Monday, February 25, 2013

Could the low testosterone problem be a mirage?

Low testosterone (a.k.a. “low T”) is caused by worn out glands no longer able to secrete enough T, right? At least this seems to be the most prevalent theory today, a theory that reminds me a lot of the “tired pancreas” theory () of diabetes. I should note that this low T problem, as it is currently presented, is one that affects almost exclusively men, particularly middle-aged men, not women. This is so even though T plays an important role in women’s health.

There are many studies that show associations between T levels and all kinds of diseases in men. But here is a problem with hormones: often several hormones vary together and in a highly correlated fashion. If you rely on statistics to reach conclusions, you must use techniques that allow you to rule out confounders; otherwise you may easily reach wrong conclusions. Examples are multivariate techniques that are sensitive to Simpson’s paradox and nonlinear algorithms; both of which are employed, by the way, by modern software tools such as WarpPLS (). Unfortunately, these are rarely, if ever, used in health-related studies.

Many low T cases may actually be caused by something other than tired T-secretion glands, perhaps a hormone (or set of hormones) that suppress T production; a T “antagonist”. What would be a good candidate? The figure below shows two graphs. It is from a study by Starks and colleagues, published in the Journal of the International Society of Sports Nutrition in 2008 (). The study itself is not directly related to the main point that this post tries to make, but the figure is.

Look at the two graphs carefully. The one on the left is of blood cortisol levels. The one on the right is of blood testosterone levels. Ignore the variation within each graph. Just compare the two graphs and you will see one interesting thing – cortisol and testosterone levels are inversely related. This is a general pattern in connection with stress-induced cortisol elevations, repeating itself over and over again, whether the source of stress is mental (e.g., negative thoughts) or physical (e.g., intense exercise).

And the relationship between cortisol and testosterone is strong. Roughly speaking, an increase in cortisol levels, from about 20 to 40 μg/dl, appears to bring testosterone levels down from about 8 to 5 ηg/ml. A level of 8 ηg/ml (the same as 800 ηg/dl) is what is normally found in young men living in urban environments. A level of 5 ηg/ml is what is normally found in older men living in urban environments.

So, testosterone levels are practically brought down to almost half of what they were before by that variation in cortisol.

Chronic stress can easily bring your cortisol levels up to 40 μg/dl and keep them there. More serious pathological conditions, such as Cushing’s disease, can lead to sustained cortisol levels that are twice as high. There are many other things that can lead to chronically elevated cortisol levels. For instance, sustained calorie restriction raises cortisol levels, with a corresponding reduction in testosterone levels. As the authors of a study () of markers of semistarvation in healthy lean men note, grimly:

“…testosterone (T) approached castrate levels …”

The study highlights a few important phenomena that occur under stress conditions: (a) cortisol levels go up, and testosterone levels go down, in a highly correlated fashion (as mentioned earlier); and (b) it is very difficult to suppress cortisol levels without addressing the source of the stress. Even with testosterone administration, cortisol levels tend to be elevated.

Isn't possible that cortisol levels go up because testosterone levels go down - reverse causality? Possible, but unlikely. Evidence that testosterone administration may reduce cortisol levels, when it is found, tends to be rather weak or inconclusive. A good example is a study by Rubinow and colleagues (). Not only were their findings based on bivariate (or unadjusted) correlations, but also on a chance probability threshold that is twice the level usually employed in statistical analyses; the level usually employed is 5 percent.

Let us now briefly shift our attention to dieting. Dieting is the main source of calorie restriction in modern urban societies; an unnatural one, I should say, because it involves going hungry in the presence of food. Different people have different responses to dieting. Some responses are more extreme, others more mild. One main factor is how much body fat you want to lose (weight loss, as a main target, is a mistake); another is how low you expect body fat to get. Many men dream about six-pack abs, which usually require single-digit body fat percentages.

The type of transformation involving going from obese to lean is not “cost-free”, as your body doesn’t know that you are dieting. The body “sees” starvation, and responds accordingly.

Your body is a little bit like a computer. It does exactly what you “tell” it to do, but often not what you want it to do. In other words, it responds in relatively predictable ways to various diet and lifestyle changes, but not in the way that most of us want. This is what I call compensatory adaptation at work (). Our body often doesn’t respond in the way we expect either, because we don’t actually know how it adapts; this is especially true for long-term adaptations.

What initially feels like a burst of energy soon turns into something a bit more unpleasant. At first the unpleasantness takes the form of psychological phenomena, which were probably the “cheapest” for our bodies to employ in our evolutionary past. Feeling irritated is not as “expensive” a response as feeling physically weak, seriously distracted, nauseated etc. if you live in an environment where you don’t have the option of going to the grocery store to find fuel, and where there are many beings around that can easily kill you.

Soon the responses take the form of more nasty body sensations. Nearly all of those who go from obese to lean will experience some form of nasty response over time. The responses may be amplified by nutrient deficiencies. Obesity would have probably only been rarely, if ever, experienced by our Paleolithic ancestors. They would have never gotten obese in the first place. Going from obese to lean is as much a Neolithic novelty as becoming obese in the first place, although much less common.

And it seems that those who have a tendency toward mental disorders (e.g., generalized anxiety, manic-depression), even if at a subclinical level under non-dieting conditions, are the ones that suffer the most when calorie restriction is sustained over long periods of time. Most reports of serious starvation experiments (e.g., Roy Walford’s Biosphere 2 experiment) suggest the surfacing of mental disorders and even some cases of psychosis.

Emily Deans has a nice post () on starvation and mental health.

But you may ask: What if my low T problem is caused by aging; you just said that older males tend to have lower T? To which I would reply: Isn’t possible that the lower T levels normally associated with aging are in many cases a byproduct of higher stress hormone levels? Take a look at the figure below, from a study of age-related cortisol secretion by Zhao and colleagues ().

As you can see in the figure, cortisol levels tend to go up with age. And, interestingly, the range of variation seems very close to that in the earlier figure in this post, although I may be making a mistake in the conversion from nmol/l to ηg/ml. As cortisol levels go up, T levels should go down in response. There are outliers. Note the male outlier at the middle-bottom part, in his early seventies. He is represented by a filled circle, which refers to a disease-free male.

Dr. Arthur De Vany claims to have high T levels in his 70s. It is possible that he is like that outlier. If you check out De Vany’s writings, you’ll see his emphasis on leading a peaceful, stress-free, life (). If money, status, material things, health issues etc. are very important for you when you are young (most of us, a trend that seems to be increasing), chances are they are going to be a major source of stress as you age.

Think about individual property accumulation, as it is practiced in modern urban environments, and how unnatural and potentially stressful it is. Many people subconsciously view their property (e.g., a nice car, a bunch of shares in a publicly-traded company) as their extended phenotype. If that property is damaged or loses value, the subconscious mental state evoked is somewhat like that in response to a piece of their body being removed. This is potentially very stressful; a stress source that doesn’t go away easily. What we have here is very different from the types of stress that our Paleolithic ancestors faced.

So, what will happen if you take testosterone supplementation to solve your low T problem? If your problem is due to high levels of cortisol and other stress hormones (including some yet to be discovered), induced by stress, and your low T treatment is long-term, your body will adapt in a compensatory way. It will “sense” that T is now high, together with high levels of stress.

Whatever form long-term compensatory adaptation may take in this scenario, somehow the combination of high T and high stress doesn’t conjure up a very nice image. What comes to mind is a borderline insane person, possibly with good body composition, and with a lot of self-confidence – someone like the protagonist of the film American Psycho.

Again, will the high T levels, obtained through supplementation, suppress cortisol? It doesn’t seem to work that way, at least not in the long term. In fact, stress hormones seem to affect other hormones a lot more than other hormones affect them. The reason is probably that stress responses were very important in our evolutionary past, which would make any mechanism that could override them nonadaptive.

Today, stress hormones, while necessary for a number of metabolic processes (e.g., in intense exercise), often work against us. For example, serious conflict in our modern world is often solved via extensive writing (through legal avenues). Violence is regulated and/or institutionalized – e.g., military, law enforcement, some combat sports. Without these, society would break down, and many of us would join the afterlife sooner and more violently than we would like (see Pinker’s take on this topic: ).

Sir, the solution to your low T problem may actually be found elsewhere, namely in stress reduction. But careful, you run the risk of becoming a nice guy.

Monday, February 11, 2013

The War of the End of the World: The health puzzle posed by its survivors

The War of Canudos took place in Brazil in 1896 and 1897. Canudos was a settlement of several thousand deeply religious Christians, led by a man known as Antonio Conselheiro. They opposed the recent establishment of the Republic of Brazil, particularly the institution of income taxes and civil marriage; the former was considered government-sponsored theft and the latter a sacrilege. The republic had been declared in 1889 following a military coup that deposed Dom Pedro II, an emperor beloved by the common people and under whose rule slavery had recently been abolished.

Canudos was located in the Brazilian sertão, an inhospitable semi-arid region in the northeastern part of the country. The inhabitants of Canudos were the sertanejos. The term jagunço was used to refer to the males, especially the outlaws. Many of the sertanejos lived in semi-starvation, in poor sanitary conditions, and with very limited (if any) access to healthcare. Infant mortality was very high at the time. Those who reached adulthood were typically of small stature, and very thin; not lean, thin – often described as “skin and bones”.

Below is what a typical young jagunço would look like at the time of the War of Canudos. (Some authors differentiate between jagunços and cangaceiros based on small differences in cultural and dress traditions; e.g., the hat in the photo is typical of cangaceiros.) The jagunços tended to be the best fed among the sertanejos. They were also known as cold-blooded killers. The photo is a cropped version of the original one; the grizzly original is at the top of a recent blog post by Juan Pablo Dabove (). The blog post discusses Vargas Llosa’s historical fiction book based on the War of Canudos, the masterpiece titled “The War of the End of the World” ().

Jorge Mario Pedro Vargas Llosa, a Peruvian-Spanish writer and politician, was the recipient of the 2010 Nobel Prize in Literature; “The War of the End of the World” is considered one of his greatest literary achievements. Euclides da Cunha wrote the most famous non-fictional account on the War of Canudos, another masterpiece that has been called “Brazil’s greatest book”, titled “Rebellion in the Backlands” (). The Portughese title is “Os Sertões”. Vargas Llosa’s book is based on da Cunha’s.

Sergio Rezende’s movie, “Guerra de Canudos” (), is a superb dramatization of the War of Canudos. I watched this movie after reading Vargas Llosa’s and da Cunha’s books, and was struck by two things: (a) the outstanding performances, especially by José Wilker, Cláudia Abreu, Marieta Severo, and Paulo Betti; and (b) the striking resemblance of the latter (Betti) to Royce Gracie (), a very nice man whom I interviewed () for my book on compensatory adaptation (), and who is no stranger to Ultimate Fighting Championship and mixed martial arts fans ().

In a nutshell, the War of Canudos went more or less like this. There were four military campaigns against the settlement. The third was a major one, led by one of Brazil’s most accomplished military leaders at the time, Colonel Antônio Moreira César. The jagunços, resorting to guerrilla warfare, fought off the government troops in the first three. The fourth, led by General Arthur Oscar de Andrade Guimarães, saw the jagunços defeated in a war of attrition primarily due to lack of access to food and water, after heavy losses among government troops. At the end, nearly all of the surviving jagunços were executed, by knife – to their absolute horror, and the perverse pleasure of the executioners bent on revenge, as the victims believed that they would not go to heaven if their lives were ended by knife, even against their will.

Ned, what is your point regarding health!?

After going through numerous sources, paper-based and online, academic and non-academic, I am convinced that a significant number of the survivors of the Canudos War lived to their 90s and beyond. This conclusion is based chiefly on comparisons of various dates, especially of interviews with survivors. No single source dedicated to this particular health-related aspect of the War of Canudos seems to exist. There is a video clip that shows some of the survivors (), speaking in Portuguese, with their ages shown in subtitles (“years”, in Portuguese, is “anos”). One of them, a man, is listed as being a supercentenarian.

In modern USA those who live to the age of 90 and beyond are outliers. Less than 2 percent of the population reach the age of 90 (). Most of them are women. My impression is that among the survivors of the War of Canudos, the 90+ percentage was at least 5 times higher; even with access to sanitation and healthcare in modern USA being much better at any age.

If my impression is correct, how can it be explained?

I think that some of the readers of this blog will be tempted to explain the high longevity based on calorie restriction. But the empirical evidence suggests that poor nutrition, in terms of micronutrients and macronutrients, is associated with increased mortality, not the other way around (, , ). Mortality due to poor nutrition is frequently from infectious diseases, in the young and the old. Degenerative diseases are widespread among the overnourished, not the well nourished, and kill mostly at later ages. It is not uncommon for infectious diseases to “mask” as degenerative diseases – e.g., viral diabetes ().

Often people point at hunter-gatherer populations and argue that they are healthy because of their low calorie intake. But mortality from infectious diseases among hunter-gatherers is very high, particularly in children. Others point to the absence of industrial foods engineered for overconsumption, which I think is definitely a factor in terms of degenerative diseases. Some say that a main factor is retention of lean body mass as one ages, referring mostly to muscle tissue, a hypothesis to which the case of the sertanejos poses a problem – what lean body mass!? And, on top of all of their problems, the sertanejos regularly faced long droughts, which may be why they typically had a “dry” look.

Yet others point to low stress. It is reasonable to think that stress is a mediating factor in the development of many modern diseases. Still, the sertanejos living in Canudos have had to endure quite a lot of stress, before and after the War of Canudos. In fact, the depictions of their lives at around the time of the War of Canudos suggest very stressful, miserable lives, prior to the conflict; which in part explains the early success of a religious settlement where life was marginally better.

By the way, the traditional Okinawans have also endured plenty of stress (), and they have had the highest longevity rates in recorded history. Food scarcity has frequently been combined with stress in their case, as with many other long-living groups. Causality is complex here, probably changing direction in different subsets of the data, but I have long suspected that the combination of stress and overnourishment is a particular unnatural one, to which humans are badly maladapted.

A main factor is almost always forgotten: the effective immune systems of those who have been subjected to starvation, poor sanitation, lack of healthcare, and other challenges – especially in childhood – and survived to adulthood. And here some counterintuitive things can happen. For example, someone may be very sickly early in life and barely survive childhood, and then become very resistant to infectious diseases later, thus appearing to be very healthy, to the surprise of relatives and friends who remember “that sickly child”. Immunocompetence is something that the body builds up in response to exposure.

As they say in northeastern Brazil, in characteristic drawl: “Ol’ sihtaneju ain’t die easy”.