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Charmed Substances
It’s been thirteen years this month since John Ioannidis published an article in PLoS Medicine entitled Why Most Published Research Findings Are False. Arguably, this article kicked off interest in the replication crisis. He’s back again, this time in JAMA, to warn us to be skeptical of nutrition research, as if we needed that warning. “The field needs radical reform.”
The majority of nutritional advice advocating the consumption or avoidance of specific foods (superfoods, killer foods) is based on epidemiological studies. Ioannidis notes that “…almost all foods revealed statistically significant associations with mortality risk.” Yet the causal connection is rarely established even as dietary recommendations are made based on such studies. Taken at face value, the results lead to unlikely conclusions that fail the sniff test:
Assuming the meta-analyzed evidence from cohort studies represents life span–long causal associations, for a baseline life expectancy of 80 years, eating 12 hazelnuts daily (1 oz) would prolong life by 12 years (ie, 1 year per hazelnut), drinking 3 cups of coffee daily would achieve a similar gain of 12 extra years, and eating a single mandarin orange daily (80 g) would add 5 years of life. Conversely, consuming 1 egg daily would reduce life expectancy by 6 years, and eating 2 slices of bacon (30 g) daily would shorten life by a decade, an effect worse than smoking. Could these results possibly be true?
One obvious logical error is that “much of the literature silently assumes disease risk is modulated by the most abundant substances; for example, carbohydrates or fats.” Since foods consist of dozens or hundreds of chemical constituents, this is naive. Even “seemingly similar foods vary in exact chemical signatures.”
Ioannidis observes that there is a precedent for such foolishness.
For decades, genome linkage scans struggled to link large chromosomal areas to disease risk. According to current knowledge, these previous efforts were doomed: each chromosomal area contains thousands of genetic variants. Linkage scans resulted in numerous articles, but limited useful information.
In short, the early work was bunk, and for similar reasons. There may be more wisdom about nutrition in a 45-year-old movie.
My favorite charmed substance is the egg. What are yours?
Published in Healthcare
Hunters in places as different as the Arctic and Tanzania (just off the top of my head) have been observed taking the small intestines of herbivores big enough to make it worthwhile, cutting out a hunk of the small intestine and sticking one end into their mouths and milking the partially digested vegetation into their mouth as a sort of ready to eat salad.
Nature’s own vitamax.
Then they crack the bones and suck out the marrow.
I could have gone my whole life without reading that!
Probably tastes like chicken ;). Actually the upper small intestine contents at least in ruminants are probably a bit tangy due to residual hydrochloric acid from the last stomach (abomasum,) though that’s just a partially digested guess.
Come to think of it, we have members who have undergone SERE and other advanced survival training who may be able to provide first hand experience.
There are scientific studies which establish a causal connection between elevated serum (blood) cholesterol and heart disease.
Patients with homozygous familial hypercholesterolemia have no LDL receptors in the liver and their total cholesterol levels from birth are usually greater than 800 mg/dL. The frequency of this genetic defect is 1 in 1 million. This subset of the population often suffers heart attacks before they are 20 years old.
Michael Brown and Joseph Goldstein were the ones who discovered the LDL receptor and received the Nobel Prize for doing so.
There is also another genetic defect, hypobetalipoproteinemia, which results in extremely low levels of LDL in the blood. People with this genetic mutation have 80 percent less risk of suffering a heart attack than the general population. With LDL levels so low, it is difficult for significant amounts of plaque to form within the cardiovascular system.
This, in addition to the information obtained from “Medical Marco Polos,” provided more evidence of the role of elevated LDL in the development of heart disease.
Correct. Michael Brown and Joseph Goldstein wrote about the way dietary saturated fat works to reduce the number of LDL receptors in the liver, resulting in elevated LDL in the blood.
In normal people (those without the genetic defect resulting in extremely low LDL levels), even a diet very low in saturated fat and dietary cholesterol could probably not bring LDL levels down to zero. If someone achieves low LDL levels by consuming a healthy diet and regular exercise, this would be a sign of health. However, if someone obtains low LDL levels because they have undiagnosed cancer, obviously the low LDL is not a sign of health.
Correct. Some researchers have developed equations whereby one can try to roughly calculate someone’s LDL based on their saturated fat and dietary cholesterol intake. Since there is genetic variation among people, this equation will not be perfectly accurate for everyone. But it will be close for most people.
Saturated fat intake impacts serum cholesterol levels more than dietary cholesterol does. So, here, we are in agreement.
I understand that you wanted mechanisms. I haven’t had a chance to get back to my computer to respond to your previous post.
Yes, you are correct that our liver synthesizes cholesterol. We agree.
I also agree that adjustment for confounding factors is an feature of research.
I mentioned that work of Dr. Conelius De Langen, the Dutch doctor assigned to the hospitals in the Dutch colonies 100 years ago as a way of introducing what many researchers believe was the first “diet-lipid” trial.
As for mechanisms, I think reading about the work of Michael Brown and Joseph Goldstein and their discovery of the LDL receptor and the way the production of LDL receptors are downregulated based on ones diet is one way of learning about one of the most powerful mechanisms impacting heart disease. But there isn’t just a single mechanism. High blood pressure and elevated blood glucose levels combined with high LDL levels will impact the cardiovascular system too.
To some extent, our discussion might have hit an epistemological wall in the sense that you could, if you wanted to, disagree with Nobel Prize winners Michael Brown and Joseph Goldstein and argue that their discovery of the LDL receptor is fraudulent. I would have no way of responding to that kind of accusation.
So, at some point, we have to determine which “experts” we think are credible. Some choose Nina Teicholz. I don’t.
As for me being a vegan or vegetarian. I don’t know if I would qualify as a vegan because a vegan is primarily concerned about the treatment of animals. I have, however, substantially cut back on my consumption of beef, chicken, pork, turkey, eggs, butter, cheese and yogurt. But I have not completely eliminated these foods from my diet throughout the year. These days those foods are more of special occasion thing, not something I eat every day. If that disqualifies me from weighing in on clinical nutrition, oh well.
The following from Chris Masterjohn is, I think a better understanding that what has been on the table so far:
In another related discussion, he points out that LDL receptor production is regulated by thyroid hormone… and that thyroid extract had a profound effect on heart disease in a study that predated Brown and Goldstein’s work by two decades, and which fits extremely well with LDL receptor genomics
Nah, the worst the cadre did to my group was make the female in our team suck the eyeball out of the skull of the rabbit we killed, before we skinned and stewed it.
Did you know rabbits scream when you attempt to wack the base of the skull with a club and don’t do it forcefully enough? Very disconcerting.
Yes, they do. A research group I worked for after college kept bunnies to use for protein preps. I saw what you’re talking about. The postdoc took the legs home for his wife to cook.
The even better deal was the marine biologist whose research required that he spend the summers on a dive boat in the Sea of Cortez. Or the guy whose research system involved a prep from lobster eyestalk muscle. The rest of the lobster (paid for by his grant, of course) was of no use to the lab so he would take it home for proper disposal.
The other group I worked for did mouse research. That was kind of nasty.
Scarred me for life. Mouse poop looks surprisingly like cardamom seeds and is about the same size.
That’s cardamom.
Since that job if I need cardamom seed I buy the pods.
@HeavyWater
Thank you for your response. Do you have a review article on the regulation of the LDL receptor handy?
My main concerns are with basal metabolic rate (how tissues determine what degree of energy is stored as fat versus kept available for burning) and sensation of satiation / appetite
Normal tissue level thyroid (tissue receptor density and sensitivity, and particularly in females (though males with central obesity often lose androgen dominance due to excessive conversion of testosterone to estrogen,) proper estrogen function.
Insulin and leptin sensitivity also affect fat storage. The thing the remember is that isocaloric ≠ isometabolic, and exactly what effect what macronutrients have depends on the underlying metabolic state. If you are insulin resistant and not keto-adapted, you will have problems with fat deposition at surprisingly low caloric intake, particularly if thyroid function (which mean not just TSH and T4 and maybe T3) are not optimal.
People who are extremely insulin resistant will have a hard time fasting until they ketoadapt and regain some insulin senistivity; insulin sensitivity is another (indirect) player with appetite, and there are multiple complex interactions such as leptin and ghrelin.
Many people who are a couple of years in on fat adaptation and good insulin sensitivity seem to be able to fast with little problem, and often with no hunger for 1-2 days. Part of the reason for satiety with fats is that fatty acids are stored in enterocytes and released over the next 12-18 hours.
And it’s much weirder than you think. Many people who undergo bariatric surgery regain insulin sensitivity very quickly… before they lose weight.
Thomas Seyfried is a researcher who began in the ketogenic diet/epilepsy space, has been active in understanding what the effects of metabolic ketosis are, and is working at some additional applications.
If you want to hear an interesting interview, Andrew Scarborough took Dr. Seyfried’s work to a new level in an n of 1 so far (5 years) successful attempt to deal with an anaplastic astrocytoma.
Scarborogh’s blog is here.
The role of thyroid hormones does not surprise me. Thyroid hyperactivity is associated with highly active metabolism, including high body temperature.
I would just google Brown and Goldstein LDL receptor. You’ll probably be able to quickly find PubMed articles on the LDL receptor and homozygous familial hypercholesterolemia. Or maybe find a cardiology text book at a used book store.
Here is a video of Michael Brown and Joseph Goldstein discussing Familial Hypercholesterolemia.
Brown and Goldstein (U Texas Southwestern): Molecular Basis of Familial Hypercholesterolemia
As you can see at the 1:50 mark, one patient they treated had a total serum cholesterol level of 850 mg/dL, had angina (chest pain) at age 3 and a heart attack at age 6.
The discussion runs about 20 minutes.
Apropos of nothing, I once heard an internist from an academic medical center spend over an hour of time in a basic medical biochemistry class discussing some rare inborn error of metabolism. It was interesting, and illustrated what goes wrong if some essential something or other is defective. Then one of the students asked a question:
That is a very true. And not only people with heart problems, but anyone who has taken a fall that has injured their head, in a way that blood circulation to the brain is no longer optimal. They certainly can experience a decline in the ability to think positive, to have decent short term memory recall and a host of other matters.
Also sometimes a decline in circulation to the brain occurs after an operation.
Here’s a lecture by Michael Brown of the Brown & Goldstein duo.
A Century of Cholesterol and Coronaries.
The lecture starts at about 5:30
First rule I learned in the lab is to never use a textbook. They are almost always outdated the moment they are written.
Review articles are where you go for background on a subject typically. Since you seemed to be focused on this topic, I figured you might have a few review articles already bookmarked.
Not really. I don’t usually bookmark the articles I read. I usually figure that if I need to read them again in the future, I can simply use the Google thingy and find them.
Most people I talk to about the relationship between nutrition and health aren’t really interested in biochemical reactions and the complexities of metabolism. They just want to know how to sort out the conflicting claims on the internet where 1,000 different people are saying 1,000 different things.
The news media, seeking readers and ratings, tells you that food X is healthy on Mondays, Wednesdays and Fridays, but unhealthy on the other days of the week. A non-expert has a tough time separating the nutrition cranks and scam artists and supplement salesmen from those who know what they are talking about.
Always leery of pronouncements where the cause/effect mechanism cannot be demonstrated.
To this I would offer 2 responses.
[1] Let’s do a thought experiment. You get home from work and turn on the television. You learn that today in the city you live in, 22 people have died. The age of death of these people range from 22 years old to 58 years old. There is one thing they all have in common: They all ate tilapia purchased at the local Whole Foods Market (WFM).
Your spouse gets home from work a half hour later and says, “I stopped at WFM on the way home. I’ve got some tilapia that we can cook for our dinner tonight.”
You could decide, since you don’t know the cause/effect mechanism by which the 22 people who ate WFM tilapia died, to go ahead and eat the tilapia. After all, correlation is not causation. The television news said that health authorities suspect that the WFM tilapia caused these 22 deaths. But they don’t know for sure. And they don’t know exactly what in the tilapia caused these deaths. Maybe there are all kinds of confounding factors involved. Maybe they all drank tainted energy drinks that morning and the WFM tilapia had nothing to do with their deaths.
When it comes to the relationship between serum (blood) cholesterol and cardiovascular disease, it’s much more complicated than the WFM tilapia situation. In normal people, elevated levels of blood cholesterol cause cardiovascular disease over a period of decades, not over the course of a single meal. And given other risk factors such as smoking, high blood pressure and high fasting glucose levels, some people with blood cholesterol levels of 240 mg/dL will die of cancer instead of a heart attack while some people with blood cholesterol levels of 170 mg/dL will die of heart attacks. Some people with certain genetics will have high blood cholesterol levels and live to be 102 years old.
But if you are 50 years old and have 2 young daughters and you are the only income earner for the family, you might go ahead and look at the data showing a correlation between high blood cholesterol over ones lifetime (not just during a single blood draw) and heart disease incidence and decide to figure out (healthy) ways to bring your blood cholesterol levels down. If you give yourself a chance to live longer, you might eventually learn the biochemistry and the physiology required to understand the detailed cause/effect mechanisms involved in heart disease or if these subjects bore you, you could just use the extra years on earth enjoying time with your daughters.
What I am saying is that we don’t normally remain 100 percent agnostic about issues like this until 100 percent of the information is known. I’ll get to my 2nd response in the next comment.
Here is my 2nd response. I found a paper written by the Nobel Prize winners Michael Brown and Joseph Goldstein titled A Receptor Mediated Pathway for Cholesterol Homeostasis. It’s in pdf form. But I’ll post an excerpt from it.
You might want to read the whole thing or just the excerpt I quoted here.
A proactive approach, involving more than cholesterol:
fasting blood sugar 85-95
Hemoglobin A1c < 5.7, ideally low 5s or high 4s.
Fasting insulin <5.0
High sensitivity C-Reactive Protein; target value < 0.55 in men.
Homocysteine < 7.2 . This is also an indication of B12, folate and other B vitamin issues and is an independent cardiovascular disease and cognitive decline risk factor. Studies so far lowering it with B vitamin supplementation haven’t showed a lowered disease risk but current thinking is that the lab reference range is too high and the optimum is in the range I mentioned.
Better cardiovascular disease predictors than total cholesterol: Triglyceride:HDL ratio; should be <2; 6 or more is alarming. Red blood cell omega 3:omega 6 ratio in conjunction with total levels may be a useful predictor; permits fine tuning of polyunsaturate intake.
Vitamin D50-60; if you have any inflammatory or autoimmune disease: also test parathyroid hormone and supplement with D until PTH is in the lower 1/2 (good) or 1/3 (better) of the lab reference range. Also about 100µg/d ± of vitamin K2 (unless you’re on blood thinners that preclude messing with green veg intake.) Liver, egg yolks for animal source vitamin A. If you need to take a lot of D, also take retinyl or retinol palmitate vitamin A supplements and a broad spectrum vitamin E supplement.
Ferritin: men, postmenopausal women: 33-263. Cycling women, 10-122. If you have a lot of inflammation, consider giving blood to keep it in the lower end of normal and see if that makes a difference. Or if it makes you more tired. YMMV.
If blood sugar is
JERF: Just Eat Real Food.
Unless critical labs are way off, use real food first before high doses of supplementation.
Leafy greens. Every color, especially dark blue and purple. (Skittles and M&Ms don’t count.) Protein intake should include organ meats, such as liver, heart, etc. About 20-30% of the US population does a lousy job of converting carotenoids to vitamin A, and will not do well long term as a vegan or evan a vegetarian.
My half kidding mini medical history for men:
I’ve found that sometimes the more a person talks, the less that person says.
Isn’t that weird..?
This is a must-post video: