The Truth About The Genetics Of Obesity.

Evolutionary selection favored those who became fat easily. That's the essence of the "thrifty gene hypothesis". It's like Madonna. On the wrong side of 50, and ripe to be dethroned by something with greater sex appeal. In this case the contender's name is the "drifty gene hypothesis". Here is why you shouldn't be too dazzled about it. [tweet this].    

Exactly 50 years ago, Neel suggested that the high rate of diabetes in our society is the result of  evolutionary selection which favored those of our ancestors whose genes made them store fat more efficiently during periods of food abundance [1]. It's such a marvelously simple explanation that it doesn't take the brains of an Einstein to chatter about it at any dinner party where one wants to be remembered as quite the hobby geneticist. But to every party there is a party pooper. In this case two of them. John R. Speakman and Klaas R. Westerterp are telling us that the high prevalence rate of obesity and diabetes actually disproves the thrifty gene hypothesis [2].

In a nutshell their argument goes like this: our human and hominin ancestors have gone through so many feast and famine cycles over the past 2 million years, that, if it was for genetic selection, we should by now all be carriers of the genes that made caveman survive and modern man fat and diabetic. Since this is clearly not the case, the TGH can't be correct. 

I'm a sucker for theories which challenge common wisdoms, so I enthusiastically read the authors' arguments. Now, let's see how this enthusiasm evaporated.

To a considerable extent, obesity is determined by genes. If you want to put a number on it, genetic factors explain about 60% of the variance in obesity metrics, such as the body mass index (BMI). That's the numbers we are getting from studies, which compare such metrics between identical twins and other sibling types [3]. Just as an aside: When you consider genes as the one condition which you can't change, 60% heritability still leaves a lot of wiggling room for you to fashion your own fate. That's good because obesity comes with a host of nasty diseases, none of which makes your life longer or more pleasant. Think diabetes. Of course, you know all that, and it is not really our subject here. We want to know why there is such a high prevalence of obesity prone people.

To answer this question Speakman and Westerterp compiled some insights from genetics and put them through a mathematical blender. That sounds far simpler than it really was. For that blender to give you an intelligent answer you need to feed it with intelligent data. Otherwise it's the old nonsense-in-nonsense-out" paradigm. In our case at hand there are three data segments which need to be considered. 

First, there is biology: what happens to a human organism when it is exposed to fasting? How long will it survive?

Second, there is genetics: what do we know about those 60% of genetic causes? Are they concentrated in a handful of genes, or are they spread over hundreds? And what do we know about the mutation rates of genes?  Obviously, the more causative genes, and the smaller the mutation rates the longer it will take for any genetic mutation (or allele) to become fixed in the genetic pool. "Fixed" being geneticist speak for "(almost) everybody has it".

Third, there is evolution & environment: how often did famines happen, and how many of our ancestors were affected by them at any one event?

Get the figures slightly wrong in any of those three segments and your result will be off track. And so will be your conclusions.  

To get intelligent data, the two authors first went through an exemplary exercise of modeling what happens to a human organism when it is exposed to a zero-intake famine. That's not as straight forward as you might think, because our metabolism goes through at least three distinct phases when fasting in the extreme. These three phases are determined by our organism's way of storing energy reserves. 

First, there is glucose, the building block of virtually all carbohydrates in our food. While our brain thrives almost exclusively on glucose, the body's glucose stores are remarkably small. Glucose is predominantly stored in the form of glycogen in muscle and liver tissue. It is these reserves which are tapped first, and they are typically depleted within 24 hours. If you are a marathon runner you do this depletion business a lot faster, say after 20 miles or so. 

Since your brain still needs glucose, your body then starts to produce its own. Largely from lactate and glycerol, a component of fat. Which brings us to the second phase, where the body metabolizes its fat reserves. But even fat reserves don't last forever. Once they are depleted, the body begins to cannibalize its protein. Actually, weight loss in phase 2 is never a pure loss fat only. Proteins are being burnt at the same time but a at a lesser rate, until fat reserves have been depleted. And that's where fasting gets critical, because to your body, burning proteins for energy is like burning banknotes for warming your house: you go broke in no time. And "broke" means "dead" to your body. 

Since time to death is a critical element in the mathematical model, the authors went through an exemplary effort of mapping the course from fully fed to fully dead. Interestingly, everybody reacts differently to this fasting business. Some people survive longer than others, even when they have the same BMI to start with. That's why Speakman and Westerterp applied three different models to predict survival time, all models representing those known different ways of adapting to starvation. For a severely obese 1.64 m tall female weighing 100 kg, the models predicted a survival time of 249-289 days. Imagine, that's about 8-9 months with no food at all. 

Onto the genetics assumptions. The one thing we know for sure is that obesity is a multi-gene condition. Very multi-gene in fact, because genome-wide association studies (GWAS) have thrown up about 30 odd genes with a combined effect of explaining only 7% of those 60% of weight variance. So, we are assuming that the unexplained difference resides within another 200 or so genes, which we haven't even identified yet. Speakman translated this knowledge into an assumption of each individual gene having a net effect on fat storage of about 80g. That is, a carrier of a gene's "thrifty mutation" (or allele) would store 80g more fat than his peer with the "lean" version of the gene, with those 80g, translating into a 0.25% better chance of surviving a famine. With these assumptions the authors could then calculate how many famines it would take to weed out the unlucky ones whose "lean" genes didn't give them the 80g advantage. That calculation in itself is no rocket science. The authors took a given population size of 5 million people, exposed them to a virtual famine, after which the population had been appropriately decimated, and the percentage of "thrifty gene" carriers among the survivors had increased. They all mated happily after that until the population again reached 5 million. Then the next virtual famine struck, and so on. 

How many famines would it take to eliminate the lean gene from the gene pool? Under the authors' assumptions about 6000 famine events.  

They then made their final assumption: one famine happening every 150 years. That's 900000 years altogether for those 6000 famine events. Their conclusion: if the thrifty gene hypothesis and its assumption of selection pressure from catastrophic events was correct, we all should be obese today. Since we are not, the TGH is false. 

The alternative explanation, which the authors offer is a "drifty gene hypothesis" as opposed to the thrifty version. "Drifty" referring to genetic drift, meaning that mutations of the genes, which regulate fat storage were never really subject to selection pressure, and what we see today is simply the result of a natural drift of genetic mutations over the eons of human existence. 

The authors argue further that excessive fat storage was a distinct disadvantage for our earliest hominin ancestors, for reasons of predation. Think of it like that: while neither a fat man nor a lean man can outrun a saber toothed tiger, it's enough for the lean guy to run just a little faster than his fat bro'. Call it a stone-age version of the "first come, first serve" principle, at least from the tiger's perspective: the first man I get is the first man to serve me as breakfast. 

The authors then suggest that once our ancestors discovered fire and spears and other things which placed them on top of the food chain, the selective pressure for the lean gene had vanished. Its thrifty sibling started to flourish, not because it was favored by famine-based selection pressure, but simply because man had taken tiger and co. out of the equation, and with it the selective pressure to NOT get fat. During those zillions of generations which separate the man-known-for-throwing-spears from the man-known-for-throwing-tantrum-when-the-iphone-doesn't-work, those 200 odd genes accumulated just enough mutations for many, but not all, of us to become obese and diabetic. 

Up to this point one might buy into Speakman's and Westerterp's story. But here is the twist:  

Speakman has written about the subject before. With a different tagline. In his 2006 paper he suggested that the selection pressure of famines in human history was too small to have caused the effects attributed to it by the thrifty gene hypothesis [4]. According to that paper, famines with severe mortality rates were rare and, most tellingly, a phenomenon of agricultural societies. 

Indeed, the consensus view on famines in pre-agricultural vs. agricultural societies is that our hunter/gatherer ancestors were better fed and better protected against famines than their agricultural descendents. The hunter simply doesn't depend on a crop. Whereas when a crop fails, food shortage is inevitable for the agriculturalist. But even then, a true famine, where there is no food at all, typically requires a back-to-back failure of crops in consecutive years. And even then, as Speakman pointed out in his 2006 paper, mortality rates rarely exceeded 10% of the population, with those 10% coming almost exclusively from those who are either too young or too old to reproduce and thereby contribute to the gene pool after the famine is over. The author's message in 2006:  Genetic mutations towards thrifty genes didn't have sufficient advantage or time to spread. 

This little twist shows us that somebody is taking potshots at TGH: 

Shot 1 (2006): Famines haven't been with us for long enough nor with sufficient severity to have exerted the selective pressure on which the thrifty gene hypothesis rests. Ergo, TGH is wrong.

   

Shot 2: Famines were so numerous and severe during human history that their combined selective pressure on the thrifty genes was sufficient to have made them a fixture in EVERYBODY'S genetic make-up. Since this is not the case, the TGH is wrong.

Science shouldn't be about taking potshots. Science is about the testing of falsifiable hypotheses in reproducible experiments. A mathematical model, such as the one presented in Speakman's most recent paper does not qualify as such.  

Here is why: Given that mutations happen at the rate of 1.1 per 30-100 million base pairs, we all carry about 100 to 200 mutations in our DNA [5].  Not necessarily do those mutations affect actual genes coding for proteins. And if they do, most mutations confer a slight disadvantage, many have no effect on an organism's fitness, and only a few are favorable. Natural selection will weed out the deleterious ones, quickly fix the favorable ones and let the neutral ones accumulate at the given mutation rate. To complicate matters, all those processes happen at vastly different rates depending on the location on the DNA. That much we do know. What we don't know is how much these rates differ. We certainly can't know it for those genes, which we haven't even identified yet, as is the case for most of the hypothesized fat storage genes. That's why the mathematical model with which Speakman supports his argument against the validity of the thrifty gene hypothesis is in all likelihood not reflective of what has happened throughout evolution. Which means, it doesn't add any quantitative or objective evidence against the TGH. 

In my next post I will tell you why I believe that the entire discussion misses the point. What we really want to know now is how to help people avoid becoming fat and diabetic in the first place. Decoding the genome and its evolutionary history doesn't do that trick. Because genes do not make us fat and diabetic, genes make proteins, nothing else. One part of those proteins are the hormones. They drive our moods and emotions, our likes and our dislikes and, believe it or not, all our behaviors, from feeding to physical activity. For those latter two I have suggested an explanatory model in my dissertation thesis. 

This model tries not only to explain why we eat too much and move too little, despite having the best intentions to do otherwise, and while being aware of all the life threatening consequences. But, more importantly, without having to have a complete understanding of all those hormonal happenings, the model suggests a practical and testable solution to oppose those genetically encoded mechanisms for a longer and healthier life. Think of your car: You don't need to understand the mechanism of its gearbox to operate it for an optimal ride. 

Achieving the same thing with your life could turn out to be a gratifying pastime while my geneticist colleagues work on unraveling the enigma of the genetics of obesity. Whatever newer and sexier model they develop to explain the genetic origins of obesity, we might look at it like we look at Madonna and her variants: offering lots of entertainment value, but little of practical use. [tweet this].    

1. Neel JV: Diabetes mellitus: a "thrifty" genotype rendered detrimental by "progress"? Am J Hum Genet 1962, 14:353-362.

2. Speakman JR, Westerterp KR: A mathematical model of weight loss under total starvation and implications of the genetic architecture of the modern obesity epidemic for the thrifty-gene hypothesis. Disease models & mechanisms 2012.

3. Segal NL, Allison DB: Twins and virtual twins: bases of relative body weight revisited. Int J Obes Relat Metab Disord 2002, 26(4):437-441.

4. Speakman JR: Thrifty genes for obesity and the metabolic syndrome--time to call off the search? Diabetes & vascular disease research : official journal of the International Society of Diabetes and Vascular Disease 2006, 3(1):7-11.

5. Xue Y, Wang Q, Long Q, Ng BL, Swerdlow H, Burton J, Skuce C, Taylor R, Abdellah Z, Zhao Y et al: Human Y chromosome base-substitution mutation rate measured by direct sequencing in a deep-rooting pedigree. Curr Biol 2009, 19(17):1453-1457.

NEEL JV (1962). Diabetes mellitus: a "thrifty" genotype rendered detrimental by "progress"? American journal of human genetics, 14, 353-62 PMID: 13937884

Speakman JR, & Westerterp KR (2012). A mathematical model of weight loss under total starvation and implications of the genetic architecture of the modern obesity epidemic for the thrifty-gene hypothesis. Disease models & mechanisms PMID: 22864023

Segal NL, & Allison DB (2002). Twins and virtual twins: bases of relative body weight revisited. International journal of obesity and related metabolic disorders : journal of the International Association for the Study of Obesity, 26 (4), 437-41 PMID: 12075568

Speakman JR (2006). Thrifty genes for obesity and the metabolic syndrome--time to call off the search? Diabetes & vascular disease research : official journal of the International Society of Diabetes and Vascular Disease, 3 (1), 7-11 PMID: 16784175

Xue Y, Wang Q, Long Q, Ng BL, Swerdlow H, Burton J, Skuce C, Taylor R, Abdellah Z, Zhao Y, Asan, MacArthur DG, Quail MA, Carter NP, Yang H, & Tyler-Smith C (2009). Human Y chromosome base-substitution mutation rate measured by direct sequencing in a deep-rooting pedigree. Current biology : CB, 19 (17), 1453-7 PMID: 19716302

Why your heart attack may just be collateral damage in big pharma's turf wars.

When a pharmaceutical company tells you that its drug is safer than it really is, it probably plays with your health. And possibly with your life. That's not a very nice thing to do. But it's also very profitable. Which is why it happens more often that you care to know. 

 These days Takeda Pharmaceuticals has gotten some bad press from a whistle blower suit which claims that TP deliberately withheld trial data for Actos, a drug which treats diabetes. The active ingredient is Pioglitazone, which improves the body's sensitivity to insulin and therefore your ability to metabolize glucose.

You remember one of my earlier blogs, in which I introduced you to the concept of "cherchez l'argent". The simple strategy of finding motives behind actions. Particularly within the health care environment. Which is why I want you to keep a few facts in mind before I tell you a little suspense story which plays out more often in the universe of medicine, than you and I would like to.

The Villains

TP's Actos generates annually 2.6 Billion Dollars for TP. 

It's patent expires in 2016.

GlaxoSmithKline's Avandia is, or was, Actos' competitor. Its active ingredient is Rosiglitazone, whose patent expires this year. Until 2005, Avandia saw yearly sales of 2.5 Billion dollars.

A few years back, the FDA became concerned with the entire class of drugs, the so called thiazolidinediones, because of serious side effects, such as an increased risk of heart disease, stroke and heart failure. Within it's 'adverse events reporting system', the FDA collects data on serious adverse events of drugs, which enables it to compare drugs based on benefits AND risk.

The Beginning

In 2007 the New England Journal of Medicine published the results of Dr. Nissen's meta-analysis of publicly available trial data on the cardiovascular effects of Avandia [1]. In his analysis of 42 published studies he came to the conclusion that there was a significant increase in the risk of heart attacks in patients taking Avandia. Interestingly, Dr. Nissen also pointed out that he did not have access to the source data of these trials, which prevented him from conducting a "more statistically powerful time-to-event analysis". So his conclusion was, correctly, that "more comprehensive evaluations are required" to address these cardiovascular risks. Not an unreasonable demand, given that two thirds of diabetics die of such events. Which is why they are prescribed drugs like Avandia and Actos in the first place. Dr. Nissen expressed his hopes for the yet to be published results of the RECORD trial, which was under way at that time. Financed by GSK, mind you.

The Assassination

In a highly unethical move, one journal reviewer leaked the draft of the Nissen paper to GSK a few days after its submission. The source of the leak was no lesser than a professor of medicine at the University of Texas Health Sciences Center, Dr. Steve Haffner. Why would he do such a thing? Maybe, because he also happened to be a consultant to GSK? Your guess is as good as mine. Cherchez l'argent. 

GSK's own scientists found Nissen's statistical methods beyond reproach. Not so GSK's marketing goons. They promptly showed up at Nissen's Cleveland Clinics in Ohio. But Nissen was prepared for the worst, as he expected GSK to apply some pressure tactics, as it had done in the past with Dr. John Buse, a professor of medicine at the University of North Carolina.

Buse had been at the receiving end of GSK's intimidation tactics for the same reason: openly voicing concerns about the cardiovascular risks associated with Avandia. The issue had gone to head, with the U.S. Senate Committee on Finance investigating the case and coming to the conclusion that "Had Dr. Buse been able to continue voicing his concerns, without being characterized as a “renegade” and without the need to sign a “retraction letter,” it appears that the public good would have been better served".

Buse had warned Nissen in a private email about GSK's corporate persuasion program. With this in mind Nissen secretly taped the entire conversation with the GSK representatives.

Anyway, Nissen was no push-over, and so his meta-analysis was published. Again, ethical considerations took a leave, this time from the RECORD trial, whose investigators were made to prematurely milk it for whatever results could be used to counter the Nissen paper. The manuscript submitted to the New England Journal of Medicine (NEJM) interpreted the results of the trial as contradicting the Nissen meta-analysis. Only the journal editors didn't think so. They simply couldn't reconcile the data with the authors' interpretation. That's why NEJM's reviewers and editors told GSK that "an explanation for the continued use of Avandia is needed in this manuscript".  The paper was finally published on 5th July 2007 concluding that "The data do not allow a conclusion as to whether treatment with rosiglitazone results in a higher rate of myocardial infarction..." [2].

The FDA had somewhat different data. On July 30th 2007 their scientists concluded that Avandia had caused 83,000 excess heart attacks (in the U.S. only) since it had entered the market. But preventing heart attacks in diabetics is what these drugs are all about! So, what's the point of a drug, which controls your blood sugar but  INCREASES your chance of a heart attack? The FDA wondered, too, and subsequently required the drug to be sold only under very strict conditions. Sales dwindled to a fraction of the 2.5 Billion US$ of 2006. But it continues to rake in over a Billion US$ worldwide.

Two years later the same authors who had glossed over Avandia's performance data conceded that those patients who took Avandia had a more than 2-fold risk of developing heart failure compared to those who didn't take that drug [3]. Again the U.S. Senate Committee on Finance had to investigate the matter and came to the conclusion of misconduct on the part of GSK. 

The Payback

 

Guess who followed the GSK drama with delight? Correct, Takeda Pharmaceuticals. With Actos being beautified as the safer drug, and Avandia being seriously clobbered by stiff FDA restrictions and the senate committee's investigations, Actos had cornered the market. But the party mood is over.

Because now Takeda suddenly finds itself in the same hot seat which GSK has kept warm all the while. Dr. Ge's suit alleges that TP deliberately did not report heart failure cases, which, by right, should have been registered in the FDA's database.  Dr. Ge claims that TP terminated her employment after she had complained to 3 superiors about the underreporting of events. Without the whistle blower suit Takeda would have stood another 4 years of market dominance (until its patent expires).

The Surprise Finale

Now here comes the twist: While Dr Ge does not name Dr. Nissen or Cleveland Clinics as a defendant, she insists that investigators of her claims should consider the financial connections between Takeda and Dr. Nissen's Cleveland Clinics.

And all the while you thought only John Grisham novels delivered suspense.

So, what else will we see and hear from the next senate committee report? Whatever it is, you'll see again that playing around with your health is big business. It wasn't if the old rule of the Hippocratic Oath would find its way back into the business of medicine: "Never do harm to anyone!"

Armed with our knowledge about these business ethics, we should suspect the degree of deception to correlate closely with the potential for profits. So, am I right with my 'cherchez l'argent' method? Before you answer, just keep one thing in mind: If successful with her suit, Dr Ge stands to get a sizeable chunk of the settlement. Enough for you AND me to comfortably retire for life. Very comfortably. So let's stay tuned to this unfolding opera. 

In my next post I want to give you a glimpse at how deeply entrenched the ballgame with your health really is. And how you can safeguard yourself against being the unfortunate avoidable heart attack, also known as collateral damage.   

1.           Nissen, S.E. and K. Wolski, Effect of rosiglitazone on the risk of myocardial infarction and death from cardiovascular causes. New England Journal of Medicine, 2007. 356(24): p. 2457-71.

2.           Home, P.D., et al., Rosiglitazone Evaluated for Cardiovascular Outcomes — An Interim Analysis. New England Journal of Medicine, 2007. 357(1): p. 28-38.

3.           Home, P.D., et al., Rosiglitazone evaluated for cardiovascular outcomes in oral agent combination therapy for type 2 diabetes (RECORD): a multicentre, randomised, open-label trial. Lancet, 2009. 373(9681): p. 2125-35.

Nissen, S.E. (2007). Effect of Rosiglitazone on the Risk of Myocardial Infarction and Death from Cardiovascular Causes New England Journal of Medicine, 357 (1), 100-100 DOI: 10.1056/NEJMx070038

Home, P., Pocock, S., Beck-Nielsen, H., Gomis, R., Hanefeld, M., Jones, N., Komajda, M., & McMurray, J. (2007). Rosiglitazone Evaluated for Cardiovascular Outcomes — An Interim Analysis New England Journal of Medicine, 357 (1), 28-38 DOI: 10.1056/NEJMoa073394

Home, P., Pocock, S., Beck-Nielsen, H., Curtis, P., Gomis, R., Hanefeld, M., Jones, N., Komajda, M., & McMurray, J. (2009). Rosiglitazone evaluated for cardiovascular outcomes in oral agent combination therapy for type 2 diabetes (RECORD): a multicentre, randomised, open-label trial The Lancet, 373 (9681), 2125-2135 DOI: 10.1016/S0140-6736(09)60953-3

To hell with exercise

Who says that exercise is medicine? For one, the American College of Sports Medicine (ACSM) of which I'm a professional member. Then, how can I say it isn't?

Let's look first at the conventional view of the benefits of exercise. There is a large and increasing amount of evidence which clearly tells us that exercise prevents today's number 1 killer: cardiovascular disease. That is, heart attack, stroke and peripheral vascular disease. Mind you, what is common knowledge today emerged only some 50 years ago when Morris and colleagues discovered that UK bus conductors, the guys climbing up and down the double-decker London buses, had better fitness and fewer heart attacks than their all-day-seated driver colleagues [1].

In the years since then our knowledge about the effects of physical activity on cardiovascular, metabolic and mental health has virtually exploded. From this evidence the U.S. Dept. of Health and Human Services (HHS) concluded in 2008 that the most active people of the population have a 35% reduced risk of dying from cardiovascular disease compared to the least active people [2]. The WHO lists insufficient physical activity (PA) as the 4th leading cause of death world wide after high blood pressure, tobacco use and high blood glucose. What's wrong with this picture? High blood pressure and high blood glucose are known consequences of a sedentary lifestyle. So is obesity, which ranks 5th place on the WHO killer list. Which is why physical inactivity deserves top spot on that list.

What most people don't know is the way lack of physical activity causes all those diseases, from insulin resistance and diabetes to arterial dysfunction and atherosclerosis, and from there to heart attack, stroke, kidney failure. The mechanisms are extremely complex, and, while we have untangled quite some of them, there are probably a lot more to discover. I'll try to make this the subject of one of the next blog posts. 

Now you are probably asking yourself, how the hell, with all this evidence, will I ever be able to make my point that physical activity is not a medicine. Ok, here it comes: it's a matter of viewpoint. The one I'm taking is the one of evolutionary biology. Let me play its advocate and present as evidence a couple of insights.

First, our human ancestors, who had roamed this Earth as hunter/gatherers for the most part of human existence, had, by necessity, a much more physically active lifestyle. A lifestyle which required at least 1.7 to 2 times the normal resting energy expenditure [3]. [To get an idea about resting energy expenditure and physical activity levels and how they are calculated, simply follow the links to the videos.] Those ancestors' genes are what we have inherited. And these genes are exposed to a lifestyle which is vastly different from the ones under which these genes evolved. Specifically with a view to physical activity, which brings me to evidence no 2:

What we typically observe today are physical activity levels with factors of somewhere between 1.2 and 1.4 of our resting energy expenditure. That's true for most people.

Even if you were to follow the ACSM's recommendation of 30 minutes of moderate to vigorous exercise on at least 5 days per week, would you NOT reach the level of 1.7 if you are working in a typical office job or doing house work. Which means, the physical activity levels which we recommend today, do not add a behavioral type of medicine into our lives, they merely reduce the extent of a "poisonous" behavior called sedentism. It's like cutting down from 2 packs of cigarettes per day to 1 pack. Would you call this a "medicine"? Would the ACSM call that a medicine? With respect to exercise they do.

So, OK, if you had been attracted to this post in the hope of finding some excuse for not doing exercise, or some argument to get those exercise evangelists, like myself, off your back, I'm sorry to have disappointed you. No, actually, I'm not sorry. And neither will you be, if you get your physical activity level above those 1.7. Then you may just start calling exercise a medicine. Until then, chances are you will still go to hell with exercise, because you get too little of it. Certainly too little to stay out of that hell of heart disease, stroke, diabetes and many cancers.

1.           Morris, J.N. and P.A. Raffle, Coronary heart disease in transport workers; a progress report. Br J Ind Med, 1954. 11(4): p. 260-4.

2.           Physical Activity Guidelines Advisory Committee, Physical Activity Guidelines Advisory Committee Report, 2008, U.S. Department of Health and Human Services: Washington, D.C.

3.           Eaton, S.B. and S.B. Eaton, An evolutionary perspective on human physical activity: implications for health. Comp Biochem Physiol A Mol Integr Physiol, 2003. 136(1): p. 153-9.

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MORRIS JN, & RAFFLE PA (1954). Coronary heart disease in transport workers; a progress report. British journal of industrial medicine, 11 (4), 260-4 PMID: 13208943
Eaton, S., & Eaton, S. (2003). An evolutionary perspective on human physical activity: implications for health Comparative Biochemistry and Physiology - Part A: Molecular & Integrative Physiology, 136 (1), 153-159 DOI: 10.1016/S1095-6433(03)00208-3

The three hidden barriers to chronic health, weight loss and weight maintenance.

Into The Age of Chronic Health

The most amazing thing about modern health care systems is that they let most of us die from chronic diseases which we know how to prevent. So why don't we?

As a public health scientist I have devoted the past 15 years of my life to answering this question. Many of my colleagues outdo each other with doom and gloom predictions of aging societies buckling under the economic burden of aging related diseases. I believe that the age of chronic health and longevity is about to begin. With you. And with a radically new approach to make the prevention of heart attacks, strokes diabetes and cancers finally work.     

Because, until now, it doesn't. But don't just take my word for it, let's look at some of the facts first:

You have probably heard that obesity is the new smoking. In fact for every American who stopped smoking in 2011 another one became obese.   

Today, for the first time in human history there are more overfed than malnourished people walking this planet. And their lifestyles of too much food and too little exercise have become the number one risk factor for the number one chronic disease and killer: cardiovascular disease with its most well-known end points - heart attack, stroke and heart failure. With nasty other diseases on the side: diabetes, kidney failure and certain cancers.

You probably also heard about major studies, like the U.S. government funded Diabetes Prevention Program, and the Look AHEAD trial, which proudly, and correctly, report weight loss and major reductions in cardiovascular risk factors among participants in the lifestyle arms of these trials. What you don't hear so often, is that within 3-4 years after enrollment, most participants will have regained not only most of their weight but also all their risk factors.

Ok then, lifestyle change prevents disease. But what prevents lifestyle change?

Why is it that over the last 30 years of public health efforts we have not seen a demonstration of any program that results in a clinically meaningful weight loss that can be maintained for more than 2-3 years in the majority of participants and at low cost?  That's the question which Dr. Richard Khan threw at an assembly of public health advocates, who had gathered earlier this year under the event's message "Prevention works!".  Dr. Khan, who teaches medicine at the University of North Carolina, was the chief scientific officer of the American Diabetes Association for 25 years. The man certainly knows what he is talking about. 

Now think about the implication. If you chose a lifestyle of which you know might increase risk of disease and premature death, then you make that choice either willingly or it is not your free will which makes that choice.

My money is on the latter. Because how else could we explain that an obese child maintains her fattening habits despite experiencing the same psychological agony as a child with cancer? How else could we explain that obese adults maintain their bulk when it significantly reduces their chances of getting an academic education, a job and a mate? How else could we explain that over the past 20 years the obesity rate in the US went up by 60% when, during the same period, Americans doubled their spending on weight loss products to US$ 60 billion annually? They WANT to lose weight, but they don't. The explanations are called addiction, hormones and hyperbole.  

Food addiction

The neurohormonal architecture which drives an addict to crave and consume his drug, despite knowing and hating the consequences, is exactly the same architecture that keeps us going for the sweet, fatty and salty stuff in restaurants, hawker centers and vending machines. Does that explain, why the food industry adds sugars to so many foods in which you least expect it? You bet. In fact we shouldn't be afraid of calling ourselves food addicts, because this is what Mother Nature intended us to be all along. With this addiction she drove our ancestors for millions of years to what is naturally sweet in the natural human habitat: fruits. They deliver not only the carbohydrates for which we have very little storage capacity in our bodies and without which our brain can't function. Fruits also pack a punch of essential micronutrients. Unlike the cokes and cakes and cookies which deliver more sugar than we need and no other nutrients with it.  

Hormones

Once you have changed your figure into the shape of a beached whale, you will also have changed the way the hormones of your gut and of your fat tissue work. It's a rather complicated picture unfolding in the labs of biomedicine, but one emerging theme is a colossal malfunction of the satiety and appetite signaling pathways. Instead of feeling full, you are now ready to add a tiramisu to a lunch that would have satiated a family of four in rural Bangladesh.

Hyperbole

Actually it's called hyperbolic discounting, and it's a simple mathematical formula, which behavioral scientists have found to neatly describe why we will still grab that tiramisu tomorrow even though we swear today that we won't. It has to do with how we more steeply discount the relatively larger but more distant reward of staying healthy against the relatively smaller but immediate reward of enjoying the tiramisu. It doesn't operate only in humans. The behaviors of rats, pigeons and apes, for example, follow the same formula. Which means, Mother Nature must have found out early during evolution that this principle is a recipe for survival in her species. We simply inherited this survival tool.   

With all these issues stacked in favor of an ever expanding population of chronically ill people, why do I believe that we might be close to the age of chronic health and longevity? For three reasons: Because Wall Street is getting into the act, because we can outfox our brain, and because biomedical science has got the tools ready.

How we will enter the age of chronic health is the subject of the next episode, so stay tuned!

In the meantime, visit my crowd funding campaign, watch the videos, recommend the campaign to your friends and, if you like what you see, participate in our chronic health project: www.indiegogo.com/adiphea

The daily super stimulus to prevent diabetes, or maybe not?

The daily super stimulus to prevent diabetes, or maybe not?

Today a newly released case report in the British Medical Journal caught my attention: "Towards creating a superstimulus to normalise glucose metabolism in the prediabetic: a case-study in the feast-famine and activity-rest cycle". Normalizing glucose metabolism in the prediabetic person means nothing less than preventing diabetes in those at high risk. Naturally I sought enlightenment. 

According to the report, a healthy subject was fasted for close to 2 days (water consumption was allowed). During that period he performed 3 aerobic sessions of neuromuscular electrical stimulation exercise (NMES). And surprise, surprise, the energy used by the muscle came almost entirely from fat. The subject also went into a hypoglycemic state, which is doctor-speak for low blood sugar. The authors concluded that this may indicate the depletion of carbohydrate stores. And they go on to suspect that this could be the equivalent of "a metabolic super stimulus mimicking the famine-activity periods of our ancestors". A stimulus which they correctly find to be absent from our modern environment. And which might be considered a contributor to the diabetes epidemic, which we are facing in our environment.

Now first what is NMES? It is what it sounds like: the application of an electrical stimulus to muscles. If a muscle gets stimulated in this way it contracts. Once the stimulus is switched off, it relaxes. Do this with a certain frequency and your muscle does almost the same as when you voluntarily move it, by exercising for example. I say "almost" and I will get back to that point in a short while. Now when your muscle contracts it burns energy, typically in the form of carbohydrate or fat. It doesn't matter whether your muscle does its contraction thing because your brain tells him to or whether a NMES device sends its juice through the nerves which otherwise carry the brain's commands to that muscle. if it moves, it burns. That's why NMES is typically applied for muscle rehabilitation, or to prevent muscle wastage when you can't move a limb, or when your personal trainer gets the idea of strengthening it beyond what you already achieved in the gym (not necessarily an effective idea). It's certainly not a substitute for doing exercise. Otherwise we could simply have ourselves full-body-wired to some NMES, flick the switch and start bopping around on the sofa while watching TV, feeding our face, and not getting fat at the same time because the NMES makes our muscles BURN all that fat. 

Come to think about it, why don't you try it and let me know the result? But please don't tell anybody that I asked you to. Specifically not your doctor and also not my ethics board.

But anyway, back to serious thoughts. Why are the results of this case study so underwhelming? First of all, we know, that human carbohydrate stores are so limited, in fact approximately the equivalent of 1600 calories, that your body will go into carb preservation mode much earlier than after 44 hours of fasting. 

We have made in our laboratory tests on people after a simple overnight fast. Their resting resting energy expenditure came almost exclusively from fat. And when we put them on a bicycle to exercise at the intensity which the study authors applied to their NMES guy (50% of VO2max), they also burned fat almost exclusively. The reason is simple: your brain needs glucose, the building block of carbs, to function. So your body starts to burn fat preferentially, once glucose supplies dwindle. When we gave our subjects a banana to eat or some buns or muesli, their bodies switched  to burn carbs almost exclusively within a matter of 15 to 20 minutes. At rest and while exercising.

The message is clear: if you want to burn away your fat reserves, you MUST NOT eat or drink carbs before you exercise. Don't let any gym rat or self-styled guru tell you otherwise. The human body is biased to preserve its fat stores. That was Mother Nature's survival policy for our ancestors for millions of years. Only when glucose levels dwindle will that preference be put on the backburner, so to speak.

So what has this study added to our body of knowledge about the prevention of diabetes? You judge for yourself. But my take is, even if that "super-stimulus" was worth something, who will go through the fun of staying without food for 2 days? And what comes after the 2 days, when you start eating again?

But one message clearly is being reinforced here, a message which I always like to give, specifically to those who are overweight and in need of losing a few pounds of fat: ideally do your aerobic exercise in the morning, every morning, after an overnight fast and before breakfast. And don't you dare take that bottle of energy drink with you on your run. In this way you can create your personal feast famine cycle within the 24 hours of your day, ideally every day. Initially it may be tough. I know because I do it myself. But I also know, after a while you begin to truly enjoy that morning routine. I'm doing this since more than 10 years now. And so does my wife. She has the diabetic gene in her family, but her blood glucose values and her insulin sensitivity are all in the deep green zone. Maybe because of her daily super-stimulus.  

So when will you get yours?