it turns out that there’s an epidemiological relationship between fevers and cancer:

“Since the 19th century, it has been repeatedly observed that spontaneous cancer regressions were coincided with acute infections and the cancer patients had a remarkable disease-free history before the onset of cancer [1]–[4]. In the 20th century, an inverse association between infectious diseases, particularly febrile ones, and cancer risk has also been consistently found for malignant melanoma and glioma using modern epidemiological methods [1], [3], [5]–[7].

“With the widespread introduction of antibiotics and antipyretics since the beginning of the last century, however, the critical role played by fever has often been overlooked, resulting in considerable changes to the clinical course and magnitude of the immune response that develops following acute infections [1], [8]. These changes may be part of the reasons for the substantial increase in the age-adjusted incidences or mortalities of malignant diseases during the early part of the last century in western countries [9] and in the late of the last century in China [10]. It has been observed that every 2% reduction in infectious disease mortality was followed by a 2% increase in cancer mortality over a 10-year interval from 1895 to 1963 in Italy [9].” (Su, 2012)

Medicine, like Economics, is full of unintended consequences. It wouldn’t surprise me at all to discover that messing with the immune system messes with the immune system in unexpected ways...

Original post: May 23, 2012.

References

Su, Yi, Lu-Ying Tang, Li-Juan Chen, et al. 2012. “Joint Effects of Febrile Acute Infection and an Interferon-γ Polymorphism on Breast Cancer Risk.” PloS One 7 (5): e37275. https://doi.org/10.1371/journal.pone.0037275.

Yikes.

“Obesity levels have risen dramatically in research animals and others living close to humans, suggesting environmental factors are encouraging everyone to gain weight, according to new findings…” (Arnold, 2010)

The authors of the paper looked at in this news article (Klimentidis, 2010) essentially looked at animals that are wholly under the control of the human food environment:

• Three populations of rhesus macaques (a monkey) in research labs.

• Chimpanzees in captivity.

• Vervet monkeys in captivity.

• Marmoset monkeys in captivity.

• Lab rats and mice.

• Domestic dogs.

• Domestic cats.

• Wild rats, urban and rural.

I'll note that all the animals in this study are eating diets provided by humans, or derived from human diets (feral rats). Even rural rats likely live in areas around humans and eat human crops.

What about wild animals eating traditional diets?

They didn’t look at any of those.

Scientists can be so dense...

Additionally, one of those macaque populations, in Wisconsin, was part of a reconciled diet-longevity study. You’ll note from the graph above that they had different levels of weight gain. Want to guess which group was eating corn oil?

I’ll cover that some other time.

After going paleo/primal myself, I did the same for my dog, after noting most of the available dog foods are all grain, soy, and veggie oils. He didn't overeat, and didn't have an ounce of fat on him.

My current dogs are the same. They eat until they are full, and then walk away from the plate, even if it has more food sitting on it.

They gain no weight.

Original post December 8, 2010.

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References

Arnold, Carrie. 2010. “Animals Are Getting Fatter, Too.” The Scientist, November 25. https://www.the-scientist.com/animals-are-getting-fatter-too-42960.

Klimentidis, Yann C., T. Mark Beasley, Hui-Yi Lin, et al. 2010. “Canaries in the Coal Mine: A Cross-Species Analysis of the Plurality of Obesity Epidemics.” Proceedings of the Royal Society B: Biological Sciences 278 (1712): 1626–32. https://doi.org/10.1098/rspb.2010.1890.

I’m not going to discuss possible causes in this post, just therapies that worked very well for me.

My first choice would be to walk or run uphill, and ensure your heel touches the ground at each step, while wearing zero-drop shoes, or barefoot. This is what I’ve used for Achilles’ tendon issues in my bad leg. (My bad leg is now my good leg, at least for the time being.)

If you can’t for whatever reason do that, an eccentric heel drop is the exact same movement.

But, since it’s come up, folks have asked for some decent videos.

I’d first suggest listening to this podcast by the (insane) Doctor Håkan Alfredson who invented the eccentric heel drop while trying to rupture his Achilles’ tendon so his boss would have to operate on it and relieve him of his Achilles tendonopathy.

Instead, he cured it. Whoops.

Having listened to that, and determining that you most definitely do not want Dr. Alfredson scraping your tendons to sever the nerves, you can try his exercises.

The videos below are the training for a study to evaluate the usefulness of orthotics for treating achilles tendinopathy (Munteanu, 2009).

“Achilles tendinopathy is a common condition that can cause marked pain and disability. Numerous non-surgical treatments have been proposed for the treatment of this condition, but many of these treatments have a poor or non-existent evidence base. The exception to this is eccentric calf muscle exercises, which have become a standard non-surgical intervention for Achilles tendinopathy.”

The videos look useful, and are based on Alfredson’s protocol. I’d skip the marshmallow shoes shown in the video, and do them barefoot. I’d also avoid orthotics... But that’s just me.

(I’d also avoid taking any medical advice from any doctor from Latrobe University, where this study is being conducted, as the quack Dr. Payne is a professor of podiatry there. I’ll not link to Dr. Payne’s site again, but you can find it at the bottom of that link.)

I’ll also note that Dr. Alfredson says that the bent-knee heel drops are crucial. Did I mention that you should listen to his podcast before trying out these exercises?

One more observation: I’m not a doctor, or a physical therapist, just a foot-deformed westerner trying to run the way I was born to. Also, you should never believe anything you read on the internet, it’s all crap.

OK, now that the caveats are out of the way, here are the videos. I’ll note that the videos are also available for download in the study—search for m4v in (Munteanu 2009).

P.S. Lest you think I’m being too tough on Latrobe, and podiatrists, Dr. Munteanu, who is conducting the aforementioned study, has this advice:

“...If you are a runner, ensure that you have your footwear professionally fitted and replace your runners [sneakers] at least every 500km/6 months....”

I wonder if that’s been shown to be effective? Anyway...

Part 1:

Part 2:

Part 3:

Part 4:

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Original post December 20, 2011.

References

Munteanu, Shannon E., Karl B. Landorf, Hylton B. Menz, Jill L. Cook, Tania Pizzari, and Lisa A. Scott. 2009. “Efficacy of Customised Foot Orthoses in the Treatment of Achilles Tendinopathy: Study Protocol for a Randomised Trial.” Journal of Foot and Ankle Research 2 (1): 27. https://doi.org/10.1186/1757-1146-2-27.

Yasui, Youichi, Ichiro Tonogai, Andrew J. Rosenbaum, Yoshiharu Shimozono, Hirotaka Kawano, and John G. Kennedy. 2017. “The Risk of Achilles Tendon Rupture in the Patients with Achilles Tendinopathy: Healthcare Database Analysis in the United States.” BioMed Research International 2017 (1): 7021862. https://doi.org/10.1155/2017/7021862.

Nick asked me to do a YouTube livestream to go over some research he had been doing. He drilled down on a reference in a high-profile cardiology guideline article and discovered that the authors had inverted the research finding in the referenced paper to claim the inverse of what it actually showed.

We discussed this, and then I gave some more context about the matter and one of the authors.

We discussed this post:

Guest info

“Nick Jikomes is a neuroscientist, plant chemistry researcher, data scientist, and podcast host. He received a PhD in Neuroscience from Harvard University and a Bachelor of Science in Genetics from the University of Wisconsin. Nick currently works in the legal cannabis industry in the US.”

https://www.nickjikomes.com/about

Home page, with links to writing and podcasts.

https://www.nickjikomes.com/

Tucker Goodrich

Substack:

Tucker Goodrich: yelling Stop

Building a Healthy Diet & Lifestyle.

Twitter: https://twitter.com/TuckerGoodrich

Youtube: https://www.youtube.com/tuckergoodrich0

Apple podcast:

Spotify podcast:

Podcast: https://sites.libsyn.com/408758

Blog (deprecated, but still a lot there!):

http://yelling-stop.blogspot.com/

If you have any questions about sources for things discussed please ask in the comments.

When Stephan Guyenet recommended I read Gary Taubes’ Good Calories, Bad Calories (Taubes, 2008: All quotes in bold and italic, unless otherwise cited), he warned that it was a little dry. I found it to be a page-turner, and quickly finished it. I was new to the topic of diet and health, and the Taubes hypothesis of that era (that carbohydrates caused obesity and perhaps the related diseases) sounded pretty good after one read Gary’s book.

My experience was a little different from that described in the book, however. While Taubes emphasized the dangers of sugar in that book, I had been on a low-sugar diet quite diligently since 1986 or so, when my dentist had told me that I could stop getting cavities if I stopped eating so much sugar. I despise visits to the dentist, and countless cavities and eight pulled teeth had given me ample opportunities to learn that dislike.

So cutting out sugar seemed like a no-brainer to me. I learned to like coffee without sugar, stopped drinking soft drinks, and diligently started reading labels and avoiding anything with added sugar (you can even find jelly without added sugar, for my formerly beloved peanut butter & jelly sandwiches).

It worked.

Since 1986 or so I have had a single, minor cavity—due to the unfortunate introduction of a mint bowl at the office—and my dental health is excellent. Since my current dentist is also my father-in-law, I get excellent feedback on how things look.

However, I also got fat and sick, in the manner Taubes attributes to sugar.

When I finally started to learn about diet, and fixed all my chronic diseases, I actually wound up increasing my sugar consumption, since I learned that the cavity-healing diet described by Weston Price (Price, 1938) actually had more sugar in it than I was eating!

So I took the book with a grain of salt, so to speak.

There’s a corollary to Knoll’s Law of Media Accuracy (above), which is Michael Crichton’s Gell-Mann Amnesia. This is the effect where having noted that a particular bit of reporting with which you have knowledge is nonsense, you immediately forget that the source is unreliable, and go on to read the rest as if it were faultless. I probably should have kept that in mind when reading GCBC.

What Causes Obesity?

So Gary and I have a disagreement here. I’ve done a few posts about it in the past:

And recently:

I won’t go into that discussion any further here, but it has led to further discussion, from me an others.

The Bigger Picture

In a thread started on X by Gary about how low-carb used to be standard medicine (which is true), he got a response from (@exfatloss on X):

“This worked before so many people were PUFA'd with seed oils”

Gary replied:

And in another fork of the thread replied:

I replied with a quote from (Taubes, 2008).

Gary dismissed it:

“…While this is an example of Key's hypothesis failing an experimental test, and of the selection bias used to establish it as dogma, that's about all this study is good for.”

The “experimental test” was that increasing seed oils would reduce the rate of heart disease. Here’s the next paragraph after the quote above:

“As I implied earlier, we can only know if a recommended intervention is a success in preventive medicine if it causes more good than harm, and that can be established only with randomized, controlled clinical trials. Moreover, it’s not sufficient to establish that the proposed intervention reduces the rate of only one disease—say, heart disease. We also have to establish that it doesn’t increase the incidence of other diseases, and that those prescribed the intervention stay healthier and live longer than those who go without it.”

So what these studies showed is that increasing seed oils caused an increase, not a decrease, in heart disease.

Gary is claiming this study isn’t able to show that seed oil Ω-6 PUFA is harmful, it doesn’t meet his request for “evidence that it actually causes harm”, yet it shows exactly that according to his criteria in GCBC.

Good Calories, Bad Calories

So I went back and took a look at what Gary had said in the book that made his career.

“The only way to establish cause and effect with any reliability is to do ‘controlled’ experiments, or controlled trials, as they’re called in medicine. Such trials attempt to avoid all the chaotic complexities of comparing populations, towns, and ethnic groups. Instead, they try to create two identical situations—two groups of subjects, in this case—and then change only one variable to see what happens.”

Sure enough, (Frantz, 1989) fits the bill:

“The Minnesota Coronary Survey was a 4.5-year, open enrollment, single end-time, double-blind, randomized clinical trial that was conducted in six Minnesota state mental hospitals and one nursing home. It involved 4393 institutionalized men and 4664 institutionalized women.” (Frantz, 1989)

It was a RCT (randomized, controlled trial) in other words, exactly what Gary is looking for.

“The Minnesota Coronary Survey was, by far, the largest diet-heart trial carried out in the United States…”

Those quotes are from the section of (Taubes, 2008, Chapter 2, “The Inadequacy of Lesser Evidence”) in which he discusses the evidence for what’s known as the Diet-Heart Hypothesis, which I discussed in this post:

By Gary’s standards, this test should be the gold standard. It’s an RCT, it’s well-conducted, it’s large, and it’s only testing one intervention. Gary himself implies that this should be a valid bit of evidence.

“Proponents of Keys’s hypothesis who considered the Helsinki Mental Hospital Study reason enough to propose a cholesterol-lowering diet for the entire nation, never cited the Minnesota Coronary Survey as a reason to do otherwise.”

A “cholesterol-lowering diet” is a diet high in seed oils (Nelson, 1995; Taubes, 2008), so according to Gary, the MCS is a valid experiment showing that it is harmful.

But we begin to run into some problems.

What Are We Testing?

The Diet-Heart Hypothesis changed the goalposts as it evolved. Originally it was an idea that fat caused increased cholesterol, and hence we should pursue a low-fat diet. However, experimental evidence soon showed that this was not accurate. The “Keys” Gary mentioned above was of course Ancel Keys.

“Keys eventually accepted that animal fats tend to raise cholesterol and vegetable fats to lower it, only after he managed to replicate Groen’s finding with his schizophrenic patients in Minnesota.”

They still, however, thought that cholesterol in the blood was what was driving heart disease. So the focus shifted from a low-fat diet to a moderate-fat, high-polyunsaturated-fat diet.

In the 1961 paper in which the American Heart Association kicked off the diet revolution (a point on which Gary and I agree), the AHA (including Keys) recommended “a diet moderate in calories and fat”, but only for “coronary-prone persons”.

Gary describes this repeatedly as a low-fat diet.

The two AHA interventions are:

1. Moderate-fat diet

2. Substitute polyunsaturated fat (PUFA) for saturated fat (SFA).

As Gary puts it:

“…the new report argued the opposite—“the best scientific evidence of the time” strongly suggested that Americans would reduce their risk of heart disease by reducing the fat in their diets, and replacing saturated fats with polyunsaturated fats.”

Research Committee Trial

“Only these two trials ever tested the benefits and risks of the kind of low-fat diet that the American Heart Association has recommended we eat since 1961, and that the USDA food pyramid recommends when it says to ‘use fats and oils sparingly.’”

However these diets are not “the kind of low-fat diet” that the AHA recommended.

The second of these trials, which is quite well-known, compared two groups:

“One group was placed on a low-fat diet, while the control group continued with their normal diet.”

However:

“The nature of the fat consumed was not altered, nor were any additional unsaturated fats given.” (A Research Group, 1965)

That’s an average of 20% of energy as fat vs 43%. So the AHA diet recommendation (25% to 35%) is indeed moderate; and the diet tested here is not the diet that the AHA recommended, on either count.

So with a similar intake of type of fat, but a large decrease in quantity of fat, no change was noted, and the authors observe, as Gary quotes:

“A low-fat diet has no place in the treatment of myocardial infarction.”

Who could resist quoting that?

(Why Mischaracterize These Diets?)

A bit of an aside here, because it bothers me that Gary is not accurately representing these diets. I think it’s a bit of a tell…

In 1995, another study looked at the effect of a strictly-controlled low-fat diet on serum cholesterol (they found no effect), and used 22% vs 39% fat as the low- and high- fat diets (Nelson, 1995).

And since we’re talking about Ancel Keys, he looked at the diets of the groups in the Eight Countries he was researching (Yugoslavia split into Serbia and Croatia during the study) and found a range of fat consumption, from almost 50% in the U.S. to 13.2% in Japan. 13.2% is a low-fat diet! But Italy was at 32.8% (Kromhout, 1995). That’s solidly in the moderate fat range, and is certainly not low fat. You’ll note it’s the high end of the AHA prudent diet, discussed next. (Keys retired to Italy, by the way, and lived to a ripe old age.)

I don’t know why Gary calls what are pretty objectively not low-fat diets as being such throughout his book. But it’s a bad sign, in my opinion. It’s a sign of his innate bias.

Mystifyingly, in chapter nine, Gary states:

“Diets that lowered cholesterol by replacing saturated fat with polyunsaturated fats would have accomplished such a balancing act, but there was legitimate concern that polyunsaturated fats were carcinogenic, and so the AHA had simply recommended fat reduction in general.”

The AHA has been recommending increased PUFA consumption from 1956 to the current day. We can let the AHA itself address what its recommendations are:

“A common misconception is that the AHA currently recommends the intake of large quantities of polyunsaturated fats. It is true that the recommendation is to increase the mean intake for the U.S. public from its present 5-6% to an upper limit of 10%.” (Grundy, 1982)

End aside.

Anti-Coronary Club Trial (Prudent Diet)

“In all the other trials, cholesterol levels were lowered by changing the fat content of the diet, rather than the total amount of fat consumed. Polyunsaturated fats replaced saturated fats, without altering the calorie content.”

This is also not correct.

Gary notes:

“In total, the prudent diet was barely 30 percent fat calories, and the proportion of polyunsaturated to saturated fat was four times greater than that of typical American diets.”

It’s described by the authors:

“The diet contains about 30% to 33% of total calories as fat with a ratio of polyunsaturated to saturated fatty acids of 1.25-1.50 compared to the P/S ratio of 0.3-0.4 for the American diet…. (The P/S ratio, without consideration of technical qualifications, is substantially the amount of polyunsaturated fatty acids divided by the amount of saturated fatty acids present in a given diet pattern.)” (Christakis, 1966)

While it is, again, not low-fat, it’s a direct trial of the AHA diet at the time of the AHA recommendation.

Despite what Gary said above, this trial also reduced fat consumption. That was a crucial part of the AHA prescription at this point.

At inception, fat consumption for the intervention group ranged from 36% to 40% (Singman, 1980).

Gary misses another crucial point about this trial. It was the only trial that was running at the time of the writing of (Page, 1961), the AHA’s diet recommendation. It’s the only trial that are listed in what Gary notes were “a half-page of ‘recent scientific references on dietary fat and atherosclerosis’” in (Page, 1961). It was testing the AHA diet recommendation, the so-called Prudent Diet.

“In the mid-1950s, Irvine Page, Norman Jolliffe, Ancel Keys… and others devised a diet, which was called the “Prudent Diet” [115], to test the lipid–heart hypothesis.

This diet, which was introduced to the American public in 1956 in a nationally televised fundraiser for the AHA…

The Anti-Coronary Club Study (1957–1966) was a 10-year study of the Prudent Diet… with and without diagnosed heart disease.” (Newport, 2024)

So how did this high-seed-oil, moderate fat diet work out?

“…In November 1966, just nine months later, the Anti-Coronary Club investigators published a second article, revealing that twenty-six members of the club had died during the trial, compared with only six of the men whose diet had not been prudent. Eight members of the club died from heart attacks, but none of the controls.”

I’ve characterized this trial as seed oils vs. smoking.

“At the initiation of the study, smoking was not stressed as a CHD risk factor. Our data indicated that there were significantly more smokers at entry in the control group than in the active experimental group at both age levels. In the 50 to 59-year-old group 17.7% of the active experimental group and 36.0% of the control group smoked (P = 0.00 1). In the younger age category 25.9% of the active experimental group smoked compared to 44.3% of the control group (P = 0.03).” (Singman, 1980)

So a high-seed-oil, ‘prudent’ diet is worse for you than smoking and eating imprudently.

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“...Conclusions: Linoleic acid [LA] has a pro-inflammatory effect on cartilage whereas oleic acid and palmitic acid seem to inhibit cartilage destruction. These results indicate that altered fatty acid levels may influence loss of cartilage structure in OA.”

Monounsaturated and Saturated, but Not Ω-6 Polyunsaturated Fatty Acids Decrease Cartilage Destruction under Inflammatory Conditions (Bastiaansen-Jenniskens et al, 2013)

There’s another way to read that, of course, if one assumes that high levels of LA are not normal....

This next study is hilarious; yes, if you assume that high levels of LA (which don’t exist naturally) are “normal” this would be a mystifying result:

“We report here the finding that normal, young cartilages, in distinction from all other tissues examined, have unusually high levels of n-9 eicosatrienoic (20:3 cis-i5’8”) acid [Mead acid] and low levels of n-6 polyunsaturated fatty acids (n-6 PUFA)....

“...The finding of low levels of n-6 PUFA and high levels of unusual n-9 fatty acids, characteristic of EFA deficiency, in normal cartilage is remarkable in view of the fact that normal levels of EFA are present in serum, muscle, liver, kidney, and bone of the same animals (Tables 1-4). To properly understand this finding, it is important to recognize that when tissue from an EFA-deficient animal is transplanted into a nutritionally normal recipient, the EFA-deficient tissue rapidly recovers and regains a normal fatty acid profile within a period of 5 days (19). Thus it seemed implausible that a tissue should exhibit features characteristic of EFA deficiency in an animal with normal levels of EFA in its other tissues. Yet this phenomenon was consistently seen in normal cartilage of all species so far investigated (chicken, calf, human, rabbit, and pig).”

Unique Fatty Acid Composition of Normal Cartilage: Discovery of High Levels of N-9 Eicosatrienoic Acid and Low Levels of N-6 Polyunsaturated Fatty Acids (Adkisson et al, 1991)

If high LA is not normal, but is a result of a novel diet, these studies might be alarming.

Especially if we’d been seeing a rise in the incidence of injuries to cartilage.... (Mall et al, 2014)

More to come...

Original post February 25, 2016.

References

Adkisson, H. D., Risener, F. S., Zarrinkar, P. P., Walla, M. D., Christie, W. W., & Wuthier, R. E. (1991). Unique fatty acid composition of normal cartilage: Discovery of high levels of n-9 eicosatrienoic acid and low levels of n-6 polyunsaturated fatty acids. The FASEB Journal, 5(3), 344–353. https://doi.org/10.1096/fasebj.5.3.2001795

Bastiaansen-Jenniskens, Y. M., Siawash, M., van de Lest, C. H. A., Verhaar, J. A. N., Kloppenburg, M., Zuurmond, A.-M., Stojanovic-Susulic, V., Van Osch, G. J. V. M., & Clockaerts, S. (2013). Monounsaturated and Saturated, but Not n-6 Polyunsaturated Fatty Acids Decrease Cartilage Destruction under Inflammatory Conditions: A Preliminary Study. CARTILAGE, 4(4), 321–328. https://doi.org/10.1177/1947603513494401

Mall, N. A., Chalmers, P. N., Moric, M., Tanaka, M. J., Cole, B. J., Bach, B. R., & Paletta, G. A. (2014). Incidence and trends of anterior cruciate ligament reconstruction in the United States. The American Journal of Sports Medicine, 42(10), 2363–2370. https://doi.org/10.1177/0363546514542796

“The most recent American Dietary Guidelines (2020–2025) recommend shifting dietary fats from solid saturated fats to unsaturated oils. Dietary oils contain different compositions of unsaturated fatty acids (UFA). Oleic acid (OA) and linoleic acid (LA) are the most common UFA in dietary oils. How individual UFA in oils regulate immune cell function and cancer risk remains unclear.” (Jin 2021—all quotes from this source in Bold and Italic.)

This is certainly a neat paper.

Going all the way back to the 1960s, it’s been observed that there was a connection between increased consumption of seed oils and increased rates of cancer. Immigrants to the U.S. often see an increased rate of certain types of cancer (breast and colon, for instance), until their cancer risk ultimately matches the American population.

And it’s well recognized that the seed oil metabolite 4-HNE can cause mutations, notably to the P53 tumor-suppressor gene, especially in colon and liver cancer.

See this post for a model where our favorite obesogenic rodent diet, D12492, causes liver tumors.

When I first started reading about nutrition and disease, there was an English researcher, Barry Groves, who stated that early organ-transplant surgeons had used seed oils to suppress the immune systems of patients, but had to stop because of the increased rates of cancer they saw.

“But the transplant doctors were then astonished to see how quickly their patients developed cancers and the treatment was stopped.” (Groves, 2007)

It’s certainly true that immune suppression causes increased rates of cancer in transplant patients.

“The most significant cancer-related risk for organ transplant recipients, however, is associated with the very immunosuppressive medications that are required to prevent rejection of the organs but also can render the immune system less able to identify and kill tumor cells or battle cancer-linked infections….

A 30-year cohort study in Finland that examined roughly 6500 transplant recipients, for example, found that nearly 1 in 4 eventually contracted cancer; this translated to a 3.6-fold higher risk. For non-melanoma skin cancers, such as basal cell and squamous cell carcinomas, the rate is even higher: Studies have documented anywhere from a 25- to 250-fold increase in risk.” (Nelson, 2025)

But I had never seen a paper demonstrating what the mechanism might be for seed oils impeding immune function, until now.

Linoleic vs. Oleic

This is just what we want to see. A pretty straight-forward bake-off.

They’re using three diets, low-fat (LFD) with 10% soybean oil, a linoleic acid diet (Safflower) with 10% soybean oil and 35% safflower oil, and an oleic acid diet (Olive) with 10% soybean and 35% olive oil

They even give us the fatty-acid composition of the two added oils. Safflower has a lot more LA than even a high-LA olive oil would, so it’s a clear delineation. (In the graphs to follow, Safflower or LA are red. 18:2 is LA, 18:1 is OA.)

Remember, the body makes saturated and monounsaturated fats in the proportions in which they are needed, and so the LFD diet is effectively a lower-LA diet, with the SFA and MUFA made from carbs and the Ω-3 in soybean oil.

They do tell us the effect of the diets on the mice in terms of body weight:

The higher-LA diet produces more obesity in this model, but neither curve looks like what you would get with D12492. Visceral fat is also higher in Safflower as one would expect, but insulin is a smidge lower, which Peter (Hyperlipid) will appreciate.

Safflower Kills Cancer-Killing Cells

We have a variety of white blood cells, and two of them are the T cells, CD8 and CD4. They’re like a sniper team: CD8 is the killer, and CD4 is the spotter, or helper cell, as it’s known. These cells are produced in the thymus, and then released into the general circulation. They go through a period where they are “naive”, which is to say they’ve not been assigned something to kill.

One of the things that these cells can kill is cancer cells. In fact, in several types of cancer better survival is associated with higher numbers of these cells. In HIV, a higher ratio of killer to helper cells is associated with a lower incidence of cancer.

So it seems that killing these cells would be a bad thing.

Sure enough, Safflower kills off the T cells, both as they’re developing in the thymus and after they’re released while they’re still naive.

Fewer Killer Cells Means More Cancer Cells

This isn’t an ideal model. The mice don’t get cancer in this model, they’re given it. They implant E0771 breast cancer cells into the mammary tissue of the three groups of mice, and see how they do.

“…We observed a significant acceleration of mammary tumor growth in the safflower oil–fed mice compared with the olive oil–fed or LFD-fed mice (Fig. 3A).”

And they note that it wasn’t just obesity that was driving tumor growth.

“This observation of uncoupling obesity from tumor growth in mice on the olive oil diet suggests that not all dietary oil-induced obesity is tumorigenic.”

You’ll note that Olive is a smidge higher than LFD, as one would expect from the higher LA percentage.

Fewer Killer Cells, and Weaker Too

After COVID, we’ve all heard of cytokines. Tumor Necrosis Factor Alpha (TNFa) is a cytokine that is produced by CD8 cells, and it is an anti-cancer drug, to oversimplify things. It can cause cancer cells to die (via apoptosis, a controlled cell death) and it also damages the blood cells that feed the tumor.

Unfortunately, Safflower also reduces production of TNFa.

“In line with in vivo data collected from safflower oil–fed or olive oil–fed mice, LA, but not OA induced significant death of CD8+ and CD4+ T cells (Fig. 4A and B). Intracellular staining showed that LA treatment in vitro significantly inhibited the production of TNFa…”

“Altogether, our data indicate that LA in safflower oil–fed mice and in culture negatively affect naive T-cell survival and TNFa production.”

Having your T cells unable to make an anti-tumor chemical is unfortunate.

How Did The T Cells Die?

There are basically three pathways describing how cells die (assuming it’s not from physical injury, like a wound). They are apoptosis, mentioned previously; necrosis, an uncontrolled cell death where the contents of the cells often escape into the general circulation; and ferroptosis, which is defined (erroneously, I think) as an iron-dependent type of cell death.

Next they gave T cells three chemicals which prevent each of the three types of cell death, and then exposed them to LA or OA.

Apoptosis, it turns out, is the culprit.

LA caused an increase in Reactive Oxygen Species (ROS) in the cells. N-acetylcysteine (NAC) is a ROS inhibitor. It is a precursor for glutathione, the most powerful antioxidant in the body.

As you can see, NAC almost totally inhibited the lethality of LA in both CD4 and CD8 T cells. Now here’s the crux of the analysis.

“LA impairs T-cell responses by promoting mitochondrial dysregulation….

“Interestingly, when we measured the production of mitochondrial ROS (Mitosox) in T cells treated with LA, OA, or BSA, we found that LA treatment significantly promoted mitochondrial ROS production in both CD8+ T and CD4+ cells compared with BSA or OA-treated groups (Fig. 5A–C). In line with increased mitochondrial ROS production, LA treatment increased mitochondria, but did not affect peroxisomes in T cells (Fig. 5D). In contrast, OA treatment did not induce significant increase of mitochondria in CD8+ and CD4+ T cells (Fig. 5E and F).

This suggests to me that the mitochondria are trying to compensate for LA-induced damage via lipid peroxidation (fats going rancid), but OA does not induce damage or the need to adapt to it.

Cardiolipin (CL) is a unique fat structure that’s only found in mitochondria, and is an essential part of the energy generation function of the electron transport chain.

“Given that 18:2 LA was the predominant composition of CL, a unique class of phospholipids in mitochondrial inner membrane, and 18:2 LA was more sensitive to ROS-mediated lipid peroxidation than 18:1 OA, we postulated that treatment with LA, but not OA, would induce mitochondrial lipid peroxidation. Indeed, 4-HNE, a common byproduct of lipid peroxidation, was significantly upregulated in both CD8+ and CD4+ T cells in response to LA treatment (Fig. 5G–I). These data demonstrated that LA specifically induced mitochondrial ROS and lipid peroxidation, thus leading to mitochondrial dysfunction in T cells.”

4-HNE is of course only produced from Ω-6 fats, and is highly toxic to cells.

We saw a similar destruction of mitochondria upon seed oil consumption in this study.

Since N-acetyl-L-cysteine (NAC) is an important antioxidant that neutralizes ROS and is a scavenger of α,β-unsaturated aldehydes, we used it to abolish the formation of 4-HNE adducts…. The data indicated that NAC is a reliable 4-HNE-scavenging agent. (Manea, 2015)

“Scavenging” means it removes 4-HNE, and its ability to do damage; and allows it to be excreted harmlessly.

It’s known that 4-HNE is produced from high-LA cardiolipin (Liu, 2011), and that oxidized LA in cardiolipin induces apoptosis (Kagan, 2005).

So the pathway appears to be: increased LA → increased LA in cardiolipin → iron-catalyzed peroxidation of cardiolipin → production of 4-HNE → inducement of apoptosis.

“…CL was the only mitochondrial phospholipid that underwent peroxidation during apoptosis.” (Kagan, 2005)

I’m rather pleased with this finding, as this was exactly the pathway that I described back in 2016:

Blocking Linoleic Acid Prevents T Cell Death and Impedes Tumor Growth

Fatty Acid Binding Protein (FABP) is a protein that transports fats like LA or OA into the cell. E-FABP is a version that is found in large number in T cells.

T cells from mice without E-FABP (E-FABP-/-) are unable to take up LA when cultured with it. This causes several changes to the cell, including a reduction in uncoupling protein 2 (UCP2), which is part of the LA disposal pathway.

“Importantly, E-FABP deficiency significantly reduced mitochondrial lipid peroxidation in T cells (Fig. 6K). Accordingly, LA-induced T-cell death in [wild-type] T cells was significantly reduced when E-FABP was absent (Fig. 6L).”

I discussed disposal of LA as an indication of its toxicity and UCP as a disposal pathway in this post.

Next they fed E-FABP genetic knock-out mice Safflower to see what would happen. This genetic modification did not protect from obesity, but they did have higher levels of CD8 and CD4 T cells, and those cells were able to produce more TNFa than the unmodified mice were.

Then they injected mice with and without E-FABP with breast cancer cells, as above. Mice without E-FABP had a 50% lower tumor load than normal mice.

“These results clearly demonstrated that E-FABP expression in CD8+ T cells was critical in mediating safflower oil-impaired T-cell responses.”

Conclusion

Given:

• The many similarities between mice and men when it comes to the effects of seed oil consumption.

• The demonstrated increase of certain types of cancer when people immigrate to a high-seed-oil-consumption country like the U.S.

• The demonstrated effect impairing immune-system function has on cancer incidence in humans.

It seems wise to avoid seed oils to reduce the risk of cancer.

For the first time, I can also conclude that if you have cancer, elimination of seed-oil consumption should be a first-order alteration to diet, as the potential increase of killer T cells could help fight the disease.

Sadly this also implies that the diet offered in hospitals, in which seed oils are the primary source of fat, should be considered a cancer-promoting diet.

“Dietary Fats High in Linoleic Acids Impair Antitumor T-cell Responses by Inducing E-FABP–Mediated Mitochondrial Dysfunction” (Jin, 2021

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References

Groves, Barry. 2007. “Immunity to Infections: Part 2: Polyunsaturated Fats Suppress The Immune System.” Blog. Second Opinions, February 20. http://www.second-opinions.co.uk/immunity2.html.

Jin, Rong, Jiaqing Hao, Yanmei Yi, et al. 2021. “Dietary Fats High in Linoleic Acids Impair Antitumor T-Cell Responses by Inducing E-FABP–Mediated Mitochondrial Dysfunction.” Cancer Research 81 (20): 5296–310. https://doi.org/10.1158/0008-5472.CAN-21-0757.

Kagan, Valerian E., Vladimir A. Tyurin, Jianfei Jiang, et al. 2005. “Cytochrome C Acts as a Cardiolipin Oxygenase Required for Release of Proapoptotic Factors.” Nature Chemical Biology 1 (4): 4. https://doi.org/10.1038/nchembio727.

Liu, Wei, Ned A. Porter, Claus Schneider, Alan R. Brash, and Huiyong Yin. 2011. “Formation Of 4-Hydroxynonenal From Cardiolipin Oxidation: Intramolecular Peroxyl Radical Addition And Decomposition.” Free Radical Biology & Medicine 50 (1): 166–78. https://doi.org/10.1016/j.freeradbiomed.2010.10.709.

Manea, Adrian, Simona-Adriana Manea, Andra Todirita, et al. 2015. “High-Glucose-Increased Expression and Activation of NADPH Oxidase in Human Vascular Smooth Muscle Cells Is Mediated by 4-Hydroxynonenal-Activated PPARα and PPARβ/Δ.” Cell and Tissue Research 361 (2): 593–604. https://doi.org/10.1007/s00441-015-2120-0.

Nelson, Bryn, and William Faquin. 2025. “Amid a Boom in Organ Donation, a Heightened Focus on Cancer Risk in Transplant Recipients: Immunosuppression, Transmissible Infections and Tumors, and Improved Long‐Term Survival Among Organ Recipients Are Requiring More Vigilance for Skin Cancers and Other Malignancies.” Cancer Cytopathology 133 (2): e22932. https://doi.org/10.1002/cncy.22932.

Introduction

It’s well-known that lipid peroxidation is involved in aging and longevity. But what can we do about it? Dr. Shchepinov has been researching using deuterium to ‘shore up’ the PUFAs like those in seed oils to prevent them become toxic metabolites. He’s had some interesting successes, and we discuss at length his new book: “Breaking the Chains of Aging”

Amazon link:

https://amzn.to/46A29KX

Book website

https://www.breakingaging.com

Research:

https://scholar.google.com/citations?user=0kQp8lEAAAAJ&hl=en

Biography:

Mikhail Shchepinov trained in Moscow (PhD, Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry, 1994), then moved to Oxford to work on DNA microarray technology, combinatorial chemistry, and oligonucleotide dendrimers.

He worked in academia and biotech in Oxford, UK and San Diego, USA, and is affiliated with several universities.

From: https://www.breakingaging.com/author

Tucker Goodrich

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If you haven’t been paying attention, he’s mentioned about 1700 times in the Jeffrey Epstein email release. I’m not going to attempt to link to all the interesting emails, I’m sure you all can find them easily enough, there are only a few.

Apparently, he was in contact with Epstein from 2014 to 2019, and had a number of meetings and visits with him. Most of the emails, apparently, are about arranging meetings.

It’s important to note: at this point nothing in the emails so far disclosed suggests any illegal activity.

While my initial reaction was that this really wasn’t that big of an issue if he had a medical relationship with Epstein, Attia has released a statement saying that he was not Epstein’s doctor.

Physicians traditionally have an obligation to treat anyone who comes to them for help, or at least to try to get them help (an eye doctor won’t be much help for your cancer diagnosis, for instance, but he might help you find a specialist).

If he had been trying to help Epstein with some health problem, this would have been a fair explanation of his relationship with him.

In my opinion, that fact that this was not a medical relationship makes it worse for Attia.

So someone offered to introduce Attia to Epstein. Peter says that he was aware of Epstein’s conviction, but proceeded anyway.

Don’t Fraternize with Felons

I am reminded of a job interview I did once. We were looking for a consultant to work on our accounting system. The fellow we interviewed came highly recommended from a consulting firm we had used for years. He was very intelligent, and while he didn’t have specific knowledge of our system, his general knowledge of accounting was peerless. He had been a foreign exchange trader at a bank.

But it was rather odd that a fellow like this would want a short-term, gig like this, which seemed pretty far below his pay grade.

So of course I Googled the guy. It took about a half an hour, and would have been shorter if I hadn’t read a bunch of the documents that turned up.

It turned out that he had been convicted of bank robbery, and was awaiting sentencing (!).

He had done this by manipulating the bank’s accounting system to get paid bonuses for profits he had never made.

Hence his deep knowledge of accounting systems and principles.

The idiot who recommended him didn’t initially understand why we were so upset that he had sent this guy to us. The relationship never recovered.

Now let’s imagine that we had hired the felon. Can you imagine what the response of our investors and the regulatory authorities would have been?

Do Your Homework

Obviously asking the bank robber wouldn’t have been a good idea. “So, do you plan on using your access to our system to rob us?” That wouldn’t have cut it.

“Shortly after we met, I asked him directly about his 2008 conviction. He characterized it as prostitution-related charges.”

That’s from Attia’s mea culpa. As due diligence, it’s a joke. By 2014 there were lots of accounts online discussing what exactly he’d been convicted of.

Instead, Attia waited until a 2018 article came out: “In 2018 I came to learn this was grossly minimized…”

Attia could have saved himself a lot of trouble with the query above.

No Evidence of Criminal Behavior.

Attia points out in his mea culpa that he didn’t do anything criminally wrong with Epstein. There’s no evidence that he did, in the DOJ document release, or anywhere else.

That’s a low bar for a physician.

Does Poor Judgement Matter In A Physician?

It’s well understood that we have an epidemic of opioid overuse and overdose in the U.S.

What’s not so well understood is that the critical failure that led to this epidemic was not Purdue Pharmaceutical’s fraudulent claims about the alleged non-addictive nature of their OxyContin. It was that physicians as a class largely failed us—one can also note the Sackler brothers who owned Purdue were all physicians. Physicians have a monopoly on prescribing these drugs, and they are supposedly trained to evaluate the claims and evidence that pharmaceutical companies use to justify prescribing a new drug to the physicians’ patients. Instead they accepted weak or nonexistent marketing evidence from Purdue, along with “branded promotional items such as OxyContin fishing hats, stuffed plush toys, and music compact discs (‘Get in the Swing With OxyContin’)” (Van Zee, 2009). They exercised poor judgement, believed some absurd claims, and kicked off an opioid-abuse epidemic that at last accounting, had resulted in 600,000 deaths, and still continues.

So yes, judgement matters in a physician.

Promoting Dubious Longevity Drugs

I’ve listened to Attia’s podcast since he started producing it. He’s had some terrific guests on, and a number of the episodes have been quite educational. But one theme that has been pretty consistent is Attia’s infatuation with various drugs that have been proposed to be longevity enhancers, particularly metformin and rapamycin. In the episodes that he’s produced with experts on these drugs, they’ve been far more measured in their evaluation of the drugs than Attia has, in fact, a good part of the reason I’m skeptical about these drugs (rapamycin especially) was from listening to these experts! Rapamycin may be proved to be a longevity drug at some point, but the evidence does not exist yet. Attia stopped taking metformin after realizing that it was harmful for adaptation to exercise, and a big part of his longevity protocol is low-grade aerobic exercise. There’s no good evidence for metformin as a longevity drug, and while he’s ceased promoting it, It boggles my mind that he ever did.

I’m not a physician, I don’t have the training he has, and I don’t have access to the research team and experts that he does. So if I’m able to figure out before he does that metformin is a bad idea, why would I want his health information?

“Avoid the obvious mito-toxins, like seed oils, statins, metformin, and feed yourself correctly.”

Promoting Incorrect Health Information

I was shocked to hear Attia say in one of his podcasts that running was bad for your knees. This is misinformation that has been known to be such for decades, and a physician who brags about his research team should know better. This is, unfortunately, a medical myth that ill-informed physicians continue to propagate.

Worse are his views on cardiovascular disease. He said in one podcast that cardiovascular disease is essentially a part of our genetic heritage, which is the logical conclusion of the belief that the lipoprotein ApoB causes heart attacks.

Unfortunately this idea was pretty definitively debunked in the 1960s.

One of the better interviews Attia did was with Dr. Eric Topol. This is what Topol had to say about Attia’s mea culpa.

“…But the man you are today vs 10 years ago has not changed w/r to arrogance. Moreover, these days you are riddled with conflicts as a huckster for David Bars, AG-1 supplement, and so many other things that diminish your credibility. That's a shame.”

I don’t even know what the AG-1 supplement is, and based on Attia’s previous infatuations, I don’t really care. Guilt by association.

However…

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So I follow Attia’s podcast for his guests, which have been excellent, if very conventional. But as compared to other physicians, he’s not terrible. His basic advice is to eat well, get exercise, and it’s pretty hard to agree with those views. He’s probably better than the average physician, in fact.

Conclusion

So Attia’s problem is that he’s got poor judgement, basically. Does he have worse judgement than the average physician? As we can see from the OxyContin fiasco, there are lots of physicians with poor judgement, who get suckered by claims that shouldn’t fool a “trained professional”. The list of such claims are long, unfortunately, as most medical interventions are poorly supported by scientific evidence.

“Most medical decisions, however, come with far less certainty. The BMJ clinical evidence team reviewed 3000 treatments used in the UK’s National Health Service and found that about one half were of unknown effectiveness and only 11% were clearly beneficial.” (Mandrola, 2019)

Ultimately, Attia’s problem is that he’s a physician, and he was trained as a surgeon. Arrogance and over-confidence in Medicine is unfortunately typical of such professionals.

While I do know some good, conservative physicians, and I’m sure there are more out there, they are unfortunately the exception.

So ultimately the lesson of the Attia affair is to be wary of any over-confident physician, and always double-check their work.

(I did a little less referencing than usual on this one, to get it out the door. If you have any requests, let me know in the comments.)

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References

Mandrola, John, Adam Cifu, Vinay Prasad, and Andrew Foy. 2019. “The Case for Being a Medical Conservative.” The American Journal of Medicine 132 (8): 900–901. https://doi.org/10.1016/j.amjmed.2019.02.005.

Van Zee, Art. 2009. “The Promotion and Marketing of OxyContin: Commercial Triumph, Public Health Tragedy.” American Journal of Public Health 99 (2): 221–27. https://doi.org/10.2105/AJPH.2007.131714.

Looks like a good movie. But why is he on a juice fast?

Because vegan physician ‘Dr.’ Joel Fuhrman told him to eat this way. Poor Joe Cross.

In the trailer Joe describes how he likes to eat two pizzas. That’s not slices, he points out, that’s pizzas. Joe has a wheat belly, as you can clearly see.

Joe mentions that he’s got urticarial vasculitis, which is a rare, chronic auto-immune disease of unknown cause.

Hmm... Wheat belly and a chronic auto-immune disease. Could it be?

“Dermatitis Herpetiformis Presenting as Chronic Urticaria“ (Powell, 2004)

Dermatitis Herpetiformis is also known as celiac disease, which is a subset of wheat poisoning. Sure enough. Of course the juice diet wouldn’t include any wheat, one would imagine. Urticarial vasculitis and chronic urticaria seem to be two aspects of one disease (Krause, 2023).

Joe Cross is a perfect candidate for a paleo/primal diet. The fast he does in the movie is a high-fat diet, as he’s using the stored fat in his body to fuel himself. A low-carb paleo/primal diet replicates this, sustainably, unlike the mostly-vegan approach Fuhrman advocates, which starts out high-fat, but turns low-fat as soon as Joe runs out of body fat. High-fat diets are sustainable, low-fat diets are not.

Fuhrman’s diet, which is some ways is a vegan take on the paleo diet, is way better than the two-pizzas-a-day diet, but it’s not optimal.

And I feel for Joe, I really do. I did the Fat, Sick, and Nearly Dead thing myself, and it sucks.

P.S. How’s Joe doing?

“JC: At the beginning of the movie I was 310, after juicing for 60 days I lost about 80-85 pounds – thereabouts. I lost another 20 pounds for the next three months by just eating plant foods, such as fruits, vegetables, nuts, until I was off full medication. So that was five months of me like that and I was down to 210. Then since that – Feb. 8th – and three and a half years later – I’ve fluctuated 220 on the low side and 240 on the high side. Most of the time I sit at about 230. So that’s about a 85-90 pound consistent weight loss.”

“Chronic urticaria: A cutaneous manifestation of celiac disease”:

“Celiac disease, or gluten-sensitive enteropathy, is an immune-mediated disease of the small bowel that results in malabsorption. It classically presents with gastrointestinal symptoms including chronic diarrhea, weight loss, abdominal bloating and anorexia. It is becoming more frequently identified in asymptomatic patients with a diagnosis of deficiencies related to malabsorption of iron, folic acid, vitamin B12 and vitamin D. It is increasingly identified as a cause for early or refractory osteoporosis. Occasionally, celiac disease presents with cutaneous manifestations alone. Dermatitis herpetiformis is a well-recognized cutaneous manifestation of celiac disease. Other cutaneous manifestations include alopecia, angular stomatitis and aphthous ulcerations. Described here is a case of a 24-year-old woman who presented with intermittent urticaria and gastrointestinal complaints. She was found to have celiac disease on small-bowel biopsy. Both her gastrointestinal symptoms and urticaria resolved when she was put on a gluten-free diet, suggesting that her urticaria was a cutaneous manifestation of celiac disease.”

Original post March 8, 2011

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References

Krause, Karoline, Hanna Bonnekoh, Jannis Jelden‐Thurm, et al. 2023. “Differential Diagnosis Between Urticarial Vasculitis and Chronic Spontaneous Urticaria: An International Delphi Survey.” Clinical and Translational Allergy 13 (10): e12305. https://doi.org/10.1002/clt2.12305.

Powell, Gavin R., Anna L. Bruckner, and William L. Weston. 2004. “Dermatitis Herpetiformis Presenting as Chronic Urticaria.” Pediatric Dermatology 21 (5): 564–67. https://doi.org/10.1111/j.0736-8046.2004.21509.x.

Introduction

I am honored to be joined by John Speakman, a leading authority on energy balance in animals, and in the use of the doubly-labeled water method of determining energy balance. This has led him into the study of obesity, among other topics, where he has become a recognized expert.

We have an enlightening discussion on the potential role of deuterium in obesity and chronic disease.

Biography:

“John Roger Speakman (born 1958) FRS FRSE FRSB FRSA FMedSci FRSS is a British biologist working at the University of Aberdeen, Institute of Biological and Environmental Sciences, for which he was Director from 2007 to 2011. He leads the University’s Energetics Research Group, which is one of the world’s leading groups using doubly labeled water (DLW) to investigate energy expenditure and balance in animals. Between 2011-2020, he was a ‘1000 talents’ Professor at the Institute of Genetics and Developmental Biology, Chinese Academy of Sciences, in Beijing, China, where he ran the molecular energetics group. In 2020 he moved to the Shenzhen Institutes of Advanced Technology, Chinese Academy of Sciences in Shenzhen, China where he works at the Center for Energy Metabolism and Reproduction and Head of the Shenzhen Key laboratory of Metabolic Health.”

https://en.wikipedia.org/wiki/John_Speakman

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Tucker Goodrich

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Show Notes

Boros, Laszlo, Que Collins, and Gábor Somlyai. 2018. “Deuterium and Metabolic Water Matter – What This Means Biochemically and Clinically.” September 24. https://www.science.org/doi/10.1126/sciadv.aat7314#elettersSection.

If you have any questions about sources for things discussed please ask in the comments.

Four weeks later I got cramps at work. I had to lie on the floor until it passed. Then I drove to my doctor’s office, and he told me that I had diverticulitis, and I had to go to the emergency room.

I drove myself, and barely made it. I was in agony; I nearly passed out again while they were interviewing me to see if it was “serious”.

That’s a good trick to get through triage quickly, by the way. I heard the nurse yelling “Medic!” A little while later I had a doctor screaming, “Morphine!” down the hall, I was in so much pain.

Turns out I had a perforated colon. That’s right, a hole in my colon, with bubbles of air trickling out to my abdomen. I spent the next four days in the pre-operative ward, so if it got worse they could cut me open immediately. I lost 10 pounds. Then I started bleeding from my behind, and I realized these were all the same symptoms that I had had 14 years before. My blood pressure got so low that the automated blood-pressure machine wouldn’t work, it thought I was dying, and would alarm immediately.

Diverticulitis is supposed to be age-related in industrial countries—people in non-industrial countries don’t get it (Trowell, 1981). 70% of of people have it by the time you reach 80, which is why all the old folks eat fiber. It usually starts occurring at 40; I had turned 40 a week earlier! But the first attack in the 20s... I mentioned to all three of the doctors I saw that I had had constant diarrhea for the last 14 years (Cohen, 2013), since the first attack, and they shrugged. They told me to eat more fiber, and whole wheat, even though that was what I had been eating for the last 20 years. So I avoided surgery, started eating salad with salad dressing (containing industrial seed oils) and lots of whole wheat. And lots of running, since I’d read running helped diverticulitis. (Got my 5k PR at that point, still haven’t beaten it. As I was telling people, I was running from a man with a knife!)

But the more salad and whole wheat I ate, the worse it got. I couldn’t understand why. Finally had to have eight inches of my colon removed. The diarrhea continued, so obviously the cause remained.

So in 2010, I stopped eating industrial seed oils (veggie oils). In two days the diarrhea stopped. Eat the oils, it started again. I no longer craved starch or sugar, so I didn’t eat any wheat for a week, without meaning to. Then I had a sandwich, felt like crap, and had diarrhea the next morning. Hmm... but I didn’t have a problem with wheat! I ate tons of it! How could I have a problem with wheat? Another week went by, and I had two slices of pizza. I thought I was having a heart attack. So now I could turn the symptoms of the last 16 years on or off, based on eating veggie oils or wheat. Wow!

Stephen Guyenet says that chronic intestinal issues are an excellent indicator of a wheat problem, and now I believe him. I read Nina Planck’s Real Food one year before my surgery, and now I realize that if I’d just followed what that woman said, I could have avoided the whole thing, most likely.

Now I’ve learned that diverticulitis is one of the most common misdiagnoses of celiac, and erroneous bowel resections are common for people who are subsequently found to be celiac—some have died (Arvanitakis, 1977). And the 14 years of chronic diarrhea? Chronic diarrhea of the sort I had (I’ll spare you the details) are also typical of a wheat problem.

And none of my doctors ever mentioned any of this as a possibility.

Lots of people have serious problems with wheat, and come back negative on celiac tests. I think celiac is just one aspect of wheat poisoning (yeah, I know, a strong term) for people with a specific immune system profile. Apparently wheat causes leaky gut syndrome in almost everyone... It took them over 2000 years just to figure out that celiac was caused by wheat! Science and Medicine know very little about it.

Hopefully this story will help my readers, but after going through all this, and then realizing not only I, but my wife and daughters, all have wheat problems, it’s been quite an eye-opener. And the veggie oils are just plain toxic. Not fit for human consumption.

So that’s just part of the introduction. Next I’ll go into more detail on how I figured out what was going on.

Original post August 17, 2010.

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Original Comments

References

Arvanitakis, Constantine. 1977. “Recurrent Colonic Ulcers in Celiac Sprue, an Unrecognized Fatal Complication: Report of a Case.” Diseases of the Colon & Rectum 20 (7): 613. https://doi.org/10.1007/BF02586629.

Cohen, Erica, Garth Fuller, Roger Bolus, et al. 2013. “Increased Risk for Irritable Bowel Syndrome After Acute Diverticulitis.” Clinical Gastroenterology and Hepatology 11 (12): 1614–19. https://doi.org/10.1016/j.cgh.2013.03.007.

Trowell, Hubert Carey, and Denis P. Burkitt. 1981. Western Diseases, Their Emergence and Prevention. Harvard University Press. https://www.hup.harvard.edu/catalog.php?isbn=9780674950207.

I was in shock.

This blog is about barefoot running and healthy, paleo-style diets, ultimately. These two topics have utterly changed my and my family’s life in the past five years prior to this news.

I learned about the barefoot running movement, like most of us, from Chris McDougall’s Born to Run.

I’ve gotten to know Chris, and Barefoot Ted, ran a race with Caballo Blanco, toured Dan Lieberman’s lab, helped design some shoes, and helped some folks fix their diets and change their lives.

I learned about Born to Run from an ad at the bottom of an item in Google Reader.

I clicked the link, watched the video, and at the end Chris put on a pair of Vibram Fivefinger Sprints. In the three years I’d had my Sprints, this was the only time I’d seen another human being who had a pair. I immediately bought the book. Thank God.

Through that book, I learned about the paleo diet from Justin Owings, who sent me a link to this post at Stephan Guyenet’s Whole Health Source. The fact that diet could control dental development (my dental development was seriously impaired growing up) blew my mind, and I started following that blog in Google Reader. Six months later, I fixed my diet and changed my life.

I had a stroke at 38, a colon resection after coming close to dying from a perforated colon at 40, and I strongly suspect I was getting osteoporosis. I don’t know where I’d be today.

Those problems are gone thanks to what I found by dumb luck through Google Reader.

“Our hypothesis (that we’ve been testing for the last 45 years) is that bioenergetic dysfunction lies at the nexus of the genetic and environmental “causes”; and that the “common-complex” diseases are bioenergetic diseases, and not anatomical diseases.” 7:07.

“Now each cell has hundreds of thousands of these mitochondrial DNAs, and they’re constantly replicating inside your cells right now. And if you doubt that they’re active and vital in there, talking to each other; tonight when it’s very very quiet and your spouse is not snoring if you just concentrate you’ll feel them wiggling in there.” 16:49

Discussing cells with different mitochondrial genotypes from mutation and division:

“Some with good mitochondrial DNAs and high energy, some with bad mitochondrial DNAs and low energy, and if it’s below the minimum energy for that tissue, then you will get a phenotype. The equivalent of a biological, a metropolitan brownout. So if there was a line voltage decline in LA, all the electrical systems wouldn’t fail at one time. The first thing that would go would be the fluorescent light bulbs, then certain elevators, then certain electrical motors, but the incandescent light bulbs would just get dimmer and dimmer.

“Well the same is true for your body. Different parts of your body rely on energy to different extents, so as the energy declines, you’re going to get organ-specific symptoms of a systemic defect.” 17:35

Noting the wild variation in expression between mitochondrial defects:

“If you inherit that from your mother you’re fine until midlife, and then you’ll lose your hearing (sensory-neural hearing loss). But if you get treated by aminoglycoside antibiotics, you’ll go deaf within a week. OK? Mutation in the tRNA leucine gene, another protein synthesis mutation at 3243; at 30 % mutant will give you diabetes, 50% mutant give your neuromuscular disease, 100% mutant and you are dead.” 18:55

He goes on with many more examples.

“So we have a quantitative genetics with totally different clinical phenotypes.” 20:15

“So why would there be tissue-specific symptomatology? Well because different tissues rely on mitochondrial energy for different extents [sic]... [Examples] ...So in fact when you think energetically, much of anatomy is about energetics, not anatomy.” 21:12

"If the, in fact, the cells are sick, they cannot undergo apoptosis, then the mitochondria are released into the bloodstream, and they are perfectly good bacteria, and you're going to get inflammation. And that's why we believe all of these diseases have an inflammatory component." 23:54

He doesn't discuss my favorite topic, the impact of omega-6 fats on mitochondria and therefore health, but it fits nicely with his hypothesis. For instance, the part of mitochondria that causes the immune reaction and inflammation he describes is cardiolipin released with oxidized linoleic acid into the blood stream. [2]

Do watch the whole thing!

Original post January 8, 2020.

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References

1. A Mitochondrial Etiology of Common Complex Diseases. UCLA CTSI; 2017.

. Accessed December 20, 2019.

2. Tuominen Anu, Miller Yury I., Hansen Lotte F., Kesäniemi Y. Antero, Witztum Joseph L., Hörkkö Sohvi. A Natural Antibody to Oxidized Cardiolipin Binds to Oxidized Low-Density Lipoprotein, Apoptotic Cells, and Atherosclerotic Lesions. Arteriosclerosis, Thrombosis, and Vascular Biology. 2006;26(9):2096-2102. doi:10.1161/01.ATV.0000233333.07991.4a

“Glycogen losses or gains are reported (2) to be associated with an additional three to four parts water, so that as much as 5 kg weight change might not be associated with any fat loss.”

From here:

“Glycogen Storage: Illusions of Easy Weight Loss, Excessive Weight Regain, and Distortions in Estimates of Body Composition.” (Kreitzman, 1992)

The referenced paper (2) in Kreitzman is:

Variation in Total Body Water with Muscle Glycogen Changes in Man. (Olsson, 1970)

Interesting. So how did they get to that number?

“The total body water increased 2.2 1 which is assumed to be caused by the glycogen storage in the muscles and the liver. The amount of glycogen stored was calculated to be at least 500 g, which means that 3—4 g of water is bound with each gram of glycogen.” (Olsson, 1970)

Emphasis mine. Wait, they assumed? Has anyone checked this?

Sure enough:

“In 1970, Olsson and Saltin… measured total body water after manipulating exercise and diet to supercompensate muscle glycogen stores in human skeletal muscle….

“Muscle water content expressed as mumol H2O lost/g wet tissue weight or made relative to protein content showed no consistent relationship to the glycogen content. These data, therefore, do not support the commonly accepted muscle glycogen-to-water ratio of 1.0:2.7 (g:g). Further work is necessary to quantify the exact amount of water that is actually associated with the glycogen complex.” (Sherman, 1982)

And here:

“The extent to which muscle glycogen concentrations can be increased during exposure to maximal insulin concentrations and abundant glucose was investigated in the isolated perfused rat hindquarter preparation.... Total muscle water concentration decreased during glycogen loading of the muscles.” (Richter, 1988)

I can’t find any evidence that anyone’s tried to confirm this assumption in man.

An assumption does not equal knowledge. It’s a guess, however educated. And a guess is not “science”.

I do think, however, that body weight can go up with glycogen increase. But the water’s not in the muscles, it’s in the gut, buffering the sugar that is generally used to replenish muscle glycogen:

“What he discovered was that if he drank sugary water, his body reacted to it by flooding his stomach with water.

“...Two lights went on over my head on hearing this. The first is that this explains diabetics’ frequent thirst and urination: they’re thirsty because diabetics consume a lot of sugar, which requires their bodies to dump water into their guts. They need to replenish this water in their systems, and perhaps drinking the water helps in diluting the sugar in their guts.” (Goodrich, 2013)

And going on a low-carb diet allows the body to lose the water that’s in the gut (doing you no good from a running performance perspective), not the muscles.

At least that’s n=1, not n=SWAG.

[Scientific Wild-Ass Guess]

P.S.

OK, it’s not just me:

“...Several attempts have been made to estimate the amount of water stored in muscle in association with glycogen, but this is not easily quantified. Early data suggested a value of about 3 g of water for each gram of glycogen (Olsson & Saltin, 1970). However, a subsequent study by Sherman et al. (1982), in which the muscle glycogen content of rats was manipulated by exercise and diet, suggested that there was no consistent association between the amount of glycogen stored in a muscle and the muscle water content. Richter, Hansen, and Hansen (1988) found a decrease in muscle water concentration after muscle glycogen loading. Nygren, Karlsson, Norman, and Kaijser (2001) have also suggested that glycogen loading may alter the disposition of water molecules within the muscle. These apparently conflicting data may result from different amounts of water storage with different structural forms of glycogen and changes in the proportions of these different forms as the total amount of glycogen changes.

“Notwithstanding the uncertainties, there is good evidence of gross changes in body mass as a consequence of diet and exercise manipulations designed to induce alterations in glycogen storage in humans. Any major change in the amount of glycogen stored in muscle will result in a change in body mass, with the major part of the mass change being a consequence of the storage of the associated water (Olsson & Saltin, 1970)....” (Maughan, 2007)

The studies they cite are the studies linked to above. They’re not particularly logical with that last statement, however, as there’s still no evidence for the proposition that glycogen is stored with water.

But that’s how scientific myths stay alive!

P.P.S.

The whole point of the glycogen molecule is to store glucose without water...

“Glycogen is also a suitable storage substance due to its insolubility in water, which means it does not affect the osmotic pressure of a cell.”

That was what Wikipedia said when I first wrote this post. Which as we can see is correct.

Wikipedia now quotes (Kreitzman, 1992), and says:

“Glycogen in muscle, liver, and fat cells is stored in a hydrated form, composed of three or four parts of water per part of glycogen associated with 0.45 millimoles (18 mg) of potassium per gram of glycogen.^[5]”

Sob. Wikipedia is a propaganda machine, not a reliable source of information.

P.P.P.S

I had a back-and-forth about this with Kevin Hall on X:

The first paper is (Geddes, 1977) which says in the abstract:

“Hydrodynamic studies indicated that all fractions of glycogen of mol.wt. exceeding 25 x 106 had about 1.1 g of water per g of polysaccharide associated with them.”

This sounds authoritative. However they clarify in the text:

“As pointed out by Ogston (1953), the amount of water which we have shown (1.1 g/g of polysaccharide) to be associated with the particles is some sort of average and could well be different under different hydrodynamic conditions.”

How did this water get into the glycogen in their experiment?

“Solutions of known glycogen concentration were prepared by dissolving an accurately weighed quantity of previously dehydrated glycogen in a known volume of pure water.” (Geddes, 1977).

Dehydrated glycogen. Right.

So it’s not a relationship, just an average, as the water is “loosely associated” (Geddes, 1977). Hall’s quote “extensively hydrated” isn’t to be found in either paper, but the second paper says “It is hydrated extensively [31]” (Channareddy, 1996). [31] is a reference to (Geddes, 1977), not so some separate demonstration.

Original Post: April 7, 2014, and the comments:

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References

Channareddy, Sreelatha, Sherilyn S. Jose, and Nathan Janes. 1996. “Ethanol Binding to a Model Carbohydrate, Glycogen.” Biochemical Pharmacology 52 (12): 1911–14. https://doi.org/10.1016/S0006-2952(96)00695-8.

Goodrich, Tucker D. 2013. “What Does Sugary Water Do To Your Body? Thoughts On Racing With A Water Balloon.” Blog. Yelling Stop, August 29. https://yelling-stop.blogspot.com/2013/08/what-does-sugary-water-do-to-your-body.html.

Kreitzman, S. N., A. Y. Coxon, and K. F. Szaz. 1992. “Glycogen Storage: Illusions of Easy Weight Loss, Excessive Weight Regain, and Distortions in Estimates of Body Composition.” The American Journal of Clinical Nutrition 56 (1 Suppl): 292S-293S. https://doi.org/10.1093/ajcn/56.1.292S.

Maughan, Ronald J., Susan M. Shirreffs, and John B. Leiper. 2007. “Errors in the Estimation of Hydration Status from Changes in Body Mass.” Journal of Sports Sciences 25 (7): 797–804. https://doi.org/10.1080/02640410600875143.

Olsson, K. E., and B. Saltin. 1970. “Variation in Total Body Water with Muscle Glycogen Changes in Man - Olsson - 1970 - Acta Physiologica Scandinavica - Wiley Online Library.” Acta Physiologica Scandinavica 80 (1): 11–18. https://doi.org/10.1111/j.1748-1716.1970.tb04764.x.

Richter, E. A., S. A. Hansen, and B. F. Hansen. 1988. “Mechanisms Limiting Glycogen Storage in Muscle During Prolonged Insulin Stimulation.” The American Journal of Physiology 255 (5 Pt 1): E621-628. https://doi.org/10.1152/ajpendo.1988.255.5.E621.

Sherman, W. M., M. J. Plyley, R. L. Sharp, et al. 1982. “Muscle Glycogen Storage and Its Relationship with Water.” International Journal of Sports Medicine 3 (1): 22–24. https://doi.org/10.1055/s-2008-1026056.

I listened to this podcast interview with David “Wolverine” Smith:

David “Wolverine” Smith – Survivor (Davis, 2013)

It’s a remarkable, if completely infuriating, story about medical malpractice and human resilience. In short, through a series of gross medical mishaps after a minor procedure, he wound up having his large and small intestines removed, and then replaced with a transplanted large and small intestine.

I discovered Wolverine’s site in 2011, posted a comment, and engaged in a email dialog with him which was most interesting.

He eats basically a paleo diet:

“I eat mostly meat from grass fed animals (I own a small farm and raise my own cattle for meat). I knew that I would have to eat very nutritionally dense foods, because the transplanted organ does not work at 100%. I have to avoid sugary beverages, especially any containing caffeine, because they cause me to dehydrate. I only have a total of about 22 inches of colon, so I can dehydrate easily. I am the only member of the transplant patients from 2010 who does not require to have a port for hydration fluid infusions. Because I only drink water (and [raw] milk). I add a small amount of Himalayan sea salt to my water to add in minerals and electrolytes that I lose due to having a short colon.”

This was the part of the interview that I found particularly fascinating, as they apply directly to training. I’d not read Dr. Tim Noakes’ Waterlogged when I first encountered Wolverine, and so really didn’t put two and two together.

One of the things I’ve noticed since going Paleo three-and-a-half years ago (post to come!) is that my hydration requirements are much lower than they used to be, and follow a particular pattern. I used to get thirsty regularly, and pee regularly. I’ve since learned that this is a symptom of diabetes, and since my doctor had informed me that I was pre-diabetic, I was happy to see it go. But I didn’t understand why it happened.

The new pattern is that I drink some fluids, and then need to urinate within a short period of time. Then nothing, until I drink more fluids. It’s as if my body’s water sensor senses incoming fluids and feels free to release fluids. It works quite well, and means that unscheduled potty breaks (or waking up at night) no longer occur.

Wolverine, in the interview above, describes his experiences with dehydration, which are an elaboration of the quote above.

After having his intestines removed, but prior to his intestinal transplant, he had a short length of small intestine descending from his stomach which was routed out to a bag outside his body. There was no connection to his colon. In the normal course of business, your colon absorbs most, if not all, of the water you consume. In Wolverine’s case, since the colon was no longer having water routed through it, he needed IV hydration.

What he discovered was that if he drank sugary water, his body reacted to it by flooding his stomach with water. This flowed into what little bit of small intestine he had, and thence into the ostomy bag. (The cause of his dehydration was revealed to him by a pharmacist, as the doctors, unsurprisingly, were clueless about how the body worked.)

Wolverine had already learned about toxicity of sugar to the body the hard way: he was being fed by having sugar and soybean oil pumped directly into his veins, and his veins would break down from sugar poisoning. It seems that the stomach has a self-defense mechanism: flood the stomach with water to dilute the sugar.

Unfortunately in Wolverine’s case, this was a problem, since his body couldn’t reabsorb the water. It turned out to really be a problem when he drank some sweetened ice tea. His body reacted by dumping nearly three gallons of water into his stomach, and then into his ostomy bag. Which required a great deal of IV replenishment, and put his life in jeopardy. The combination of caffeine and sugar is a dangerous one, apparently.

In a person with a normal intestinal system, all of this water would be gradually absorbed back into the body, of course. But in the meanwhile it sits in the intestines, doing nothing but protecting your body from sugar poisoning.

Two lights went on over my head on hearing this. The first is that this explains diabetics’ frequent thirst and urination: they’re thirsty because diabetics consume a lot of sugar, which requires their bodies to dump water into their guts. They need to replenish this water in their systems, and perhaps drinking the water helps in diluting the sugar in their guts. Secondly, they’re peeing a lot because as their body reabsorbs all this water, they have too much in their blood, and the body starts dumping it the only way it can. It’s a vicious cycle.

The second light was that if you’re running a race or training, the last thing in the world you want to do is cause your body to need to dump a lot of water into your gut, when it would be better off by maintaining a normal hydration balance. The water in your gut does nothing to help you to keep cool through sweating, and only makes you more thirsty. And what do runners love to drink? Sugary water like Gatorade. Back to the vicious cycle. So the runner weighs more, needs to carry more water, and is going to wind up with a lot of water getting reabsorbed back into the blood stream, necessitating urination. Moreover, having this load of water getting reabsorbed by your colon means that you’re at increased risk of hyponatremia (water poisoning), which is the topic of Waterlogged.

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(I’ve often observed that runners in endurance races seem to be trying to induce diabetes. This may be more true than I thought.)

Now as Noakes points out in his book, you’re at no risk of dehydration in a short race. There’s no need, normally, for your body to drink. And unless you’re a sugar-burner, there’s no requirement for sugar. (If you are a sugar-burner, you can train your body not to be, and be healthier and faster for it.) And, as Noakes also points out, losing water weight is a big advantage in a running race: if you want to find the most dehydrated runner in a race; the runner who’s lost the most weight, look to the top of the winner’s podium. It certainly does you no good sloshing around in your gut; it’s dead weight.

Since reading Noakes’ book and going low-carb (not in that order); I’ve discovered that I can go hours and hours in warm temperatures with no water. I’ve lost 8-10 pounds with no ill effects. And I’ve gotten faster.

There’s an argument that really elite athletes may need some sugar for maximum performance, but non-elite athletes over-consume water and sugar. To the detriment of their performance, I think.

The other comment Wolverine made above was about adding a smidge of salt to his water. When you drink water, your body tries to normalize the salt content (blood is as salty as sea water). I think this is a lot less important, as Noakes wrote, your body is normally pretty good at managing sodium balance, but it might explain why these athletes dumping sugar into their guts are craving salt; their bodies are trying to bring the salt content of the water they’re consuming up to normal.

I did a long run recently, and ate a couple of beef snack sticks in the middle of it, but no carbohydrates. They were a lot saltier than I was expecting, and I think the salt was a big mistake: I immediately became madly thirsty, and started cramping at once. Cramping in your feet for 10 miles ain’t fun. I’ll not repeat that mistake… But that said, I’ve never craved salt on a run. Usually I’m dumping salt in sweat, which, as Noakes notes, is a normal state for an over-salted person. (This was a fine example of why you try experiments like those beef sticks on a training run.)

Do read Wolverine’s story on his site, and listen to the podcast above. His story is incredibly informative, even if it does leave you shaking with anger, as it did me. And Noakes’ book, as you may have gathered from my many references to it, is a fascinating read.

Original post: August 29, 2013

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References

Smith, David, guest. 2013. David “Wolverine” Smith - Survivor. Episode 63. Hosted by Bryan Davis. Doc Fermento Discovers The World. iVoox, August 2. Mp3, 01:18:27. https://www.ivoox.com/63-david-wolverine-smith-survivor-audios-mp3_rf_6272505_1.html.

I discuss the nutritional transitions that led to man being man, and the chronic diseases that were introduced along the way, along with mechanisms for causation, both known and proposed.

References (if you are coming from the old post) are below. They are slide-by-slide, some slides don’t have any refs or no new refs, so they are skipped.

Health fallout from a visit to LA and a stay in a hotel: “How Much Seed Oil Is Too Much? Short-term Consequences of Going Off The Wagon”

Notes from the last one I attended, in 2012. (Pictures are mostly missing, as they were links.)

“Thoughts on the Ancestral Health Symposium 2012“

Thanks to Tess Falor, Naomi Norwood, and of course Aaron Blaisdell and all the rest of the folks that put this fine event together. And to Chris Knobbe for getting me on the program!

Original posts August 26, 2021 and August 9, 2021.

Slides

Slide 11:

“Thus, as modern food preparation techniques spread throughout the world during the 19th century, so did dental crowding [malocclusion].” (Rose & Roblee, 2009)

Slide 18:

“Between 1900 and 1920… the death rate from diabetes, despite improved treatment of the disease, had increased by as much as 400 percent... It had increased fifteen-fold since the end of the Civil War.” (Taubes, 2008)

Slide 20:

“Sesame seed first cultivated ~5 Kya, in India, oil extracted by crushing” (Fuller, 2003)

Sesame seed oil spread into Egypt, the Mediterranean, and Africa

Safflower was cultivated in Egypt, use was common in Ptolemaic period, but references begin 3.5 Kya

Used as food and for lamps

Animal fat illegal in Ptolemaic Egypt (!) (Sandy, 1989)

Slide 21

Modern mass-production of seed oils started in 19th century, 200 ya

“By the early 19th century, Russian farmers were growing over 2 million acres of sunflower”

(The National Sunflower Association)

American production was mostly cottonseed oil, first a toxic waste product

“Generally the manufacturers in the United States make no pretence [sic] of exporting pure lard….

“The chief adulterant found is cotton seed oil”

(Dominion of Canada, 1890)

Hydrogenated cottonseed oil (Crisco) introduced in 1911, taking vegetable fats mainstream

Slide 22

Cottonseed ruled until soybean oil introduced

Biggest change in diet in modern era is increase in seed oils

(Blasbalg et al., 2011)

Slide 23

“The Nutrition Transition: New Trends in the Global Diet”

“By the 1990s,soybean oil accounted for about 70% of… edible oils and fats in the [US]… soybeans now account for the bulk of vegetable oil consumption worldwide

“This dramatic difference was largely accounted for by a major increase in the consumption of vegetable fats by poor and rich nations alike

“Although meat consumption declined in high-income countries (by 6-9%), there was little overall reduction in fat intakes, as animal fats were replaced by a greater proportion of vegetable oils and products”

(Drewnowski & Popkin, 1997)

Slide 24

“Fifty years later, I still cannot cite a definite mechanism or mediator by which saturated fat is shown to kill people.”

(Lands, 2008)

Slide 27

HNE is involved in every aspect of Chronic Disease

Marker/mediator of Oxidative Stress
(Tsimikas, 2006; Žarković et al., 1999)

Induces

Atherosclerosis (Willeit et al., 2020; Witztum & Steinberg, 1991)

Insulin resistance (Ingram et al., 2012; Pillon et al., 2012)

DNA damage (Chung et al., 2003; Hu et al., 2002)

Inflammation (Poli & Schaur, 2000; Trevisani et al., 2007)

Mitochondrial Dysfunction (Gomes et al., 2014)

Fibrosis (Chiarpotto et al., 2005; Gomes et al., 2014)

Pain (C. Li et al., 2018; Trevisani et al., 2007) (Mis-cited as Trevisani et al., 2017; Chen et al., 2018)

Etc (Poli & Schaur, 2000; Shoeb et al., 2014; Sottero et al., 2019)

HNE is derived exclusively from n-6 fats (Ayala et al., 2014)

Slide 28

“So few subjects in the present survey were found to have any of the conventional signs of coronary disease that it would be futile to analyze the data with any hope of defining the existence of risk factors for this disease within this population. ” (Sinnett & Whyte, 1973b)

Slide 29

Cardiovascular Disease (CVD) is a modern disease

While it existed in Ancient Egypt… (Finch, 2011)

“Heart disease was an uncommon cause of death… at the beginning of the 20th century. By midcentury it had become the commonest cause” (Dalen et al., 2014)

And when heart attack was unknown, some ate lots of animal fat (Michaels, 1966)

CVD is still unknown in populations eating ancestrally—no industrially-produced food (Kaplan et al., 2017)

Slide 30

In the 1960s, researchers looked at CVD in different countries. (Lee et al., 1964)

They used heart attack determined by autopsy, an extremely reliable method

Was CVD genetic, or environmental?

They used thousands of autopsies, even bringing some hearts back to the US to confirm diagnosis

What they found confirms the earlier studies…

Slide 32

So what could the environmental factor be?

In the 1970s, Brown and Goldstein attempted to induce the first step of atherosclerosis (Goldstein et al., 1979)

It failed

LDL would not convert macrophages to foam cells

They discovered the LDL must be modified

Slide 33

Steinberg and Witztum demonstrated the nature of the modification (Witztum & Steinberg, 1991)

Fats in the LDL must be oxidized, when they are sufficently oxidized, foam cells (poisoned macrophages) will form

OxLDL is cytotoxic: toxic to cells.

The toxins in oxLDL are oxidized n-6 fats, such as HNE

Slide 34

Human studies show that dietary seed oils lead to LDL oxidation (Reaven et al., 1993; Witztum & Steinberg, 1991)

Several human RCTs demonstrate higher CVD events with seed oil feeding (Ramsden et al., 2016 Appendix part 2)

One RCT reduced n-6 intake to an evolutionarily-appropriate level, saw a 70% decline in CVD events (de Lorgeril et al., 1994)

“…if you… remove [oxLDL] from “LDL-C” to derive a corrected LDL-C, corrected LDL-C is NO LONGER predictive of events.” (Willeit et al., 2020)

Tsimikas tweet thread.

Slide 36

Chart (Hiraga, 2014)

Slide 38

“The diet consisted almost entirely of sweet potato, carbohydrate providing over 90% of the calories.”

“No clinical evidence of diabetes mellitus was found in this survey.” (Sinnett & Whyte, 1973a, 1973b)

Slide 39

And since you’re wondering… (Lai et al., 2013)

They do eat less sucrose, but compare to Chinese children (Afeiche et al., 2018)

Data in graphs from sources cited above.

Slide 41

Lots of populations ate/eat traditional diets w/out T2DM

“…their mean two-hour post-glucose level of 121 mg/ 100 ml could be regarded as falling within the “diabetic” range.”

“…the relative carbohydrate intolerance of our primitive Bushmen subjects is at first glance rather surprising.” (Joffe et al., 1971)

“…the prolonged increase after two hours in both San series certainly suggested a diabetes-like condition in the San…” (T. Jenkins et al., 1974)

Slide 42

!Kung eat lots of mongongo fruit and nuts

As much as 1/3 of their calories. (Bindon, 2009)

Mongongo nut season is when the diabetic OGTT was taken (Bindon, 2009; Guyenet, 2010; Joffe et al., 1971)

One other non-diabetic OGTT was taken of HG !Kung, not stated when. (Wilmsen, 1982)

!Kung eating non-HG diet did not test diabetic. (H. C. Jenkins et al., 2010)

Mongongo nuts are high in n-6 (Gwatidzo et al., 2017)

Slide 43

1961: soybean oil introduced as an IV food supplement—Intralipid (Gura, 2020)

1964: Noted that Intralipid induces insulin resistance and hyperglycemia (Felber & Vannotti, 1964)

2014: “Infusion of Intralipid, comprised predominantly of polyunsaturated fatty acids [linoleic (44–62%)…]… is an established model for producing lipid-induced insulin resistance.” In humans (Chow et al., 2014; Jensen et al., 2003)

Slide 44

“The lack of… gluconeogenesis in the Clinoleic vs. the Intralipid group suggests that different classes of fatty acids exert different effects on glucose kinetics in preterm infants.”

Proposed mechanism is IR (van Kempen et al., 2006)

Clinoleic is an olive-oil infusion, low in n-6

Of course eating something is vastly different from injecting something

Slide 45

In humans, IR precedes T2DM by years (Martin et al., 1992)

OxLDL is associated with IR, and precedes it by years (Carantoni et al., 1998; Park et al., 2009)

As discussed, seed oils lead to LDL oxidation

Other sources of oxLDL (smoking, sepsis) also induce IR (Attvall et al., 1993; Behnes et al., 2008; Carlson, 2003; Lymperaki et al., 2015)

“Unexpectedly,… targeting oxidized LDL [via antibodies] improves insulin sensitivity…” in monkeys (S. Li et al., 2013)

Slide 46

Switching from high to low n-6 oils lowers insulin resistance (Nigam et al., 2014)

Dose-dependent relationship to n-6 content of seed oils

Liver fat also improved—NAFLD patients

“… 15–21% protein… 55–70% carbohydrates, and 20% fats.”

Slide 48

Lowering n-6:n-3 ratio lowers insulin resistance (Van Name et al., 2020)

“The intervention diet consisted of a low n–6 to n–3 PUFA ratio of 4:1…”

“…macronutrient content was 50%–55%... carb., 20% from protein, and 25%–30% from fat…”

Diet monitored by blood biomarkers, including oxLAMs

No control, performed at Yale

Slide 51

“In 1616, Ieyasu Tokugawa, the founder of the Edo government died. It is said he had been overeating fish fried in sesame oil.”

From “Tempura... Another Usage of Lamp Oil”

(Walker, 2003 quoting Ishige, 1980)

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References:

Afeiche, M. C., Koyratty, B. N. S., Wang, D., Jacquier, E. F., & Lê, K.-A. (2018). Intakes and sources of total and added sugars among 4 to 13-year-old children in China, Mexico and the United States. Pediatric Obesity, 13(4), 204–212. https://doi.org/10.1111/ijpo.12234

Attvall, S., Fowelin, J., Lager, I., Schenck, H. V., & Smith, U. (1993). Smoking induces insulin resistance—A potential link with the insulin resistance syndrome. Journal of Internal Medicine, 233(4), 327–332. https://doi.org/10.1111/j.1365-2796.1993.tb00680.x

Ayala, A., Muñoz, M. F., & Argüelles, S. (2014, May 8). Lipid Peroxidation: Production, Metabolism, and Signaling Mechanisms of Malondialdehyde and 4-Hydroxy-2-Nonenal [Review Article]. Oxidative Medicine and Cellular Longevity; Hindawi. https://doi.org/10.1155/2014/360438

Behnes, M., Brueckmann, M., Liebe, V., Liebetrau, C., Lang, S., Putensen, C., Borggrefe, M., & Hoffmann, U. (2008). Levels of oxidized low-density lipoproteins are increased in patients with severe sepsis. Journal of Critical Care, 23(4), 537–541. https://doi.org/10.1016/j.jcrc.2008.09.002

Bindon, J. R. (2009). Foraging with the !Kung [Educational]. University of Iowa, Anthropology Dept., Unknown. https://anthropology.ua.edu/bindon/ant476/topics/Foragers.pdf

Blasbalg, T. L., Hibbeln, J. R., Ramsden, C. E., Majchrzak, S. F., & Rawlings, R. R. (2011). Changes in consumption of omega-3 and omega-6 fatty acids in the United States during the 20th century. The American Journal of Clinical Nutrition, 93(5), 950–962. https://doi.org/10.3945/ajcn.110.006643

Carantoni, M., Abbasi, F., Warmerdam, F., Klebanov, M., Wang, P.-W., Chen, Y.-D. I., Azhar, S., & Reaven, G. M. (1998). Relationship Between Insulin Resistance and Partially Oxidized LDL Particles in Healthy, Nondiabetic Volunteers. Arteriosclerosis, Thrombosis, and Vascular Biology, 18(5), 762–767. https://doi.org/10.1161/01.ATV.18.5.762

Carlson, G. L. (2003). Insulin resistance in sepsis. BJS, 90(3), 259–260. https://doi.org/10.1002/bjs.4081

Chiarpotto, E., Castello, L., Leonarduzzi, G., Biasi, F., & Poli, G. (2005). Role of 4-hydroxy-2,3-nonenal in the pathogenesis of fibrosis. BioFactors, 24(1–4), 229–236. https://doi.org/10.1002/biof.5520240127

Chow, L. S., Mashek, D. G., Austin, E., Eberly, L. E., Persson, X.-M., Mashek, M. T., Seaquist, E. R., & Jensen, M. D. (2014). Training status diverges muscle diacylglycerol accumulation during free fatty acid elevation. American Journal of Physiology-Endocrinology and Metabolism, 307(1), E124–E131. https://doi.org/10.1152/ajpendo.00166.2014

Chung, F.-L., Pan, J., Choudhury, S., Roy, R., Hu, W., & Tang, M. (2003). Formation of trans-4-hydroxy-2-nonenal- and other enal-derived cyclic DNA adducts from ω-3 and ω-6 polyunsaturated fatty acids and their roles in DNA repair and human p53 gene mutation. Mutation Research/Fundamental and Molecular Mechanisms of Mutagenesis, 531(1), 25–36. https://doi.org/10.1016/j.mrfmmm.2003.07.001

Dalen, J. E., Alpert, J. S., Goldberg, R. J., & Weinstein, R. S. (2014). The Epidemic of the 20th Century: Coronary Heart Disease. The American Journal of Medicine, 127(9), 807–812. https://doi.org/10.1016/j.amjmed.2014.04.015

de Lorgeril, M., Renaud, S., Mamelle, N., Salen, P., Martin, J. L., Monjaud, I., Guidollet, J., Touboul, P., & Delaye, J. (1994). Mediterranean alpha-linolenic acid-rich diet in secondary prevention of coronary heart disease. Lancet (London, England), 343(8911), 1454–1459. https://doi.org/10.1016/s0140-6736(94)92580-1

Dominion of Canada. (1890). Sessional Papers of the Dominion of Canada (Vol. 1). Dominion of Canada. https://books.google.com/books?id=JA0xAQAAMAAJ&printsec=frontcover&source=gbs_ge_summary_r&cad=0#v=onepage&q=cotton%20seed&f=false

Drewnowski, A., & Popkin, B. M. (1997). The nutrition transition: New trends in the global diet. Nutrition Reviews, 55(2), 31–43. https://doi.org/10.1111/j.1753-4887.1997.tb01593.x

Felber, J. P., & Vannotti, A. (1964). EFFECTS OF FAT INFUSION ON GLUCOSE TOLERANCE AND INSULIN PLASMA LEVELS. Medicina Experimentalis: International Journal of Experimental Medicine, 10, 153–156. https://doi.org/10.1159/000135410

Finch, C. E. (2011). Atherosclerosis is an old disease: Summary of the Ruffer Centenary Symposium, The Paleocardiology of Ancient Egypt, a meeting report of the Horus Study team. Experimental Gerontology, 46(11), 843–846. https://doi.org/10.1016/j.exger.2011.08.011

Fuller, D. Q. (2003). Further evidence on the Prehistory of sesame. Asian Agri-History(India). https://agris.fao.org/agris-search/search.do?recordID=IN2003000892

Goldstein, J. L., Ho, Y. K., Basu, S. K., & Brown, M. S. (1979). Binding site on macrophages that mediates uptake and degradation of acetylated low density lipoprotein, producing massive cholesterol deposition. Proceedings of the National Academy of Sciences of the United States of America, 76(1), 333–337. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC382933/

Gomes, K. M. S., Campos, J. C., Bechara, L. R. G., Queliconi, B., Lima, V. M., Disatnik, M.-H., Magno, P., Chen, C.-H., Brum, P. C., Kowaltowski, A. J., Mochly-Rosen, D., & Ferreira, J. C. B. (2014). Aldehyde dehydrogenase 2 activation in heart failure restores mitochondrial function and improves ventricular function and remodelling. Cardiovascular Research, 103(4), 498–508. https://doi.org/10.1093/cvr/cvu125

Gura, K. M. (2020). The Power of Networking and Lessons Learned From Omegaven. The Journal of Pediatric Pharmacology and Therapeutics : JPPT, 25(8), 663–674. https://doi.org/10.5863/1551-6776-25.8.663

Guyenet, S. (2010, November 20). Whole Health Source: Glucose Tolerance in Non-industrial Cultures. Whole Health Source. http://wholehealthsource.blogspot.com/2010/11/glucose-tolerance-in-non-industrial.html

Gwatidzo, L., Botha, B. M., & McCrindle, R. I. (2017). Fatty acid profile of Manketti (Schinziophyton rautanenii) nut oil: Influence of extraction method and experimental evidence on the existence of -eleostearic acid. Journal of Cereals and Oilseeds, 8(5), 33–44. https://doi.org/10.5897/JCO2017.0175

Hiraga, M. (2014, June 3). Increase of Vegetable Oil Consumption Under Food Regimes: A Preceding Example of Japan to Be Compared with Rapid Increase of Vegetable Oil Availability in Asian Countries Especially in China (oral presentation at the 4th Annual LCIRAH Conference, 2014 London) [Slideshow]. 4th Annual LCIRAH Conference, Birkbeck College, London, United Kingdom. https://www.academia.edu/7815526/_Increase_of_Vegetable_Oil_Consumption_Under_Food_Regimes_A_Preceding_Example_of_Japan_to_Be_Compared_with_Rapid_Increase_of_Vegetable_Oil_Availability_in_Asian_Countries_Especially_in_China_oral_presentation_at_the_4th_Annual_LCIRAH_Conference_2014_London_

Hu, W., Feng, Z., Eveleigh, J., Iyer, G., Pan, J., Amin, S., Chung, F.-L., & Tang, M. (2002). The major lipid peroxidation product, trans- 4-hydroxy-2-nonenal, preferentially forms DNA adducts at codon 249 of human p53 gene, a unique mutational hotspot in hepatocellular carcinoma. Carcinogenesis, 23(11), 1781–1789. https://doi.org/10.1093/carcin/23.11.1781

Ingram, K. H., Hill, H., Moellering, D. R., Hill, B. G., Lara-Castro, C., Newcomer, B., Brandon, L. J., Ingalls, C. P., Penumetcha, M., Rupp, J. C., & Garvey, W. T. (2012). Skeletal Muscle Lipid Peroxidation and Insulin Resistance in Humans. The Journal of Clinical Endocrinology and Metabolism, 97(7), E1182–E1186. https://doi.org/10.1210/jc.2011-2963

Jenkins, H. C., Joffe, B. I., Panz, V. R., Ramsey, M., & Seftel, H. C. (2010). Transition from a hunter-gatherer to a settled life-style among the !Kung San (bushmen): Effect on glucose tolerance and insulin secretion. 3. https://journals.co.za/doi/abs/10.10520/AJA00382353_5362

Jenkins, T., Lehmann, H., & Nurse, G. T. (1974). Public health and genetic constitution of the San (“Bushmen”): Carbohydrate metabolism and acetylator status of the Kung of Tsumkwe in the North-western Kalahari. British Medical Journal, 2(5909), 23–26. https://doi.org/10.1136/bmj.2.5909.23

Jensen, C. B., Storgaard, H., Holst, J. J., Dela, F., Madsbad, S., & Vaag, A. A. (2003). Insulin Secretion and Cellular Glucose Metabolism after Prolonged Low-Grade Intralipid Infusion in Young Men. The Journal of Clinical Endocrinology & Metabolism, 88(6), 2775–2783. https://doi.org/10.1210/jc.2002-021430

Joffe, B. I., Jackson, W. P. U., Thomas, M. E., Toyer, M. G., Keller, P., Pimstone, B. L., & Zamit, R. (1971). Metabolic Responses to Oral Glucose in the Kalahari Bushmen. British Medical Journal, 4(5781), 206–208. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1799259/

Kaplan, H., Thompson, R. C., Trumble, B. C., Wann, L. S., Allam, A. H., Beheim, B., Frohlich, B., Sutherland, M. L., Sutherland, J. D., Stieglitz, J., Rodriguez, D. E., Michalik, D. E., Rowan, C. J., Lombardi, G. P., Bedi, R., Garcia, A. R., Min, J. K., Narula, J., Finch, C. E., … Thomas, G. S. (2017). Coronary atherosclerosis in indigenous South American Tsimane: A cross-sectional cohort study. The Lancet, 389(10080), 1730–1739. https://doi.org/10.1016/S0140-6736(17)30752-3

Lai, Y.-C., Huang, C.-L., Chan, C.-F., Lien, C.-Y., & Liao, W. C. (2013). Studies of sugar composition and starch morphology of baked sweet potatoes (Ipomoea batatas (L.) Lam). Journal of Food Science and Technology, 50(6), 1193–1199. https://doi.org/10.1007/s13197-011-0453-6

Lands, B. (2008). A critique of paradoxes in current advice on dietary lipids. Progress in Lipid Research, 47(2), 77–106. https://doi.org/10.1016/j.plipres.2007.12.001

Lee, K. T., Nail, R., Sherman, L. A., Milano, M., Lee, K. T., Deden, C., Imai, H., Goodale, F., Nam, S. C., Lee, K. T., Goodale, F., Scott, R. F., Snell, E. S., Lee, K. T., Daoud, A. S., Jarmolych, J., Jakovic, L., & Florentin, R. (1964). Geographic Pathology of Myocardial Infarction: Part I. Myocardial infarction in orientals and whites in the United States; Part II. Myocardial infarction in orientals in Korea and Japan; Part III. Myocardial infarction in Africans in Africa and negroes and whites in the United States; Part IV. Measurement of amount of coronary arteriosclerosis in Africans, Koreans, Japanese and New Yorkers. The American Journal of Cardiology, 13(1), 30–40. https://doi.org/10.1016/0002-9149(64)90219-X

Li, C., Sun, W., Gu, C., Yang, Z., Quan, N., Yang, J., Shi, Z., Yu, L., & Ma, H. (2018). Targeting ALDH2 for Therapeutic Interventions in Chronic Pain-Related Myocardial Ischemic Susceptibility. Theranostics, 8(4), 1027–1041. https://doi.org/10.7150/thno.22414

Li, S., Kievit, P., Robertson, A.-K., Kolumam, G., Li, X., von Wachenfeldt, K., Valfridsson, C., Bullens, S., Messaoudi, I., Bader, L., Cowan, K. J., Kamath, A., van Bruggen, N., Bunting, S., Frendéus, B., & Grove, K. L. (2013). Targeting oxidized LDL improves insulin sensitivity and immune cell function in obese Rhesus macaques. Molecular Metabolism, 2(3), 256–269. https://doi.org/10.1016/j.molmet.2013.06.001

Lymperaki, E., Makedou, K., Iliadis, S., & Vagdatli, E. (2015). Effects of acute cigarette smoking on total blood count and markers of oxidative stress in active and passive smokers. Hippokratia, 19(4), 293–297. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5033137/

Martin, B. C., Warram, J. H., Krolewski, A. S., Bergman, R. N., Soeldner, J. S., & Kahn, C. R. (1992). Role of glucose and insulin resistance in development of type 2 diabetes mellitus: Results of a 25-year follow-up study. Lancet (London, England), 340(8825), 925–929. https://doi.org/10.1016/0140-6736(92)92814-v

Michaels, L. (1966). Aetiology of coronary artery disease: An historical approach. British Heart Journal, 28(2), 258–264. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC459067/

Nigam, P., Bhatt, S., Misra, A., Chadha, D. S., Vaidya, M., Dasgupta, J., & Pasha, Q. M. A. (2014). Effect of a 6-Month Intervention with Cooking Oils Containing a High Concentration of Monounsaturated Fatty Acids (Olive and Canola Oils) Compared with Control Oil in Male Asian Indians with Nonalcoholic Fatty Liver Disease. Diabetes Technology & Therapeutics, 16(4), 255–261. https://doi.org/10.1089/dia.2013.0178

Park, K., Gross, M., Lee, D.-H., Holvoet, P., Himes, J. H., Shikany, J. M., & Jacobs, D. R. (2009). Oxidative Stress and Insulin Resistance. Diabetes Care, 32(7), 1302–1307. https://doi.org/10.2337/dc09-0259

Pillon, N. J., Croze, M. L., Vella, R. E., Soulère, L., Lagarde, M., & Soulage, C. O. (2012). The Lipid Peroxidation By-Product 4-Hydroxy-2-Nonenal (4-HNE) Induces Insulin Resistance in Skeletal Muscle through Both Carbonyl and Oxidative Stress. Endocrinology, 153(5), 2099–2111. https://doi.org/10.1210/en.2011-1957

Poli, G., & Schaur, J. R. (2000). 4-Hydroxynonenal in the Pathomechanisms of Oxidative Stress. IUBMB Life, 50(4–5), 315–321. https://doi.org/10.1080/713803726

Ramsden, C. E., Zamora, D., Majchrzak-Hong, S., Faurot, K. R., Broste, S. K., Frantz, R. P., Davis, J. M., Ringel, A., Suchindran, C. M., & Hibbeln, J. R. (2016). Re-evaluation of the traditional diet-heart hypothesis: Analysis of recovered data from Minnesota Coronary Experiment (1968-73). BMJ, 353. https://doi.org/10.1136/bmj.i1246

Reaven, P., Parthasarathy, S., Grasse, B. J., Miller, E., Steinberg, D., & Witztum, J. L. (1993). Effects of oleate-rich and linoleate-rich diets on the susceptibility of low density lipoprotein to oxidative modification in mildly hypercholesterolemic subjects. Journal of Clinical Investigation, 91(2), 668–676. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC288008/

Rose, J. C., & Roblee, R. D. (2009). Origins of dental crowding and malocclusions: An anthropological perspective. Compendium of Continuing Education in Dentistry (Jamesburg, N.J.: 1995), 30(5), 292–300. https://www.aegisdentalnetwork.com/cced/2009/06/interdisciplinary-analysis-origins-of-dental-crowding-and-malocclusions-an-anthropological-perspective

Sandy, D. B. (1989). The Production and Use of Vegetable Oils in Ptolemaic Egypt. Scholars Press. https://www.google.com/books/edition/The_Production_and_Use_of_Vegetable_Oils/mg1tQgAACAAJ?hl=en

Shoeb, M., Ansari, N. H., Srivastava, S. K., & Ramana, K. V. (2014). 4-hydroxynonenal in the pathogenesis and progression of human diseases. Current Medicinal Chemistry, 21(2), 230–237.

Sinnett, P. F., & Whyte, H. M. (1973a). Epidemiological studies in a highland population of new guinea: Environment, culture, and health status. Human Ecology, 1(3), 245–277. https://doi.org/10.1007/BF01531185

Sinnett, P. F., & Whyte, H. M. (1973b). Epidemiological studies in a total highland population, Tukisenta, New Guinea: Cardiovascular disease and relevant clinical, electrocardiographic, radiological and biochemical findings. Journal of Chronic Diseases, 26(5), 265–290. https://doi.org/10.1016/0021-9681(73)90031-3

Sottero, B., Leonarduzzi, G., Testa, G., Gargiulo, S., Poli, G., & Biasi, F. (2019). Lipid Oxidation Derived Aldehydes and Oxysterols Between Health and Disease. European Journal of Lipid Science and Technology, 121(1), 1700047. https://doi.org/10.1002/ejlt.201700047

Taubes, G. (2008). Good Calories, Bad Calories: Fats, Carbs, and the Controversial Science of Diet and Health. Penguin RandomHouse. https://www.penguinrandomhouse.com/books/176680/good-calories-bad-calories-by-gary-taubes/9781400033461

The National Sunflower Association. (n.d.). History of the Amazing Sunflower [Advertisement]. The National Sunflower Association. Retrieved August 3, 2021, from https://www.sunflowernsa.com/all-about/history/

Trevisani, M., Siemens, J., Materazzi, S., Bautista, D. M., Nassini, R., Campi, B., Imamachi, N., Andrè, E., Patacchini, R., Cottrell, G. S., Gatti, R., Basbaum, A. I., Bunnett, N. W., Julius, D., & Geppetti, P. (2007). 4-Hydroxynonenal, an endogenous aldehyde, causes pain and neurogenic inflammation through activation of the irritant receptor TRPA1. Proceedings of the National Academy of Sciences, 104(33), 13519–13524. https://doi.org/10.1073/pnas.0705923104

Tsimikas, S. (2006). Measures of Oxidative Stress. Clinics in Laboratory Medicine, 26(3), 571–590. https://doi.org/10.1016/j.cll.2006.06.004

van Kempen, A. A. M. W., van der Crabben, S. N., Ackermans, M. T., Endert, E., Kok, J. H., & Sauerwein, H. P. (2006). Stimulation of gluconeogenesis by intravenous lipids in preterm infants: Response depends on fatty acid profile. American Journal of Physiology-Endocrinology and Metabolism, 290(4), E723–E730. https://doi.org/10.1152/ajpendo.00303.2005

Van Name, M. A., Savoye, M., Chick, J. M., Galuppo, B. T., Feldstein, A. E., Pierpont, B., Johnson, C., Shabanova, V., Ekong, U., Valentino, P. L., Kim, G., Caprio, S., & Santoro, N. (2020). A Low ω-6 to ω-3 PUFA Ratio (n–6:n–3 PUFA) Diet to Treat Fatty Liver Disease in Obese Youth. The Journal of Nutrition, 150(9), 2314–2321. https://doi.org/10.1093/jn/nxaa183

Walker, H. (2003). The Fat of the Land: Proceedings of the Oxford Symposium on Food and Cooking 2002. Oxford Symposium. https://www.google.com/books/edition/The_Fat_of_the_Land/ZJ5qBQAAQBAJ?hl=en

Willeit, P., Yeang, C., Moriarty, P. M., Tschiderer, L., Varvel, S. A., McConnell, J. P., & Tsimikas, S. (2020). Low-Density Lipoprotein Cholesterol Corrected for Lipoprotein(a) Cholesterol, Risk Thresholds, and Cardiovascular Events. Journal of the American Heart Association, 9(23), e016318. https://doi.org/10.1161/JAHA.119.016318

Wilmsen, E. N. (1982). Studies in diet, nutrition, and fertility among a group of Kalahari Bushmen in Botswana. Social Science Information, 21(1), 95–125. https://doi.org/10.1177/053901882021001006

Witztum, J. L., & Steinberg, D. (1991). Role of oxidized low density lipoprotein in atherogenesis. Journal of Clinical Investigation, 88(6), 1785–1792. https://doi.org/10.1172/JCI115499

Žarković, N., Žarković, K., Schaur, R. J., Štolc, S., Schlag, G., Redl, H., Waeg, G., Borović, S., Lončarić, I., Jurić, G., & Hlavka, V. (1999). 4-Hydroxynonenal as a second messenger of free radicals and growth modifying factor. Life Sciences, 65(18), 1901–1904. https://doi.org/10.1016/S0024-3205(99)00444-0

“Hepatic Adaptation to Chronic Metabolic Stress Primes Tumorigenesis” (Tsouanas, 2025; all references to this paper in bold & italic unless otherwise cited.)

I downloaded, skimmed it (it’s very dense) and decided I didn’t need to discuss it.

Why not?

“Our HFD liver injury recapitulated many of the cardiometabolic comorbidities seen in patients with MASLD including obesity (higher body weight), dyslipidemia (elevated serum cholesterol), systemic insulin resistance (impaired glucose tolerance), and hepatocellular damage (increased alanine aminotransferase levels) (Figures 1A–1D and S1).”

MASLD = NAFLD, by the way. So since I’ve just published a number of posts looking at diet and NAFLD:

I didn’t really see the point of adding this one in. It is interesting, as it’s looking at the progression of NAFLD to liver cancer (hepatocellular carcinoma, HCC); “…the second-leading cause of years of life lost to cancer,” but it’s a little off-topic at the moment.

I did post this [1]:

But then I started seeing all the takes on this, such as [2]:

That’s just wrong. It’s not a “fatty diet” per se, it’s an omega-6-rich diet, as I noted above.

We interviewed the author of a study looking specifically at what causes fatty liver disease in these models:

“Ability of High Fat Diet to Induce Liver Pathology Correlates with the Level of Linoleic Acid and Vitamin E in the Diet.” (Graham, 2023)

The variables in this study were linoleic acid (the predominant Ω-6 fat in the human diet) and saturated fat (from hydrogenated coconut oil).

We’ll ignore the vitamin E part for the moment. We do discuss it in the podcast.

So both the researchers at Harvard and MIT, and Mario Nawfal (who relied on them, he’s not a scientist or a physician) got this wrong.

Fat does not cause fatty liver, only Ω-6 fats do.

Next we have Nick Norwitz [3], a ketogenic diet proponent (I am also a ketogenic diet proponent, btw, but…).

Nick’s right about checking the diets. He mischaracterizes this one, however.

More than 9 times out of 10, a so-called “high-fat diet” is actually a high-fat, high-sugar diet.

Often the authors specify a research diet code. You can copy that description, paste it into Google, and see the diet’s composition for yourself. In this case, it’s a diet heavy in soybean oil, lard, sugar, and refined carbohydrates.

D12492 is the diet I described in this post (and many others):

I included this chart:

As you can see, D12492 has 7% energy sugar, and a total 20% carbohydrate. The other two diets both have more sugar and more carbohydrate (D12451: 17% sugar, 35% carbohydrate; D12450B: 35% sugar and 70% carbohydrate).

D12492 is only “heavy” in sugar and refined carbohydrate compared to a ketogenic diet. It is the low-carb, low-sugar diet in (Ricci, 2005) and (Tsouanas, 2025).

Why is this important? Let’s look at (Tsouanas, 2025): HFD (high-fat diet) is D12492, CD (control diet) is D12450J.

In the graph above I used D12450B, which is a high-sugar, non-obesogenic, non-harmful control diet, to match D12492, since that’s what Research Diets used (Ricci, 2005). But it’s not the only control diet offered for D12492. Thanks, I suspect, to Gary Taubes’ misinformation about the obesogenic effect of sugar, they now offer a sugar-matched control, D12450J (Research Diets, 2012).

This diet has the exact same amount of sugar as D12492.

And here’s the chart, comparing the two diets:

Nick had said: “In this case, it’s a diet heavy in soybean oil, lard, sugar, and refined carbohydrates.” In fact, it’s only “heavy” in lard. It has the exact same amount of soybean oil, maltodextrin, and sucrose, and it’s far lower (zero) in “refined carbohydrates” (corn starch) than the D12450J control diet.

As we can see in (Tsouanas, 2025), the increased lard in D12492 results in obesity (orange is HFD, blue is CD):

Poor blood glucose control (a.k.a. Type 2 Diabetes):

And, since this is ultimately a cancer study, tumor load:

So in fact, adding sugar and refined carbohydrates would improve these mice’s diets significantly. Here’s D12492 vs. the two control diets.

Nick concludes: “Rather, it’s a consequence of how standard scientific terminology gets translated into headlines and hot takes.”

That’s not really accurate. Most researchers, like Nick and the authors of (Tsouanas, 2025), just haven’t taken the time to understand the diets and what is actually driving these diseases. See here for more:

Homo Op(t)imus

The Hidden PUFAs Inside Rodent High-Fat Diets

TLDR: Most mouse studies claiming a “high-fat diet” (HFD) effect in rodent studies are not actually testing saturated fat. They’re testing a processed rodent chow loaded with oxidized omega-6 lipids from poor quality lard and soybean oil. Nearly every obesity, metabolic syndrome, inflammation, or chronic disease study using the standard HFD model relies…

Read more

5 months ago · 8 likes · 7 comments · Eric Brown, PhD

Last, but not least [4]:

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D12492 is in fact a low-carb diet. Depending on the definition used, it’s at the high end (20% energy from carbohydrate), but it’s in the range. Given that the “typical” American diet is 50% carbohydrate, this is dramatically lower (Last, 2006).

The results of these studies are definitely generalizable to eating dietary fat in general, if you are eating the fats that cause the negative effects, as most Americans do. Soybean oil, the most common high-Ω-6 fat in the American diet, has been shown to cause NAFLD and liver cancer in humans. He does specify this in a reply [5]:

But it’s probably worth being a little more explicit about what’s actually going on.

Conclusion

I was surprised that 75% of the respondents to my poll (linked above) thought that a high-carb, high-sugar diet would be most fattening, and most unhealthy.

But you can see from the reaction to this study why this would be the case. When institutions like Harvard Medical School continue to propagate inaccurate information, and misrepresent the findings of their own studies, it’s very difficult to, well, shout into a hurricane.

And just like with the anti-fat campaign which started in the 1950s and ‘60s, the anti-carb campaign has had a significant impact on American’s perception of a healthy diet.

Unfortunately, they have made the exact same mistake as the anti-fat crew did, and missed the target.

References

I see that X integration is working in Substack again. Yay! Nevertheless, I’m going to copy the text of those tweets here just in case it stops working or the tweets get deleted.

[1] Yes indeed!

It's the old high-fat diet bait-and-switch.

Show a picture of a cheese burger and a doughnut (low-Ω-6 beef fat), but use high-Ω-6 lard and soybean oil (D12492) to actually induce the disease.

Fatty liver isn't caused by dairy fat, kids.

Only by seed oils.

[2] MIT scientists just exposed how greasy eating doesn't just hurt your liver - it turns it into a cancer playground.

Liver cells under constant fat-stress devolve into immature, stem-like states. It’s a survival move, but one that leaves them wide open for cancer.

These cells shut down normal functions like metabolism and protein production and flip on genes that help them divide, survive - and eventually mutate into tumors.

In mice fed high-fat diets, almost all developed liver cancer.

And yes - researchers found the same gene changes happening in humans with fatty liver disease, long before cancer shows up.

Good news? Several genes driving this regression - like SOX4 and thyroid hormone receptors - are already being targeted by new drugs.

Bad news? This process might quietly unfold in humans over 20 years.

Your cheat days may be aging your liver faster than you think.

Source: Cell

[3] Another paper is circulating claiming that “high-fat diets” are harmful.

Here’s a simple reality check when you see this:

Go to the actual paper.

Scroll to the Methods section.

More than 9 times out of 10, a so-called “high-fat diet” is actually a high-fat, high-sugar diet.

Often the authors specify a research diet code. You can copy that description, paste it into Google, and see the diet’s composition for yourself. In this case, it’s a diet heavy in soybean oil, lard, sugar, and refined carbohydrates.

I don’t believe this is usually intentional or misleading on the part of the researchers.

Rather, it’s a consequence of how standard scientific terminology gets translated into headlines and hot takes.

It’s going to keep happening. So, now you know.

[4] A quick reminder because this gets confused constantly:

A ‘high-fat diet’ in research is not a low-carb, keto, or carnivore diet. And results of these studies are not generalizable to eating dietary fat in general.

The diet is typically 40–60% of calories from fat (often lard and soybean oil) and contains a substantial amount of refined carbohydrates.

The diet is intentionally designed to cause insulin resistance, fatty liver, inflammation, and chronic metabolic dysfunction so researchers can study disease mechanisms.”

[5] Yeah, or a high-PUFA mixed-fuel overload diet

Graham, Dalton S., Gang Liu, Ailar Arasteh, Xiao-Ming Yin, and Shengmin Yan. 2023. “Ability of High Fat Diet to Induce Liver Pathology Correlates with the Level of Linoleic Acid and Vitamin E in the Diet.” PLOS ONE 18 (6): e0286726. https://doi.org/10.1371/journal.pone.0286726.

Last, Allen R., and Stephen A. Wilson. 2006. “Low-Carbohydrate Diets.” American Family Physician 73 (11): 1942–48.

Research Diets, Inc. 2012. “D12450J Formula.” Advertisement. OpenSource Diets. https://researchdiets.com/formulas/d12450j.

Ricci, Matthew R, Michael A Pellizzon, Edward A Ulman, John Denier, and Eric Arlund. 2005. “Diet-Induced Obesity (DIO) Is Affected by Level of Dietary Fat and Gender in C57BL/6 Mice.” September. https://www.researchgate.net/profile/Michael-Pellizzon/publication/297568490_Diet-induced_obesity_DIO_is_affected_by_level_of_dietary_fat_and_gender_in_C57B16_mice/links/573c6b0708ae9ace840fd4d3/Diet-induced-obesity-DIO-is-affected-by-level-of-dietary-fat-and-gender-in-C57B1-6-mice.pdf.

Tzouanas, Constantine N., Jessica E. S. Shay, Marc S. Sherman, et al. 2025. “Hepatic Adaptation to Chronic Metabolic Stress Primes Tumorigenesis.” Cell 189 (0): 1–26. https://doi.org/10.1016/j.cell.2025.11.031.

You can find the original 5 pieces above for free.

D12492 is the most widely-used experimental diet to induce obesity. I’ve discussed it a number of times in the past, most notably in my big overview of what causes obesity:

But more recently here:

D12492 is great because it’s used in so many studies that the obesogenic component has been clearly isolated via a variety of methodologies—see above, but also here:

In a nutshell, if you remove the linoleic acid from a diet like D12492, and replace it with, say, sugar, saturated fat, or synthetic trans-fat, you get a diet that is less obesogenic (Alvheim, 2012, Kubant, 2015). There are a few other ways of skinning this cat, using different methods (surgery, drugs, genetic modification) but they all boil down to linoleic acid being the ingredient that causes obesity.

Physicians know this as well. If you ask a physician to prescribe something to make you gain weight, it’s a formula similar to D12492: seed oils and other stuff (Abbott, 2020).

So one could (and I have) spend lots of time reading various different papers and connecting the dots. But it’s tedious. To do, and to write about.

So I love seeing papers that do all the hard work. In this paper, they examine what happens when you give a specific type of mouse D12492’s less-bad older brother, D12451:

“The genesis of D12492 traces back to its predecessor, D12451, formulated in 1996 with a fat content of 45 kcal%. However, the scientific community needed a diet with even higher fat in the hope of accelerating and intensifying the onset of the obesity phenotype…”

So D12451 is just a less-obesogenic version of D12492. What effects does D12451 have?

“Translational Characterization of the Temporal Dynamics of Metabolic Dysfunctions in Liver, Adipose Tissue and the Gut During Diet-Induced NASH Development in Ldlr-/-.Leiden Mice” (Gart, 2023; all quotes are from here unless otherwise noted.)

Boy, that’s a mouthful, but it just means they put mice in a cage and fed them junk food, and watched what happened.

(NASH is non-alcoholic steatohepatitis, a more-advanced state of NAFLD. For the experienced readers out there, these are 94% the standard C57BL/6J mice, with a cross to knock out their LDL receptor.)

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I meant for the last post in this series to be, well, the last post. But I forgot to post this chart:

It’s important because it makes clear that these things are all happening in parallel. Obesity is not causing T2DM (Type 2 Diabetes Mellitus), rather they are both being caused by the same factor in the diet.

Similarly, inflammation (the red-bordered bars) is happening in parallel, starting in the gut and the lymphatic system.

It’s also important to note that the first measurement is at eight weeks, so while in fact some of these changes may be happening before others, they’re all happening pretty quickly.

Some of my favorite biomarkers/causes of these processes became detectable rather later. Mitochondrial dysfunction, tracked here by a decline from normal in adiponectin and mitochondrial biogenesis, happens at the 30-week measurement. 4-HNE increasing ‘significantly’ happens at 16 weeks, after both obesity and insulin resistance have already appeared. I suspect that’s because 4-HNE has overflowed the initial pathways, and starts becoming detectable, but that’s just my bias showing.

On that same observation, obesity appears at 8 weeks, but most of the biomarkers appear at 16 weeks (the second measurement) or later. DAGs, which can cause insulin resistance, reach ‘significance’ after insulin resistance; so to does oxLDL appear after hyperlipidemia. For the biomarkers where we have a pretty good idea of causation, this study finds them after what they supposedly cause has happened.

It suggests that statistical significance (once again) isn’t a good indicator of clinical significance. However, I used that as my breakpoint for normal/not-normal, as that’s what the paper used.

You’ll also notice that subcutaneous White Adipose Tissue (sWAT) stays ‘normal’.

“Hypertrophy in mWAT and sWAT is a much slower process and these depots do not appear to reach maximal expansion within the period studied.”

Hence crown-like structures (CLS) do not appear in those tissues. This may not be just a factor of time, but of species, as CLS are a typical feature of obese humans (scWAT=sWAT) (Fisk, 2020)

CLS have appeared in the livers of these mice by 16 weeks.

Mouse Time vs. Human Time

One of the most fundamental differences between people and mice is metabolic rate and thus lifespan. To make things more complicated, the relationship between mouse and human aging varies during lifespan.

In this study, the obesogenic diet was not administered until adulthood, which started at 16-17 weeks. Eight weeks to an adult mouse is equivalent to approximately 20 years to a human adult (2.6 mouse days = 1 human year, so 8 weeks (56 days) = ~21 years). Considering that a human is mature at about 20 years of age, we’re looking at an equivalent of 40 years old (in humans) for the first set of measurements at 8 weeks after maturity (in mice).

So, similar to a modern American, by the time these mice are an equivalent of 40 years old, they are obese, insulin resistant, and are developing fatty liver and heart disease.

It’s important to note that the effects of this diet are not immediate—they take time to manifest.

Of course modern humans don’t start the obesogenic diet at adulthood. So when you consider that non-alcoholic fatty liver disease didn’t exist prior to about 1980 (Ludwig, 1980), you can understand what is happening when you see headlines like this:

“Non-Alcoholic Fatty Liver Disease: A New Epidemic in Children” (Ciocca, 2016)

And That’s Not All!

Associated with these diseases are many other conditions.

“20 weeks of HF diet treatment induced marked obesity, glucose intolerance, and early osteoarthritis (OA), including osteophytes and cartilage tidemark duplication. (Barboza, 2017)

These authors examine the effect of D12492 vs. D12450B, high-Ω-6 fat vs. high sugar.

I discussed these diets in this post:

But you know by now that D12492 (high-fat, low-sucrose, HFLS) was most successful for inducing osteoarthritis.

Conclusion—For Now

It should be pretty clear that these diseases are not “associated”, they share a common cause. Excess dietary Ω-6 fats have consistent negative effects on all animals I’ve seen studied, especially including humans.

Reducing these fats in our diets should be the highest priority to fix out pandemic of chronic disease, or just to improve your own personal health.

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References

Barboza, Erika, Joanna Hudson, Wan-Pin Chang, et al. 2017. “Profibrotic Infrapatellar Fat Pad Remodeling Without M1 Macrophage Polarization Precedes Knee Osteoarthritis in Mice With Diet-Induced Obesity.” Arthritis & Rheumatology 69 (6): 1221–32. https://doi.org/10.1002/art.40056.

Ciocca, Mirta, Margarita Ramonet, and Fernando Alvarez. 2016. “Non-Alcoholic Fatty Liver Disease: A New Epidemic in Children.” Archivos Argentinos de Pediatria 114 (6): 563–69. https://doi.org/10.5546/aap.2016.eng.563.

Dutta, Sulagna, and Pallav Sengupta. 2016. “Men and Mice: Relating Their Ages.” Life Sciences 152 (May): 244–48. https://doi.org/10.1016/j.lfs.2015.10.025.

Fisk, Helena Lucy. 2021. “Adipose Tissue Inflammation in Obesity and the Influence of Marine Long Chain Polyunsaturated Omega-3 Fatty Acids.” PhD, University of Southampton. https://eprints.soton.ac.uk/449021/.

Ludwig, J., T. R. Viggiano, D. B. McGill, and B. J. Oh. 1980. “Nonalcoholic Steatohepatitis: Mayo Clinic Experiences with a Hitherto Unnamed Disease.” Mayo Clinic Proceedings 55 (7): 434–38.