You’ve probably heard the news by now. There’s a new risk factor for heart attack. Move over cigarette smoking, high blood pressure, obesity, and diabetes, and make way for… car ownership.

That’s right. In a study published in the January 11 issue of the European Heart Journal, researchers found that people who owned a car [and a television set] were 27% more likely to have a heart attack that those who didn’t. Surprisingly, this hasn’t led to a sudden spike in rental car sales or a flood of title transfers.

In fact, despite the correlation found in the study, neither the authors of the study nor anyone in the popular media who’ve reported on it have even hinted that owning a car causes heart attacks. Nor have they suggested that the correlation has to do with prolonged steering wheel clutching, toxic car fabrics, city dwelling, asphalt inhalation, road rage, or any of an almost limitless number of potential explanations. Rather, they’ve suggested instead that the real culprit behind the risk increase is something only tangentially associated with car ownership:  sedentary behavior. Sedentary behavior, which has nothing at all to do directly with the act of buying or driving a car, is postulated as the hidden variable causing heart attacks in car owners.

Now let’s contrast this with how a recently published study demonstrating a correlation between red meat consumption and stroke risk is reported (we could choose just about any dietary study to make this point). Here we have the exact same type of data – folks who ate more red meat had a slightly higher incidence of stroke, just as folks who had heart attacks were more likely to own a car. In the study on stroke and red meat, however, there’s no mention of any potentially confounding hidden variables. This time, it isn’t something tangentially associated with red meat consumption that’s postulated to account for the correlation. No, despite the fact that once again we could propose an almost limitless number of potential explanations for this correlation, this time we’re led to believe that there’s a direct link between the two, and that these findings “support current recommendations to limit how much red meat people eat.”

To reiterate, when the correlation is between car/TV ownership and heart attacks, the notion of a causal link between the two factors is too absurd to even consider. In the study on red meat and cancer, however, the possibility that there could even be confounding variables isn’t even mentioned.

The truth is, neither of these studies – particularly the conclusions being drawn from them – are examples of good science in action. This type of data should never be used as a basis for health advice, nor does it ever warrant a headline. It represents the lowest quality of scientific evidence – hardly a source for basic truth. At best, correlations like these can only suggest a hypothesis that can be tested further in a more rigorous fashion. The inherent plausibility of any particular hypothesis is simply a reflection of the biases of those interpreting the data.

Yet, this is the type of low quality data, and this is the type of sloppy, careless reasoning that has led to the current prevailing wisdom about proper nutrition. This same error of causal attribution - one that is immediately rejected by all sentient beings as absurd in the study on heart attacks and car ownership – lies at the heart of why we’re told that minimizing animal fat and cholesterol intake is one of the keys to optimum health.

So just what happens when you do make public health recommendations based on low quality data and sloppy reasoning? This:  

And in case you’re wondering if this is just because folks aren’t heeding this brilliant advice:

Source: USDA

Human metabolism is a dizzingly complicated process. Every time we eat, our food must be first broken into smaller components by digestive enzymes, then absorbed across the gut into circulation, then shunted into various chemical pathways so that eventually it can be burned for energy, incorporated into our tissue structure, or excreted as waste. In a system with so many moving parts, there are an almost incomprehensible number of ways in which it can go wrong. Thousands of genes are involved in encoding the machinery involved in this process. One little mistake in any of them and the whole thing can unravel, typically with disastrous consequences. The fact that this happens so rarely is remarkable.

But, there are exceptions, classified as disorders of metabolism. These are genetic disorders, usually the result of a mistake in the DNA sequence for an enzyme that catalyzes a particular step in the metabolic process. Defects in the synthesis and breakdown of glycogen are known as the “glycogenoses,” defects in lipid metabolism the “lipodoses,” and so forth. One of the primary consequences of a missing enzyme is that it creates a bottleneck – a specific reaction in the metabolic dance can’t proceed, leading to pathological build-up of the reactants in various bodily tissues (which can be seen microscopically).

Many times this toxic sludge of metabolites builds up in the nervous system. When it does, it leads to progressive degeneration of nervous tissue and resultant loss of function – dementia, movement disorders, seizures, muscle weakness and so forth — until death occurs from the complications of this devastated state. In Globoid Cell Leukodystrophy, just to choose a random example, the absence of the lysosomal galactocerebrosidase enzyme (due to a recessively inherited mutation in the GALC gene) results in the inability to cleave galactose from ceramide derivatives inside the lysosomes. This leads to defects in myelin production, clumps of multinucleated “globoid cells” swollen with galactocerebroside, and brain cell death. Clinically, it is causes progressive loss of cognitive and motor skills, muscle rigidity, seizures, deafness, blindness, and eventually death.

To recap, in all of these neurodegenerative disorders of metabolism, the fundamental problem is a flaw in the metabolic apparatus itself. A particular metabolite can’t be cleared, and its excess becomes toxic. The trash is being taken to the street, but the trucks aren’t coming to pick it up.  Eventually, the trash piles up in brain tissue, and the brain stops working as it should.

But what if the problem is that there’s just too much trash to begin with? What if, week after week, we’re bringing more than the trucks can carry?

We don’t typically think of the neurodegenerative diseases of adults as disorders of metabolism, as they’re commonly viewed as fundamentally distinct from the metabolic disorders of childhood that affect the brain. As such, little research has focused on the role of metabolism in adult-onset neurodegeneration, even though the scarcity of dementia amongst the elders in modern day hunter gatherer populations should’ve long ago steered us in that direction. Yet, as discussed in my last post, we now know that at least one metabolic disorder — diabetes — contributes directly to the risk of Alzheimer’s disease, likely via the accelerated formation of advanced glycation end products (AGEs) in the brain. Defective insulin secretion and insulin resistance in the tissues means too much glucose in the blood and in the brain. That this abundance of glucose leads to Alzheimer’s disease is yet another observation beckoning us to reconceptualize Alzheimer’s as a disorder of metabolism.

But that’s not all. AGEs, along with other signs of oxidative damage, have been found lurking inside the pathology of many other adult-onset neurodegenerative disorders, including Pick’s disease, Parkinson’s, Progressive Supranuclear Palsy, Lewy Body Dementia, and ALS. Each of these involves a progressive decline in neurological function with deficits that may include dementia, movement disorders, seizures, muscle weakness and so forth. And each is associated with pathological buildup of gunk that can be seen microscopically in nervous tissue.

Sound familiar?

I don’t think these similarities are coincidental, nor should they be surprising. As stated, pathological accumulation of metabolites can arise either from the inability to break them down (i.e. – trash trucks stop coming) or from consumption of particular dietary components in excess of what their obligate metabolic pathway can handle (i.e. – too much trash). Our hunter gatherer metabolic machinery can’t cope with 150 pounds of sugar or 50 pounds of industrial vegetable oil a year (in fact, likely only a small fraction of this). And, just as in the metabolic disorders of childhood, that excess becomes toxic, with results that are just as devastating.

If it walks like a duck…

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According to epidemiological data, those with diabetes have anywhere from a two to five-fold increased risk of Alzheimer’s-type dementia (AD). I’ve known of this link for a while, but have had my doubts about its validity. To me, it was equally plausible that these supposed cases of Alzheimer’s were just misdiagnosed cases of vascular dementia. Diabetes unequivocally leads to widespread atherosclerotic disease, including in the vascular beds supplying the brain, and “vascular” dementia is a clear consequence of this process. In these cases, though, the pathology is distinct from dementia of the Alzheimer’s type, as are the typical clinical features. But few patients receive the type of evaluation that can tease out these differences, and misdiagnoses commonly occur. Any correlations based on epidemiological studies that use this diagnostic data, then, are suspect.

The other problem with this correlation is that our pathogenetic model for Alzheimer’s doesn’t account for it. Ever since Alois Alzheimer presented the case of Auguste D in 1906, senile plaques and neurofibrillary tangles have been recognized as the pathologic signature of Alzheimer’s disease in the brain — the former clumps of beta-amyloid protein, the latter “paired helical filaments” of hyperphosphorylated tau.

Based on this pathology, the prevailing idea was that some intrinsic abnormality in one of these proteins was the driving force behind AD. As such, the central debate within the Alzheimer’s research community in recent years revolved around whether we should be trying to figure out how to keep beta amyloid from clumping or tau from phosphorylating, with the amyloidists and tauists arguing over whose piece of the funding pie should be larger. Nowhere in these competing models was there a mechanism by which impaired glucose clearance (i.e. diabetes) led to the Alzheimer’s pathology. So, if the link is real, it means that either both the amyloidists and tauists are wrong or the connection between diabetes and AD risk is false.

Supposing for a moment that the diabetes-Alzheimers link is legit, just how might one lead to the other? The fundamental problem in diabetes is the inability to adequately clear glucose from the bloodstream, and complications arise through the formation of “Advanced Glycation End Products” (AGEs) — a glucose molecule, left hanging around in the circulation for too long, ends up sticking to proteins in bodily tissues, disrupting their structure and function. Any sugar molecule (i.e. not just glucose), in fact, may react with a protein and form an AGE. The more AGEs, the greater the tissue damage, until you end up with widespread tissue destruction — particularly in places where cell turnover is low (nerves, retina, kidney). Conceivably, the accumulation of AGEs in the brain could result in cognitive decline. But what does this have to do with those plaques and tangles that are the sine qua non of the Alzheimer’s brain? We still don’t have a mechanistic connection between hyperglycemia and the AD pathology.

 AGEs and Alzheimers

More recent investigations have revealed that there’s a little more to the Alzheimer’s pathology than we initially thought. As it turns out, when you look a little closer at the contents of both beta-amyloid plaques and neurofibrillary tangles, guess what you find?

Advanced Glycation End Products.

You also find receptors for AGEs (known as RAGEs) on the surface of diseased brain cells — receptors that are now known to play a role in oxidative damage. Strengthening the case even further is the fact that AGEs have been shown to both stimulate beta amyloid production and induce tau phosphorylation.

So, here we have several lines of converging evidence suggesting that AGEs are a significant — if not essential — component of Alzheimer’s pathogenesis. Plaques and tangles may well be the final outcome of a process first set in motion with AGEs. Such a story would provide us with the mechanistic connection we need between hyperglycemia and AD pathology. But, then, what about those plaques and tangles in non-diabetics? Does this AGE-incorporated model have any relevance for those with intact glycoregulation mechanisms?

Glycation without the Glucose

The following study was reported in the October 5th issue of the journal Neurology. It was probably read by a small handful of people, and certainly nobody in the popular media appreciated its potential significance.  But it is the first prospective study I know of to investigate the effects of AGEs on cognitive function in non-diabetics.

The study involved 920 people without dementia, roughly half of whom were diabetic. At the start of the study, subjects were divided into three groups according to the levels of pentosidine in their urine. Pentosidine is a well established marker of AGEs — the more pentosidine in the urine, the more protein glycation that’s occurring in the body. Several measures of cognitive function were recorded at the beginning of the study and over the ensuing nine years.

At the start of the study, all groups — low, moderate, and high pentosidine — were equal in their cognitive scores, each averaging around 90 on a 100 point scale. At the nine year mark, however, things were no longer the same. The low pentosidine (surrogate for low AGEs) group had declined 2.5 points over that interval, the moderate group 5.4, and the high group 7.0. The p-value for these between group differences was <0.001.  In sum, elevated AGE levels at the onset of the study, irrespective of diabetic status, predicted cognitive decline.

This study suggests two important things. One, that diabetics with only low level protein glycation (presumably from adequate pharmacologic control of blood glucose) don’t have any heightened risk of cognitive decline compared to non-diabetics — the path to cognitive decline (and presumably Alzheimer’s) in diabetics then appears to be through hyperglycemia and AGEs. Second, that non-diabetics with high levels of protein glycation have the same risk of cognitive decline as diabetics. In other words, if we’re trying to avoid cognitive decline and Alzheimer’s, it’s just as important for those without diabetes as it is for those with it to focus on minimizing AGEs.

Well Isn’t That Special???           

So, how the heck does a person without diabetes avoid AGE accumulation in the brain? After all, if it wasn’t glucose causing all that glycation in those normoglycemic non-diabetics, then just what exactly was it?

Could it be perhaps, I don’t know…

FRUCTOSE?!!!

(That’s right, I’m bringing the Church Lady back.  Deal with it.)

As it turns out, there’s more than one way to glycate your bodily proteins. And if you’re not diabetic and thus adequately handling your dietary glucose load, then glucose isn’t likely a major culprit. Fructose, on the other hand, is about ten times more likely than glucose to form AGEs. And, unlike glucose, which can be metabolized in all cells of the body, fructose (like other toxins), can only be metabolized in the liver. The average American consuming an almost unfathomable 150-180 pounds of sugar (which is half glucose, half fructose) a year is easily overwhelming his or her liver’s capacity to metabolize fructose, which leaves it free to glycate like mad.

Not that we really needed another reason to avoid sugar, or, more specifically, fructose. Already implicated as a major contributor to the pathogenesis of obesity, fatty liver disease, insulin resistance, diabetes, and cancer, we’d have to be delusional to still cling to the notion that it’s just an “empty calorie”. But Alzheimer’s, too? Could it really be a primary instigator of this wretched, self-robbing disease of the mind?

Back when Dr. Alzheimer first presented the case of Auguste D in 1906, “presenile dementia” was a medical curiosity, scarce enough to warrant an anecdotal case report. Since that time, the average American’s sugar consumption has more than tripled.  And 5.4 million of those Americans now suffer from Alzheimer’s disease.

Just sayin’…..

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Three years ago, if you’d told me I’d be starting a blog about diet and nutrition, I probably would have thought you were nuts. I’m a Neurologist, and my primary interests lean towards disorders of higher cortical function (language, memory, learning, etc.). That said, I do tend to be intellectually restless, and the internet is filled with intriguing diversions. Such was the case with my own detour into the topic of ancestral health and nutrition, which began a couple of years ago with an innocent encounter with Kurt Harris’s Archevore (then “PaNu”) blog. When I first stumbled upon it, I had no idea that my entire conception of chronic disease was about to be turned upside down. But his ideas were too compelling to ignore, despite being completely at odds with what I thought I knew about diet, nutrition, and disease. For years — since early in medical school I suppose — I’d generally accepted the conventional nutritional dogma as truth, which was that a low-fat, low-cholesterol, high-carbohydrate diet was the cornerstone of healthy eating. This is generally treated in medical circles and popular culture as established, proven fact.

But it isn’t.

In fact, it’s completely, utterly, horribly wrong.  And it has created a public health nightmare.

Like many who’ve followed along this path, I was profoundly influenced by Gary Taubes’s Good Calories, Bad Calories, a book that may one day be widely regarded as the spark that ignited a paradigm shift. It is an eye-opening and disheartening account of how science — in this case the science of nutrition — can be perverted by the corrupting influence of hubris, greed, carelessness, corporate interests and hasty, misinformed public policy making. It also so thoroughly dismantles the saturated fat/cholesterol/heart disease hypothesis that it is impossible for anyone with a half-open mind to come away believing any shred of it.

Yet, the fat/heart disease hypothesis is at the heart of mainstream nutritional dogma. It is the foundation upon which everything has been built for the past forty years, and almost all research published since the hypothesis gained widespread acceptance has been interpreted through the distortion of its lens. Without it, we wouldn’t have the public-health-disaster that is the USDA food pyramid, nor would we find ourselves in the midst of an ever-expanding epidemic of diabetes and obesity.

In spite of how far afield we’ve gotten ourselves, I remain confident that in the end good science will prevail. At some point, the mainstream nutritional edifice has to collapse under the weight of the evidence against it — a process that in some respects has already begun. It is my hope that the internet can accelerate this process. The more voices of reason and thoughtful dissension there are, the faster this will happen.

Which in the end is how a Neurologist starts a blog about nutrition.

Righting the Ship

Thankfully, we have a very reasonable guiding principle from which to re-build our foundation. It is a principle that has been conspicuously absent from the field of nutrition over the past several decades, despite the fact that it has been instrumental in fueling the advances that have been made in the biological sciences for over a century. It is the principle of evolution by natural selection.

Over two million years, the human species has roamed planet Earth. And for the vast majority of that time, the human diet consisted of the animals we killed and the plants we foraged. Those who thrived on these foods lived long enough to pass their genes on to subsequent generations. Those who didn’t perished. In this manner, the human genome became exquisitely adapted to the diet of the hunter-gatherer. Not surprisingly, humans on this diet are lean, fit and free of chronic illness. They are physical specimens worthy of our species’ position on the top of the food chain.

The diet of our hunter-gatherer ancestors didn’t include wheat.

It didn’t include refined sugar.

It didn’t include vegetable and seed oils.

These items were introduced only very recently in the course of human history — roughly 10,000 years ago — through the adoption of agriculture.  10,000 years is a blip on an evolutionary scale, nowhere near enough time to adapt to such a radical change in our internal metabolic environment.  Moreover, there is minimal selection pressure for such adaptation to occur, since the diseases wrought by the modern diet do not affect fecundity. And the health consequences of this transition are clear, as demonstrated by numerous observational accounts of modern day hunter-gatherer societies who transition to a post-agriculural diet. The very same diseases that strain our bloated healthcare system — diabetes, heart disease, obesity, hypertension, cancer — are all a consequence of this nutritional transition. They are “diseases of civilization,” and as such are all entirely preventable.

Alas, preventing them requires that we first correctly identify their root causes. The evolutionary perspective provides us with an ideal framing device for doing so. It is a perspective supported by sound a priori reasoning, compelling observational evidence, basic science, and an impressive and ever-expanding collection of anecdotal experiences.

Naturally, I’m particularly interested in the diseases of civilization that affect the nervous system, which include (but are likely not limited to) Stroke, Dementia (Alzheimer’s included), Multiple Sclerosis, Parkinson’s and Migraine. I find it both maddening and exhilarating to think that all the suffering wrought by these illnesses is largely optional. This will be the primary focus of this blog:  employing an ancestral health perspective to understand the ways in which we can preserve and protect our trillions of neuronal connections from disease, and maintain optimal brain function.  In other words, how to save our synapses.