on in my head about those beta carotene studies with smokers. Apparently smokers endanger their health if they overdo it on beta carotene; they're supposedly more likely to get lung cancer. I thought, "Oh, I wonder if the cancer cells are using the beta carotene to protect themselves and live longer to proliferate?"

    Which clicked *another* puzzle piece into place about parabens and breast cancer--supposedly, parabens are found in high concentrations in some breast cancer tumors. Again... parabens are a class of preservatives. Probably have some antioxidant function. *checks Wikipedia* Hm. The article there says parabens are mostly bactericidal and fungicidal. But if you click on the link to para-hydroxybenzoic acid, of which parabens are an ester (chemical formed by condensing an acid with an alcohol), para-hydroxybenzoic acid is... an antioxidant. It's 2am and I'm not gonna try to figure out if it ceases being an antioxidant once it's converted to an ester, and leave that to people much better versed in chemistry to possibly verify or deny after me here.

    If it *is* an antioxidant once it's converted, though? That would be very, very interesting.


  16. ...had to break this up into two comments, it was too long...

    ...So then we come to cholesterol. Cholesterol is already seen in some quarters as a compound that has protective effects in the body. It is surely not a toxin, since every cell in the body makes it and it is not a waste material. At the least I've seen it postulated that cholesterol has a protective effect in arteries where they have weakened to some extent, which may explain the presence of plaques in a person with cardiovascular disease. I don't know, I'm just parroting what I've heard suggested.

    So... anyway... Is it that much of a stretch to wonder whether a cancer tumor might not also find uses for cholesterol in its protective role? Again, many (if not all) cancer cells may be vulnerable to oxidative damage to a greater degree than healthy cells. Does cholesterol protect against oxidation? I seem to recall hearing somewhere that it does. But I can't be sure, and right now I'm not going to go looking for it.

    I just wanted to say something, even though I can't be sure about anything I just shared, because if there *is* something to this, then maybe it goes back to what Chris has been posting about not confusing correlation with causation.

    Again... Cholesterol is made by every cell in the body. And it is not a waste product. Nor is it a toxin. (I don't know of any animal that makes toxins in every cell of its body. Usually, last I knew, animal-produced toxins are stored in specialized organs, not distributed throughout the body. Which is why rattlesnakes are safe to eat.) In fact we're already finding evidence that letting cholesterol go too low in the body has deleterious effects on mental function, if not other aspects of health. So maybe we should stop trying to "prove" that cholesterol is deadly poison, and start taking a much less biased look at its various roles in the body.

    I mean, I'm sort of a dummy, but I've at least figured *that* much out. You know?

  17. I believe the most dangerous chemical in the high fat 'western' feed is 'ethoxyquin'. It's documented to be toxic -particularly to the liver and kidneys

    When they carried out toxicity tests for dogs the dose used was 2.5 mg/kg

    The doses used in high fat mouse feed diets is usually much higher and similar to the following:

    Note this is 0.04g/kg -that's 40mg/kg -16x bigger than the toxicology tests that were shown to affect dog's liver pigment.

    Scarily, ethoxyquin is approved for use as an antioxidant in spices, such as chilli powder and paprika at 150ppm -that's 0.15mg/kg

    Ethoxyquin has been strongly linked a host of problems in dogs and has been limited to 0.075mg/kg in dog feed.


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