Monday, May 20, 2013

Sudden cholesterol increase? It may be psychological

There are many published studies with evidence that cholesterol levels are positively associated with heart disease. In multivariate analyses the effects are usually small, but they are still there. On the other hand, there is also plenty of evidence that cholesterol is beneficial in terms of health. Here of course I am referring to the health of humans, not of the many parasites that benefit from disease.

For example, there is evidence () that cholesterol levels are negatively associated with mortality (i.e., higher cholesterol leading to lower mortality), and are positively associated with vitamin D production from skin exposure to sunlight ().

Most of the debris accumulated in atheromas are made up of macrophages, which are specialized cells that “eat” cell debris (ironically) and some pathogens. The drug market is still hot for cholesterol-lowering drugs, often presented in TV and Internet ads as effective tools to prevent formation of atheromas.

But what about macrophages? What about calcium, another big component of atheromas? If drugs were to target macrophages for atheroma prevention, drug users may experience major muscle wasting and problems with adaptive immunity, as macrophages play a key role in muscle repair and antibody formation. If drugs were to target calcium, users may experience osteoporosis.

So cholesterol is the target, because there is a “link” between cholesterol and atheroma formation. There is also a link between the number of house fires in a city and the amount of firefighting activity in the city, but we don’t see mayors announcing initiatives to reduce the number of firefighters in their cities to prevent house fires.

When we talk about variations in cholesterol, we usually mean variations in cholesterol carried by LDL particles. That is because LDL cholesterol seems to be very “sensitive” to a number of factors, including diet and disease, presenting quite a lot of sudden variation in response to changes in those factors.

LDL particles seem to be intimately involved with disease, but do not be so quick to conclude that they cause disease. Something so widespread and with so many functions in the human body could not be primarily an agent of disease that needs to be countered with statins. That makes no sense.

Looking at the totally of evidence linking cholesterol with health, it seems that cholesterol is extremely important for the human body, particularly when it is under attack. So the increases in LDL cholesterol associated with various diseases, notably heart disease, may not be because cholesterol is causing disease, but rather because cholesterol is being used to cope with disease.

LDL particles, and their content (including cholesterol), may be used by the body to cope with conditions that themselves cause heart disease, and end up being blamed in the process. The lipid hypothesis may be a classic case of reverse causation. A case in point is that of cholesterol responses to stress, particularly mental stress.

Grundy and Griffin () studied the effects of academic final examinations on serum cholesterol levels in 2 groups of medical students in the winter and spring semesters (see table below). During control periods, average cholesterol levels in the two groups were approximately 213 and 216 mg/dl. During the final examination periods, average cholesterol levels were 248 and 240 mg/dl. These measures were for winter and spring, respectively.

One could say that even the bigger increase from 213 to 248 is not that impressive in percentage terms, approximately 16 percent. However, HDL cholesterol does not go up significantly response to sustained (e.g., multi-day) stress, it actually goes down, so the increases reported can be safely assumed to be chiefly due to LDL cholesterol. For most people, LDL particles are the main carriers of cholesterol in the human body. Thus, in percentage terms, the increases in LDL cholesterol are about twice those reported for total cholesterol.

A 32-percent increase (16 x 2) in LDL cholesterol would not go unnoticed today. If one’s LDL cholesterol were to be normally 140 mg/dl, it would jump to 185 mg/dl with a 32-percent increase. It looks like the standard deviations were more than 30 in the study. (This is based on the standard errors reported, and assuming that the standard deviation equals the standard error multiplied by the square root of the sample size.) So we can guess that several people might go from 140 to 215 or more (this is LDL cholesterol, in mg/dl) in response to the stress from exams.

And the effects above were observed with young medical students, in response to the stress from exams. What about a middle-aged man or woman trying to cope with chronic mental stress for months or years, due to losing his or her job, while still having to provide for a family? Or someone who has just been promoted, and finds himself or herself overwhelmed with the new responsibilities?

Keep in mind that sustained dieting can be a major stressor for some people, particular when one gets to that point in the dieting process where he or she gets regularly into negative nitrogen balance (muscle loss). So you may have heard from people saying that, after months or years of successful dieting, their cholesterol levels are inexplicably going up. Well, this post provides one of many possible explanations for that.

The finding that cholesterol goes up with stress has been replicated many times. It has been known for a long time, with studies dating back to the 1950s. Wertlake and colleagues () observed an increase in average cholesterol levels from 214 to 238 (in mg/dl); also among medical students, in response to the mental and emotional stress of an examination week. A similar study to the one above.

Those enamored with the idea of standing up the whole day, thinking that this will make them healthy, should know that performing cognitively demanding tasks while standing up is a known stressor. It is often used in research where stress must be induced to create an experimental condition. Muldoon and colleagues () found that people performing a mental task while standing experienced an increase in serum cholesterol of approximately 22 points (in mg/dl).

What we are not adapted for is sitting down for long hours in very comfortable furniture (, ). But our anatomy clearly suggests adaptations for sitting down, particularly when engaging in activities that resemble tool-making, a hallmark of the human species. Among modern hunter-gatherers, tool-making is part of daily life, and typically it is much easier to accomplish sitting down than standing up.

Modern urbanites could be seen as engaging in activities that resemble tool-making when they produce things at work for internal or external customers, whether those things are tangible or intangible.

So, stress is associated with cholesterol levels, and particularly with LDL cholesterol levels. Diehard lipid hypothesis proponents may argue that this is how stress is associated with heart disease: stress increases cholesterol which increases heart disease. Others may argue that one of the reasons why LDL cholesterol levels are sometimes found to be associated with heart disease-related conditions, such as chronic stress, and other health conditions is that the body is using LDL cholesterol to cope with those conditions.

Specifically regarding mental stress, a third argument has been put forth by Patterson and colleagues, who claimed that stress-mediated variations in blood lipid concentrations are a secondary result of decreased plasma volume. The cause, in their interpretation, was unspecified – “vascular fluid shifts”. However, when you look at the numbers reported in their study, you still see a marked increase in LDL cholesterol, even controlling for plasma volume. And this is all in response to “10 minutes of mental arithmetic with harassment” ().

I tend to think that the view that cholesterol increases with stress because cholesterol is used by the body to cope with stress is the closest to the truth. Among other things, stress increases the body’s overall protein demand, and cholesterol is used in the synthesis of many proteins. This includes proteins used for signaling, also known as hormones.

Cholesterol also seems to be a diet marker, tending to go up in high fat diets. This is easier to explain. High fat diets increase the demand for bile production, as bile is used in the digestion of fat. Most of the cholesterol produced by the human body is used to make bile.

Tuesday, May 7, 2013

The Neurobiology of the Obesity Epidemic

I recently read an interesting review paper by Dr. Edmund T. Rolls titled "Taste, olfactory and food texture reward processing in the brain and the control of appetite" that I'll discuss in this post (1).  Dr. Rolls is a prolific neuroscience researcher at Oxford who focuses on "the brain mechanisms of perception, memory, emotion and feeding, and thus of perceptual, memory, emotional and appetite disorders."  His website is here.

The first half of the paper is technical and discusses some of Dr. Rolls' findings on how specific brain areas process sensory and reward information, and how individual neurons can integrate multiple sensory signals during this process.  I recommend reading it if you have the background and interest, but I'm not going to cover it here.  The second half of the paper is an attempt to explain the obesity epidemic based on what he knows about the brain and other aspects of human biology.

Read more »

Monday, May 6, 2013

Trip to South Korea: Hidden reasons for the leanness of its people

In September last year (2012) I went to South Korea to speak about nonlinear data analysis with WarpPLS (), initially for business and engineering faculty and students at Korea University in Seoul, and then as a keynote speaker at the HumanCom 2012 Conference () in Gwangju. Since Seoul is in the north part of the country, and Gwangju in the south, I had the opportunity to see quite a lot of the land and the people in this beautiful country.

(Korea University’s main entrance, Anam campus)

(In front of Korea University’s main Business School building)

Korea University is one of the most prestigious universities in South Korea. In the fields of business and engineering, it is arguably the most prestigious. It also has a solid international reputation, attracting a large number of highly qualified foreign students.

I wanted to take this opportunity and try to understand why obesity prevalence is so low in South Korea, which is a common characteristic among Southeast Asian countries, even though the caloric intake of South Koreans seems to be relatively high. Foods that are rich in carbohydrates, such as rice, are also high-calorie foods. At 4 calories per gram, carbohydrates are not as calorie-dense as fats (9 calories per gram), but they sure add up and can make one obese.

Based on my observations, explanations for the leanness that are too obvious or that focus on a particular dietary item (e.g., kimchi, green tea etc.) tend to miss the point.

Let us take for example a typical South Korean meal, like the one depicted in the photos below, which we had at a restaurant in Seoul. If you are a foreigner, this type of meal would be difficult to have without a local accompanying you, because it is not easy to make yourself understood in a traditional restaurant in South Korea speaking anything other than Korean.

(Main items of a traditional South Korean meal)

(You cook your own meal)

The meal started with thin-sliced meat (with some fat, but not much) and vegetables, with the obligatory side dishes, notably kimchi (). This part of the meal was low in calories and high in nutrients. Then we had two high-calorie low-nutrient items: noodles and rice. The rice was used in the end to soak up the broth left in the pot, so it ended adding to the nutrition value of the meal.

Because we started the meal with the low-calorie high-nutrient items, the meat and vegetables, our consumption of noodles and rice was not as high as if we had started the meal with those items. In a meal like this, a good chunk of calories would come from the carbohydrate-rich items. Still, it seems to me that we ingested plenty of calories, enough to make one fat over the long run, eating these types of meals regularly.

A side note. As I said here before, the caloric value of protein is less than the commonly listed 4 calories per gram, essentially because protein is a multi-purpose macronutrient.

In our meal, the way in which at least one of the carbohydrate-rich items was prepared possibly decreased its digestible carbohydrate content, and thus its calorie content, in a significant way. I am referring to the rice, which had been boiled, cooled and stored, way before it was re-heated and served. This likely turned some of its starch content into resistant starch (). Resistant starch is essentially treated by our digestive system as fiber.

Another factor to consider is the reduction in the glycemic load (not to be confused with glycemic index) of the rice. As I noted, the rice was used to soak up the broth from the pot. This soaking up process significantly reduces the rice’s glycemic load, because of a unique property of rice. It has an amazing capacity of absorbing liquid and swelling in the process.

This was one of several traditional Korean meals I had, and all of them followed a similar pattern in terms of the order in which the food items were consumed, and the way in which the carbohydrate-rich items were prepared. The order in which you eat foods affects your calorie intake because if you eat high nutrient-to-calorie ratio foods before, and leave the low nutrient-to-calorie ones for later, my experience is that you will eat less of the latter.

Another possible hidden reason for the low rate of obesity in South Korea is what seems to be a cultural resistance to industrialized foods, particularly among older generations; a sort of protective cultural inertia, if you will. Those foods are slowly being adopted – my visit left me with that impression – by not as quickly as in other countries. And there is overwhelming evidence that consumption of highly industrialized foods, especially those rich in refined carbohydrates and sugars, is a major cause obesity and a host of other problems.

Cultural resistance to, or cultural inertia against the adoption of, highly industrialized foods among pregnant mothers limits one’s exposure to those foods at a particularly critical time in one’s life – the 9-month gestation period in the mother’s womb. This could have a major impact on a person’s propensity to become obese or have other metabolic derangements later on in life. Some refer to this phenomenon as a classic example of modern epigenetics, whereby acquired traits appear to induce innate traits across generations.

Another reason I was excited about this trip to South Korea was my interest in table tennis. I wanted to know more about their table tennis “culture”, and how it was influenced by their general culture. China dominates modern table tennis, with such prodigies as Ma Lin, Ma Long, Wang Hao, Wang Liqin, and Zhang Jike. South Korea is not far behind; two of my all-time favorite South Korean players are Kim Taek-Soo and former Olympic champion Ryu Seung-Min.

Another side note. The best table tennis player of all time is arguably Jan-Ove Waldner (), from Sweden. I talked about him in my book on compensatory adaptation (). Waldner has been one of the few players outside China to be able to consistently beat the best Chinese players at times when they were at the top of the games, including Ma Lin ().

But, as I soon learned, as far as sports are concerned, it is not table tennis that most South Koreans are interested in these days. It is soccer.

A nice surprise during this trip was a tour in Gwangju in which we visited a studio that converted standard movies to stereoscopic three-dimensional ones (photo below). These folks were getting a lot of business, particularly from the USA, in a market that is very competitive.

(A standard-to-3D movie conversion studio in Gwangju)

Let’s get back to the health angle of the post. So there you have it, two possible “hidden” reasons for the low prevalence of obesity in South Korea, and maybe in other Southeast Asian countries. One is the way in which foods are prepared and consumed, and the other is cultural inertia. These are not very widely discussed, but future research may change that.

Thursday, May 2, 2013

Speaking at AHS13

The 2013 Ancestral Health Symposium will be held in Atlanta, GA, August 14-17.  Last year was a great conference, and I look forward to more informative talks and networking.  Tickets go fast, so reserve yours now if you plan to attend!

This year, I'll be speaking on insulin and obesity.  My talk will be titled "Insulin and Obesity: Reconciling Conflicting Evidence".  In this talk, I'll present the evidence for and against the idea that elevated insulin contributes to the development of obesity.  One hypothesis states that elevated insulin contributes to obesity, while the other states that elevated insulin is caused by obesity and does not contribute to it.  Both sides of the debate present evidence that appears compelling, and it often seems like each side is talking past the other rather than trying to incorporate all of the evidence into a larger, more powerful model.

There's a lot evidence that can be brought to bear on this question, but much of it hasn't reached the public yet.  I'll explore a broad swath of evidence from clinical case studies, observational studies, controlled trials, animal research, physiology, and cell biology to test the two competing hypotheses and outline a model that can explain all of the seemingly conflicting data.  Much of this information hasn't appeared on this blog.  My goal is to put together a talk that will be informative to a researcher but also accessible to an informed layperson.

On a separate note, my AHS12 talk "Digestive Health, Inflammation and the Metabolic Syndrome" has not been posted online because the video recording of my talk has mysteriously disappeared.  I think many WHS readers would be interested in the talk, since it covers research on the important and interdependent influence of gut health, inflammation, and psychological stress on the metabolic syndrome (the quintessential modern metabolic disorder).  I'm going to try to find time to make a narrated slideshow so I can post it on YouTube.