Stephanie's Page

How Statins Really Work Explains Why They Don't Really Work

2011-03-26T07:07:00.000-07:00

Introduction

The statin industry has enjoyed a thirty year run of steadily increasing profits, as they find ever more ways to justify expanding the definition of the segment of the population that qualify for statin therapy. Large, placebo-controlled studies have provided evidence that statins can substantially reduce the incidence of heart attack. High serum cholesterol is indeed correlated with heart disease, and statins, by interfering with the body's ability to synthesize cholesterol, are extremely effective in lowering the numbers. Heart disease is the number one cause of death in the U.S. and, increasingly, worldwide. What's not to like about statin drugs?

I predict that the statin drug run is about to end, and it will be a hard landing. The thalidomide disaster of the 1950's and the hormone replacement therapy fiasco of the 1990's will pale by comparison to the dramatic rise and fall of the statin industry. I can see the tide slowly turning, and I believe it will eventually crescendo into a tidal wave, but misinformation is remarkably persistent, so it may take years.

I have spent much of my time in the last few years combing the research literature on metabolism, diabetes, heart disease, Alzheimer's, and statin drugs. Thus far, in addition to posting essays on the web, I have, together with collaborators, published two journal articles related to metabolism, diabetes, and heart disease (Seneff1 et al., 2011), and Alzheimer's disease (Seneff2 et al., 2011). Two more articles, concerning a crucial role for cholesterol sulfate in metabolism, are currently under review (Seneff3 et al., Seneff4 et al.). I have been driven by the need to understand how a drug that interferes with the synthesis of cholesterol, a nutrient that is essential to human life, could possibly have a positive impact on health. I have finally been rewarded with an explanation for an apparent positive benefit of statins that I can believe, but one that soundly refutes the idea that statins are protective. I will, in fact, make the bold claim that nobody qualifies for statin therapy, and that statin drugs can best be described as toxins.

2. Cholesterol and Statins

2011-03-26T07:06:00.000-07:00

I would like to start by reexamining the claim that statins cut heart attack incidence by a third. What exactly does this mean? A meta study reviewing seven drug trials, involving in total 42,848 patients, ranging over a three to five year period, showed a 29% decreased risk of a major cardiac event (Thavendiranathan et al., 2006). But because heart attacks were rare among this group, what this translates to in absolute terms is that 60 patients would need to be treated for an average of 4.3 years to protect one of them from a single heart attack. However, essentially all of them will experience increased frailty and mental decline, a subject to which I will return in depth later on in this essay.

The impact of the damage due to the statin anti-cholesterol mythology extends far beyond those who actually consume the statin pills. Cholesterol has been demonized by the statin industry, and as a consequence Americans have become conditioned to avoid all foods containing cholesterol. This is a grave mistake, as it places a much bigger burden on the body to synthesize sufficient cholesterol to support the body's needs, and it deprives us of several essential nutrients. I am pained to watch someone crack open an egg and toss out the yolk because it contains "too much" cholesterol. Eggs are a very healthy food, but the yolk contains all the important nutrients. After all, the yolk is what allows the chick embryo to mature into a chicken. Americans are currently experiencing widespread deficiencies in several crucial nutrients that are abundant in foods that contain cholesterol, such as choline, zinc, niacin, vitamin A and vitamin D.

Cholesterol is a remarkable substance, without which all of us would die. There are three distinguishing factors which give animals an advantage over plants: a nervous system, mobility, and cholesterol. Cholesterol, absent from plants, is the key molecule that allows animals to have mobility and a nervous system. Cholesterol has unique chemical properties that are exploited in the lipid bilayers that surround all animal cells: as cholesterol concentrations are increased, membrane fluidity is decreased, up to a certain critical concentration, after which cholesterol starts to increase fluidity (Haines, 2001). Animal cells exploit this property to great advantage in orchestrating ion transport, which is essential for both mobility and nerve signal transport. Animal cell membranes are populated with a large number of specialized island regions appropriately called lipid rafts. Cholesterol gathers in high concentrations in lipid rafts, allowing ions to flow freely through these confined regions. Cholesterol serves a crucial role in the non-lipid raft regions as well, by preventing small charged ions, predominantly sodium (Na+) and potassium (K+), from leaking across cell membranes. In the absence of cholesterol, cells would have to expend a great deal more energy pulling these leaked ions back across the membrane against a concentration gradient.

In addition to this essential role in ion transport, cholesterol is the precursor to vitamin D3, the sex hormones, estrogen, progesterone, and testosterone, and the steroid hormones such as cortisone. Cholesterol is absolutely essential to the cell membranes of all of our cells, where it protects the cell not only from ion leaks but also from oxidation damage to membrane fats. While the brain contains only 2% of the body's weight, it houses 25% of the body's cholesterol. Cholesterol is vital to the brain for nerve signal transport at synapses and through the long axons that communicate from one side of the brain to the other. Cholesterol sulfate plays an important role in the metabolism of fats via bile acids, as well as in immune defenses against invasion by pathogenic organisms.

Statin drugs inhibit the action of an enzyme, HMG coenzyme A reductase, that catalyses an early step in the 25-step process that produces cholesterol. This step is also an early step in the synthesis of a number of other powerful biological substances that are involved in cellular regulation processes and antioxidant effects. One of these is coenzyme Q10, present in the greatest concentration in the heart, which plays an important role in mitochondrial energy production and acts as a potent antioxidant (Gottlieb et al., 2000). Statins also interfere with cell-signaling mechanisms mediated by so-called G-proteins, which orchestrate complex metabolic responses to stressed conditions. Another crucial substance whose synthesis is blocked is dolichol, which plays a crucial role in the endoplasmic reticulum. We can't begin to imagine what diverse effects all of this disruption, due to interference with HMG coenzyme A reductase, might have on the cell's ability to function.

3. LDL, HDL, and Fructose

2011-03-26T07:05:00.000-07:00

We have been trained by our physicians to worry about elevated serum levels of low density lipoprotein (LDL), with respect to heart disease. LDL is not a type of cholesterol, but rather can be viewed as a container that transports fats, cholesterol, vitamin D, and fat-soluble anti-oxidants to all the tissues of the body. Because they are not water-soluble, these nutrients must be packaged up and transported inside LDL particles in the blood stream. If you interfere with the production of LDL, you will reduce the bioavailability of all these nutrients to your body's cells.

The outer shell of an LDL particle is made up mainly of lipoproteins and cholesterol. The lipoproteins contain proteins on the outside of the shell and lipids (fats) in the interior layer. If the outer shell is deficient in cholesterol, the fats in the lipoproteins become more vulnerable to attack by oxygen, ever-present in the blood stream. LDL particles also contain a special protein called "apoB" which enables LDL to deliver its goods to cells in need. ApoB is vulnerable to attack by glucose and other blood sugars, especially fructose. Diabetes results in an increased concentration of sugar in the blood, which further compromises the LDL particles, by gumming up apoB. Oxidized and glycated LDL particles become less efficient in delivering their contents to the cells. Thus, they stick around longer in the bloodstream, and the measured serum LDL level goes up.

Worse than that, once LDL particles have finally delivered their contents, they become "small dense LDL particles," remnants that would ordinarily be returned to the liver to be broken down and recycled. But the attached sugars interfere with this process as well, so the task of breaking them down is assumed instead by macrophages in the artery wall and elsewhere in the body, through a unique scavenger operation. The macrophages are especially skilled to extract cholesterol from damaged LDL particles and insert it into HDL particles. Small dense LDL particles become trapped in the artery wall so that the macrophages can salvage and recycle their contents, and this is the basic source of atherosclerosis. HDL particles are the so-called "good cholesterol," and the amount of cholesterol in HDL particles is the lipid metric with the strongest correlation with heart disease, where less cholesterol is associated with increased risk. So the macrophages in the plaque are actually performing a very useful role in increasing the amount of HDL cholesterol and reducing the amount of small dense LDL.

The LDL particles are produced by the liver, which synthesizes cholesterol to insert into their shells, as well as into their contents. The liver is also responsible for breaking down fructose and converting it into fat (Collison et al., 2009). Fructose is ten times more active than glucose at glycating proteins, and is therefore very dangerous in the blood serum (Seneff1 et al., 2011). When you eat a lot of fructose (such as the high fructose corn syrup present in lots of processed foods and carbonated beverages), the liver is burdened with getting the fructose out of the blood and converting it to fat, and it therefore can not keep up with cholesterol supply. As I said before, the fats can not be safely transported if there is not enough cholesterol. The liver has to ship out all that fat produced from the fructose, so it produces low quality LDL particles, containing insufficient protective cholesterol. So you end up with a really bad situation where the LDL particles are especially vulnerable to attack, and attacking sugars are readily available to do their damage.

4. How Statins Destroy Muscles

2011-03-26T07:04:00.000-07:00

Europe, especially the U.K., has become much enamored of statins in recent years. The U.K. now has the dubious distinction of being the only country where statins can be purchased over-the-counter, and the amount of statin consumption there has increased more than 120% in recent years (Walley et al, 2005). Increasingly, orthopedic clinics are seeing patients whose problems turn out to be solvable by simply terminating statin therapy, as evidenced by a recent report of three cases within a single year in one clinic, all of whom had normal creatine kinase levels, the usual indicator of muscle damage monitored with statin usage, and all of whom were "cured" by simply stopping statin therapy (Shyam Kumar et al., 2008). In fact, creatine kinase monitoring is not sufficient to assure that statins are not damaging your muscles (Phillips et al., 2002).

Since the liver synthesizes much of the cholesterol supply to the cells, statin therapy greatly impacts the liver, resulting in a sharp reduction in the amount of cholesterol it can synthesize. A direct consequence is that the liver is severely impaired in its ability to convert fructose to fat, because it has no way to safely package up the fat for transport without cholesterol (Vila et al., 2011). Fructose builds up in the blood stream, causing lots of damage to serum proteins.

The skeletal muscle cells are severely affected by statin therapy. Four complications they now face are: (1) their mitochondria are inefficient due to insufficient coenzyme Q10, (2) their cell walls are more vulnerable to oxidation and glycation damage due to increased fructose concentrations in the blood, reduced choleserol in their membranes, and reduced antioxidant supply, (3) there's a reduced supply of fats as fuel because of the reduction in LDL particles, and (4) crucial ions like sodium and potassium are leaking across their membranes, reducing their charge gradient. Furthermore, glucose entry, mediated by insulin, is constrained to take place at those lipid rafts that are concentrated in cholesterol. Because of the depleted cholesterol supply, there are fewer lipid rafts, and this interferes with glucose uptake. Glucose and fats are the main sources of energy for muscles, and both are compromised.

As I mentioned earlier, statins interfere with the synthesis of coenzyme Q10 (Langsjoen and Langsjoen, 2003), which is highly concentrated in the heart as well as the skeletal muscles, and, in fact, in all cells that have a high metabolic rate. It plays an essential role in the citric acid cycle in mitochondria, responsible for the supply of much of the cell's energy needs. Carbohydrates and fats are broken down in the presence of oxygen to produce water and carbon dioxide as by-products. The energy currency produced is adenosine triphosphate (ATP), and it becomes severely depleted in the muscle cells as a consequence of the reduced supply of coenzyme Q10.

The muscle cells have a potential way out, using an alternative fuel source, which doesn't involve the mitochondria, doesn't require oxygen, and doesn't require insulin. What it requires is an abundance of fructose in the blood, and fortunately (or unfortunately, depending on your point of view) the liver's statin-induced impairment results in an abundance of serum fructose. Through an anaerobic process taking place in the cytoplasm, specialized muscle fibers skim off just a bit of the energy available from fructose, and produce lactate as a product, releasing it back into the blood stream. They have to process a huge amount of fructose to produce enough energy for their own use. Indeed, statin therapy has been shown to increase the production of lactate by skeletal muscles (Pinieux et al, 1996).

Converting one fructose molecule to lactate yields only two ATP's, whereas processing a sugar molecule all the way to carbon dioxide and water in the mitochondria yields 38 ATP's. In other words, you need 19 times as much substrate to obtain an equivalent amount of energy. The lactate that builds up in the blood stream is a boon to both the heart and the liver, because they can use it as a substitute fuel source, a much safer option than glucose or fructose. Lactate is actually an extremely healthy fuel, water-soluble like a sugar but not a glycating agent.

So the burden of processing excess fructose is shifted from the liver to the muscle cells, and the heart is supplied with plenty of lactate, a high-quality fuel that does not lead to destructive glycation damage. LDL levels fall, because the liver can't keep up with fructose removal, but the supply of lactate, a fuel that can travel freely in the blood (does not have to be packaged up inside LDL particles) saves the day for the heart, which would otherwise feast off of the fats provided by the LDL particles. I think this is the crucial effect of statin therapy that leads to a reduction in heart attack risk: the heart is well supplied with a healthy alternative fuel.

This is all well and good, except that the muscle cells get wrecked in the process. Their cell walls are depleted in cholesterol because cholesterol is in such short supply, and their delicate fats are therefore vulnerable to oxidation damage. This problem is further compounded by the reduction in coenzyme Q10, a potent antioxidant. The muscle cells are energy starved, due to dysfunctional mitochondria, and they try to compensate by processing an excessive amount of both fructose and glucose anaerobically, which causes extensive glycation damage to their crucial proteins. Their membranes are leaking ions, which interferes with their ability to contract, hindering movement. They are essentially heroic sacrificial lambs, willing to die in order to safeguard the heart.

Muscle pain and weakness are widely acknowledged, even by the statin industry, as potential side effects of statin drugs. Together with a couple of MIT students, I have been conducting a study which shows just how devastating statins can be to muscles and the nerves that supply them (Liu et al, 2011). We gathered over 8400 on-line drug reviews prepared by patients on statin therapy, and compared them to an equivalent number of reviews for a broad spectrum of other drugs. The reviews for comparison were selected such that the age distribution of the reviewers was matched against that for the statin reviews. We used a measure which computes how likely it would be for the words/phrases that show up in the two sets of reviews to be distributed in the way they are observed to be distributed, if both sets came from the same probability model. For example, if a given side effect showed up a hundred times in one data set and only once in the other, this would be compelling evidence that this side effect was representative of that data set. Table 1 shows several conditions associated with muscle problems that were highly skewed towards the statin reviews.

I believe that the real reason why statins protect the heart from a heart attack is that muscle cells are willing to make an incredible sacrifice for the sake of the larger good. It is well acknowledged that exercise is good for the heart, although people with a heart condition have to watch out for overdoing it, walking a careful line between working out the muscles and overtaxing their weakened heart. I believe, in fact, that the reason exercise is good is exactly the same as the reason statins are good: it supplies the heart with lactate, a very healthy fuel that does not glycate cell proteins.

Table 1: Statins and Muscle Damage

2011-03-26T06:52:00.000-07:00

Counts of the number of reviews where phrases associated with various symptoms related to muscles appeared, for 8400 statin and 8400 non-statin drug reviews, along with the associated p-value, indicating the likelihood that this distribution could have occurred by chance.
Side Effect	Statin Reviews	Non-Statin Reviews	P-value
Muscle Cramps	678	193	0.00005
General Weakness	687	210	0.00006
Muscle Weakness	302	45	0.00023
Difficulty Walking	419	128	0.00044
Loss of Muscle Mass	54	5	0.01323
Numbness	293	166	0.01552
Muscle Spasms	136	57	0.01849

5. Membrane Cholesterol Depletion and Ion Transport

2011-03-26T06:49:00.000-07:00

As I alluded to earlier, statin drugs interfere with the ability of muscles to contract through the depletion of membrane cholesterol. (Haines, 2001) has argued that the most important role of cholesterol in cell membranes is the inhibition of leaks of small ions, most notably sodium (Na+) and potassium (K+). These two ions are essential for movements, and indeed, cholesterol, which is absent in plants, is the key molecule that permits mobility in animals, through its strong control over ion leakage of these molecules across cell walls. By protecting the cell from ion leaks, cholesterol greatly reduces the amount of energy the cell needs to invest in keeping the ions on the right side of the membrane.

There is a widespread misconception that "lactic acidosis," a condition that can arise when muscles are worked to exahustion, is due to lactic acid synthesis. The actual story is the exact opposite: the acid build-up is due to excess breakdown of ATP to ADP to produce energy to support muscle contraction. When the mitochondria can't keep up with energy consumption by renewing the ATP, the production of lactate becomes absolutely necessary to prevent acidosis (Robergs et al., 2004). In the case of statin therapy, excessive leaks due to insufficient membrane cholesterol require more energy to correct, and all the while the mitochondria are producing less energy.

In in vitro studies of phospholipid membranes, it has been shown that the removal of cholesterol from the membrane leads to a nineteen fold increase in the rate of potassium leaks through the membrane (Haines, 2001). Sodium is affected to a lesser degree, but still by a factor of three. Through ATP-gated potassium and sodium channels, cells maintain a strong disequilibrium across their cell wall for these two ions, with sodium being kept out and potassium being held inside. This ion gradient is what energizes muscle movement. When the membrane is depleted in cholesterol, the cell has to burn up substantially more ATP to fight against the steady leakage of both ions. With cholesterol depletion due to statins, this is energy it doesn't have, because the mitochondria are impaired in energy generation due to coenzyme-Q10 depletion.

Muscle contraction itself causes potassium loss, which further compounds the leak problem introduced by the statins, and the potassium loss due to contraction contributes significantly to muscle fatigue. Of course, muscles with insufficient cholesterol in their membranes lose potassium even faster. Statins make the muscles much more vulnerable to acidosis, both because their mitochondria are dysfunctional and because of an increase in ion leaks across their membranes. This is likely why athletes are more susceptible to muscle damage from statins (Meador and Huey, 2010, Sinzinger and O'Grady, 2004): their muscles are doubly challenged by both the statin drug and the exercise.

An experiment with rat soleus muscles in vitro showed that lactate added to the medium was able to almost fully recover the force lost due to potassium loss (Nielsen et al, 2001). Thus, production and release of lactate becomes essential when potassium is lost to the medium. The loss of strength in muscles supporting joints can lead to sudden uncoordinated movements, overstressing the joints and causing arthritis (Brandt et al., 2009). In fact, our studies on statin side effects revealed a very strong correlation with arthritis, as shown in the table.

While I am unaware of a study involving muscle cell ion leaks and statins, a study on red blood cells and platelets has shown that there is a substantial increase in the Na+-K+-pump activity after just a month on a modest 10 mg/dl statin dosage, with a concurrent decrease in the amount of cholesterol in the membranes of these cells (Lijnen et al., 1994). This increased pump activity (necessitated by membrane leaks) would require additional ATP and thus consume extra energy.

Muscle fibers are characterized along a spectrum by the degree to which they utilize aerobic vs anaerobic metabolism. The muscle fibers that are most strongly damaged by statins are the ones that specialize in anaerobic metabolism (Westwood et al., 2005). These fibers (Type IIb) have very few mitochondria, as contrasted with the abundant supply of mitochondria in the fully aerobic Type 1A fibers. I suspect their vulnerability is due to the fact that they carry a much larger burden of generating ATP to fuel the muscle contraction and to produce an abundance of lactate, a product of anaerobic metabolism. They are tasked with both energizing not only themselves but also the defective aerobic fibers (due to mitochondrial dysfunction) and producing enough lactate to offset the acidosis developing as a consequence of widespread ATP shortages.

6. Long-term Statin Therapy Leads to Damage Everywhere

2011-03-26T06:48:00.000-07:00

Statins, then, slowly erode the muscle cells over time. After several years have passed, the muscles reach a point where they can no longer keep up with essentially running a marathon day in and day out. The muscles start literally falling apart, and the debris ends up in the kidney, where it can lead to the rare disorder, rhabdomyolysis, which is often fatal. In fact, 31 of our statin reviews contained references to "rhabdomyolysis" as opposed to none in the comparison set. Kidney failure, a frequent consequence of rhabdomyolysis, showed up 26 times among the statin reviews, as opposed to only four times in the control set.

The dying muscles ultimately expose the nerves that innervate them to toxic substances, which then leads to nerve damage such as neuropathy, and, ultimately Amyloid Lateral Sclerosis (ALS), also known as Lou Gehrig's disease, a very rare, debilitating, and ultimately fatal disease which is now on the rise due (I believe) to statin drugs. People diagnosed with ALS rarely live beyond five years. Seventy-seven of our statin reviews contained references to ALS, as against only 7 in the comparison set.

As ion leaks become untenable, cells will begin to replace the potassium/sodium system with a calcium/magnesium based system. These two ions are in the same rows of the periodic table as sodium/potassium, but advanced by one column, which means that they are substantially larger, and therefore it's much harder for them to accidentally leak out. But this results in extensive calcification of artery walls, heart valves, and the heart muscle itself. Calcified heart valves can no longer function properly to prevent backflow, and diastolic heart failure results from increased left ventricular stiffness. Research has shown that statin therapy leads to increased risk to diastolic heart failure (Silver et al., 2004, Weant and Smith, 2005). Heart failure shows up 36 times in our statin drug data as against only 8 times in the comparison group.

Once the muscles can no longer keep up with lactate supply, the liver and heart will be further imperilled. They're now worse off than they were before statins, because the lactate is no longer available, and the LDL, which would have provided fats as a fuel source, is greatly reduced. So they're stuck processing sugar as fuel, something that is now much more perilous than it used to be, because they are depleted in membrane cholesterol. Glucose entry into muscle cells, including the heart muscle, mediated by insulin, is orchestrated to occur at lipid rafts, where cholesterol is highly concentrated. Less membrane cholesterol results in fewer lipid rafts, and this leads to impaired glucose uptake. Indeed, it has been proposed that statins increase the risk to diabetes (Goldstein and Mascitelli, 2010, Hagedorn and Arora, 2010). Our data bear out this notion, with the probability of the observed distributions of diabetes references happening by chance being only 0.006.

Table 2: Statistics on Statins and Other Major Health Issues

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Counts of the number of reviews where phrases associated with
various symptoms related to major health issues appeared, besides
muscle problems, for 8400 statin and 8400 non-statin drug reviews,
along with the associated p-value, indicating the likelihood that this
distribution could have occurred by chance.

Side Effect	Statin Reviews	Non-Statin Reviews	P-value
Rhabdomyolysis	31	0	0.02177
Liver Damage	326	133	0.00285
Diabetes	185	62	0.00565
ALS	71	7	0.00819
Heart Failure	36	8	0.04473
Kidney Failure	26	4	0.05145
Arthritis	245	120	0.01117
Memory Problems	545	353	0.01118
Parkinson's Disease	53	3	0.01135
Neuropathy	133	73	0.04333
Dementia	41	13	0.05598

7. Statins, Caveolin, and Muscular Dystrophy

2011-03-26T06:31:00.002-07:00

Lipid rafts are crucial centers for transport of substances (both nutrients and ions) across cell membranes and as a cell signaling domain in essentially all mammalian cells. Caveolae ("little caves") are microdomains within lipid rafts, which are enriched in a substance called caveolin (Gratton et al., 2004). Caveolin has received increasing attention of late due to the widespread role it plays in cell signaling mechanisms and the transport of materials between the cell and the environment (Smart et al., 1999).

Statins are known to interfere with caveolin production, both in endothelial cells (Feron et al., 2001) and in heart muscle cells, where they've been shown to reduce the density of caveolae by 30% (Calaghan, 2010). People who have a defective form of caveolin-3, the version of caveolin that is present in heart and skeletal muscle cells, develop muscular dystrophy as a consequence (Minetti et al., 1998). Mice engineered to have defective caveolin-3 that stayed in the cytoplasm instead of binding to the cell wall at lipid rafts exhibited stunted growth and paralysis of their legs (Sunada et al., 2001). Caveolin is crucial to cardiac ion channel function, which, in turn, is essential in regulating the heart beat and protecting the heart from arrhythmias and cardiac arrest (Maguy et al, 2006). In arterial smooth muscle cells, caveolin is essential to the generation of calcium sparks and waves, which, in turn, are essential for arterial contraction and expansion, to pump blood through the body (Taggart et al, 2010).

In experiments involving constricting the arterial blood supply to rats' hearts, researchers demonstrated a 34% increase in the amount of caveolin-3 produced by the rat's hearts, along with a 27% increase in the weight of the left ventricle, indicating ventricular hypertrophy. What this implies is that the heart needs additional caveolin to cope with blocked vessels, whereas statins interfere with the ability to produce extra caveolin (Kikuchi et al., 2005).

8. Statins and the Brain

2011-03-26T06:31:00.001-07:00

While the brain is not the focus of this essay, I cannot resist mentioning the importance of cholesterol to the brain and the evidence of mental impairment available from our data sets. Statins would be expected to have a negative impact on the brain, because, while the brain makes up only 2% of the body's weight, it houses 25% of the body's cholesterol. Cholesterol is highly concentrated in the myelin sheath, which encloses axons which transport messages long distances (Saher et al., 2005). Cholesterol also plays a crucial role in the transmission of neurotransmitters across the synapse (Tong et al, 2009). We found highly skewed distribution of word frequencies for dementia, Parkinson's disease, and short term memory loss, with all of these occurring much more frequently in the statin reviews than in the comparison reviews.

A recent evidence-based article (Cable, 2009) found that statin drug users had a high incidence of neurological disorders, especially neuropathy, parasthesia and neuralgia, and appeared to be at higher risk to the debilitating neurological diseases, ALS and Parkinson's disease. The evidence was based on careful manual labeling of a set of self-reported accounts from 351 patients. A mechanism for such damage could involve interference with the ability of oligodendrocytes, specialized glial cells in the nervous system, to supply sufficient cholesterol to the myelin sheath surrounding nerve axons. Genetically-engineered mice with defective oligodendrocytes exhibit visible pathologies in the myelin sheath which manifest as muscle twitches and tremors (Saher et al, 2005). Cognitive impairment, memory loss, mental confusion, and depression were also significantly present in Cable’s patient population. Thus, his analysis of 351 adverse drug reports was largely consistent with our analysis of 8400 reports.

9. Cholesterol's Benefits to Longevity

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The broad spectrum of severe disabilities with increased prevalence in statin side effect reviews all point toward a general trend of increased frailty and mental decline with long-term statin therapy, things that are usually associated with old age. I would in fact best characterize statin therapy as a mechanism to allow you to grow old faster. A highly enlightening study involved a population of elderly people who were monitored over a 17 year period, beginning in 1990 (Tilvis et al., 2011). The investigators looked at an association between three different measures of cholesterol and manifestations of decline. They measured indicators associated with physical frailty and mental decline, and also looked at overall longevity. In addition to serum cholesterol, a biometric associated with the ability to synthesize cholesterol (lathosterol) and a biometric associated with the ability to absorb cholesterol through the gut (sitosterol) were measured.

Low values of all three measures of cholesterol were associated with a poorer prognosis for frailty, mental decline and early death. A reduced ability to synthesize cholesterol showed the strongest correlation with poor outcome. Individuals with high measures of all three biometrics enjoyed a 4.3 year extension in life span, compared to those for whom all measures were low. Since statins specifically interfere with the ability to synthesize cholesterol, it is logical that they would also lead to increased frailty, accelerated mental decline, and early death.

For both ALS and heart failure, survival benefit is associated with elevated cholesterol levels. A statistically significant inverse correlation was found in a study on mortality in heart failure. For 181 patients with heart disease and heart failure, half of those whose serum cholesterol was below 200 mg/dlk were dead three years after diagnosis, whereas only 28% of the patients whose serum cholesterol was above 200 mg/dl had died. In another study on a group of 488 patients diagnosed with ALS, serum levels of triglycerides and fasting cholesterol were measured at the time of diagnosis (Dorstand et al., 2010). High values for both lipids were associated with improved survival, with a p-value < 0.05.

10. What to do Instead to Avoid Heart Disease

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If statins don't work in the long run, then what can you do to protect your heart from atherosclerosis? My personal opinion is that you need to focus on natural ways to reduce the number of small dense LDL particles, which feed the plaque, and alternative ways to supply the product that the plaque produces (more about that in a moment). Obviously, you need to cut way back on fructose intake, and this means mainly eating whole foods instead of processed foods. With less fructose, the liver won't have to produce as many LDL particles from the supply side. From the demand side, you can reduce your body's dependency on both glucose and fat as fuel by simply eating foods that are good sources of lactate. Sour cream and yogurt contain lots of lactate, and milk products in general contain the precursor lactose, which gut bacteria will convert to lactate, assuming you don't have lactose intolerance. Strenuous physical exercise, such as a tread machine workout, will help to get rid of any excess fructose and glucose in the blood, with the skeletal muscles converting them to the much coveted lactate.

Finally, I have a set of perhaps surprising recommendations that are based on research I have done leading to the two papers that are currently under review (Seneff3 et al, Seneff4 et al.). My research has uncovered compelling evidence that the nutrient that is most crucially needed to protect the heart from atherosclerosis is cholesterol sulfate. The extensive literature review my colleagues and I have conducted to produce these two papers shows compellingly that the fatty deposits that build-up in the artery walls leading to the heart exist mainly for the purpose of extracting cholesterol from glycated small dense LDL particles and synthesizing cholesterol sulfate from it, providing the cholesterol sulfate directly to the heart muscle. The reason the plaque build-up occurs preferentially in the arteries leading to the heart is so that the heart muscle can be assured an adequate supply of cholesterol sulfate. In our papers, we develop the argument that the cholesterol sulfate plays an essential role in the caveolae in the lipid rafts, in mediating oxygen and glucose transport.

The skin produces cholesterol sulfate in large quantities when it is exposed to sunlight. Our theory suggests that the skin actually synthesizes sulfate from sulfide, capturing energy from sunlight in the form of the sulfate molecule, thus acting as a solar-powered battery. The sulfate is then shipped to all the cells of the body, carried on the back of the cholesterol molecule.

Evidence of the benefits of sun exposure to the heart is compelling, as evidenced by a study conducted to investigate the relationship between geography and cardiovascular disease (Grimes et al., 1996). Through population statistics, the study showed a consistent and striking inverse linear relationship between cardiovascular deaths and estimated sunlight exposure, taking into account percentage of sunny days as well as latitude and altitude effects. For instance, the cardiovascular-related death rate for men between the ages of 55 and 64 was 761 in Belfast, Ireland but only 175 in Toulouse, France.

Cholesterol sulfate is very versatile. It is water soluble so it can travel freely in the blood stream, and it enters cell membranes ten times as readily as cholesterol, so it can easily resupply cholesterol to cells. The skeletal and heart muscle cells make good use of the sulfate as well, converting it back to sulfide, and synthesizing ATP in the process, thus recovering the energy from sunlight. This decreases the burden on the mitochondria to produce energy. The oxygen released from the sulfate molecule is a safe source of oxygen for the citric oxide cycle in the mitochondria.

So, in my view, the best way to avoid heart disease is to assure an abundance of an alternative supply of cholesterol sulfate. First of all, this means eating foods that are rich in both cholesterol and sulfur. Eggs are an optimal food, as they are well supplied with both of these nutrients. But secondly, this means making sure you get plenty of sun exposure to the skin. This idea flies in the face of the advice from medical experts in the United States to avoid the sun for fear of skin cancer. I believe that the excessive use of sunscreen has contributed significantly, along with excess fructose consumption, to the current epidemic in heart disease. And the natural tan that develops upon sun exposure offers far better protection from skin cancer than the chemicals in sunscreens.

11. Concluding Remarks

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Every individual gets at most only one chance to grow old. When you experience your body falling apart, it is easy to imagine that this is just due to the fact that you are advancing in age. I think the best way to characterize statin therapy is that it makes you grow older faster. Mobility is a great miracle that cholesterol has enabled in all animals. By suppressing cholesterol synthesis, statin drugs can destroy that mobility. No study has shown that statins improve all-cause mortality statistics. But there can be no doubt that statins will make your remaining days on earth a lot less pleasant than they would otherwise be.

To optimize the quality of your life, increase your life expectancy, and avoid heart disease, my advice is simple: spend significant time outdoors; eat healthy, cholesterol-enriched, animal-based foods like eggs, liver, and oysters; eat fermented foods like yogurt and sour cream; eat foods rich in sulfur like onions and garlic. And finally, say "no, thank-you" to your doctor when he recommends statin therapy.

References for "Why Statins Don't Really Work"

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[1] K.D. Brandt, P. Dieppe, E. Radin, "Etiopathogenesis of osteoarthritis". Med. Clin. North Am. 93 (1): 1–24, 2009.

[2] J. Cable, "Adverse Events of Statins - An Informal Internet-based Study," JOIMR, 7(1), 2009.

[3] S. Calaghan, "Caveolae as key regulators of cardiac myocyte beta2 adrenoceptor signalling: a novel target for statins" Research Symposium on Caveolae: Essential Signalosomes for the Cardiovascular System, Proc Physiol Soc 19, SA21, University of Manchester, 2010.

[4] K.S. Collison, S.M. Saleh, R.H. Bakheet, R.K. Al-Rabiah, A.L. Inglis, N.J. Makhoul, Z.M. Maqbool, M. Zia Zaidi, M.A. Al-Johi and F.A. Al-Mohanna, "Diabetes of the Liver: The Link Between Nonalcoholic Fatty Liver Disease and HFCS-55" Obesity, 17(11), 2003-2013, Nov. 2009.

[5] J. Dorstand, P. Ku ̈hnlein, C. Hendrich, J. Kassubek, A.D. Sperfeld, and A.C. Ludolph. "Patients with elevated triglyceride and cholesterol serum levels have a prolonged survival in amyotrophic lateral sclerosis," J Neurol. in Press:Published online Dec. 3 2010.

[6] O. Feron, C. Dessy, J.-P. Desager, andJ.-L. Balligand, "Hydroxy-Metholglutaryl-Coenzyme A Reductase Inhibition Promotes Endothelial Nitric Oxide Synthase Activation Through a Decrease in Caveolin Abundance," Circulation 103, 113-118, 2001.

[7] M.R. Goldstein and L. Mascitelli, "Statin-induced diabetes: perhaps, its the tip of the iceberg," QJM, Published online, Nov 30, 2010.

[8] S.S. Gottlieb, M. Khatta, and M.L. Fisher. "Coenzyme Q10 and congestive heart failure." Ann Intern Med, 133(9):745–6, 2000.

[9] J.-P. Gratton, P. Bernatchez, and W.C. Sessa, "Caveolae and Caveolins in the Cardiovascular System," Circulation Research, 94:1408-1417, June 11, 2004.

[10] D.S. Grimes, E. Hindle and T. Dyer, "Sunlight, Cholesterol and Coronary Heart Disease," Q. J. Med 89, 579-589, 1996; http://www.ncbi.nlm.nih.gov/pubmed/8935479

[11] J. Hagedorn and R. Arora, "Association of Statins and Diabetes Mellitus," American Journal of Therapeutics, 17(2):e52, 2010.

[12] T.H. Haines, "Do Sterols Reduce Proton and Sodium Leaks through Lipid Bilayers?" Progress in Lipid Research, 40, 299-324., 2001; http://www.ncbi.nlm.nih.gov/pubmed/11412894

[13] T. Kikuchi, N. Oka, A. Koga, H. Miyazaki, H. Ohmura, and T. Imaizumi, "Behavior of Caveolae and Caveolin-3 During the Development of Myocyte Hypertrophy," J Cardiovasc Pharmacol. 45:3, 204-210, March 2005.

[14] P.H. Langsjoen and A.M. Langsjoen, "The clinical use of HMG CoA-reductase inhibitors and the associated depletion of coenzyme Q10. A review of animal and human publications." Biofactors, 18(1):101–111, 2003.

[15] P. Lijnen, H. Celis, R. Fagard, J. Staessen, and A. Amery, "Influence of cholesterol lowering on plasma membrane lipids and cationic transport systems," J. Hypertension, 12:59-64, 1994.

[16] J. Liu, A. Li and S. Seneff, "Automatic Drug Side Effect Discovery from Online Patient-Submitted Reviews: Focus on Statin Drugs." Submitted to First International Conference on Advances in Information Mining and Management (IMMM) Jul 17-22, 2011, Bournemouth, UK.

[17] A. Maguy, T.E. Hebert, and S. Nattel, "Involvement of Lipid rafts and Caveolae in cardiac ion channel function," Cardiovascular Research, 69, 798-807, 2006.

[18] B.M. Meador and K.A. Huey, "Statin-Associated Myopathy and its Exacerbation with Exercise," Muscle and Nerve, 469-79, Oct. 2010.

[19] C. Minetti, F. Sotgia, C. Bruno, et al., "Mutations in the caveolin-3 gene cause autosomal dominant limb-girdle muscular dystrophy," Nat. Genet., 18, 365-368, 1998.

[20] O.B. Nielsen, F. de Paoli, and K. Overgaard, "Protective effects of lactic acid on force production in rat skeletal muscles." J. Phhsiology 536(1), 161-166, 2001.

[21] P.S. Phillips, R.H. Haas, S. Bannykh, S. Hathaway, N.L. Gray, B.J. Kimura, G. D. Vladutiu, and J.D.F. England. "Statin-associated myopathy with normal creatine kinase levels," Ann Intern Med, October 1, 2002;137:581–5.

[22] G. de Pinieux, P. Chariot, M. Ammi-Said, F. Louarn, J.L. LeJonc, A. Astier, B. Jacotot, and R. Gherardi, "Lipid-lowering drugs and mitochondrial function: effects of HMG-CoA reducase inhibitors on serum ubiquinone and blood lactate/pyruvate ratios." Br. J. Clin. Pharmacol. 42: 333-337, 1996.

[23] R.A. Robergs, F. Ghiasvand, and D. Parker, "Biochemistry of exercise-induced metabolic acidosis." Am J Physiol Regul Integr Comp Physiol 287: R502–R516, 2004.

[24] G. Saher, B. Brügger, C. Lappe-Siefke, et al. "High cholesterol level is essential for myelin membrane growth." Nat Neurosci 8:468-75, 2005.

[25] S. Seneff, G. Wainwright, and L. Mascitelli, "Is the Metabolic Syndrome Caused by a High Fructose, and Relatively Low Fat, Low Cholesterol Diet?" Archives of Medical Science, 7(1), 8-20, 2011; DOI: 10.5114/aoms.2011.20598

[26] S. Seneff, G. Wainwright, and L. Mascitelli, "Nutrition and Alzheimer's Disease: the Detrimental Role of a High Carbohydrate Diet," In Press, European Journal of Internal Medicine, 2011.

[27] S. Seneff, G. Wainwright and B. Hammarskjold, "Cholesterol Sulfate Supports Glucose and Oxygen Transport into Erythrocytes and Myocytes: a Novel Evidence Based Theory," submitted to Hypotheses in the Life Sciences.

[28] S. Seneff, G. Wainwright and B. Hammarskjold, "Atherosclerosis may Play a Pivotal Role in Protecting the Myocardium in a Vulnerable Situation," submitted to Hypotheses in the Life Sciences.

[29] H. Sinzinger and J. O’Grady, "Professional athletes suffering from familial hypercholesterolaemia rarely tolerate statin treatment because of muscle problems." Br J Clin Pharmacol 57,525-528, 2004.

[30] E.J. Smart, G.A. Graf, M.A. McNiven, W.C. Sessa, J.A. Engelman, P.E. Scherer, T. Okamoto, and M.P. Lisanti, "Caveolins, Liquid-Ordered Domains, and Signal Transduction," Molecular and Cellular Biology, 19, 7289–7304, Nov. 1999.

[31] A.J. Shyam Kumar, S.K. Wong, and G. Andrew, "Statin-induced muscular symptoms : A report of 3 cases." Acta Orthop. Belg. 74, 569-572, 2008.

[32] M.A. Silver, P.H. Langsjoen, S. Szabo, H. Patil, and A. Zelinger, "Effect of atorvastatin on left ventricular diastolic function and ability of coenzyme Q10 to reverse that dysfunction." The American Journal of Cardiology, 94(10):1306–1310, 2004.

[33] Y. Sunada, H. Ohi, A. Hase, H. Ohi, T. Hosono, S. Arata, S. Higuchi, K. Matsumura, and T. Shimizu, "Transgenic mice expressing mutant caveolin-3 show severe myopathy associated with increased nNOS activity," Human Molecular Genetics 10(3) 173-178, 2001. http://hmg.oxfordjournals.org/content/10/3/173.abstract

[34] M. J. Taggart, "The complexity of caveolae: a critical appraisal of their role in vascular function," Research Symposium on Caveolae: Essential Signalosomes for the Cardiovascular System, Proc Physiol Soc 19, SA21, University of Manchester, 2010.

[35] P. Thavendiranathan, A.Bagai, M.A. Brookhart, and N.K. Choudhry, "Primary prevention of cardiovascular diseases with statin therapy: a meta-analysis of randomized controlled trials," Arch Intern Med. 166(21), 2307-13., Nov 27, 2006.

[36] R.S. Tilvis, J.N. Valvanne, T.E. Strandberg and T.A. Miettinen "Prognostic significance of serum cholesterol, lathosterol, and sitosterol in old age; a 17-year population study," Annals of Medicine, Early Online, 1–10, 2011.

[37] J. Tong, P.P. Borbat, J.H. Freed, and Y. Shin, "A scissors mechanism for stimulation of SNARE-mediated lipid mixing by cholesterol." Proc Natl Acad Sci U S A 2009;106:5141-6.

[38] L. Vila, A. Rebollo, G.S. Ađalsteisson, M. Alegret, M. Merlos, N. Roglans, and J.C. Laguna, "Reduction of liver fructokinase expression and improved hepatic inflammation and metabolism in liquid fructose-fed rats after atorvastatin treatment," Toxicology and Applied Pharmacology 251, 32–40, 2011.

[39] Walley T., Folino-Gallo P., Stephens P et al, "Trends in prescribing and utilisation of statins and other lipid lowering drugs across Europe 1997-2003," Br J Clin Pharmacol 60, 543-551, 2005.

[40] K.A. Weant and K.M. Smith, "The Role of Coenzyme Q10 in Heart Failure," Ann Pharmacother, 39(9), 1522-6, Sep. 2005.

[41] F. R. Westwood, A. Bigley, K. Randall, A.M. Marsden, and R.C. Scott, "Statin-induced muscle necrosis in the rat: distribution, development, and fibre selectivity," Toxicologic Pathology, 33:246-257, 2005.

Could Sulfur Deficiency be a Contributing Factor in Obesity, Heart Disease, Alzheimer's and Chronic Fatigue Syndrome?

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1. Introduction

Obesity is quickly becoming the number one health issue confronting America today, and has also risen to epidemic proportions worldwide. Its spread has been associated with the adoption of a Western-style diet. However, I believe that the widespread consumption of food imports produced by U.S. companies plays a crucial role in the rise in obesity worldwide. Specifically, these "fast foods" typically include heavily processed derivatives of corn, soybeans, and grains, grown on highly efficient mega-farms. Furthermore, I will argue in this essay that one of the core underlying causes of obesity may be sulfur deficiency.

Sulfur is the eighth most common element by mass in the human body, behind oxygen, carbon, hydrogen, nitrogen, calcium, phosphorus, and potassium. The two sulfur-containing amino acids, methionine and cysteine, play essential physiological roles throughout the body. However, sulfur has been consistently overlooked in addressing the issues of nutritional deficiencies. In fact, the American Food and Drug Administration has not even assigned a minimum daily requirement (MDR) for sulfur. One consequence of sulfur's limbo nutritional status is that it is omitted from the long list of supplements that are commonly artificially added to popular foods like cereal.

Sulfur is found in a large number of foods, and, as a consequence, it is assumed that almost any diet would meet the minimum daily requirements. Excellent sources are eggs, onions, garlic, and leafy dark green vegetables like kale and broccoli. Meats, nuts, and seafood also contain sulfur. Methionine, an essential amino acid, in that we are unable to synthesize it ourselves, is found mainly in egg whites and fish. A diet high in grains like bread and cereal is likely to be deficient in sulfur. Increasingly, whole foods such as corn and soybeans are disassembled into component parts with chemical names, and then reassembled into heavily processed foods. Sulfur is lost along the way, and there is a lack of awareness that this matters.

Experts have recently become aware that sulfur depletion in the soil creates a serious deficiency for plants [Jez2008], brought about in part by improved efficiency in farming and in part, ironically, by successful attempts to clean up air pollution. Over the last two decades, the U.S. farming industry has steadily consolidated into highly technologized mega farms. The high yield per acre associated with these farms results in greater depletion of sulfur each year by the tall, densely planted crops. Plants require sulfur in the form of the sulfate radical (SO₄^-2). Bacteria in well aerated soil, similar to nitrogen fixing bacteria, can convert elemental sulfur into sulfate through an oxidation process. Coal contains a significant amount of sulfur, and factories that burn coal for energy release sulfur dioxide into the air. Over time, sun exposure converts the sulfur dioxide to sulfate, a significant contributor to acid rain. Acid rain is a serious pollutant, in that hydrogen sulfate, a potent acid, penetrates lakes, making them too acidic for lifeforms to thrive. The Clean Air Act, enacted by congress in 1980, has led to substantial decreases in the amount of acid rain released into the atmosphere. Factories have introduced highly effective scrubbing technologies to comply with the law, and, as a consequence, less sulfate makes its way back into the soil.

Modern farmers apply highly concentrated fertilizer to their soil, but this fertilizer is typically enriched in phosphates and often contains no sulfur. Excess phosphates interfere with sulfur absorption. In the past, organic matter and plant residues remained after the fruit and grain were harvested. Such accumulating organic matter used to be a major source of recyclable sulfur. However, many modern machinery-based methods remove a great deal more of the organic matter in addition to the edible portions of the plant. So the sulfur in the decaying organic matter is also lost.

It is estimated that humans obtain about 10% of their sulfur supply from drinking water. Remarkably, people who drink soft water have an increased risk to heart disease compared to people who drink hard water [Crawford1967]. Many possible reasons have been suggested for why this might be true ( Proposed theories for soft water/hard water differences in heart disease), and just about every trace metal has been considered as a possibility [Biorck1965]. However, I believe that the real reason may simply be that hard water is more likely to contain sulfur. The sulfate ion is the most useful form of sulfur for humans to ingest. Water softeners provide a convenient environment for sulfur-reducing bacteria, which convert sulfate (SO₄^-2) into sulfide (S^-2), emitting hydrogen sulfide gas. Hydrogen sulfide gas is a poison that has been known to cause nausea, illness and, in extreme cases, death. When the bacteria are thriving, the gas will diffuse into the air and give off a foul odor. Obviously, it is rare that the concentration is sufficiently high to cause severe problems. But the sulfate ion is lost through the process. Water that is naturally soft, such as water collected from rain run-off, also contains little or no sulfur, because it has gone through an evaporation-condensation cycle, which leaves behind all the heavier molecules, including sulfur.

2. Sulfur Availability and Obesity Rates

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The ultimate source of sulfur is volcanic rock, mainly basalt, spewed up from the earth's core during volcanic eruptions. It is generally believed that humans first evolved from a common ape ancestor in the African rift zone, a region that would have enjoyed an abundance of sulfur due to the heavy volcanic activity there. The three principle suppliers of sulfur to the Western nations are Greece, Italy and Japan. These three countries also enjoy low rates of heart disease and obesity and increased longevity. In South America, a line of volcanoes tracks the backbone of Argentina. Argentinians have a much lower obesity rate than their neighbors to the east in Brazil. In the United States, Oregon and Hawaii, two states with significant volcanic activity, have among the lowest obesity rates in the country. By contrast, the highest obesity rates are found in the midwest and southern farm country: the epicenter of the modern agricultural practices (mega farms) that lead to sulfur depletion in the soil. Among all fifty states, Oregon has the lowest childhood obesity rates. Significantly, Hawaii's youth are faring less well than their parents: while Hawaii ranks as the fifth from the bottom in obesity rates, its children aged 10-17 weigh in at number 13. As Hawaii has recently become increasingly dependent on food imports from the mainland to supply their needs, they have suffered accordingly with increased obesity problems.

3. Why Does Sulfur Deficiency Lead to Obesity?

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To summarize what has been said thus far, (1) foods are becoming depleted in sulfur, and (2) locations with naturally high sulfur deposits enjoy protection against obesity. Now comes the difficult question: why does sulfur deficiency lead to obesity? The answer, like much of biology, is complicated, and part of what I theorize is conjecture.

Sulfur is known as a healing mineral, and a sulfur deficiency often leads to pain and inflammation associated with various muscle and skeletal disorders. Sulfur plays a role in many biological processes, one of which is metabolism. Sulfur is present in insulin, the essential hormone that promotes the utilization of sugar derived from carbohydrates for fuel in muscle and fat cells. However, my extensive literature search has led me to two mysterious molecules found in the blood stream and in many other parts of the body: vitamin D3 sulfate and cholesterol sulfate [Strott2003]. Upon exposure to the sun, the skin synthesizes vitamin D3 sulfate, a form of vitamin D that, unlike unsulfated vitamin D3, is water soluble. As a consequence, it can travel freely in the blood stream rather than being packaged up inside LDL (the so-called "bad" cholesterol) for transport [Axelsona1985]. The form of vitamin D that is present in both human milk [Lakdawala1977] and raw cow's milk [Baulch1982] is vitamin D3 sulfate (pasteurization destroys it in cow's milk, and the milk is then artificially enriched with vitamin D2, an unsulfated plant-derived form of the vitamin).

Cholesterol sulfate is also synthesized in the skin, where it forms a crucial part of the barrier that keeps out harmful bacteria and other microorganisms such as fungi [Strott2003]. Cholesterol sulfate regulates the gene for a protein called profilaggrin, by interacting like a hormone with the nuclear receptor ROR-alpha. Profilaggrin is the precursor to filaggrin, which protects the skin from invasive organisms [Sandilands2009, McGrath2008]. A deficiency in filaggrin is associated with asthma and arthritis. Therefore, cholesterol sulfate plays an important role in protection from asthma and arthritis. This explains why sulfur is a healing agent.

Like vitamin D3 sulfate, cholesterol sulfate is also water-soluble, and it too, unlike cholesterol, does not have to be packaged up inside LDL for delivery to the tissues. By the way, vitamin D3 is synthesized through a couple of simple steps from cholesterol, and its chemical structure is, as a consequence, nearly identical to that of cholesterol.

Here I pose the interesting question: where do vitamin D3 sulfate and cholesterol sulfate go once they are in the blood stream, and what role do they play in the cells? Surprisingly, as far as I can tell, nobody knows. It has been determined that the sulfated form of vitamin D3 is strikingly ineffective for calcium transport, the well-known "primary" role of vitamin D3 [Reeve1981]. However, vitamin D3 clearly has many other positive effects (it seems that more and more are being discovered every day), and these include a role in cancer protection, increased immunity against infectious disease, and protection against heart disease ( Vitamin D Protects against Cancer and Autoimmune Diseases). Researchers don't yet understand how it achieves these benefits, which have been observed empirically but remain unexplained physiologically. However, I strongly suspect it is the sulfated form of the vitamin that instantiates these benefits, and my reasons for this belief will become clearer in a moment.

One very special feature of cholesterol sulfate, as opposed to cholesterol itself, is that it is very agile: due to its polarity it can freely pass through cell membranes almost like a ghost [Rodriguez1995]. This means that cholesterol sulfate can easily enter a fat or muscle cell. I am developing a theory which at its core proposes an essential role for cholesterol sulfate in the metabolism of glucose for fuel by these cells. Below, I will show how cholesterol sulfate may be able to protect fat and muscle cells from damage due to exposure to glucose, a dangerous reducing agent, and to oxygen, a dangerous oxidizing agent. I will further argue that, with insufficient cholesterol sulfate, muscle and fat cells become damaged, and as a consequence become glucose intolerant: unable to process glucose as a fuel. This happens first to muscle cells but eventually to fat cells, as well. Fat cells become storage bins for fats to supply fuel to the muscles, because the muscles are unable to utilize glucose as fuel. Eventually, fat cells also become too disabled to release their stored fats. Fatty tissue then accumulates on the body.

4. Sulfur and Glucose Metabolism

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In order to understand my theory, you will need to know more about glucose metabolism. Skeletal muscle cells and fat cells break down glucose in the presence of oxygen in their mitochondria, and in the process they produce ATP, the basic energy currency of all cells. A glucose transporter called GLUT4 is present in the cytoplasm of muscle cells, and it migrates to the cell membrane upon stimulation by insulin. GLUT4 essentially acts as a key that unlocks the door, letting glucose into the cell, but, like a key, it only works when it's inserted in the membrane. Both glucose and oxygen, unless they are carefully managed, can cause harm to the cell's proteins and fats. The glucose enters the cell within special cholesterol rich sites in the cell wall called lipid rafts [Inoue2006]. This is likely orchestrated to protect the cell wall from damage, because extra cholesterol allows the vulnerable lipoproteins in the cell wall to pack more tightly and reduce their risk of exposure. In muscle cells, myoglobin is able to store additional oxygen, bound to an iron molecule safely sequestered in an interior cavity within the myoglobin protein.

Sulfur is a very versatile molecule, because it can exist in several distinct oxidative states, ranging from +6 (in the sulfate radical) to -2 (in hydrogen sulfide). Glucose, as a powerful reducing agent, can cause significant glycation damage to exposed proteins, leading to the formation of Advanced Glycation End Products (AGE's) that are extremely destructive to health: they are believed to be a major contributor to heart disease risk [Brownlee1988]. So, I hypothesize that, if sulfur (+6) is made available to glucose as a decoy, the glucose will be diverted into reducing the sulfur rather than glycating some vulnerable protein such as myoglobin.

In searching the Web, I came across an article written in the 1930's about the striking ability of iron sulfate, in the presence of the oxidizing agent hydrogen peroxide, to break down starch into simple molecules, even in the absence of any enzymes to catalyze the reaction [Brown1936]. The article pointedly mentioned that iron works much better than other metals, and sulfate works much better than other anions. In the human body, starch is first converted to glucose in the digestive system. The muscle and fat cells only need to break down glucose. Thus, their task is easier, because the iron sulfate is now starting from an intermediate breakdown product of starch rather than from starch itself.

Where would the iron sulfate come from? It seems to me that the cholesterol sulfate, having hopped across the cell membrane, could transfer its sulfate radical to the myoglobin, whose iron molecule could provide the other half of the formula. In the process, the sulfur molecule's charge would be driven down from +6 to -2, releasing energy and absorbing the impact of the reducing effects of glucose, and therefore serving as a decoy to protect the proteins in the cell from glycation damage.

When the cell is exposed to insulin, its mitochondria are triggered to start pumping both hydrogen peroxide and hydrogen ions into the cytoplasm, essentially gearing up for the assault by glucose. If cholesterol sulfate enters the cell alongside the glucose, then all the players are available. I conjecture that cholesterol sulfate is the catalyst that seeds the lipid raft. Iron sulfate is then formed by bonding the iron in the heme unit in myoglobin to a sulfate ion provided by cholesterol sulfate. The cholesterol is left behind in the cell wall, thus enriching the newly forming lipid raft with cholesterol. The hydrogen peroxide, provided by the mitochondria upon insulin stimulation, catalyzes the dissolution of glucose by the iron sulfate. The pumped hydrogen can pair up with the reduced sulfur (S^-2) to form hydrogen sulfide, a gas that can easily diffuse back across the membrane for a repeat cycle. The oxygen that is released from the sulfate radical is picked up by the myoglobin, sequestered inside the molecule for safe travel to the mitochondria. Glucose breakdown products and oxygen are then delivered to the mitochondria to complete the process that ends with water, carbon dioxide, and ATP -- all while keeping the cell's cytoplasmic proteins safe from glucose and oxygen exposure.

If I'm right about this role for cholesterol sulfate both in seeding the lipid raft and in providing the sulfate ion, then this process breaks down miserably when cholesterol sulfate is not available. First of all, the lipid raft is not formed. Without the lipid raft, the glucose can not enter the cell. Intense physical exercise can allow glucose to enter the muscle cells even in the absence of insulin [Ojuka2002]. However, this will lead to dangerous exposure of the cell's proteins to glycation (because there is no iron sulfate to degrade the glucose). Glycation interferes with the proteins' ability to perform their jobs, and leaves them more vulnerable to oxidation damage. One of the important affected proteins would be myoglobin: it would no longer be able to effectively carry oxygen to the mitochondria. Furthermore, oxidized myoglobin released into the blood stream by crippled muscle cells leads to painful and crippling rhabdomyolysis, and possible subsequent kidney failure. This explanation accounts for the observation that sulfur deficiency leads to muscle pain and inflammation.

5. The Metabolc Syndrome

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The metabolic syndrome is a term used to encapsulate a complex set of markers associated with increased risk to heart disease. The profile includes (1) insulin resistance and dysfunctional glucose metabolism in muscle cells, (2) excess triglycerides in the blood serum, (3) high levels of LDL, particularly small dense LDL, the worst kind, (4) low levels of HDL (the "good" cholesterol) and reduced cholesterol content within the individual HDL particles, (5) elevated blood pressure, and (6) obesity, particularly excess abdominal fat. I have argued previously that this syndrome is brought on by a diet that is high in empty carbohydrates (particularly fructose) and low in fats and cholesterol, along with a poor vitamin D status [Seneff2010]. While I still believe that all of these factors are contributory, I would now add another factor as well: insufficient dietary sulfate.

I have described in a previous essay, my interpretation of obesity as being driven by a need for abundant fat cells to convert glucose to fat because the muscle cells are unable to efficiently utilize glucose as fuel. With sulfur deficiency comes the answer as to why muscle cells would be defective in glucose management: they can't come up with enough cholesterol sulfate to seed the lipid raft needed to import the glucose.

An alternative way to ovecome a muscle cell's defective glucose metabolism is to exercise vigorously, so that the generated AMPK (an indicator of energy shortage) induces the GLUT4 to migrate to the membrane even in the absence of insulin [Ojuka2002]. Once the glucose is inside the muscle cell, however, the iron-sulfate mechanism just described is dysfunctional, both because there's no cholesterol sulfate and because there's no hydrogen peroxide. Additionally, with intensive exercise there's also a reduced supply of oxygen, so the glucose must be processed anaerobically in the cytoplasm to produce lactate. The lactate is released into the blood stream and shipped to the heart and brain, both of which are able to use it as fuel. But the cell membrane remains depleted in cholesterol, and this makes it vulnerable to future oxidative damage.

Another way to compensate for defective glucose metabolism in the muscle cells is to gain weight. Fat cells must now convert glucose into fat and release it into the blood stream as triglycerides, to fuel the muscle cells. In the context of a low fat diet, sulfur deficiency becomes that much worse a problem. Sulfur deficiency interferes with glucose metabolism, so it's a much healthier choice to simply avoid glucose sources (carbohydrates) in the diet; i.e. to adopt a very low-carb diet. Then the fat in the diet can supply the muscles with fuel, and the fat cells are not burdened with having to store up so much reserve fat.

Insulin suppresses the release of fats from fat cells [Scappola1995]. This forces the fat cells to flood the bloodstream with triglycerides when insulin levels are low, i.e., after prolonged periods of fasting, such as overnight. The fat cells must dump enough triglycerides into the bloodstream during fasting periods to fuel the muscles when the dietary supply of carbohydrates keeps insulin levels elevated, and the release of fats from the fat cells is repressed. As the dietary carbs come in, blood sugar levels rise dramatically because the muscle cells can't utilize it.

The liver also processes excess glucose into fat, and packages it up into LDL, to further supply fuel to the defective muscle cells. Because the liver is so preoccupied with processing glucose and fructose into LDL, it falls behind on the generation of HDL, the "good" cholesterol. So the result is elevated levels of LDL, triglycerides, and blood sugar, and reduced levels of HDL, four key components of the metabolic syndrome.

The chronic presence of excess glucose and fructose in the blood stream leads to a host of problems, all related to glycation damage of blood stream proteins by glucose exposure. One of the key proteins that gets damaged is the apolipoprotein, apoB, that's encased in the membrane of the LDL particles. Damaged apoB inhibits the ability of LDL to efficiently deliver its contents (fat and cholesterol) to the tissues. Fat cells again come to the rescue, by scavenging the broken LDL particles (through a mechanism that does not require apoB to be healthy), taking them apart, and extracting and refurbishing their cholesterol. In order to function properly, the fat cells must have intact ApoE, an antioxidant that cleans up oxidized cholesterol and transports it to the cell membrane for delivery to HDL particles.

6. Fat Cells, Macrophages and Atherosclerosis

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While diligently converting glucose to stored fats, the fat cells are awash in glucose, which damages their apoE through glycation [Li1997]. Once their apoE is damaged, they can no longer transport cholesterol to the membrane. Excess cholesterol accumulates inside the fat cells and eventually destroys their ability to synthesize proteins. Concurrently, their cell membrane becomes depleted in cholesterol, because they can no longer deliver it to the membrane [Seneff2010]. A fat cell that has deteriorated to this degree has no choice but to die: it sends out distress signals that call in macrophages. The macrophages essentially consume the dysfunctional fat cell, wrapping their own membrane around the fat cell's membrane that is now barely able to hold its contents inside [Cinti2005].

Macrophages are also principle players in the fatty streaks that appear along the sides of major arteries leading to the heart, and are associated with plaque build-up and heart disease. In a fascinating set of experiments, Ma et al. [Ma2008] have shown that the sulfate ion attached to oxidized forms of cholesterol is highly protective against fatty streaks and atherosclerosis. In a set of in-vitro experiments, they demonstrated diametrically opposite reactions from macrophages to 25-hydroxyl cholesterol (25-HC) versus its sulfoconjugate 25-hydroxyl cholesterol sulfate (25-HC3S). Whereas 25-HC present in the medium causes the macrophages to synthesize and store cholesterol and fatty acids, 25-HC3S has the exact opposite effect: it promotes the release of cholesterol to the medium and causes fat stores to shrink. Furthermore, while 25-HC added to the medium led to apoptosis and cell death, 25-HC3S did not. I suggest that the sulfate radical is essential for the process that feeds cholesterol and oxygen to the heart muscle.

7. Sulfur and Alzheimer's

2010-09-27T16:25:00.001-07:00

With an aging population, Alzheimer's disease is on the rise, and it has been argued that the rate of increase is disproportionately high compared to the increase in the raw number of elderly people [Waldman2009]. Because of a conviction that the amyloid beta plaque that is a signature of Alzheimer's is also the cause, the pharmaceutical industry has spent hundreds of millions, if not billions, of dollars pursuing drugs that reduce the amount of plaque accumulating in the brain. Thus far, drug trials have been so disappointing that many are beginning to believe that amyloid beta is not the cause after all. Recent drug trials have shown not only no improvement, but actually a further decline in cognitive function, compared to placebo ( New York Times Article). I have argued elsewhere that amyloid beta may actually be protective against Alzheimer's, and that problems with glucose metabolism are the true culprit in the disease.

Once I began to suspect sulfur deficiency as a major factor in Americans' health, I looked into the relationship between sulfur deficiency and Alzheimer's. Imagine my surprise when I came upon a web page posted by Ronald Roth, which shows a plot of the levels of various minerals in the cells of a typical Alzheimer's patient relative to the normal level. Remarkably, sulfur is almost non-existent in the Alzheimer's patient's profile.

To quote directly from that site: "While some drugs or antibiotics may slow, or if it should happen, halt the progression of Alzheimer's disease, sulfur supplementation has the potential of not only preventing, but actually reversing the condition, provided it has not progressed to a stage where much damage has been done to the brain."

"One major reason for the increase in Alzheimer's disease over the past years has been the bad reputation eggs have been getting in respect to being a high source of cholesterol, despite the fact of dietary intake of cholesterol having little impact on serum cholesterol - which is now also finally acknowledged by mainstream medicine. In the meantime, a large percentage of the population lost out on an excellent source of sulfur and a host of other essential nutrients by following the nutritional misinformation spread on eggs. Of course, onions and garlic are another rich source of sulfur, but volume-wise, they cannot duplicate the amounts obtained from regularly consuming eggs."

Why should sulfur deficiency be so important for the brain? I suspect that the answer lies in the mysterious molecule alpha-synuclein, which shows up alongside amyloid-beta in the plaque, and is also present in the Lewy Bodies that are a signature of Parkinson's disease [Olivares2009]. The alpha-synuclein molecule contains four methionine residues, and all four of the sulfur molecules in the methionine residues are converted to sulfoxides in the presence of oxidizing agents such as hydrogen peroxide [Glaser2005]. Just as in the muscle cells, insulin would cause the mitochondria of neurons to release hydrogen peroxide, which would then allow the alpha-synuclein to take up oxygen, in a way that is very reminiscent of what myoglobin can do in muscle cells. The lack of sufficient sulfur should directly impact the neuron's ability to safely carry oxygen, again paralleling the situation in muscle cells. This would mean that other proteins and fats in the neuron would suffer from oxidative damage, leading ultimately to the neuron's destruction.

In my essay on Alzheimer's, I argued that biologically pro-active restriction in glucose metabolism in the brain (a so-called type-III diabetes and a precursor to Alzheimer's disease) is triggered by a deficiency in cholesterol in the neuron cell membrane. Again, as in muscle cells, glucose entry depends upon cholesterol-rich lipid rafts, and, when the cell is deficient in cholesterol, the brain goes into a mode of metabolism that prefers other nutrients besides glucose.

I suspect that a deficiency in cholesterol would come about if there is insufficient cholesterol sulfate, because cholesterol sulfate likely plays an important role in seeding lipid rafts, while concurrently enriching the cell wall in cholesterol. The cell also develops an insensitivity to insulin, and, as a consequence, anaerobic metabolism becomes favored over aerobic metabolism, reducing the chances for alpha-synuclein to become oxidized. Oxidation actually protects alpha-synuclein from fibrillation, a necessary structural change for the accumulation of Lewy bodies in Parkinson's disease (and likely also Alzheimer's plaque) [Glaser2005]

8. Is The Skin a Solar-Powered Battery for the Heart?

2010-09-27T16:22:00.000-07:00

The evidence is quite compelling that sunny places afford protection from heart disease. A study described in [Grimes1996] provides an in depth anaylsis of data from around the world showing an inverse relationship between heart disease rates and sunny climate/low latitude. For instance, the cardiovascular-related death rate for men between the ages of 55 and 64 was 761 per 100,000 men in Belfast, Northern Ireland, but only 175 in Toulouse, France. While the obvious biological factor that would be impacted by sunlight is vitamin D, studies conducted specifically on vitamin D status have been inconclusive, with some even showing a significant increased risk for heart disease with increased intake of vitamin D2 supplements [Drolet2003].

I believe, first of all, that the distinction between vitamin D3 and vitamin D3-sulfate really matters, and also that the distinction between vitamin D2 and vitamin D3 really matters. Vitamin D2 is the plant form of the vitamin -- it works similarly to D3 with respect to calcium transport, but it cannot be sulfated. Furthermore, apparently the body is unable to produce vitamin D3 sulfate directly from unsulfated vitamin D3 [Lakdawala1977] (which implies that it produces vitamin D3 sulfate directly from cholesterol sulfate). I am not aware of any other food source besides raw milk that contains vitamin D3 in the sulfated form. So, when studies monitor either vitamin D supplements or vitamin D serum levels, they're not getting at the crucial aspect for heart protection, which I think is the serum level of vitamin D3 sulfate.

Furthermore, I believe it is extremely likely that vitamin D3 sulfate is not the only thing that's impacted by greater sun exposure, and maybe not even the most important thing. Given that cholesterol sulfate and vitamin D3 sulfate are very similar in molecular structure, I would imagine that both molecules are produced the same way. And since vitamin D3-sulfate synthesis requires sun exposure, I suspect that cholesterol sulfate synthesis may also exploit the sun's radiation energy.

Both cholesterol and sulfur afford protection in the skin from radiation damage to the cell's DNA, the kind of damage that can lead to skin cancer. Cholesterol and sulfur become oxidized upon exposure to the high frequency rays in sunlight, thus acting as antioxidants to "take the heat," so to speak. Oxidation of cholesterol is the first step in the process by which cholesterol transforms itself into vitamin D3. Sulfur dioxide in the air is converted nonenzymatically to the sulfate ion upon sun exposure. This is the process that produces acid rain. The oxidation of sulfide (S^-2) to sulfate (SO₄^-2), a strongly endothermic reaction [Hockin2003], converts the sun's energy into chemical energy contained in the sulfur-oxygen bonds, while simultaneously picking up four oxygen molecules. Attaching the sulfate ion to cholesterol or vitamin D3 is an ingenious step, because it makes these molecules water-soluble and therefore easily transportable through the blood stream.

Hydrogen sulfide (H₂S) is consistently found in the blood stream in small amounts. As a gas, it can diffuse into the air from capillaries close to the skin's surface. So it is conceivable that we rely on bacteria in the skin to convert sulfide to sulfate. It would not be the first time that humans have struck up a symbiotic relationship with bacteria. If this is true, then washing the skin with antibiotic soap is a bad idea. Phototrophic bacteria, such as Chlorobium tepidum, that can convert H₂S to H₂SO₄ exist in nature [Zerkle2009, Wahlund1991], for example in sulfur hot springs in Yellowstone Park. These highly specialized bacteria can convert the light energy from the sun into chemical energy in the sulfate ion.

Another possibility is that we have specialized cells in the skin, possibly the keratinocytes, that are able to exploit sunlight to convert sulfide to sulfate, using a similar phototrophic mechanism to C. tepidum. This seems quite plausible, especially considering that both human keratinocytes and C. tepidum can synthesize an interesting UV-B absorbing cofactor, tetrahydrobioptin. This cofactor is found universally in mammalian cells, and one of its roles is to regulate the synthesis of melanin [Schallreut94], the skin pigment that is associated with a tan and protects the skin from damage by UV-light exposure [Costin2007]. However, tetrahydrobiopsin is very rare in the bacterial kingdom, and C. tepidum is one of the very few bacteria that can synthesize it [Cho99].

Let me summarize at this point where I'm on solid ground and where I'm speculating. It is undisputed that the skin synthesizes cholesterol sulfate in large amounts, and it has been suggested that the skin is the major supplier of cholesterol sulfate to the blood stream [Strott2003]. The skin also synthesizes vitamin D3 sulfate, upon exposure to sunlight. Vitamin D3 is synthesized from cholesterol, with oxysterols (created from sun exposure) as an intermediate step (oxysterols are forms of cholesterol with hydroxyl groups attached at various places in the carbon chain). The body can't synthesize vitamin D3 sulfate from vitamin D3 [Lakdawala1977] so it must be that sulfation happens first, producing cholesterol sulfate or hydroxy-cholesterol sulfate, which is then optionally converted to vitamin D3 sulfate or shipped out "as is."

Another highly significant feature of skin cells is that the skin stores sulfate ions attached to molecules that are universally present in the intracellular matrix, such as heparan sulfate, chondroitin sulfate, and keratin sulfate [Milstone1994]. Furthermore, it has been shown that exposure of the melanin producing cells (melanocytes) to molecules containing reduced sulfur (-2) leads to suppression of melanin synthesis [Chu2009], whereas exposure to molecules like chondroitin sulfate that contain oxidized sulfur (+6) leads to enhancement of melanin synthesis [Katz1976]. Melanin is a potent UV-light absorber, and it would compete with reduced sulfur for the opportunity to become oxidized. It is therefore logical that, when sulfur is reduced, melanin synthesis should be suppressed, so that sulfur can absorb the solar energy and convert it to very useful chemical bonds in the sulfate ion.

The sulfate would eventually be converted back to sulfide by a muscle cell in the heart or a skeletal muscle (simultaneously recovering the energy to fuel the cell and unlocking the oxygen to support aerobic metabolism of glucose), and the cycle would continually repeat.

Why am I spending so much time talking about all of this? Well, if I'm right, then the skin can be viewed as a solar-powered battery for the heart, and that is a remarkable concept. The energy in sunlight is converted into chemical energy in the oxygen-sulfur bonds, and then transported through the blood vessels to the heart and skeletal muscles. The cholesterol sulfate and vitamin D3 sufate are carriers that deliver the energy (and the oxygen) "door-to-door" to the individual heart and skeletal muscle cells.

Today's lifestyle, especially in America, severely stresses this system. First of all, most Americans believe that any food containing cholesterol is unhealthy, so the diet is extremely low in cholesterol. Eggs are an excellent source of sulfur, but because of their high cholesterol content we have been advised to eat them sparingly. Secondly, as I discussed previously, natural food plant sources of sulfur are likely to be deficient due to sulfur depletion in the soil. Thirdly, water softeners remove sulfur from our water supply, which would otherwise be a good source. Fourthly, we have been discouraged from eating too much red meat, an excellent source of sulfur-containing amino acids. Finally, we have been instructed by doctors and other authoritarian sources to stay out of the sun and wear high SPF sunscreen whenever we do get sun exposure.

Another significant contributor is the high carbohydrate, low fat diet, which leads to excess glucose in the blood stream that glycates LDL particles and renders them ineffective in delivering cholesterol to the tissues. One of those tissues is the skin, so skin becomes further depleted in cholesterol due to glycation damage to LDL.

9. Sulfur Deficiency and Muscle Wasting Diseases

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In browsing the Web, I recently came upon a remarkable article [Dröge1997] which develops a persuasive theory that low blood serum levels of two sulfur-containing molecules are a characteristic feature of a number of diseases/conditions. All of these diseases are associated with muscle wasting, despite adequate nutrition. The authors have coined the term "low CG syndrome" to represent this observed profile., where "CG" stands for the amino acid "cysteine," and the tripeptide "glutathione," both of which contain a sulfhydryl radical "-S-H" that is essential to their function. Glutathione is synthesized from the amino acids cysteine, glutamate, and glycine, and glutamate deficiency figures into the disease process as well, as I will discuss later.

The list of diseases/conditions associated with low CG syndrome is surprising and very revealing: HIV infection, cancer, major injuries, sepsis (blood poisoning), Crohn's disease (irritable bowel syndrome), ulcerative colitis, chronic fatigue syndrome, and athletic over-training. The paper [Drage1997] is dense but beautifully written, and it includes informative diagrams that explain the intricate feedback mechanisms between the liver and the muscles that lead to muscle wasting.

This paper fills in some missing holes in my theory, but the authors never suggest that sulfur deficiency might actually be a precursor to the development of low CG syndrome. I think that, particularly with respect to Crohn's disease, chronic fatigue syndrome, and excessive exercise, sulfur deficiency may precede and provoke the muscle wasting phenomenon. The biochemistry involved is complicated, but I will try to explain it in as simple terms as possible.

I will use Crohn's disease as my primary focus for discussion: an inflammation of the intestines, associated with a wide range of symptoms, including reduced appetite, low-grade fever, bowel inflammation, diarrhea, skin rashes, mouth sores, and swollen gums. Several of these symptoms suggest problems with the interface between the body and the external world: i.e., a vulnerability to invasive pathogens. I mentioned before that cholesterol sulfate plays a crucial role in the barrier that keeps pathogens from penetrating the skin. It logically plays a similar role everywhere there is an opportunity for bacteria to invade, and certainly a prime opportunity is available at the endothelial barrier in the intestines. Thus, I hypothesize that the intestinal inflammation and low-grade fever are due to an overactive immune system, necessitated by the fact that pathogens have easier access when the endothelial cells are deficient in cholesterol sulfate. The skin rashes and mouth and gum problems are a manifestation of inflammation elsewhere in the barrier.

Ordinarily, the liver supplies cholesterol sulfate to the gall bladder, where it is mixed into bile acids, and subsequently released into the digestive system to assist in the digestion of fats. If a person consistently eats a low-fat diet, the amount of cholesterol sulfate delivered to the digestive system from the liver will be reduced. This will logically result in a digestive system that is more vulnerable to invasion by pathogens.

The sulfate that's combined with cholesterol in the liver is synthesized from cysteine (one of the two proteins that are deficient in low CG syndome). So insufficient bioavailability of cysteine will lead to a reduced production of cholesterol sulfate by the liver. This will, in turn, make it difficult to digest fats, likely, over time, compelling the person to adhere to a low-fat diet. Whether low-fat diet or sulfur deficiency comes first, the end result is a vulnerability to infective agents in the intestines, with a consequential heightened immune response.

[Dröge1997] further discussses how a reduction in the synthesis of sulfate from cysteine in the liver leads to increased compensatory activity in another biological pathway in the liver that converts glutamate to arginine and urea. Glutamate is highly significant because it is produced mainly by the breakdown of amino acids (proteins in the muscles); i.e., by muscle wasting. The muscle cells are triggered to cannibalize themselves in order to provide adequate glutamate to the liver, mainly, in my view, in order to generate enough arginine to replace the role of sulfate in muscle glucose metabolism (i.e., these activities in the liver and muscles are circular and mutually supportive).

Arginine is the major source of nitric oxide (NO) and NO is the next best thing for muscle glucose metabolism in the absence of cholesterol sulfate. NO is a poor substitue for SO₄^-2, but it can function in some of the missing roles. As you will recall, I propose that cholesterol SO₄^-2 accomplishes a number of important things in muscle cells: it delivers oxygen to myoglobin, it supplies cholesterol to the cell membrane, it helps break down glucose, protects the cell's proteins from glycation and oxidation damage, and provides energy to the cell. NO can help in reducing glycation damage, as nitrogen can be reduced from +2 to 0 (whereas sulfur was reduced from +6 to -2). It also provides oxygen, but it is unable to transfer the oxygen directly to myoglobin by binding with the iron molecule, as was the case for sulfate. NO does not supply cholesterol, so cholesterol deficiency remains a problem, leaving the cell's proteins and fats more vulnerable to oxidative damage. Furthermore, NO itself is an oxidizing agent, so myoglobin becomes disabled, due to both oxidation and glycation damage. The muscle cell, therefore, engages in mitochondrial oxidation of glucose at its own peril: better to revert to anaerobic metabolism of glucose to decrease the risk of damage. Anaerobic metabolism of glucose results in a build-up of lactic acid, which, as explained in [Dröge1997] further enhances the need for the liver to metabolize glutamate, thus augmenting the feedback loop.

Furthermore, as you'll recall, if I'm right about cholesterol sulfate seeding lipid rafts, then, with a cholesterol sulfate deficiency, the entry of both glucose and fat into the muscle cell are compromised. This situation leaves the cell with little choice but to exploit its internal proteins as fuel, manifested as muscle wasting.

In summary, a number of different arguments lead to the hypothesis that sulfur deficiency causes the liver to shift from producing cholesterol sulfate to producing arginine (and subsequently nitric oxide). This leaves the intestines and muscle cells vulnerable to oxidation damage, which can explain both the intestinal inflammation and the muscle wasting associated with Crohn's disease.

The immune system depends upon abundant cholesterol to defend against severe stress. I have previously argued that high serum cholesterol is protective against sepsis. It is worth repeating here the abstract from [Wilson2003], who studied changes in blood cholesterol levels following trauma, infection, and multiple organ failure:

"Hypocholesterolemia is an important observation following trauma. In a study of critically ill trauma patients, mean cholesterol levels were significantly lower (119 ± 44 mg/dl) than expected values (201 ± 17 mg/dl). In patients who died, final cholesterol levels fell by 33% versus a 28% increase in survivors. Cholesterol levels were also adversely affected by infection or organ system dysfunction. Other studies have illustrated the clinical significance of hypocholesterolemia. Because lipoproteins can bind and neutralize lipopolysaccharide, hypocholesterolemia can negatively impact outcome. New therapies directed at increasing low cholesterol levels may become important options for the treatment of sepsis."

Thus, many of these conditions/diseases that lead to muscle wasting may do so because cholesterol (and therefore cholesterol sulfate) is depleted from the blood serum. This results in the same feedback loop between the liver and the muscles that I discussed with regard to Crohn's disease. So I think it's plausible that the muscle wasting associated with all of these conditions is caused by this same feedback mechanism.

I have discussed the role cysteine plays in providing sulfate to the liver. But what is the role of glutathione, the other sulfur-containing protein that's depleted in low GC syndrome? Muscle cells ordinarily contain significant levels of glutathione, and its depletion leads to mitochondrial damage [Martensson1989]. Patients undergoing surgical trauma have been found to exhibit reduced glutathione levels in their skeletal muscles [Luo1996]. It is tempting to speculate that cholesterol sulfate provides the sulfur needed for glutathione synthesis, so that the deficiency would be explained by the reduced availability of cholesterol following the immune system's heightened response to surgical trauma. Glutathione is a potent antioxidant, so its deficiency will further contribute to dysfunction of the muscle cell's mitochondria, therefore greatly impairing its energy supply.

There is a growing awareness that glutathione deficiency may play a role in many diseases. You may want to check out this Web site describing a long list of diseases that may be impacted by glutathione deficiency. Whether the problems arise just due to insufficient supply of the glutathione molecule itself, or whether a more general sulfur deficiency is the root cause, is perhaps hard to say, but provocative nonetheless.

9. Sulfur Deficiency and Muscle Wasting Diseases

2010-09-27T16:09:00.000-07:00

A serious disorder known as ("Smith-Lemli-Opitz") syndrome (SLOS) is characterized by a genetic defect resulting in an inability to synthesize adequate cholesterol. Most fetuses that are unfortunate to be conceived with this genetic defect don't make it to 16 weeks of gestation before the pregnancy ends in a miscarriage. If they do manage to make it to term, they typically suffer from major brain defects, resulting in autism or other forms of mental retardation [9].

10. Summary

2010-09-27T16:08:00.000-07:00

Although sulfur is an essential element in human biology, we hear surprisingly little about sulfur in discussions on health. Sulfur binds strongly with oxygen, and is able to stably carry a charge ranging from +6 to -2, and is therefore very versatile in supporting aerobic metabolism. There is strong evidence that sulfur deficiency plays a role in diseases ranging from Alzheimer's to cancer to heart disease. Particularly intriguing is the relationship between sulfur deficiency and muscle wasting, a signature of end-stage cancer, AIDS, Crohn's disease, and chronic fatigue syndrome.

The African rift zone, where humans are believed to have first made their appearance several million years ago, would have been rich with sulfur supplied by active volcanism. It is striking that people living today in places where sulfur is abundantly provided by recent volcanism enjoy a low risk for heart disease and obesity.

In my research on sulfur, I was drawn to two mysterious molecules: cholesterol sulfate and vitamin D3 sulfate. Researchers have not yet determined the role that cholesterol sulfate plays in the blood stream, despite the fact that it is ubiquitous there. Research experiments have clearly shown that cholesterol sulfate is protective against heart disease. I have developed a theory proposing that cholesterol sulfate is central to the formation of lipid rafts, which, in turn, are essential for aerobic glucose metabolism. I would predict that deficiencies in cholesterol sulfate lead to severe defects in muscle metabolism, and this includes the heart muscle. My theory would explain the protective role of cholesterol sulfate in heart disease and muscle wasting diseases.

I have also argued that cholesterol sulfate delivers oxygen to myoglobin in muscle cells, resulting in safe oxygen transport to the mitochondria. I argue a similar role for alpha-synuclein in the brain. There is a striking relationship between Alzheimer's and sulfur depletion in neurons in the brain. Sulfur plays a key role in protectiing proteins in neurons and muscle cells from oxidative damage, while maintaining adequate oxygen supply to the mitochondria.

When muscles become impaired in glucose metabolism due to reduced availability of cholesterol sulfate, proliferating fat cells become involved in converting glucose to fat. This provides an alternative fuel for the muscle cells, and replenishes the cholesterol supply by storing and refurbishing cholesterol extracted from defective LDL. Thin people with cholesterol and sulfur deficiency are vulnerable to a wide range of problems, such as Crohn's disease, chronic fatigue syndrome, and muscle wasting, because fat cells are not available to ameliorate the situation.

Cholesterol sulfate in the epithelium protects from invasion of pathogens through the skin, which greatly reduces the burden placed on the immune system. Perhaps the most intriguing possibility presented here is the idea that sulfur provides a way for the skin to become a solar-powered battery: to store the energy from sunlight as chemical energy in the sulfate molecule. This seems like a very sensible and practical scheme, and the biochemistry involved has been demonstrated to work in phototrophic sulfur-metabolizing bacteria found in sulfur hot springs.

The skin produces vitamin D3 sulfate upon exposure to sunlight, and the vitamin D3 found in breast milk is also sulfated. In light of these facts, it is quite surprising to me that so little research has been directed towards understanding what role sulfated vitamin D3 plays in the body. It is recently becoming apparent that vitamin D3 promotes a strong immune system and offers protection against cancer, yet how it achieves these benefits is not at all clear. I strongly suspect that it is vitamin D3 sulfate that carries out this aspect of vitamin D3's positive influence.

Modern lifestyle practices conspire to induce major deficiencies in cholesterol sulfate and vitamin D3 sulfate. We are encouraged to actively avoid sun exposure and to minimize dietary intake of cholesterol-containing foods. We are encouraged to consume a high-carbohydrate/low-fat diet which, as I have argued previously (Seneff2010), leads to impaired cholesterol uptake in cells. We are told nothing about sulfur, yet many factors, ranging from the Clean Air Act to intensive farming to water softeners, deplete the supply of sulfur in our food and water.

Fortunately, correcting these deficiencies at the individual level is easy and straightforward. If you just throw away the sunscreen and eat more eggs, those two steps alone may greatly increase your chances of living a long and healthy life.

Could Sulfur Deficiency be a Contributing Factor to Obesity, Heart Disease, Alzheimer's and Chronic Fatigue Syndrome? by Stephanie Seneff is licensed under a Creative Commons Attribution 3.0 United States License.

References for Sulfur Essay

2010-09-27T16:02:00.000-07:00

1. Axelson1985
Magnus Axelson, "25-Hydroxyvitamin D3 3-sulphate is a major circulating form of vitamin D in man," FEBS Letters (1985), Volume 191, Issue 2, 28 October, Pages 171-175; doi:10.1016/0014-5793(85)80002-8

2. Crawford1967
T. Crawford and Margaret D. Crawford, "Prevalence and Pathological Changes of Ischaemic Heart-Disease in a Hard-water and in a Soft-water Area," The Lancet (1967) Saturday 4 February

3. Biorck1965
Biorck, G., Bostrom, H., Widstrom, A. "Trace Elements and Cardiovascular Diseases", Acta med. scand. (1965) 178, 239.

4. Brownlee1988
Brownlee M, Cerami A and Vlassara H. "Advanced glycosylation end products in tissue and the biochemical basis of diabetic complications." N Engl J Med (1988) 318: pp. 1315¬1321.

5. Brown1936
"W. R. Brown, the hydrolysis of starch by hydrogen peroxide and ferrous sulfate." J. Biol. Chem. (1936) 113: 417-425.

6. Boulch1982
N Le Boulch, L. Cancela and L. Miravet, "Cholecalciferol sulfate identification in human milk by HPLC," Steroids (1982) Volume 39, Issue 4, April, Pages 391-398; doi:10.1016/0039-128X(82)90063-0

7. Cho99
Cho SH, Na JU, Youn H, Hwang CS, Lee CH, Kang SO, "Sepiapterin reductase producing L-threo-dihydrobiopterin from Chlorobium tepidum." Biochem J (1999) 340 ( Pt g2);497-503. PMID: 10333495

8. Cinti2005
Cinti S, Mitchell G, Barbatelli G, Murano I, Ceresi E, Faloia E, Wang S, Fortier M, Greenberg AS and Obin MS. "Adipocyte death deﬁnes macrophage localization and function in adipose tissue of obese mice and humans." J Lipid Res (2005) 46: pp. 2347-2355.

9. Costin2007
Gertrude-E. Costin and Vincent J. Hearing, "Human skin pigmentation: melanocytes modulate skin color in response to stress," The FASEB Journal (2007), 21:976-994; doi: 10.1096/fj.06-6649rev.

10. Chu2009
Heuy-Ling Chu, Bor-Sen Wang and Pin-Der Duh, "Effects of Selected Organo-sulfur Compounds on Melanin Formation," J. Agric. Food Chem. (2009) 57 (15), pp 7072–7077; DOI: 10.1021/jf9005824.

11. Dröge1997
Wulf Dröge and Eggert Holm, "Role of cysteine and glutathione in H1V infection and other diseases associated with muscle wasting and immunological dysfunction," The FASEB Journal (1997) Vol. 11, November, pp. 1077-1089.

12. Drolet2003
Marie-Claude Drolet, Marie Arsenault, and Jacques Couet, "Experimental Aortic Valve Stenosis in Rabbits," J. Am. Coll. Cardiol. (2003) Vol. 41, pp. 1211-1217.

13. Glaser2005
Charles B. Glaser, Ghiam Yamin, Vladimir N. Uversky, and Anthony L. Fink, "Methionine oxidation, a-synuclein and Parkinson’s disease," Biochimica et Biophysica Acta (2005) Vol. 1703, pp. 157–169

14. Grimes1996
D.S. Grimes, E. Hindle, and T. Dyer, "Sunlight, cholesterol and coronary heart disease." Q. J. Med. (1996) 89:579-589.

15. Hockin2003
Simon L. Hockin and Geoffrey M. Gadd, "Linked Redox Precipitation of Sulfur and Selenium under Anaerobic Conditions by Sulfate-Reducing Bacterial Biofilms," Applied and Environmental Microbiology (2003) Dec., p. 7063–7072, Vol. 69, No. 12; DOI: 10.1128/AEM.69.12.7063–7072.2003

16. Inoue2006
Inoue, M., Chiang, S.H., Chang, L., Chen, X.W. and Saltiel, A.R. "Compartmentalization of the exocyst complex in lipid rafts controls Glut4 vesicle tethering." Mol. Biol. Cell (2006) 17, 2303–2311

17. Jez2008
Joseph Jez, "Sulfur: a Missing Link between Soils, Crops, and Nutrition." Agronomy Monograph #50. (2008) American Society of Agronomy, Inc. Crop Science Society of America, Inc., Soil Science Society of American, Inc.

18.Katz1976
Katz IR, Yamauchi T, Kaufman S. "Activation of tyrosine hydroxylase by polyanions and salts. An electrostatic effect." Biochim Biophys Acta. (1976) Mar 11;429(1):84-95.

19.Lakdawala1977
Dilnawaz R. Lakdawala and Elsie M. Widdowson, "Vitamin D in Human Milk," The Lancet (1977) Volume 309, Issue 8004, 22 January, Pages 167-168.

20.Li1997
Yong Ming Li and Dennis W. Dickson, "Enhanced binding of advanced glycation endproducts (AGE) by the ApoE4 isoform links the mechanism of plaque deposition in Alzheimer's disease," Neuroscience Letters (1997), Volume 226, Issue 3, 2 May, Pages 155-158; doi:10.1016/S0304-3940(97)00266-8

21.Luo1996
J L Luo, F Hammarqvist, K Andersson, and J Wernerman, "Skeletal muscle glutathione after surgical trauma." Ann Surg. (1996) April; 223(4): 420–427.

22.Ma2008
Yongjie Ma, Leyuan Xu, Daniel Rodriguez-Agudo, Xiaobo Li, Douglas M. Heuman, Phillip B. Hylemon, William M. Pandak and Shunlin Ren, "25-Hydroxycholesterol-3-sulfate regulates macrophage lipid metabolism via the LXR/SREBP-1 signaling pathway," Am J Physiol Endocrinol Metab (2008) 295:1369-1379; doi:10.1152/ajpendo.90555.2008

23.Martensson1989
Martensson, J., and Meister,A., "Mitochondrial damage in muscle occurs after marked depletion of glutathione and is prevented by giving glutathione monoester." Proc Natl Acad Sci U S A, (1989) 86:471-475.

24.McGrath2008
John A. McGrath and Jouni Uitto "The filaggrin story: novel insights into skin-barrier function and disease," Trends in Molecular Medicine (2008) Volume 14, Issue 1, January, Pages 20-27.

25.Milstone1994
Leonard M. Milstone, Lynne Hough-Monroe, Lisa C. Kugelman, Jeffrey R. Bender and John G. Haggerty, "Epican, a heparan/chondroitin sulfate proteoglycan form of CD44, mediates cell-cell adhesion," Journal of Cell Science (1994) 107, 3183-3190

26. Ojuka2002
E.O. Ojuka, T.E. Jones, L.A. Nolte, M. Chen, B.R. Wamhoff, M. Sturek, and J.O. Holloszy, "Regulation of GLUT4 biogenesis in muscle: evidence for involvement of AMPK and Ca2+," Am J Physiol Endocrinol Metab (2002) Vol. 282, NO. 5, May.

27. Olivares2009
Olivares D, Huang X, Branden L, Greig NH, Rogers JT. "Physiological and Pathological Role of Alpha-synuclein in Parkinson's Disease Through Iron Mediated Oxidative Stress; The Role of a Putative Iron-responsive Element," Int J Mol Sci (2009) 10:1226-60.

28. Reeve1981
Lorraine E. Reeve, Hector F. DeLuca, and Heinrich K. Schnoes, "Synthesis and Biological Activity of Vitamin D3-Sulfate," The Journal of Biological Chemistry (1981) Vol. 256., NO. 2. Jan 25, pp. 823-826.

29. Rodriguez1995
W. V. Rodriguez, J. J. Wheeler, S. K. I.imuk, C. N. Kitson, and M. J. Hope, "Transbilayer Movement and Net Flux of Cholesterol and Cholesterol Sulfate between Liposomal Membranes", Biochemistry (1995) 34, 6208-6217.

30. Sandilands2009
Sandilands A, Sutherland C, Irvine AD, McLean WH, "Filaggrin in the frontline: role in skin barrier function and disease," J Cell Sci. (2009) May 1;122(Pt 9):1285-94.

31. Scappola1995
Scoppola A, Testa G, Frontoni S, Maddaloni E, Gambardella S, Menzinger G and Lala A. "Effects of insulin on cholesterol synthesis in type II diabetes patients," Diabetes Care (1995) 18: pp. 1362-1369.

32. Schallreut94
Schallreuter KU, Wood JM, Pittelkow MR, Gutlich M, Lemke KR, Rodl W, Swanson NN, Hitzemann K, Ziegler I, "Regulation of melanin biosynthesis in the human epidermis by tetrahydrobiopterin." Science (1994) 263(5152);1444-6. PMID: 8128228

33. Seneff2010
S. Seneff, G. Wainwright, and L. Mascitelli, "Is the metabolic syndrome caused by a high fructose, and relatively low fat, low cholesterol diet?", Archives of Medical Science (2010), To Appear.

34. Strott2003
Charles A. Strott and Yuko Higashi, "Cholesterol sulfate in human physiology: what's it all about?" Journal of Lipid Research (2003) Volume 44, pp. 1268-1278.

35. Wahlund1991
Wahlund, T. M., C. R. Woese, R. W. Castenholz, and M. T. Madigan, "A thermophilic green sulfur bacterium from New Zealand hot springs, Chlorobium tepidum sp." Nov. Arch. Microbiol. (1991) 159:81-90.

36. Waldman2009
M. Waldman, MD,, 9th International Conference on Alzheimer's and Parkinson's Diseases (2009) Abstract 90, Presented March 12-13.

37. Wilson2003
Robert F Wilson, Jeffrey F Barletta and James G Tyburski,"Hypocholesterolemia in Sepsis and Critically Ill or Injured Patients" Critical Care 7:413-414, 2003. http://www.medscape.com/viewarticle/511735_2

38. Zerkle2009
Aubrey L. Zerkle, James Farquhar, David T. Johnston, Raymond P. Cox, and Donald E. Canfield, "Fractionation of multiple sulfur isotopes during phototrophic oxidation of sulfide and elemental sulfur by a green sulfur bacterium," Geochimica et Cosmochimica Acta (2009) Volume 73, Issue 2, 15 January 2009, Pages 291-306; doi:10.1016/j.gca.2008.10.027

Statins and Myoglobin: How Muscle Pain and Weakness Progress to Heart, Lung and Kidney Failure

2010-02-25T17:03:00.002-08:00

Statin drug use has steadily increased over the last several decades, due to the widespread belief that cholesterol reduction is an important step in preventing heart disease. It is undeniable that statins are effective: they can decrease serum cholesterol levels from over 300 db/ml to well within the normal range in a matter of weeks. For a person who already has normal cholesterol levels, statins can drive their cholesterol down to levels not seen in nature. Statins have also been shown to reduce the relative risk of heart attacks in men in their 50's by as much as 30%, but, because heart attacks are relatively rare for this segment of the population, the absolute risk reduction is only on the order of 2%, a point that is often missed by the person being treated.

All drugs have potential side effects, and with any drug it's a matter of weighing the risk/benefit factors to decide whether the drug is warranted. Statin drugs have a remarkably diverse set of side effects, including cognitive and memory impairment, reduced libido, and muscle pain and weakness. The drug manufacturers claim that the incidence of side effects is relatively rare, but often side effects don't appear until after several months or even years into treatment. In many of these cases, it may not be obvious that the statin drug is the cause of the problem. This is especially true because these side effects can easily be attributed to increasing age. In fact, as I will show later, statin side effects can best be interpreted as an acceleration of the aging process.

In my view, statin drugs are never worth the risk of their side effects. Cholesterol is a vital nutrient, without which mammalian cells can not survive, and it is inconceivable to me that crippling the body's ability to synthesize cholesterol can ever be a good idea. In an excellent and highly informative review article published in 2009, Wainwright et al. [43] developed a strong argument that statin drugs, by depleting cholesterol, lead to a destabilization of cell membranes "from head to toe." This problem, in turn, increases risk to a long list of serious health conditions and diseases, including diabetes, multiple sclerosis, cognitive problems, hemorrhagic stroke, cancer, and even ALS (amyotrophic lateral sclerosis, also known commonly as Lou Gehrig's disease). Their arguments are backed up by references to 85 peer-reviewed journal publications. I have argued in previous essays that statins may increase the risk to Alzheimer's disease, as well as to sepsis, cancer, and heart failure.

The most commonly reported side effects to statin therapy are muscle pain and weakness. If left unchecked, these symptoms can progress to rhabdomyolysis (severe muscle damage) and kidney failure. Muscle weakness in the lungs can lead to breathing difficulties; in the heart it leads to heart failure. Statin users are reassured by their doctors that they can halt statin therapy if their liver and muscle enzymes rise too high. In practice, however, it's possible to suffer irreversible muscle damage (the problem does not go away after the statin therapy is stopped), and this can happen even when the enzyme levels are not above the normal range.

This essay will develop an argument for why, over time, a statin user may become increasingly weak, in some cases to the point of major disability. A key message is that muscles are forced to cannibalize themselves to acquire sufficient energy. But another factor is oxidative damage to muscle tissue, with subsequent disintegration of the cell walls. This is true not only for the skeletal muscles, but also for the respiratory muscles controlling breathing and the heart muscle. With continued abuse, the muscle cells disintegrate, and the debris travels in the blood stream to the kidneys, which can lead to kidney failure.

The rest of this essay will unfold as follows. In the next section, I will explain how statin drugs work, which will also show why they interfere with the synthesis not only of cholesterol but also of other essential biological substances involved in cell metabolism. The following section will present evidence that statins damage muscle cells. Sections 4 and 5 describe the biochemical pathways involved in assuring that muscles have enough energy to effect movement, especially during situations of stress such as extreme exercise. Section 6 describes the condition known as rhabdomyolysis, caused by extreme exercise but also by statin drugs, and the subsequent risk to kidney failure. Section 7 describes the role that myoglobin, a key protein found in muscle cells, plays in the disease process. After a section explaining how cholesterol protects cell membranes from oxidative damage, the four subsequent sections (sections 9-12) will be devoted to the repercussions of statin damage to the muscles, the heart, the lungs, and the pancreas, respectively. Finally, the conclusion section will summarize the essay and provide hints about my upcoming essay on ALS, a physically disabling neurodegenerative disease that is due not to muscle damage per se but to damage of the motor neurons in the spinal cord that transmit signals from the brain to the skeletal muscles.

2. The Biological Mechanism of Statin Drugs

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Why do statins cause so many side effects? To answer this question requires explaining all the crucial roles that cholesterol plays in maintaining the integrity and functioning of the body's cells. However, statins interfere not only with the synthesis of cholesterol, but also with the synthesis of an enzyme, coenzyme Q10, that plays a critical role in energy metabolism in all cells. A deficiency in both cholesterol and coenzyme Q10, over time, leads to a huge list of potential health problems. Exactly how an individual responds depends upon their genetic make-up: faced with a deficiency, the body will decide to sacrifice certain cell types in order to safeguard certain other cell types. So, one person may develop Alzheimer's because the brain's neurons are sacrificed, while another succumbs to heart failure or rhabdomyolysis (skeletal muscle wasting).

Statins suppress a critical early step in the multi-step biological pathway that leads to cholesterol synthesis. This is why statins are able to dramatically reduce the blood serum levels of cholesterol. Specifically, statins interfere with the production of the enzyme, HMG-Coenzyme A Reductase, which catalyzes production of mevalonate from its precursor, HMG-Coenzyme A. Several more steps produce cholesterol from mevalonate. Mevalonate is also the precursor to a large number of other biologically active molecules that are important for proper cell function. These include the antioxidants, coenzyme Q10 and the dolichols, as shown in the figure to the right.

The so-called "bad" cholesterol, LDL, delivers cholesterol, fats, and antioxidants from the liver to all the cells of the body. All cells need both fats and cholesterol to maintain healthy membranes, not only in the outer cell wall, but also in the membranes encasing the nucleus, the mitochondria (energy producing units), and the lysosomes (the cell's digestive system). Antioxidants are critical for neutralizing the damaging effects of oxygen exposure, always an issue whenever energy is generated in the mitochondria through a chemical reaction between food sources and oxygen.

In a double-blind placebo controlled study [18], it has been shown that statins can reduce serum levels of coenzyme Q10 by as much as 40%. Coenzyme Q10 is not only a powerful antioxidant, but it also plays a crucial role in the process that breaks down glucose in the presence of oxygen to yield carbon dioxide and water. This metabolic pathway, which is essentially the burning of glucose as fuel, takes place in the mitochondria via the well-known citric acid, or Kreb's cycle. The energy that is released through this process is packaged up in the form of ATP (Adenosine Triphosphate), the currency that all cells use to store their energy reserves.

The dolichols play a special role for the lysosomes [20]. The lysosomes are walled off "rooms" that contain digestive enzymes to break down debris from damaged cell parts so that they can be recycled into useful materials. Lysosomes must maintain a highly acidic internal environment in order for the digestive enzymes to work properly. The dolichols are responsible for pumping hydrogen ions into the lysosomes to keep them highly acidic.

A final way that statins can damage cells is through their entry mechanism. Statins belong to a class of drugs called "amphiphilic" drugs [2] that manage to break through the cell wall in spite of being relatively large. They act like a soap by essentially dissolving a section of the cell membrane. This leaves behind a hole in the wall, which needs to be patched up, as well as debris which must be cleaned up and recycled by the lysosomes. To patch the hole requires new sources of both fats and cholesterol, which come from the LDL particles, whose supply is greatly reduced due to the statin drug. So it becomes increasingly difficult over time for the cell to repair all the holes introduced by the statin drug molecules. As the cell wall becomes more permeable due to previous exposure to an amphiphilic drug, the amount of drug that successfully enters the cell steadily increases over time, leading to ever greater internal concentrations of the drug.

3. Statins, Muscle Pain and Weakness, and Rhabdomyolysis

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Muscle cells have tremendous energy needs, particularly if the person has been put on an exercise regimen as part of their treatment program. The heart, in particular, never rests. It has to keep on beating 24x7 at the rate of at least once every second. Hence the heart is especially dependent on coenzyme Q10 to replenish the ATP consumed every time it contracts and pushes blood from one chamber to another and out the aorta.

The pharmaceutical industry readily admits that statin therapy may cause muscle pain and/or muscle weakness in some cases, but they claim that the incidence of these side effects is small, on the order of 2%. However, observational studies have shown that at least 10% to 15% of statin users complain of muscle pain [6][40]. The actual number who experience pain or weakness is likely to be much larger, however, because many people are unaware that this is a potential side effect. Furthermore, it sometimes takes several years of cumulative statin damage before the symptoms become intolerable. People are often willing to believe that their aches and pains and generally weakening condition are simply due to getting older.

The reaction by the general community to a relatively benign article posted by WebMD on muscle pain suggests that the problem is much worse than is generally acknowledged. Over 200 often lengthy comments describe many very sad stories; often the doctor was also misinformed, and denied that the pain could be due to the statin drug. A case in point is described in this New York Times article. A woman in Kansas had been taking a statin for years to reduce her cholesterol. Over that same time period, she experienced chronic muscle pain which neither she nor her doctor attributed to the statin therapy. It even led to a useless shoulder operation. Her problem eventually escalated into skin lesions caused by a reaction to toxic protein by-products released by her disintegrating muscles. She was given an antifungal to treat the skin lesions, another misdiagnosis. But the antifungal interacted with the statins [25] to further increase the severity of her muscle disorders. Three months later, she could barely stand, and her pulmonary muscles were so weak she couldn't breathe. She died shortly thereafter.

Rhabdomyolysis is a condition where the muscles rapidly disintegrate due to an injury, often, for example, physical trauma following an accident. But Rhabdomyolysis is also a rare side effect of statins -- essentially where the muscle pain and weakness are extreme. Some people react immediately to statin therapy with severe rhabdomyolysis, and it is often fatal, due to acute renal failure (ARF). Myoglobin is sloughed off from the muscle cells in large amounts, and it overloads the kidneys and causes them to shut down completely. Initiating statin therapy is therefore a bit like Russian roulette -- there is even a known case where a single statin dose caused rhabdomyolysis [21]. One of the statins, Baycol, was abruptly taken off the market in 2001, after 31 people died from subsequent rhabdomyolysis.

4. How Muscles Maintain their Energy Supply

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In this section and the next, I will describe the metabolic pathways involved in assuring that muscle cells have enough energy to contract. When oxygen is available, and when it can be safely exploited, the muscle can decompose food sources into carbon dioxide and water, by consuming the oxygen. But oxygen, while life-giving, is also a very dangerous substance, and if the process is not orchestrated exactly according to plan, there can be a lot of collateral damage due to the wrong substances reacting with the oxygen. As you will see later, myoglobin, which is responsible for buffering oxygen and delivering it from the cell wall to the mitochondria, picks up a lot of the collateral damage. This aerobic metabolic process is termed respiration, and it takes place inside special organelles called mitochondria, whose sole responsibility is to digest foods and generate energy for the cell.

Whenever oxygen is in short supply, or if the mitochondria are dysfunctional, the cell has alternative ways to generate energy (e.g., fermentation), which take place, in the absence of oxygen, in the main compartment of the cell, called the cytoplasm. These processes require exchanges of nutrients between the muscles and the liver, and they require the assistance of special enzymes which then show up in the blood stream. These are the very same enzymes whose concentrations are monitored to detect whether a statin drug may have damaged the muscles.

If you don't feel compelled to know the details of how all these processes work, you could skip this section and section 5, and, I think, still be able to follow the rest of the story.

In order to explain how statins damage muscles, I will first need to explain how muscles manage their energy needs. Muscles require a significant amount of energy to contract, and they get most of this energy by breaking down fatty acids and glucose obtained originally from food sources. Like all eukaryotic cells (cells containing a nucleus), muscle cells are able to generate a lot of energy through aerobic (oxygen-requiring) processes that are sequestered within special energy-generating subregions of the cell called mitochondria. This aerobic metabolic process is highly efficient, generating as many as 30 units of ATP (Adenosine Triphosphate) for each molecule of glucose. ATP can be thought of as an energy currency, because it can be easily broken down to AMP (adenosine monophosphate), releasing the stored energy in the process, which will then fuel cell contraction.

Unfortunately, the process of metabolizing food sources for energy is quite complex. I have found two images which depict food metabolism in complementary ways, where one (above, right) shows chemical reactions and the other (below, left) schematizes the regions of the cell that are involved. They use slightly different nomenclature, but I will try to link them together when necessary. When glucose first enters the cell (mediated through insulin), it is converted to pyruvate (also called pyruvic acid) in the cell's cytoplasm (the main compartment of the cell). This process releases a small amount of ATP, but does not require oxygen, which makes it useful when oxygen is in short supply. The pyruvate can also be broken down to lactate (also called lactic acid) (fermentation, oxygen absent in the figure below) in the cytoplasm, without requiring any oxygen, so-called anaerobic metabolism, to release additional energy. This pathway is important to muscle cells under conditions of extreme exercise, when oxygen supplies become depleted.

To generate a much larger amount of ATP requires the help of the mitochondria (the large oval purple-shaped object in the figure), and involves a well known process referred to multiple ways: as the respiratory or electron transport chain, the Tricarboxylic acid (TCA) cycle or the Krebs Cycle (TCA cycle, oxygen present in the figure below; Krebs Cycle, Aerobic Metabolism in the figure above). The process is tricky, because oxygen molecules (O₂) have to be split apart, and, during intermediate stages, dangerous free radicals are lying around (individual negatively charged oxygen atoms that have not yet fully combined with hydrogen (H⁺) to form the very stable molecule, water (H₂O)). These free radicals are highly reactive. Antioxidants are compounds that can absorb these free radicals and render them harmless. Two very important antioxidants that play a critical role in the electron transport chain are coenzyme Q10 (also known as ubiquinone) and cytochrome c.

The small figure to the left shows a schematic of a mitochondrion, and the larger figure below shows a more detailed explanation of the electron transport chain process that takes place along the wall enclosing the mitochondrion, generating a large percentage of the cell's energy needs in the process. The electron transport chain injects protons (H⁺) into the intermembrane space, essentially creating a battery (charge differential across the membrane) that can then complete the process of converting (spent) AMP back to ATP as a renewed energy source. If there is an insufficient supply of coenzyme Q10 (also known as "ubiquinone", the "Q" in the figure), then the electron transport chain will not work as efficiently. Hydrogen ions will leak back into the mitochondrion through a passive process, requiring a much larger expenditure of energy to push them back out [20]. The battery charge will be reduced, and there will be a decrease in the amount of ATP that can be generated. The net effect will be very similar to the effect of insufficient oxygen, with respect to energy generated. However, it will be much more damaging because, instead of being absent, the oxygen is present but is only partially converted to water (2H⁺ + 1/2 O₂ -> H₂O at the right of the figure), since the chain of events is held up at the "Q" position. Various highly toxic charged ions containing oxygen, such as -OH, H₂O₂ (hydrogen peroxide) and *OH, will linger and wreak havoc on the muscle cell, as you will see later.

There are a number of rare genetic disorders that involve mutations in genes encoding enzymes that operate within the electron transport chain [23][32]. Particularly relevant to our story are Complex I enzymes, because Coenzyme Q10 is one of them. An interesting case study involved two sisters [23], both of whom suffered from a genetic mutation leading to a defect identified to be associated with the NADH-Coenzyme Q10 complex. As would be predicted, they suffered from substantially decreased rates of respiratory metabolism (the process discussed above). They also were extremely weak and had marked intolerance to exercise. When they exercised, their levels of lactate and pyruvate rose sharply in the blood, an indication that they were relying on anaerobic fermentation in the cytoplasm rather than aerobic metabolism in the mitochondria to meet their energy needs.

5. Managing Energy Needs During Extreme Exercise

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Whenever a healthy person experiences extreme exercise, such as running a 500 meter dash, the muscles are challenged to come up with sufficient ATP to satisfy their energy needs. Both oxygen and glucose can become depleted. To compensate for these deficiencies, muscle cells have devised a complex set of strategies, which operate in the cytoplasm instead of in the mitochondria. They involve a number of enzymes that will resurface later in our story, since they are the enzymes that are monitored to determine whether statin drugs are damaging muscles and/or the liver.

As you've already seen, one option is to generate lactic acid anaerobically (without consuming oxygen), but this still provides only 1/6 as much ATP as the aerobic process taking place in the mitochondria. The process of generating energy from ATP happens in two steps: ATP is first converted to ADP (adenosine diphosphate) and finally to AMP (adenosine monophosphate). When excess amounts of AMP accumulate in the muscle cell, the cell is induced to take up extra glucose, which will soon deplete the supply (of glucose) in the blood unless the liver can efficiently regenerate more. ADP can be converted back to ATP with the help of an enzyme, creatine kinase. In addition, the conversion of pyruvate (generated anaerobically from glucose) to lactate requires the help of another enzyme, lactate dehydrogenase. Lactate builds up when oxygen is insufficient, and is released into the blood stream. Fortunately, the heart is able to utilize lactate as an alternative fuel source [9], which becomes especially important during times of extreme exercise.

In order for the liver to generate more glucose, it needs a substrate. In the short term, muscles can supply this substrate, but it requires self cannibalization. During brief periods of starvation, human muscle cells adapt quickly by breaking down muscle proteins and converting them into a basic amino acid, alanine [34]. Muscles then rely on a novel mechanism that involves an exchange system with the liver, the so-called glucose-alanine cycle. The alanine, derived from muscle protein, is released into the blood and shipped to the liver to be utilized for energy generation, as shown in the accompanying figure. The liver can then generate more glucose from the alanine through gluconeogenesis, while exporting the waste product, urea, to the kidneys for excretion. This also allows the liver to regenerate some ATP to help satisfy its own energy needs, which are very large during such stressful conditions. The glucose is shipped through the blood stream to the muscle cell, which eagerly takes it up to generate more ATP for itself. The anaerobic processing of glucose yields pyruvate which can also be turned into alanine, but it needs yet another enzyme to work. Thus, whenever pyruvate can't be sent to the mitochondria because of insufficient oxygen, it can instead be converted to alanine with the help of an enzyme, ALT (alanine aminotransferase), as long as there is a good supply of glutamate, which is converted to alpha-keto glutarate in the process.

In the above discussion, several enzymes have been identified that must be present for these cytoplasmic energy-generating processes to function. These include creatine kinase, lactate dehydrogenase, and ALT. The so-called liver enzyme test that is conducted routinely with statin users measures the concentration of ALT in the blood. Muscle enzyme tests detect creatine kinase and lactate dehydrogenase concentrations in the blood. So these tests are all measuring these particular enzymes because they signal that muscles are preferentially processing glucose anaerobically in the cytoplasm instead of aerobically in the mitochondria; i.e., the mitochondria are not working properly. You should keep this point in mind as we will revisit it later on.

6. Extreme Exercise can lead to Rhabdomyolysis

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When people engage in extreme exercise such as long distance marathon running or weight-bearing exercises, they run the risk of causing serious damage, both to their muscles and to their kidneys, due to the stress imposed on their system in trying to maintain adequate energy to fuel the muscles. It has become common practice to measure the levels of creatine kinase in the blood as a known indicator of potential damage [5]. A person whose creatine kinase level gets alarmingly high will likely need immediate medical attention to avoid renal [kidney] failure.

The cause of the kidney failure is most likely myoglobin that has been dumped into the blood stream by compromised or dead muscle cells, due to rhabdomyolysis. If too much myoglobin is released, particularly with inadequate water supply, the myoglobin can block the renal filtration system causing a condition known as "acute tubular necrosis." The problem can be easily detected by observing the color of the urine, which will be dark brown. A study published in 2009 showed that, in rhabdomyolysis, the damage to the kidneys involves direct interaction between myoglobin and the mitochondria in the kidney cells [33]. The resulting oxidation of the mitochondrial membranes leads to respiratory failure and subsequent cell death.

Myoglobinuria is the term used to describe the presence of myoglobin in the urine, usually due to rhabdomyolysis. According to [37], 15% of patients with severe myoglobinuria develop acute renal failure, and it is associated with high mortality rates. Dialysis or intravenous fluids must be introduced fast enough, or the person will not be able to recover.

As early as 1991, a group of Japanese researchers [38] demonstrated that coenzyme Q10 could be administered orally to protect rats from muscle damage due to strenuous exercise. They also noticed that rats that were administered coenzyme Q10 did not have elevated levels of creatine kinase and lactate dehydrogenase, whereas the control rats did.

7. Myoglobin: The Good, The Bad, and the Ugly

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Myoglobin is a unique protein specially adapted for muscle cells to help them with their enormous needs for oxygen. Its physical structure is schematized in the figure on the right. It resembles hemoglobin in that it contains a central heme element (schematized in red in the figure) whose active ingredient is a single charged iron atom (Fe). While hemoglobin, found in red blood cells, transports oxygen from the lungs to all the tissues of the body, myoglobin functions to store excess oxygen within the muscle cell, to help buffer supply during periods of excessive demand. It also transports oxygen from the cell wall to the mitochondria. Even with help from the myoglobin, it's often the case that muscles have to resort to anaerobic metabolism under strenuous exercise, during which lactic acid is built up and released into the blood stream.

Myoglobin exists in at least three distinct forms, which can be characterized as Mg⁺² (Ferrous), Mg⁺³ (Ferric), and Mg⁺⁴ (Ferryl), depending upon the amount of charge that is present on the central Iron atom. As Mg⁺², its healthy state, it will readily take up oxygen and store it, whereas, when converted to Mg⁺³ by the addition of a proton, it becomes inert. However, with the addition of yet another proton, it becomes Mg⁺⁴, a highly toxic reactive agent that will begin to break down the fatty acids contained in the outer cell wall of the muscle cell (so-called peroxidative damage)[35], and go on to destroy the cholesterol in the cell wall as well [31]. Myoglobin becomes Ferryl myoglobin in the presence of excess amounts of free radicals, i.e., under oxidative stress induced by highly reactive oxygen compounds like hydrogen peroxide. Recall that, with statin therapy, hydrogen peroxide is generated in the mitochondria because the process of breaking down oxygen and converting it to water is incomplete -- due to the insufficient supply of coenzyme Q10.

An excellent article describing the process by which a cell is injured by oxidative stress was written by John Farber in 1994 [13]. He wrote: "All aerobic cells generate, enzymatically or nonenzymatically, a constitutive flux of O₂^-, H₂O₂, and possibly *OH. At the same time, the abundant antioxidant defenses of most cells, again both enzymatic and nonenzymatic, prevent these species from causing cell injury. Nevertheless, there are situations in which the rate of formation of partially reduced oxygen species is increased and/or the antioxidant defenses of the cells are weakened. In either case, oxidative cell injury may result." [14, p. 17]. The process of aerobic oxidation of food sources to generate energy is confined to the mitochondria in order to protect the constituents in the cytoplasm as much as possible. But myoglobin is tasked with transporting oxygen from the cell wall through the cytoplasm to the mitochondria. It can't avoid oxygen exposure, and when it delivers the oxygen, it necessarily has to come in contact with these toxic intermediate products of the process that ultimately converts oxygen to water. One of the most important roles of coenzyme Q10 in the muscle cells is to neutralize the damage to myoglobin caused by these oxidative agents.

When a person suffers from a heart attack (ischemic event), their muscles experience an extreme lack of oxygen due to the heart's temporary inability to pump blood. However, one of the most dangerous aspects of a heart attack is the so-called reperfusion period, when blood circulation is restored, but after the cells have suffered injury as a consequence of oxygen deprivation [29]. This condition is especially problematic for the heart muscle, since it is so crucial to survival. In a study involving rats that had suffered from heart attacks, it was proposed that the injury is a direct consequence of exposure to the Fe⁺⁴ form of myoglobin (ferryl myoglobin) [1]. Because the cells have been unable to maintain their physiological state during the deprivation period, they are highly vulnerable to oxidative stress.

Once the fatty acids in a muscle's cell wall are broken down due to exposure to toxic Ferryl myoglobin, the cell rapidly disintegrates. Because the cell wall is no longer impermeable to ions, large amounts of calcium start rushing into the cell, and soon after it dies [14]. The debris of the dead and dying cells gets dispersed into the blood stream, and makes its way to the kidneys for disposal. This causes a tremendous load on the kidneys which can sometimes lead to their failure as well [47], and the situation cascades into a downward spiral.

In 1994, Mordente et al. published a paper that investigated in vitro the degree to which coenzyme Q could protect myoglobin from oxidative damage [28]. Their results showed convincingly that coenzyme Q can work as a natural antioxidant for myoglobin. To quote the last sentence of their abstract: "Collectively, these studies suggest that the proposed function of coenzyme Q as a naturally occurring antioxidant might well relate to its ability of reducing H₂O₂ [hydrogen peroxide]-activated myoglobin. Coenzyme Q should therefore mitigate cardiac or muscular dysfunctions that are caused by an abnormal generation of H₂O₂."

8. How Cholesterol Protects Membranes and Saves Energy

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Mammalian cells can not survive without cholesterol [45]. Cholesterol is found in the outer wall (cell membrane) of all cells in the body. It is also found in internal membranes that surround both the mitochondria and the lysosomes (highly acidic containers of digestive enzymes). To understand how cholesterol works, you need to know something about the structure of cell membranes. All cell membranes are built from a so-called lipid bilayer, as illustrated in the figure to the right. The lipid bilayer contains two parallel chains of phospholipids (the same phospholipids that encase LDL particles, the so-called "bad" cholesterol). Phospholipids have the unique property that one end of the molecule is hydrophobic (water insoluble) and the other is hydrophilic (water soluble). The two chains in the lipid bilayer orient themselves such that the hydrophobic sides of both layers are adjoining in the center of the membrane. This central hydrophobic layer thus contains fatty acids that are vulnerable to oxidative damage. The outer parts, facing both the exterior and the interior of the cell, are water-soluble. Cholesterol molecules are dispersed throughout the membrane at strategic locations.

An article published in 2009 by Kucerka et al. [22] nicely sums up several known roles of cholesterol in membranes: "Cholesterol is found in all animal cell membranes and is required for proper membrane permeability and fluidity. It is also needed for building and maintaining cell membranes, and may act as an antioxidant. Recently, cholesterol has also been implicated in cell signaling processes, and is suggested to enable lipid raft formation in the plasma membrane." [Ibid, p. 16358] The article goes on to describe how cholesterol is able to orient itself within the membrane either vertically (bridging across the membrane) or horizontally (sequestered within the hydrophobic central space of the membrane lipid bilayer). How it is oriented depends upon the degree to which the fatty acids in the membrane are saturated, with saturated fatty acids greatly favoring the vertical over the horizontal orientation. Cholesterol can also flip easily from one side of the bilayer to the other. All of this flexibility in its orientation within the membrane allows it to operate effectively as a signaling molecule.

A fascinating article written by Thomas Haines in 2001 proposes a novel but compelling role for cholesterol in protecting the cell membrane from sodium leaks [20]. All mammalian cells maintain an ion gradient across their outer wall, which is utilized to fuel cell chemical processes. The so-called sodium pump is an active process that constantly pumps sodium out of the cell to maintain this charge difference. The pump consumes ATP in the process. Working against the pump is a passive leakage mechanism that causes sodium to drift back into the cell. To the extent that the membrane can be constructed to resist leakage (kind of like putting insulation in the attic of a house), it will require less ATP to maintain sodium concentrations appropriate for the cell to function properly.

The Haines article argues that cholesterol plays an essential role in protecting the cell wall from sodium leakage. Sodium leakage is a much bigger problem (it leaks 7 to 11 times as fast in the absence of cholesterol) for unsaturated fatty acids as for saturated fatty acids [4]. However, unsaturated fatty acids also encourage cholesterol to arrange itself in the central layer. By accumulating there, it provides extra insulation preventing the charged sodium ions from passively hopping from the exterior to the interior of the cell. Other experiments [30] have shown that the relative sodium leakage rates are reduced by 300% in the presence of cholesterol.

9. The Evidence of Statin Damage to Muscles

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Typically in America, if a person fails a stress test or suffers from a heart attack and then is found to have a blocked coronary artery, a stent will be introduced to correct the problem and high-dose statin therapy will be initiated, with the expectation that the drug will be needed for the rest of their life. The accepted belief today is that, no matter whether their cholesterol is already low, high-dose statin therapy will yield sufficient benefit to offset any side effects it might cause. At the same time, these patients are encouraged to spend up to an hour a day exercising on a treadmill, since exercise has been shown to be highly beneficial to heart disease prognosis. The exercise, in conjunction with the metabolic deficiencies induced by the statin drug, are a potentially lethal combination.

Typically, also, the patient is not alerted that a common side effect of statin drugs is muscle pain and muscle weakness. It is often the case that such symptoms don't appear immediately. In fact, it can sometimes be years before statin therapy leads to enough damage to cause obvious symptoms. By that time, the person may well believe that the pain and weakness are simply a consequence of getting older.

It has been widely claimed, and statin users seem to have embraced this concept, that, as long as you monitor your enzyme levels, you can simply terminate statin therapy if the enzymes get too high, and all will be well. However, judging from some of the sad stories that are showing up in comment pages all over the web, this has turned out not to be the case for some people.

An article published in July, 2009 [27] investigated the association between physical muscle damage and patients' complaints of muscle weakness or pain. Patients who reported weakness said, for example, that it was difficult to get up from a seated position without arm support. Those who reported pain generally said that it was worse after physical exercise. Only one out of 44 patients examined developed overt rhabdomyolysis, with the serum level of the muscle enzyme creatine kinase measured at 57,657 U/L. This patient required hospital treatment for management of his pain.

The authors were interested in investigating the extent to which muscle damage could be seen through muscle biopsy for these patients. They compared them with 20 patients who had never taken a statin drug. Twenty five of the 44 patients taking statins had clear muscle damage. None of the 20 controls had any evidence of damage. Other than the one patient with overt rhabdomyolysis, none of the others had muscle enzyme levels above the cut-off considered the upper level of "normal." For those patients with injuries, on average 10% of their fibers were injured. The authors concluded that the lack of elevated levels of creatine kinase does not rule out structural muscle injury.

10. Statins and Heart Failure

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A paper titled simply "Lovastatin decreases coenzyme Q levels in humans" [16] states unequivocally in the abstract: "It is established that Coenzyme Q10 is indispensable for cardiac function." The heart is a muscle, and hence it is subject to all the same laws of physics as the skeletal muscles. It faces the same problem of fuel deficiency due to the various effects statins have on metabolism discussed above. Heart muscle cells would also have to cannibalize themselves to get enough fuel, and would also suffer damage to their cell membranes due to exposure to Ferryl myoglobin.

An article published in 2004 [42] provides a plausible theory for the process by which muscle cells in the heart become dysfunctional with old age, leading ultimately to heart failure. The argument blends perfectly with the logical deductions associated with the mechanism by which statins damage cells, and leads to the unavoidable conclusion that statins make you age at an accelerated pace. The process involves a downward spiral caused by deficiencies in both the mitochondria and the lysosomes. Recall that the mitochondria are responsible for providing fuel to the cell, and the lysosomes are responsible for digesting and decomposing residues of waste products. The article claims that the downward spiral is caused by "continuous physiological oxidative stress." Oxidative stress is greatly enhanced by statins, because they deplete the supply of both antioxidants like coenzyme Q10 and fresh phospholipids and cholesterol to rebuild damaged cell walls. Debris from damaged phospholipids in the cell wall, the mitochondrial walls, and the lysosome walls must be taken up by the lysosomes, digested, and disposed of. Under normal circumstances the lysosomes would easily break them down in their highly acidic environment, using their powerful digestive enzymes.

When the lysosomes are unable to digest the debris that accumulates from damaged cell walls, the residue that remains is called "lipofuscin." Lipofuscin is considered to be a signature of old age, accumulating in the liver, kidney, heart muscle, and nerve cells as we get older. Lipofuscin is believed to be the product of oxidation of unsaturated fatty acids, and is indicative of membrane damage, whether to the cell's outer wall or to the walls of the lysosomes and mitochondria [17].

For long-term statin users, lipofuscin almost certainly accumulates, because their lysosomes are dysfunctional. This condition would arise not just in the heart, but in all the cells of the body. As I mentioned earlier, statins cripple the production of the dolichols, antioxidants that play a crucial role in protecting the lysosomes from hydrogen ion leakage. Lysosomes also depend upon cholesterol in their membranes to provide additional insulation against charge dissipation. With a constant leakage outward of H⁺ ions, lysosomes can not maintain their pH at a sufficiently acidic level to allow their enzymes to work. As a consequence, undegradable debris, i.e., lipofuscin, accumulates within the lysosomes, and the cell has no backup repair system to salvage the disaster. The last sentence in the abstract of [42] says: "This interrelated mitochondrial and lysosomal damage eventually results in functional failure and death of cardiac myocytes {heart muscle cells]."

Doctor Peter Langsjoehn believes that statins are inducing an epidemic rise in the incidence of heart failure. He wrote: "In my practice of 17 years in Tyler, Texas, I have seen a frightening increase in heart failure secondary to statin usage, 'statin cardiomyopathy.' Over the past five years, statins have become more potent, are being prescribed in higher doses, and are being used with reckless abandon in the elderly and in patients with 'normal' cholesterol levels. We are in the midst of a CHF epidemic in the US with a dramatic increase over the past decade. Are we causing this epidemic through our zealous use of statins? In large part I think the answer is yes. " (Statins and Heart Failure) .

Dr. Duane Graveline, a long-time advocate of the dangers of statin therapy, has provided a very clear description ( Duane Graveline on Statins and Heart Failure) of the role of coenzyme Q10 in the heart and the reason why its inhibition by statins would lead to heart failure. You can find several references to relevant articles by Dr. Langsjoehn on that page.

A very recent study (November, 2009) [8] found that patients with diastolic heart failure who were taking statins had a significantly poorer outcome than patients who were not on statin therapy. Diastolic heart failure is distinguished from systolic heart failure in that it is associated with dysfunction of the heart during the resting phase rather than the contracting phase. However, it is the cause of nearly half of the cases of heart failure, and it is equally as fatal as the systolic form. In the study, it was confirmed that people with diastolic heart failure who were on statin therapy were more likely to have problems with their lungs and were less able to exert themselves (weaker muscles, poorer exercise tolerance) than those not on statins.

11. Statins and Lung Disease

2010-02-25T16:57:00.000-08:00

The statin industry has tried to promote the idea that statins might be beneficial in treating pneumonia. They came to this erroneous conclusion through retrospective studies, where the observed benefits come, I suspect, from the fact that those who took statins had benefited from high cholesterol for probably many years before introducing statin therapy. The industry was sufficiently encouraged by preliminary positive indications to then conduct placebo-controlled studies to try to legitimize their claim. However, the studies backfired, because they clearly showed that statin therapy not only wasn't helpful, but actually led to a significantly worse prognosis [26][12] (see ( Statins Increase Pneumonia Risk) . For pneumonia severe enough to require hospitalization, the increased risk incurred by taking a statin was an alarming 61% [12].

Statins' effects on muscles apply to the respiratory muscles as well, leading to difficulty in breathing and subsequent oxygen deprivation, which, of course, further aggravates both pneumonia and heart failure. Furthermore, it is now well known that, in rare cases, statin drugs cause severe lung disease, so-called "interstitial lung disease" (ILD) [24][44][15]. ILD is now listed as a rare side effect for all statin drugs.

In an excellent review article published in 2008, Fernandez et al. [15] identify several possibilities for how statins might cause interstitial pneumonia. They begin their discussion by drawing an analogy with amiodarone, a drug which is known to cause a very similar kind of pathology, which includes the accumulation of lysosomal inclusion bodies, i.e., lipofuscin, the cell-membrane debris that was described previously in the section under heart disease.

Amiodarone belongs to a very common class of drugs known as "amphiphilic" drugs: they have both a hydrophilic (water soluble) and a lipophilic (fat soluble) component in their chemical structure. This property allows them to cross through the membranes of cells in order to achieve their desired biochemical influence. However, the process by which they enter the cell involves degrading the lipids in the cell membrane [2] . Membrane fragments break away from the cell wall and carry the drug along with them into the cell. As a consequence of cell wall deterioration, sodium leaks will cause the cell to lose energy, with all the negative consequences that have been described before.

Fernandez et al. argue that, like amiodarone, statins have an amphiphilic structure, since they contain an apolar (lipophilic) ring and a hydrophilic side chain. A really disturbing observation they make is that, over time, amphiphilic drugs are known to become more efficient at entering cells. It seems logical that a deteriorating cell wall would allow better permeability to the drug molecule. But this then means that whatever effect the drug has on the cell will be increased, leading to accelerated damage and a destructive cascade.

Amiodarone is a potent antidysrhythmic agent, i.e., a drug used to try to correct an irregular heart beat during heart failure or post-operative. It has numerous side effects, but probably the most serious side effect is interstitial lung disease. An article written in 2001 [3] explored the likely mechanism of pulmonary damage. The authors conducted in vitro experiments on cells in lung tissue extracted from hamsters. They noted that exposure to the drug decreased the mitochondrial membrane potential (H⁺ ions leaked out of the mitochondria) and subsequently the amount of ATP in the cell dropped by 32 to 77%. Even with the addition of glucose, the mitochondria were not able to regenerate the depleted ATP; i.e., the mitochondria were not functioning properly to generate energy from glucose. Ultimately, the cells died. They concluded that mitochondrial dysfunction was the path by which the drug induced cell death.

What they describe is essentially the exact same process by which statins lead to problems in muscle cells. Fernandez et al. agree with my argument that, like amiodarone, statins may cause interstitial lung disease through their disruption of the mitochondrial electron transport chain and subsequent depletion of ATP. Lung cells are particularly vulnerable to oxidative damage, because they are tasked with capturing oxygen from the air and transporting it to the blood. I also suspect that, although the number of cases of reported interstial disease is small, there is a much larger number of people whose lungs have been compromised by statins, but whose pulmonary function has not yet deteriorated to a catastrophic point. Instead, they experience some difficulty breathing and a perceived inability to get enough oxygen. As with muscle weakness, such symptoms may go unreported, as the patient has no way of knowing that what he is experiencing is not a normal aspect of growing old. Certainly an increased susceptibility to viral pneumonia would be anticipated when the lung's cells are suffering from insufficient energy and a degraded cell wall.

12. Statins and Diabetes

2010-02-25T16:52:00.000-08:00

The JUPITER trial of the statin drug Crestor was widely heralded as evidence that statin drugs can delay heart attacks for people who have high levels of an indicator of inflammation called C-reactive protein. However, what is less known about this trial is that it uncovered a clear link between statin drugs (or, at least, Crestor) and increased risk of diabetes (JUPITER Trial and Diabetes) [36]. According to Dr. Jay Cohen, the people who took Crestor in the trial had a 25% increased risk of developing diabetes, compared to the control group. This is alarming, because diabetes itself is an extremely strong risk factor for heart disease.

The pancreas synthesizes insulin in its beta cells, and defects in insulin production (either too little of it, or a lack of response to it) is the cause of diabetes. Insulin is used by the body's cells to catalyze the transport of glucose into the cell. Without insulin, or with poorly functioning insulin, sugar piles up in the blood and the cells become energy starved.

There have been a large number of studies on the biochemistry of the beta cells and their insulin-producing machinery, and it has been determined that beta cells require both cholesterol [46] and fats [11] to be present before they will release insulin. Inadequate cholesterol and poor quality phospholipids in the beta cell's outer membrane likely impair its ability to transport insulin across the membrane. Statin drugs, of course, reduce the bioavailability of cholesterol, but also of fatty acids, because these are transported in the blood stream via the same LDL particles that statins suppress. Thus, it is easy to see why statins would cause an increased risk to diabetes.

In addition to the above defects in the cell membrane, impaired function of the mitochondria in the beta cells has also been clearly implicated in diabetes, in studies involving diabetic mice with defective mitochondrial genes [39]. These mice exhibited reduced insulin secretion when they were only five weeks old, and their mitochondria were abnormal in appearance and were unable to maintain an adequate charge gradient across their membranes. In other words, they exhibited defects that are similar to what would be expected with reduced coenzyme Q10 as a consequence of statin exposure. Older mice with the same defect were severely deficient in insulin production, as many of their pancreatic beta cells had died off.

Insulin suppresses the release of fats from both the fat cells and the liver, and therefore there will be a fat shortage in the blood supply subsequent to insulin release, unless abundant fats are already present. Thus, it is a good strategy, biologically, for the beta cells to be sure fats and cholesterol are well supplied before injecting insulin into the blood stream. I have previously written extensively on this subject (Essay on Metabolic Syndrome).

A study published in March, 2009 [41] looked at the relationship between statin drug usage and fasting blood glucose levels, the test typically conducted to assess diabetes risk. They grouped 345,417 patients into two categories: with or without a previous diabetes diagnosis. They compared fasting glucose levels before they began taking statins and then after they had been on statins for an average of two years. In both groups, they obtained a highly significant (P < 0.0001) result of increased fasting glucose levels for those on statin therapy.

A reduction in the ability of glucose to enter muscle cells, consequential to a reduction in insulin supply, would add insult onto injury for the muscle cells trying to survive with a defective aerobic metabolism factory. Because the muscles are forced to switch to the much less efficient anaerobic metabolism of glucose in order to avoid oxidative damage, they require enormously more glucose to meet their energy supply than they would require if their mitochondrial energy-generating factory were functioning properly. Yet the reduced insulin is making it harder to get enough glucose in. This will force the cell into the starvation mode that leads to cannibalization of its internal muscle protein. The perceived result over time will be extreme muscle weakness.

13. Statins and Muscle Damage: Conclusions

2010-02-25T16:47:00.000-08:00

If you live in the United States, and your doctor has identified that you are at high risk to heart attacks, he has likely prescribed a high dose statin even if your cholesterol levels are not high. You have likely also been put on a low-fat, low saturated fat diet, and you have been encouraged to work out on a treadmill every day.

My research indicates that, if you rigorously follow all of your doctor's advice, you will be facing severe muscle damage sooner or later. The statin drug's impact on the mitochondria and on the cell walls of the muscle cells is such that even modest exercise can lead to rhabdomyolysis. For some it will be obvious right away that the side effects are too damaging and the statin therapy must be terminated. For others, the damage will happen more insidiously, and will not become apparent until years after statin therapy was initiated. But often patients will find that the symptoms remain after the drug is stopped -- it will be too late to repair the muscle damage. Or, worse, they will develop kidney failure or heart failure as a consequence.

Statin drugs have many adverse side effects, but probably the most frequent complaints concern muscle pain and muscle weakness. In this essay, I have developed a physiological explanation for the mechanism responsible for this side effect. It is due to the fact that statins interfere with the synthesis of not only cholesterol, but also coenzyme Q10 and the dolichols. Statins also reduce the bioavailability to the cells of both fatty acids and all dietary antioxidants, due to the sharp reduction in serum levels of LDL, which delivers these essential nutrients to the cells.

Without sufficient coenzyme Q10, muscle cells suffer from an impaired ability to generate energy to fuel their contractions. They are forced to cannibalize their own proteins to survive. At the same time, powerful oxidative agents are generated which damage the myoglobin in the cell, rendering it both ineffective to transport oxygen and toxic to the cell wall. The oxidized myoglobin, known as "Ferryl myoglobin" is toxic to the fatty acids that are the main component of the cell wall. With insufficient cholesterol in the cell wall, the cell can't hold a charge, and this also causes it to waste energy. The lysosomes are unable to digest debris because they can't maintain a sufficiently acidic environment. The problem is further compounded by profound shortages of cholesterol, which would have offered further protection against oxidative damage to the fatty acids and ion leakage in the cell wall, the mitochondrial wall, and the lysosome wall. Eventually the cell disintegrates and the myoglobin is released into the blood stream. It makes its way to the kidneys, which try to dispose of it. But the Ferryl myoglobin is also toxic to the kidneys, which leads to severe kidney disease.

The low-fat diet and the exercise regime will both increase the likelihood that the statin drug will cause problems. Vigorous exercise increases the energy needs of the muscles, while the low-fat diet reduces even further the bioavailability of fatty acids to replace damaged cell walls. Furthermore, cell walls composed of unsaturated fats are more vulnerable to attack by the Ferryl myoglobin than those composed of saturated fats.

Because the heart is also a muscle, it also suffers from damage due to exposure to statins. This leads to a reduced likelihood of recovering from a diastolic heart attack, and an increased chance of developing heart failure. Damaged cells of the respiratory system lead to an increased risk of both pneumonia and interstitial lung disease, both of which are very dangerous for someone with a weak heart.

The JUPITER trial revealed that the treatment group had a 25% increased risk for diabetes, and I have explained above why this would be true. Diabetes is a significant risk factor for heart disease, so this outcome is disturbing, and one wonders whether the trial was terminated early to avoid making this number even worse. Dr. William Davis, a cardiologist who believes that statins should be a last resort in treating heart disease, has this to say about the JUPITER trial: "I view the foisting of Crestor via the JUPITER argument on the public as taking full advantage of the helpless situation many Americans find themselves in: Reduce fat intake, eat more healthy whole grains and . . . cholesterol and CRP skyrocket! 'You need Crestor! See, I told you it was genetic,' says the doctor after attending the nice AstraZeneca-sponsored drug dinner." ( Dr. Davis' Blog Post on JUPITER)

The news has just come out that even children are now being tested for high cholesterol, and it is being suggested that they should be put on a statin drug if they can not control their cholesterol levels (Children Taking Statins??). I find this news to be extremely disturbing, especially since none of the controlled statin trials have been conducted on children. We have no idea what negative consequences statin drugs might have on the developing nervous system of a child. However, it has been shown that statins can completely destroy the nervous system of an embryo [13].

A remarkable recent publication by Jeff Cable (December, 2009) [7] analyzes a set of 885 self-reported adverse effects of statin therapy by patients. Although the reports covered a wide range of known side effects of statins, including cognitive impairment, muscle pain and weakness, skin problems and sexual dysfunction, what was most disturbing was the large number of reports of severe neurological damage. Most distressing was the fact that there were a total of 17 reports of ALS with 2 additional reports related to motor neuron deterioration, which he counts together as 1 to give a total of 18. In ALS, nerve cells waste away or die, and can no longer send messages to muscles. This eventually leads to muscle weakening, twitching, and ultimately paralysis. As the disease progresses, swallowing and breathing become difficult. Most victims die within five years of diagnosis.

The author's comments related to neurological disorders and ALS are quoted here: "One fragment of information that was gained from the patient accounts is the apparent incidence of major neurodegenerative diseases which may well have been precipitated by statin therapy. ... The rarest of these conditions is ALS and yet in just 351 reports there were enough cases to have made the prediction (based upon incidence statistics) that an expected three million six hundred thousand accounts would have to be written before eighteen ALS/MND cases would have been revealed. This is such an astonishingly high number of cases to report within such a small participant group that it would be right to ask whether a fundamental error has been made. Absent any error it is also right to ask: What is really happening? What is the real risk posed by statin therapy?"

There is prior evidence from the literature implicating a relationship between statins and ALS -- a study of the FDA's adverse event reports [10] as well as a study showing that high cholesterol protects against ALS [19]. My next essay will be on the subject of statin drugs' likely adverse effects on the nervous system: I will argue that statins increase risk not just to ALS but to multiple sclerosis, Parkinson's disease, and Alzheimer's.

Acknowledgements for Essay on Statins and Muscle Damage

2010-02-25T16:45:00.000-08:00

I would like to thank Glyn Wainwright for pointing me to both his own excellent review paper and the very informative and fascinating article by Haines [20] on proton and sodium leaks through lipid bilayers, which played a crucial role in my arguments for statin damage to muscles.

References for Essay on Statins and Muscle Damage

2010-02-25T16:29:00.000-08:00

[1] A Arduini, L. Eddy, and P. Hochstein, "Detection of ferryl myoglobin in the isolated ischemic rat heart," Free-Radic-Biol-Med. (1990) Vol. 9, No. 6, pp. 511-3.

[2] M. Baciu, S.C. Sebai, O. Ces, X. Mulet, J.A. Clarke, G.C. Shearman, and R.V. Law, Templer RH, Plisson C, Parker CA, Gee A. "Degradative transport of cationic amphiphilic drugs across phospholipid bilayers." Philos Transact A Math Phys Eng Sci. (2006) Oct 15, Vol. 364(1847), pp. 2597-614.

[3] M.W. Bolt,J. W. Card, W.J. Racz, J.F. Brien and T.E. Massey, "Disruption of Mitochondrial Function and Cellular ATP Levels by Amiodarone and N-Desethylamiodarone in Initiation of Amiodarone-Induced Pulmonary Cytotoxicity," JPET (2001) September 1, Vol. 298, No. 3, pp. 1280-1289.

[4] S.L. Bonting, P.J. van Breugel, F.J. Daemen, "Influence of the lipid environment of the properties of rhodopsin in the photoreceptor membrane," Adv. Exp. Med. Biol. (1977) Vol. 83, pp. 175-89.

[5] P. Brancaccio, N. Maffulli, and F.M. Limongelli, "Creatine kinase monitoring in sport medicine" British Medical Bulletin (2007) Vol. 81-82. No. 1, pp. 209-230; doi:10.1093/bmb/ldm014

[6] E. Bruckert, G. Hayem, S. Dejager, et al. "Mild to moderate muscular symptoms with high-dosage statin therapy in hyperlipidemic patients -- the PRIMO study." Cardiovasc Drugs Ther (2005) Vol. 19, pp. 403-14.

[7] J. Cable, "Adverse Events of Statins -- An Informal Internet-based Study," JOIMR (2009, December, Vol. 7, No. 1; http://www.joimr.org/JOIMR_Vol7_No1_Dec2009.pdf.

[8] L.P. Cahalin, PT, PhD, et al., CHEST 2009: American College of Chest Physicians Annual Meeting, Poster 592. Presented November 4, 2009.

[9] J.C. Chatham, "Lactate - the forgotten fuel!" J Physiol. (2002) July 15; 542(Pt 2), p. 333. doi: 10.1113/jphysiol.2002.020974.

[10] E. Colman, A. Szarfman, J. Wyeth, et al., "An evaluation of a data mining signal for amyotrophic lateral sclerosis and statins detected in FDA"s spontaneous adverse event reporting system," Pharmacoepidemiol Drug Saf (2008) Vol. 17, pp. 1060-76.

[11] B.E. Corkey, J.T. Deeney, G.C. Yaney, K. Tornheim, and M. Prentki, "The Role of Long-Chain Fatty Acyl-CoA Esters in Beta-Cell Signal Transduction," American Society for Nutritional Sciences, (2000) pp. 299S-304S.

[12] S. Dublin, M.L. Jackson, J.C. Nelson, N.S. Weiss, E.B. Larson, and L.A. Jackson, "Statin use and risk of community acquired pneumonia in older people: population based case-control study," BMJ (2009) Vol. 338, p. b2137 ; doi:10.1136/bmj.b2137

[13] R.J. Edison and M. Muenke, "Central nervous system and limb anomalies in case reports of first-trimester statin exposure," N Engl J Med (2004) Vol. 350, pp. 1579-1582.

[14] J.L. Farber, "Mechanisms of cell injury by activated oxygen species." Environ Health Perspect. (1994) December; Vol. 102 (Suppl 10), pp. 17-24.

[15] A.B. Fernandez, R.H. Karas, A.A. Alsheikh-Ali, and P.D. Thompson, "Statins and interstitial lung disease: a systematic review of the literature and of food and drug administration adverse event reports." Chest, (2008) Oct, Vol. 134 No. 4, pp. 824-30. Epub 2008 Aug 8.

[16] K. Folkers, P. Langsjoen, R. Willis, P. Richardson,L.J. Xia,C.Q. Ye, and H. Tamagawa, "Lovastatin decreases coenzyme Q levels in humans," PNAS (1990) November 1, Vol. 87, No. 22, pp. 8931-8934.

[17] C. Gaugler, "Lipofuscin", Stanislaus Journal of Biochemical Reviews
May (1997).

[18] Ghirlanda G, Oradei A, Manto A, Lippa S, Uccioli L, Caputo S, Greco A, Littarru G (1993). "Evidence of plasma CoQ10-lowering effect by HMG-CoA reductase inhibitors: a double-blind, placebo-controlled study". J Clin Pharmacol 33 (3): 226-9. PMID 8463436.

[19] M.R. Goldstein, L. Mascitelli, and F. Pezzetta, "Dyslipidemia is a protective factor in amyotrophic lateral sclerosis," Neurology (2008) Vol. 71, p. 956.

[20] T. H. Haines, "Do Sterols Reduce Proton and Sodium Leaks through Lipid Bilayers?" Progress in Lipid Research (2001) Vol.40, pp. 299-324.

[21] S. Jamil and P. Iqbal, "Rhabdomyolysis induced by a single dose of a statin." Heart (2004) Jan; Vol. 90 No. 1, p. e3.

[22] N. Kucerka, D. Marquardt, T.A. Harroun, M-P Nieh, S. R. Wassall, and J. Katsaras, "The Functional Significance of Lipid Diversity: Orientation of Cholesterol in Bilayers is Determined by Lipid Species," J. Am. Chem. Soc. (2009) Vol. 131, pp. 16358-16359.

[23] J.M. Land, J.A. Morgan-Hughes, and J.B.Clark, " Mitochondrial myopathy: biochemical studies revealing a deficiency of NADH-cytochrome b reductase activity." J. Neurol. Sci. 50: 1-13, 1981.

[24] S. Lantuejoul, E. Brambilla, C. Brambilla, and G. Devouassoux, "Statin-induced Fibrotic Nonspecific Interstitial Pneumonia," Eur Respir J. (2002) Vol. 19, pp. 577-580.

[25] R.S. Lees and A.M. Lees, "Rhabdomyolysis from the Coadministration of Lovastatin and the Antifungal Agent Itraconazole," NEJM (1995) Vol. 333, pp. 664-665.

[26] S.R. Majumdar, F.A. McAlister, D.T. Eurich, R.S. Padwal, and T.J. Marrie, "Statins and outcomes in patients admitted to hospital with community acquired pneumonia: population based prospective cohort study," BMJ (2006) Vol. 333, p. 999.

[27] M.G. Mohaupt, MD, R.H. Karas, MD PhD, E.B. Babiychuk, PhD, V. Sanchez-Freire, K. Monastyrskaya, PhD, L. Iyer, PhD, H. Hoppeler, MD, F. Breil and A. Draeger, MD "Association between statin-associated myopathy and skeletal muscle damage," CMAJ (2009) July 7 Vol. 181 No. 1-2 ; doi:10.1503/cmaj.081785.

[28] A. Mordente, S. A. Santini, G. A. D. Miggiano, G. E. Martorana, T. Petitti, G. Minotti, and B. Giardina, "The Interaction of Short Chain Coenzyme Q analogs with Different Redox States of Myoglobin," The Journal of Biological Chemistry, (1994) Vol. 269, Mo. 44, pp. 27394-27400.

[29] R.A. Oleka, J. Antosiewicza, J. Popinigisa, R. Gabbianellib, D. Fedelib and G. Falcionib, "Pyruvate but not lactate prevents NADH-induced myoglobin oxidation," Free Radical Biology and Medicine (2005) June; Vol. 38, Issue 11, pp. 1484-1490; doi:10.1016/j.freeradbiomed.2005.02.018.

[30] D. Papahadjopoulosa "Na⁺-K⁺ discrimination by “pure” phospholipid membranes," Biochimica et Biophysica Acta (BBA) (1971) Vol. 241, Issue 1, 6 July 1971, pp. 254-259

[31] R.P. Patel, U. Diczfalusy, S. Dzeletovic, M.T. Wilson and V.M. Darley-Usmar, "Formation of oxysterols during oxidation of low density lipoprotein by peroxynitrite, myoglobin, and copper, "Journal of Lipid Research (1996) Vol. 37, pp. 2361-2371.

[32] S. Pitkanen, A. Feigenbaum,, R. Laframboise, and B.H. Robinson, "NADH-coenzyme Q reductase (complex I) deficiency: heterogeneity in phenotype and biochemical findings," J. Inherit. Metab. Dis. (1996) Vol. 19, pp. 675-686.

[33] E.Y. Plotnikov, A.A. Chupyrkina, I.B. Pevzner, N.K. Isaev, and D.B. Zorov, "Myoglobin causes oxidative stress, increase of NO production and dysfunction of kidney's mitochondria," Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease (2009) Vol. 1792, Issue 8, August pp. 796-803; doi:10.1016/j.bbadis.2009.06.005

[34] T. Pozefsky, R G Tancredi, R T Moxley, J Dupre, and J D Tobin "Effects of brief starvation on muscle amino acid metabolism in nonobese man." J Clin Invest. (1976) February, Vol. 57, No. 2, pp. 444-449. doi: 10.1172/JCI108295.

[35] S.I. Rao, A. Wilks, M. Hamberg, and P.R. Ortiz de Montellano, "The Lipoxygenase Activity of Myoglobin," The Journal of Biological Chemistry (1994) Vol. 269, No. 10, pp. 7210-7216.

[36] M. Rizzo, G.A. Spinas, G.B. Rinia and K. Berneis, "Is diabetes the cost to pay for a greater cardiovascular prevention?" International Journal of Cardiology (2009), article in press; doi:10.1016/j.ijcard.2009.03.001

[37] A. Shahapurkar, S. M. Tarvade, N. M. Dedhia, S. Bichu, "Exertional Myoglobinuria Leading to Acute Renal Failure: A Case Report" Indian Journal of Nephrology (2004) Vol. 14, pp. 198-199.

[38] Y. Shimomura, M. Suzuki, S. Sugiyama, Y. Hanaki, and T. Ozawa, "Protective effect of coenzyme Q10 on exercise-induced muscular injury." Biochem Biophys Res Commun. (1991) Apr 15;176(1):349-55.

[39] J.P. Silva, M. Kohler, C. Graff, A. Oldfors, M.A. Magnuson, P.O. Berggren, and N.G. Larsson, "Impaired insulin secretion and beta-cell loss in tissue-specific knockout mice with mitochondrial diabetes" Nat Genet. (2000) Nov; Vol. 26, No. 3, pp. 336-40.

[40] H. Sinzinger, R. Wolfram, and B.A. Peskar, "Muscular side effects of statins," J Cardiovasc Pharmacol (2002) Vol. 40, pp. 163-71.

[41] R. Sukhija, MD, S.Prayaga, MD, M. Marashdeh, MD, Z. Bursac, PhD, MPH, P. Kakar, MD, D. Bansal MD, R. Sachdeva, MD, S.H. Kesan, MD, and J.L. Mehta, MD, PhD, "Effect of Statins on Fasting Plasma Glucose in Diabetic and Nondiabetic Patients" Journal of Investigative Medicine (2009) March; Vol. 57, Issue 3, pp. 495-499; doi: 10.231/JIM.0b013e318197ec8b

[42] A. Termana and U.T. Brunk "The Aging Myocardium: Roles of Mitochondrial Damage and Lysosomal Degradation," Heart, Lung and Circulation (2005) June, Vol. 14, Issue 2, pp. 107-114; doi:10.1016/j.hlc.2004.12.023

[43] G. Wainwright, L. Mascitelli, and M.R. Goldstein, "Cholesterol-lowering Therapy and Cell Membranes. Stable Plaque at the Expense of Unstable Membranes?" Arch. Med. Sci. (2009) Vol. 5, No. 3, pp. 289-295.

[44] T. Walker, J. McCaffery and C. Steinfort, "Potential link between HMG-CoA reductase inhibitor (statin) use and interstitial lung disease," MJA (2007) Vol. 186, No. 2, pp. 91-94.

[45] P.L. Yeagle, The Biology of Cholesterol (1988) 242 pp. CRC Press, Boca Raton, FL.

[46] F. Xia, L. Xie, A. Mihic, X. Gao, Y. Chen, H.Y. Gaisano and R.G. Tsushima, "Inhibition of Cholesterol Biosynthesis Impairs Insulin Secretion and Voltage-Gated Calcium Channel Function in Pancreatic Beta-Cells," Endocrinology (2008) Vol. 149, No. 10, pp. 5136-5145.

[47] R.A. Zager and K.M. Burkhart, "Differential effects of glutathione and cysteine on Fe2+, Fe3+, H2O2 and myoglobin-induced proximal tubular cell attack," Kidney Inernational (1998) Vol. 53, No 6, pp. 1661-1672. doi:10.1046/j.1523-1755.1998.00919.x

APOE-4: The Clue to Why Low Fat Diet and Statins may Cause Alzheimer's

2009-12-17T06:10:00.002-08:00

Abstract:

Alzheimer's is a devastating disease whose incidence is clearly on the rise in America. Fortunately, a significant number of research dollars are currently being spent to try to understand what causes Alzheimer's. ApoE-4, a particular allele of the apolipoprotein apoE, is a known risk factor. Since apoE plays a critical role in the transport of cholesterol and fats to the brain, it can be hypothesized that insufficient fat and cholesterol in the brain play a critical role in the disease process. In a remarkable recent study, it was found that Alzheimer's patients have only 1/6 of the concentration of free fatty acids in the cerebrospinal fluid compared to individuals without Alzheimer's. In parallel, it is becoming very clear that cholesterol is pervasive in the brain, and that it plays a critical role both in nerve transport in the synapse and in maintaining the health of the myelin sheath coating nerve fibers. An extremely high-fat (ketogenic) diet has been found to improve cognitive ability in Alzheimer's patients. These and other observations described below lead me to conclude that both a low-fat diet and statin drug treatment increase susceptibility to Alzheimer's,

1. Introduction to Alzheimer's Essay

2009-12-17T06:10:00.001-08:00

Alzheimer's is a devastating disease that takes away the mind bit by bit over a period of decades. It begins as odd memory gaps but then steadily erodes your life to the point where around-the-clock care is the only option. With severe Alzheimer's, you can easily wander off and get lost, and may not even recognize your own daughter. Alzheimer's was a little known disease before 1960, but today it threatens to completely derail the health system in the United States.

Currently, over 5 million people in America have Alzheimer's. On average, a person over 65 with Alzheimer's costs three times as much for health care as one without Alzheimer's. More alarmingly, the incidence of Alzheimer's is on the rise. Between 2000 and 2006, US Alzheimer's deaths rose by 47%, while, by comparison, deaths from heart disease, breast cancer, prostate cancer, and stroke combined decreased by 11%. This increase goes far beyond people living longer: for people 85 and older, the percentage who died from Alzheimer's rose by 30% between 2000 and 2005 [2]. Finally, it's likely these are under-estimates, as many people suffering with Alzheimer's ultimately die of something else. You likely have a close friend or relative who is suffering from Alzheimer's.

Something in our current lifestyle is increasing the likelihood that we will succumb to Alzheimer's. My belief is that two major contributors are our current obsession with low-fat diet, combined with the ever expanding use of statin drugs. I have argued elsewhere that low-fat diet may be a major factor in the alarming increase in autism and adhd in children. I have also argued that the obesity epidemic and the associated metabolic syndrome can be traced to excessive low-fat diet. Statins are likely contributing to an increase in many serious health issues besides Alzheimer's, such as sepsis, heart failure, fetal damage, and cancer, as I have argued here. I believe the trends will only get worse in the future, unless we substantially alter our current view of "healthy living."

The ideas developed in this essay are the result of extensive on-line research I conducted to try to understand the process by which Alzheimer's develops. Fortunately, a great deal of research money is currently being spent on Alzheimer's, but a clearly articulated cause is still elusive. However, many exciting leads are fresh off the press, and the puzzle pieces are beginning to assemble themselves into a coherent story. Researchers are only recently discovering that both fat and cholesterol are severly deficient in the Alzheimer's brain. It turns out that fat and cholesterol are both vital nutrients in the brain. The brain contains only 2% of the body's mass, but 25% of the total cholesterol. Cholesterol is essential both in transmitting nerve signals and in fighting off infections.

A crucial piece of the puzzle is a genetic marker that predisposes people to Alzheimer's, termed "apoE-4." ApoE plays a central role in the transport of fats and cholesterol. There are currently five known distinct variants of apoE (properly termed "alleles"), with the ones labelled "2", "3" and "4" being the most prevalent. ApoE-2 has been shown to afford some protection against Alzheimer's; apoE-3 is the most common "default" allele, and apoE-4, present in 13-15% of the population, is the allele that is associated with increased risk to Alzheimer's. A person with apoE-4 allele inherited from both their mother and their father has up to a twenty-fold increased likelihood of developing Alzheimer's disease. However, only about 5% of the people with Alzheimer's actually have the apoE-4 allele, so clearly there is something else going on for the rest of them. Nonetheless, understanding apoE's many roles in the body was a key step leading to my proposed low fat/statin theory.

2. Background: Brain Biology 101

2009-12-17T06:09:00.001-08:00

Although I have tried to write this essay in a way that is accessible to the non-expert, it will still be helpful to first familiarize you with basic knowledge of the structure of the brain and the roles played by different cell types within the brain.

At the simplest level, the brain can be characterized as consisting of two major components: the gray matter and the white matter. The gray matter comprises the bodies of the neurons, including the cell nucleus, and the white matter contains the myriad of "wires" that connect each neuron to every other neuron it communicates with. The wires are known as "axons" and they can be quite long, connecting, for example, neurons in the frontal cortex (above the eyes) with other neurons deep in the interior of the brain concerned with memory and movement. The axons will figure prominently in the discussions below, because they are coated with a fatty substance called the myelin sheath, and this insulating layer is known to be defective in Alzheimer's. Neurons pick up signals transmitted through the axons at junctures known as synapses. Here the message needs to be transmitted from one neuron to another one, and various neurotransmitters such as dopamine and GABA exert excitatory or inhibitory influences on signal strength. In adidtion to a single axon, neurons typically have several much shorter nerve fibers called dendrites, whose job is to receive incoming signals from diverse sources. At a given point in time, signals received from multiple sources are integrated in the cell body and a decision is made as to whether the accumulated signal strength is above threshold, in which case the neuron responds by firing a sequence of electrical pulses, which are then transmitted through the axon to a possibly distant destination.

In addition to the neurons, the brain also contains a large number of "helper" cells called glial cells, which are concerned with the care and feeding of neurons. Three principle types of glial cells will play a role in our later discussion: the microglia, the astrocytes, and the oligodendrocytes. Microglia are the equivalent of white blood cells in the rest of the body. They are concerned with fighting off infective agents such as bacteria and viruses, and they also monitor neuron health, making life-and-death decisions: programming a particular neuron for apoptosis (intentional self-destruction) if it appears to be malfunctioning beyond hope of recovery, or is infected with an organism that is too dangerous to let flourish.

The astrocytes figure very prominently in our story below. They nestle up against the neurons and are responsible for assuring an adequate supply of nutrients. Studies on neuron cultures from rodent central nervous systems have shown that neurons depend upon astrocytes for their supply of cholesterol [40]. Neurons critically need cholesterol, both in the synapse [49] and in the myelin sheath [45], in order to successfully transmit their signals, and also as a first line of defense against invasive microbes. Cholesterol is so important to the brain that astrocytes are able to synthesize it from basic ingredients, a skill not found in most cell types. They also supply the neurons with fatty acids, and they are able to take in short chain fatty acids and combine them to form the longer-chain types of fatty acids that are especially prominent in the brain [7][24][36], and then deliver them to neighboring neurons and to the cerebrospinal fluid.

The third type of glial cell is the oligodendrocyte. These cells specialize in making sure the myelin sheath is healthy. Oligodentrocytes synthesize a special sulfur-containing fatty acid, known as sulfatide, from other fatty acids supplied to them by the cerebrospinal fluid [9]. Sulfatide has been shown to be essential for the maintenance of the myelin sheath. Children born with a defect in the ability to metabolize sulfatide suffer from progressive demyelination, and rapid loss of motor and cognitive functions, resulting in an early death before the age of 5 [29]. Depletion in sulfatide is a well-known characterization of Alzheimer's, even in early stages before it has been manifested as cognitive decline [18]. And ApoE has been shown to play a crucial role in the maintenance of sulfatide [19]. Throughout a person's life, the myelin sheath has to be constantly maintained and repaired. This is something that researchers are only beginning to appreciate, but two related properties of Alzheimer's are poor quality myelin sheath alongside a drastically reduced concentration of fatty acids and cholesterol in the cerebrospinal fluid [38].

3. Cholesterol and Lipid Management

2009-12-17T06:08:00.000-08:00

In addition to some knowledge about the brain, you will also need to know something about the processes that deliver fats and cholesterol to all the tissues of the body, with a special focus on the brain. Most cell types can use either fats or glucose (a simple sugar derived from carbohydrates) as a fuel source to satisfy their energy needs. However, the brain is the one huge exception to this rule. All cells in the brain, both the neurons and the glial cells, are unable to utilize fats for fuel. This is likely because fats are too precious to the brain. The myelin sheath requires a constant supply of high quality fat to insulate and protect the enclosed axons. Since the brain needs its fats to survive long-term, it is paramount to protect them from oxidation (by exposure to oxygen) and from attack by invasive microbes.

Fats come in all kinds of shapes and sizes. One dimension is the degree of saturation, which concerns how many double bonds they possess, with saturated fats possessing none, monounsaturated fats having only one, and polyunsaturated fats having two or more. Oxygen breaks the double bond and leaves the fat oxidized, which is problematic for the brain. Polyunsaturated fats are thus the most vulnerable to oxygen exposure, because of multiple double bonds.

Fats are digested in the intestine and released into the blood stream in the form of a relatively large ball with a protective protein coat, called a chylomicron. The chylomicron can directly provide fuel to many cell types, but it may also be sent to the liver where the contained fats are sorted out and redistributed into much smaller particles, which also contain substantial amounts of cholesterol. These particles are called "lipoproteins," (henceforth, LPP's) because they contain protein in the spherical shell and lipids (fats) in the interior. If you've had your cholesterol measured, you've probably heard of LDL (low density LPP) and HDL (high density LPP). If you think these are two different kinds of cholesterol, you would be mistaken. They are just two different kinds of containers for cholesterol and fats that serve different roles in the body. There are actually several other LPP's, for example, VLDL (very-high) and IDL (intermediate), as shown in the accompanying diagram. In this essay I will refer to these collectively as the XDL's. As if this weren't confusing enough, there is also another unique XDL that is found only in the cerebrospinal fluid, that supplies the nutritional needs of the brain and nervous system. This one doesn't seem to have a name yet, but I will call it "B-HDL," because it is like HDL in terms of its size, and "B" is for "brain [13]"

An important point about all the XDL's is that they contain distinctly different compositions, and each is targeted (programmed) for specific tissues. A set of proteins called "apolipoproteins" or, equivalently, "apoproteins" ("apo's" for short) figure strongly in controlling who gets what. As you can see from the schematic of the chylomicron shown at the right, it contains a rainbow of different apo's for every conceivable application. But the XDL's are far more specific, with HDL containing "A," LDL containing "B," VLDL containing "B" and "C," and IDL containing only "E." The apo's have special binding properties that allow the lipid contents to be transported across cell membranes so that the cell can gain access to the fats and choleseterol contained inside.

The only apo that is of concern to us in the context of this essay is apoE. ApoE is very important to our story because of its known link with Alzheimer's disease. ApoE is a protein, i.e., sequence of amino acids, and its specific composition is dictated by a corresponding DNA sequence on a protein-coding gene. Certain alterations in the DNA code lead to defects in the ability of the transcribed protein to perform its biological roles. ApoE-4, the allele associated with increased risk to Alzheimer's, is presumably unable to perform its tasks as efficiently as the other alleles. By understanding what apoE does, we can better infer how the consequences of doing it poorly might impact the brain, and then observe experimentally whether the features of the Alzheimer's brain are consistent with the roles played by apoE.

A strong clue about apoE's roles can be deduced from where it is found. As I mentioned above, it is the only apo in both B-HDL in the cerebrospinal fluid and IDL in the blood serum. Only selected cell types can synthesize it, the two most significant of which for our purposes are the liver and the astrocytes in the brain. Thus the astrocytes provide the linkage between the blood and the cerebrospinal fluid. They can usher lipids and cholesterol across the blood-brain barrier, via the special key which is apoE.

It turns out that, although apoE is not found in LDL, it does bind to LDL, and this means that astrocytes can unlock the key to LDL in the same way that they can gain access to IDL, and hence the cholesterol and fatty acid contents of LDL are accessible to astrocytes as well, as long as apoE is functioning properly. The astrocytes reshape and repackage the lipids and release them into the cerebospinal fluid, both as B-HDL and simply as free fatty acids, available for uptake by all parts of the brain and nervous system [13].

One of the critical reshaping steps is to convert the fats into types that are more attractive to the brain. To understand this process you need to know about another dimension of fats besides their degree of saturation, which is their total length. Fats have a chain of linked carbon atoms as their spine, and the total number of carbons in a particular fat characterizes it as short, medium length, or long. The brain works best when the constituent fats are long, and, indeed, the astrocytes are able to take in short chain fats and reorganize them to make longer chain fats [24].

A final dimension of fats that plays a role is where the first double bond is located in a polyunsaturated fat, which distinguishes omega-3 from omega-6 fats (position 3; position 6). Omega-3 fats are very common in the brain. Certain ones of the omega-3 and omega-6 fats are essential fatty acids, in that the human body is unable to synthesize them, and therefore depends upon their supply from the diet. This is why it is claimed that fish "makes you smart": because cold water fish is the best source of essential omega-3 fats.

Now I want to return to the subject of the XDL's. It is a dangerous journey from the liver to the brain, as both oxygen and microbes are found in abundance in the blood stream. The XDL's protective shell contains both LPP's and unesterified cholesterol, as well as the signature apo that controls which cells can receive the contents, as shown in the accompanying schematic. The internal contents are esterified cholesterol and fatty acids, along with certain antioxidants that are conveniently being transported to the cells packaged in the same cargo ship. Esterification is a technique to render the fats and cholesterol inert, which helps protect them from oxidation [50]. Having the antioxidants (such as vitamin E and Coenzyme Q10) along for the ride is also convenient, as they too protect against oxidation. The cholesterol contained in the shell, however, is intentionally not esterified, which means that it is active. One of its roles there is to guard against invasive bacteria and viruses [54]. Cholesterol is the first line of defense against these microbes, as it will alert the white blood cells to attack whenever it encounters dangerous pathogens. It has also been proposed that the cholesterol in the XDL's shell itself acts as an antioxidant [48].

HDL's are mostly depleted of the lipid and cholesterol content, and they are tasked with returning the empty shell back to the liver. Once there, cholesterol will be recommissioned to enter the digestive system as part of the bile, which is produced by the gall bladder to help digest ingested fats. But the body is very careful to conserve cholesterol, so that 90% of it will be recycled from the gut back into the blood stream, contained in the chylomicron that began our story about fats.

In summary, the management of the distribution of fats and cholesterol to the cells of the body is a complex process, carefully orchestrated to assure that they will have a safe journey to their destination. Dangers lurk in the blood stream, mostly in the form of oxygen and invasive microbes. The body considers cholesterol to be precious cargo, and it is very careful to conserve it, by recycling it from the gut back to the liver, to be appropriately distributed among the XDL's that will deliver both cholesterol and fats to the tissues that depend upon them, most especially the brain and nervous system.

4. The Relationship between Cholesterol and Alzheimer's

2009-12-17T06:07:00.000-08:00

Through retrospective studies, the statin industry has been very successful at the game of pretending that benefits derived from high cholesterol are actually due to statins, as I have described at length in an essay on the relationship between statins and fetal damage, sepsis, cancer, and heart failure. In the case of Alzheimer's, they are playing this game in reverse: they are blaming cholesterol for a very serious problem that I believe is actually caused by statins.

The statin industry has looked long and hard for evidence that high cholesterol might be a risk factor for Alzheimer's. They examined cholesterol levels for men and women of all ages between 50 and 100, looking back 30 or more years if necesssary, to see if there was ever a correlation between high cholesterol and Alzheimer's. They found only one statistically significant relationship: men who had had high cholesterol in their 50's had an increased susceptibility to Alzheimer's much later in life [3].

The statin industry has jumped on this opportunity to imply that high cholesterol might cause Alzheimer's, and, indeed, they have been very fortunate in that reporters have taken the bait and are promoting the idea that, if high cholesterol many years ago is linked to Alzheimer's, then statins might protect from Alzheimer's. Fortunately, there exist lengthy web pages (Cholesterol Doesn't Cause Alzheimer's) that have documented the long list of reasons why this idea is absurd.

Men who have high cholesterol in their 50's are the poster child for statin treatment: all of the studies that have shown a benefit for statins in terms of reducing the number of minor heart attacks involved men in their 50's. High cholesterol is positively correlated with longevity in people over 85 years old [53], and has been shown to be associated with better memory function [52] and reduced dementia [35]. The converse is also true: a correlation between falling cholesterol levels and Alzheimer's [39]. As will be discussed further later, people with Alzheimer's also have reduced levels of B-HDL, as well as sharply reduced levels of fatty acids, in the cerbrospinal fluid, i.e, impoverished supply of cholesterol and fats to the myelin sheath [38]. As we saw earlier, fatty acid supply is essential as building blocks for the sulfatide that is synthesized by oligodendrocytes to keep the myelin sheath healthy [29].

The obvious study that needs to be done is to bin the men who had high cholesterol in their 50's into three groups: those who never took statins, those who took smaller doses for shorter times, and those who took larger doses for longer times. Such a study would not be hard to do; in fact, I suspect something like it has already been done. But you'll never hear about it because the statin industry has buried the results.

In a very long term retrospective cohort study of members of the Permanente Medical Care Program in northern California, researchers looked at cholesterol data that were obtained between 1964 and 1973 [46]. They studied nearly ten thousand people who had remained members of that health plan in 1994, upon the release of computerized outpatient diagnoses of dementia (both Alzheimer's and vascular dementia). The subjects were between 40 and 45 years old when the cholesterol data were collected.

The researchers found a barely statistically significant result that people who were diagnosed with Alzheimer's had higher cholesterol in their 50's than the control group. The mean value for the Alzheimer's patients was 228.5, as against 224.1 for the controls.

The question that everybody ought to be asking is: for the Alzheimer's group, how did the people who later took statins stack up against the people who didn't? In extreme understatement, the authors offhandedly remark in the middle of a paragraph: "Information on lipid-lowering treatments, which have been suggested to decrease dementia risk [31], was not available for this study." You can be sure that, if there was any inkling that the statins might have helped, these researchers would have been allowed access to those data.

The article they refer to for support, reference [19] in [46] (which is reference [44] here) was very weak. The abstract for that article is repeated in full here in the Appendix. But the concluding sentence sums it up well: "A more than a modest role for statins in preventing AD [Alzheimer's Disease] seems unlikely." This is the best they can come up with to defend the position that statins might protect from Alzheimer's.

An intuitive explanation for why high cholesterol at an early age might be correlated with Alzheimer's risk has to do with apoE-4. People with that allele are known to have high cholesterol early in life [39], and I believe this is a protective strategy on the part of the body. The apoE-4 allele is likely defective in the task of importing cholesterol into the astrocytes, and therefore an increase in the bioavailability of cholesterol in blood serum would help to offset this deficit. Taking a statin would be the last thing a person in that situation would want to do.

5. Do Statins Cause Alzheimer's?

2009-12-17T05:52:00.000-08:00

There is a clear reason why statins would promote Alzheimer's. They cripple the liver's ability to synthesize cholesterol, and as a consequence the level of LDL in the blood plummets. Cholesterol plays a crucial role in the brain, both in terms of enabling signal transport across the synapse [49] and in terms of encouraging the growth of neurons through healthy development of the myelin sheath [45]. Nonetheless, the statin industry proudly boasts that statins are effective at interfering with cholesterol production in the brain [31][47] as well as in the liver.

Yeon-Kyun Shin is an expert on the physical mechanism of cholesterol in the synapse to promote transmission of neural messages, and one of the authors of [49] referenced earlier. In an interview by a Science Daily reporter, Shin said: "If you deprive cholesterol from the brain, then you directly affect the machinery that triggers the release of neurotransmitters. Neurotransmitters affect the data-processing and memory functions. In other words -- how smart you are and how well you remember things."

A recent review of two large population-based double-blind placebo-controlled studies of statin medications in individuals at risk for dementia and Alzheimer disease showed that statins are not protective against Alzheimer's [34]. The lead author of the study, Bernadette McGuinness, was quoted by a reporter from Science Daily as saying, "From these trials, which contained very large numbers and were the gold standard -- it appears that statins given in late life to individuals at risk of vascular disease do not prevent against dementia." A researcher at UCLA, Beatrice Golomb, when asked to comment on the results, was even more negative, saying, "Regarding statins as preventive medicines, there are a number of individual cases in case reports and case series where cognition is clearly and reproducibly adversely affected by statins." In the interview, Golomb remarked that various randomized trials have shown that statins were either adverse or neutral towards cognition, but none have shown a favorable response.

A common side effect of statins is memory dysfunction. Dr. Duane Graveline, fondly known as "spacedoc" because he served as a doctor to the astronauts, has been a strong advocate against statins on his web page where he is collecting evidence of statin side effects directly from statin users around the world. He was led to this assault on statins as a consequence of his own personal experience of transient global amnesia, a frightening episode of total memory loss which he is convinced was caused by the statin drugs he was taking at the time. He has now completed three books describing a diverse collection of damning side effects of statins, the most famous of which is Lipitor: Thief of Memory [17].

A second way (besides their direct impact on cholesterol) in which statins likely impact Alzheimer's is in their indirect negative effect on the supply of fatty acids and antioxidants to the brain. It is a given that statins drastically reduce the level of LDL in the blood serum. This is their claim to fame. It is interesting, however, that they succeed in reducing not just the amount of cholesterol contained in the LDL particles, but rather the actual number of LDL particles altogether. This means that, in addition to depleting cholesterol, they reduce the available supply to the brain of both fatty acids and antixodiants, which are also carried in the LDL particles. As we've seen, all three of these substances are essential to proper brain functioning.

I conjecture that the reasons for this indirect effect are two-fold: (1) there is inadequate cholesterol in the bile to metabolize dietary fats, and (2) the rate-limiting effect on the production of LDL is the ability to provide adequate cholesterol in the shell to assure survival of the contents during transport in the blood stream; i.e., to protect the contents from oxidation and marauding bacteria and viruses. People who take the highest 80 mg/dl dosage of statins often end up with LDL levels as low as 40mg/dl, well below even the lowest numbers observed naturally. I shudder to think of the probable long-term consequences of such severe depletion in fats, cholesterol, and antioxidants.

A third way in which statins may promote Alzheimer's is by crippling the ability for cells to synthesize coenzyme Q10. Coenzyme Q10 has the misfortune of sharing the same metabolic pathway as cholesterol. Statins interfere with a crucial intermediate step on the pathway to the synthesis of both cholesterol and coenzyme Q10. Coenzyme Q10 is also known as "ubiquinone" because it seems to show up everywhere in cell metabolism. It is found both in the mitochondria and in the lysosomes, and its critical role in both places is as an antioxidant. The inert esters of both cholesterol and fatty acids are hydrolyzed and activated in the lysosomes [8], and then released into the cytoplasm. Coenzyme Q10 consumes excess oxygen to keep it from doing oxidative damage [30], while also generating energy in the form of ATP (adenosine triphosphate, the universal energy currency in biology).

The final way in which statins should increase Alzheimer's risk is through their indirect effect on vitamin D. Vitamin D is synthesized from cholesterol in the skin, upon exposure to UV rays from the sun. In fact, the chemical formula of vitamin D is almost indistinguishable from that of cholesterol, as shown in the two attached figures (cholesterol on the left, vitamin D on the right). If LDL levels are kept artificially low, then the body will be unable to resupply adequate amounts of cholesterol to replenish the stores in the skin once they have been depleted. This would lead to vitamin D deficiency, which is a widespread problem in America.

It is well known that vitamin D fights infection. To quote from [25], "Patients with severe infections as in sepsis have a high prevalence of vitamin D deficiency and high mortality rates." As will be elaborated on later, a large number of infective agents have been shown to be present in abnormally high amounts in the brains of Alzheimers patients [27][26].

Dr. Grant has recently argued [16] that there are many lines of evidence pointing to the idea that dementia is associated with vitamin D deficiency. An indirect argument is that vitamin D deficiency is associated with many conditions that in turn carry increased risk for dementia, such as diabetes, depression, osteoporosis, and cardiovascular disease. Vitamin D receptors are widespread in the brain, and it is likely that they play a role there in fighting off infection. Vitamin D surely plays other vital roles in the brain as well, as powerfully suggested by this quote taken from the abstract of [32]: "We conclude there is ample biological evidence to suggest an important role for vitamin D in brain development and function."

6. Astrocytes, Glucose Metabolism, and Oxygen

2009-12-17T05:51:00.002-08:00

Alzheimer's is clearly correlated with a deficiency in the supply of fat and cholesterol to the brain. IDL, when functioning properly, is actually incredibly efficient in cholesterol and fat throughput from the blood across cell membranes, compared to LDL [8]. It gives up its contents much more readily than the other apo's. And it achieves this as a direct consequence of apoE. IDL (as well as LDL) in the blood delivers fats and cholesterol to the astrocytes in the brain, and the astrocytes can thus use this external source instead of having to produce these nutrients themselves. I suspect, in fact, that astrocytes only produce a private supply when the external supply is insufficient, and they do so reluctantly.

Why would it be disadvantageous for an astrocyte to synthesize its own fats and cholesterol? In my opinion, the answer has to do with oxygen. An astrocyte needs a significant energy source to synthesize fats and cholesterol, and this energy is usually supplied by glucose from the blood stream. Furthermore, the end-product of glucose metabolism is acetyl-Coenzyme A, the precursor to both fatty acids and cholesterol. Glucose can be consumed very efficiently in the mitochondria, internal structures within the cell cytoplasm, via aerobic processes that require oxygen. The glucose is broken down to produce acetyl-Coenzyme A as an end-product, as well as ATP, the source of energy in all cells.

However, oxygen is toxic to lipids (fats), because it oxidizes them and makes them rancid. Lipids are fragile if not encased in a protective shell like IDL, HDL, or LDL. Once they are rancid they are susceptible to infection by invasive agents like bacteria and viruses. So an astrocyte trying to synthesize a lipid has to be very careful to keep oxygen out, yet oxygen is needed for efficient metabolism of glucose, which will provide both the fuel (ATP) and the raw materials (acetyl-Coenzyme A) for fat and cholesterol synthesis.

What to do? Well, it turns out that there is an alternative, although much less efficient, solution: to metabolize glucose anaerobically directly in the cytoplasm. This process does not depend on oxygen (a great advantage) but it also yields substantially less ATP (only 6 ATP as contrasted with 30 if glucose is metabolized aerobically in the mitochondria). The end product of this anaerobic step is a substance called pyruvate, which could be further broken down to yield a lot more energy, but this process is not accessible to all cells, and it turns out that the astrocytes need help for this to happen, which is where amyloid-beta comes in.

7. The Crucial Role of Amyloid-Beta

2009-12-17T05:51:00.001-08:00

Amyloid-beta (also known as "abeta") is the substance that forms the famous plaque that accumulates in the brains of Alzheimer's patients. It has been believed by many (but not all) in the research community that amyloid-beta is the principal cause of Alzheimer's, and as a consequence, researchers are actively seeking drugs that might destroy it. However, amyloid-beta has the unique capability of stimulating the production of an enzyme, lactate dehydrogenase, which promotes the breakdown of pyruvate (the product of anaerobic glucose metabolism) into lactate, through an anaerobic fermentation process, with the further production of a substantial amount of ATP.

The lactate, in turn, can be utilized itself as an energy source by some cells, and it has been established that neurons are on the short list of cell types that can metabolize lactate. So I conjecture that the lactate is transported from the astrocyte to a neighboring neuron to enhance its energy supply, thus reducing its dependence on glucose. It is also known that apoE can signal the production of amyloid-beta, but only under certain poorly understood environmental conditions. I suggest those environmental triggers have to do with the internal manufacture of fats and cholesterol as opposed to the extraction of these nutrients from the blood supply. I.e., amyloid-beta is produced as a consequence of environmental oxidative stress due to an inadequate supply of fats and cholesterol from the blood.

In addition to being utilized as an energy source by being broken down to lactate, pyruvate can also be used as a basic building block for synthesizing fatty acids. So anaerobic glucose metabolism, which yields pyruvate, is a win-win-win situation: (1) it significantly reduces the risk of exposure of fatty acids to oxygen, (2) it provides a source of fuel for neighboring neurons in the form of lactate, and (3) it provides a basic building block for fatty acid synthesis. But it depends upon amyloid-beta to work.

Thus, in my view (and in the view of others [28] [20] Amyloid-Beta and Alzheimer's), amyloid-beta is not a cause of Alzheimer's, but rather a protective device against it. The abstract of reference [28] arguing this point of view is reproduced in full in the Appendix. Several variants of a genetic defect associated with amyloid precursor protein (APP), the protein from which amyloid-beta is derived, have now been identified. A defect in this protein, which is associated with an increased risk of early onset Alzheimer's, would likely lead to a reduced ability to synthesize amyloid-beta, which would then leave the brain with a big problem, since both the fuel and the basic building blocks for fatty acid synthesis would be in short supply, while oxygen trekking through the cell to the mitochondria would be exposing whatever fats were being synthesized to oxidation. The cell would likely be unable to keep up with need, and this would lead to a reduction in the number of fatty acids in the Alzheimer's cerebrospinal fluid, a well-established characteristic of Alzheimer's [38].

8. Cholesterol's Role in the Brain

2009-12-17T05:50:00.002-08:00

The brain comprises only 2% of the body's total weight, yet it contains nearly 25% of the total cholesterol in the body. It has been determined that the limiting factor allowing the growth of synapses is the availability of cholesterol, supplied by the astrocytes. Cholesterol plays an incredibly important role in the synapse, by shaping the two cell membranes into a snug fit so that the signal can easily jump across the synapse [49]. So inadequate cholesterol in the synapse will weaken the signal at the outset, and inadequate fat coating the myelin sheath will further weaken it and slow it down during transport. A neuron that can't send its messages is a useless neuron, and it only makes sense to prune it away and scavenge its contents.

The neurons that are damaged in Alzheimer's are located in specific regions of the brain associated with memory and high level planning. These neurons need to transmit signals long distances between the frontal and prefrontal cortex and the hippocampus, housed in the midbrain. The transport of these signals depends on a strong and tight connection in the synapse, where the signal is transferred from one neuron to another, and a secure transmission across the long nerve fiber, a part of the white matter. The myelin sheath which coats the nerve fiber consists mainly of fatty acids, along with a substantial concentration of cholesterol. If it is not well insulated, the signal transmission rate will slow down and the signal strength will be severely reduced. Cholesterol is crucial for the myelin as well as for the synapse, as demonstrated dramatically through experiments conducted on genetically defective mice by Gesine Saher et al. [45]. These mutant mice lacked the ability to synthesize cholesterol in myelin-forming oligodendrocytes. They had severly disturbed myelin in their brains, and exhibited ataxia (uncoordinated muscle movements) and tremor. In the abstract, the authors wrote unequivocally, "This shows that cholesterol is an indispensable component of myelin membranes."

In a post-mortem study comparing Alzheimer's patients with a control group without Alzheimer's, it was found that the Alzheimer's patients had significantly reduced amounts of cholesterol, phospholipids (e.g, B-HDL), and free fatty acids in the cerebrospinal fluid than did the controls [38]. This was true irrespective of whether the Alzheimer's patients were typed as apoE-4. In other words, reductions in these critical nutrients in the spinal fluid are associated with Alzheimer's regardless of whether the reduction is due to defective apoE. The reductions in fatty acids were alarming: 4.5 micromol/L in the Alzheimer's patients, compared with 28.0 micromol/L in the control group. This is a reduction by more than a factor of 6 in the amount of fatty acid available to repair the myelin sheath!

People with the apoE-4 allele tend to have high serum cholesterol. The question of whether this high cholesterol level might be an attempt on the part of the body to adjust for a poor rate of cholesterol uptake in the brain was addressed by a team of researchers in 1998 [39]. They studied 444 men between 70 and 89 years old at the time, for whom there existed extensive records of cholesterol levels dating back to several decades ago. Most significantly, cholesterol levels fell for the men who developed Alzheimer's prior to their showing Alzheimer's symptoms. The authors suggested that their high cholesterol might have been a protective mechanism against Alzheimer's.

One might wonder why their cholesterol levels fell. There was no mention of statin drugs in the article, but statins would certainly be an effective way to reduce cholesterol levels. The statin industry would like people to believe that high cholesterol is a risk factor for Alzheimer's, and they are quite thrilled that high cholesterol early in life is correlated with Alzheimer's much later. But these results suggest quite the opposite: that blood cholesterol levels are kept high intentionally by the body regulatory mechanisms in an attempt to compensate for the defect. A high concentration will lead to an increase in the rate of delivery to the brain, where it is critically needed to keep the myelin sheath healthy and to promote neuron signaling in the synapses.

Using MRI technology, researchers at UCLA were able to measure the degree of breakdown of myelin in specific regions of the brain [6]. They conducted their studies on over 100 people between 55 and 75 years old, for whom they also determined the associated apoE allele (2, 3, or 4). They found a consistent trend in that apoE-2 had the least amount of degradation, and apoE-4 had the most, in the frontal lobe region of the brain. All of the people in the study were thus far healthy with respect to Alzheimer's. These results show that premature breakdown of myelin sheath (likely due to an insufficient supply of fats and cholesterol to repair it) is associated with apoE-4.

To summarize, I hypothesize that, for the apoE-4 Alzheimer's patients, defective apoE has led to an impaired ability to transport fats and cholesterol from the blood stream, via the astrocytes, into the cerebrospinal fluid. The associated high blood serum cholesterol is an attempt to partially correct for this defect. For the rest of the Alzheimer's patients (the ones without the apoE-4 allele but who also have severely depleted fatty acids in their cerebrospinal fluid), we have to look for another reason why their fatty acid supply chain might be broken.

9. Infections and Inflammation

2009-12-17T05:50:00.001-08:00

To summarize what I have said so far, Alzheimer's appears to be a consequence of an inability of neurons to function properly, due to a deficiency in fats and cholesterol. A compounding problem is that the fats over time will become rancid if they cannot be adequately replenished. Rancid fats are vulnerable to attack by microorganisms such as bacteria and viruses. Amyloid-beta is part of the solution because it allows the astrocytes to be much more effective in utilizing glucose anaerobically, which protects the internally synthesized fats and cholesterol from toxic oxygen exposure, while at the same time providing the energy needed both by the astrocyte for the synthesis process and by neighboring neurons to fuel their signal firings.

Besides the astrocytes, the microglia in the brain are also implicated in Alzheimer's. Microglia promote neuron growth when all is well, but trigger neuron programmed cell death in the presence of toxic substances secreted by bacteria such as polysaccharides [55]. Microglia will defensively secrete cytokines (communication signals that promote an immune response) when exposed to infective agents, and these in turn will lead to inflammation, another well-known feature associated with Alzheimer's [1]. The microglia are able to control whether neurons should live or die, and they surely base this decision on factors related to how well the neuron functions and whether it is infected. Once enough neurons have been programmed for cell death, the disease will manifest itself as cognitive decline.

10. Evidence that Infection is Associated with Alzheimer's

2009-12-17T05:49:00.002-08:00

There is substantial evidence that Alzheimer's is related to an increased likelihood of infective agents appearing in the brain. Some researchers believe that infective agents are the principle cause of Alzheimer's. There are a number of bacteria that reside in the human digestive system and can co-exist with our own cells without any harm. However, H. pylori, one that is quite common, has been recently shown to be responsible for stomach ulcers. It has been suspected that H. Pylori might be implicated in Alzheimer's, and, indeed, a recent study showed that Alzheimer's patients had a significantly higher concentration of an antibody against H. Pylori in both their cerebrospinal fluid and their blood than non-Alzheimer's controls [26]. H. pylori was detected in 88% of the Alzheimer's patients but only 47% of the controls. In an effort to treat the Alzheimer's patients, the researchers administered a potent combination of antibiotics, and assessed the degree of mental decline over the next two years [27]. For 85% of the patients, the infection was successfully routed, and for those patients, cognitive improvement was also detected after two years had elapsed. So this was a nice example of the possibility of treating Alzheimer's through antibiotics.

C. pneumoniae is a very common bacterium, estimated to infect 40-70% of adults. But there's a big difference between a bacterium being in the blood stream and making its way into the inner sanctum of the brain. A study of post-mortem samples from various regions of the brains of Alzheimer's patients and non-Alzheimer's controls revealed a remarkably different statistic: 17 out of 19 Alzheimer's brains tested positive for the bacterium, whereas only 1 out of 19 brains from the control group tested positive [5].

Many other infective agents, both viruses and bacteria, have been found to be associated with Alzheimer's, including herpes simplex virus, picornavirus, Borna disease virus, and spirochete [23]. One proposal was that a particular bacteriophage -- a virus that infects the bacterium C. pneumoniae -- might be responsible for Alzheimer's [14]. The authors argued that the phages might make their way into the mitochondria of the host cell and subsequently initiate Alzheimer's.

11. Ketogenic Diet as Treatment for Alzheimer's

2009-12-17T05:49:00.001-08:00

One of the promising new treatment paradigms for Alzheimer's is to have the patient switch to an extremely high fat, low carb diet, a so-called "ketogenic" diet. The name comes from the fact that the metabolism of dietary fats produces "ketone bodies" as a by-product, which are a very useful resource for metabolism in the brain. It is becoming increasingly clear that defective glucose metabolism in the brain (so-called "type-3 diabetes") is an early characteristic of Alzheimer's. Ketone bodies, whether they enter the astrocyte directly or are produced in the astrocyte itself by breaking down fats, can be delivered to adjacent neurons, as shown in the accompanying figure. These neurons can utilize the ketone bodies both as an energy source (replacing and therefore relieving glucose) and as a precursor to GABA, a critical neurotransmitter that is widespread in the brain.

Evidence that a ketogenic diet might help Alzheimer's was first found through research conducted on mice who had been bred to be prone to Alzheimer's disease [21]. Researchers found that the mice's cognition improved when they were treated with a high-fat low-carb diet, and also that the amount of amyloid-beta in their brain was reduced. The latter effect would be anticipated based on the premise that amyloid-beta promotes full utilization of glucose anaerobically, as I discussed previously. By having ketone bodies as an additional source of fuel, the dependence on glucose is reduced. But another effect that may be more important than this is the availability of high-quality fats to improve the condition of the myelin sheath.

This idea is supported by other experiments done on human Alzheimer's patients [11] [42]. A placebo-controlled 2004 study [42] of the effect of dietary fat enrichment on Alzheimer's is especially informative, because it uncovered a significant difference in effectiveness for the fat-enrichment for subjects who did not have the apoE-4 allele as compared with those who did. The experimental test group were given a supplemental drink containing emulsified medium chain triglycerides, found in high concentration in coconut oil. The subjects without the apoE-4 allele showed a significant improvement in score on a standard test for Alzheimer's, whereas those with the apoE-4 allele did not. This is a strong indicator that the benefit may have to do with an increase in uptake by the astrocyte of these high-quality fats, something that the subjects with the apoE-4 allele are unable to accomplish due to the defective IDL and LDL transport mechanisms.

12. NADH Treatment: the Crucial Role of Antioxidants

2009-12-17T05:48:00.000-08:00

One of the very few promising treatments for Alzheimer's is the coenzyme, NADH (nicotinamide adenine dinucleotide) [12]. In a placebo-controlled study, Alzheimer's subjects given NADH for six months exhibited significantly better performances on verbal fluency, visual constructional ability and abstract verbal reasoning than the control subjects given a placebo.

Why would NADH be effective? In the process of converting pyruvate to lactate, lactate dehydrogenase consumes oxygen by oxidizing NADH to NAD+, as illustrated in the accompanying figure. So, if the bioavailability of NADH is increased, it stands to reason that the astrocyte would have an enhanced ability to convert pyruvate to lactate, the critical step in the anaerobic metabolic pathway that is enhanced by amyloid-beta. The process, by absorbing the toxic oxygen, would reduce the damage to the lipids due to oxygen exposure, and would also provide lactate as a source of energy for the neurons.

13. Excessive Oxygen Exposure and Cognitive Decline

2009-12-17T05:47:00.002-08:00

It has been observed that some elderly people suffer temporary and sometimes permanent cognitive decline following a lengthy operation. Researchers at the University of South Florida and Vanderbilt University suspected that this might be due to excessive exposure to oxygen [4]. Typically, during an operation, people are often administered high doses of oxygen, even as much as 100% oxygen. The researchers conducted an experiment on young adult mice, which had been engineered to be predisposed towards Alzheimer's but had not yet suffered cognitive decline. They did however already have amyloid-beta deposits in their brains. The re-engineered mice, as well as a control group that did not have the Alzheimer's susceptibility gene, were exposed to 100-percent oxygen for a period of three hours, three times over the course of several months, simulating repeated operations. They found that the Alzheimer's pre-disposed mice suffered significant cognitive decline following the oxygen exposure, by contrast with the control mice.

This is a strong indication that the excessive oxygen exposure during operations is causing oxidative damage in the Alzheimer's brain. Given the arguments I have presented above, this result makes good sense. The brain, by converting to anaerobic metabolism for generating energy (with help from amyloid-beta) is trying its best to avoid exposing the fatty acids and cholesterol to oxidative damage. But an extremely high concentration of oxygen in the blood makes it very difficult to protect the fats and cholesterol during transport through the blood, and also probably causes an unavoidable increase in oxygen uptake and therefore exposure within the brain itself.

14.Fats are a Healthy Choice

2009-12-17T05:47:00.001-08:00

You would practically have to be as isolated as an Australian Aborigine not to have absorbed the message that dietary fats, particularly saturated fats, are unhealthy. I am extremely confident that this message is false, but it is nearly impossible to turn the opinion tide due to its pervasive presence. Most people don't question why fats are bad; they assume that researchers must have done their homework, and they trust the result.

To say that the current situation with regard to dietary fats is confusing would be an understatement. We are repeatedly told to keep our total fat intake down to, ideally, 20% of our total calories. This is difficult to achieve, and I believe it is misguided advice. In direct contradiction to this "low-fat" goal, we are encouraged to consume as much as possible of the "good" kinds of fats. Fortunately, the message is finally becoming widely embraced that omega-3 fats are healthy and that trans fats are extremely unhealthy. DHA (docosahexaenoic acid) is an omega-3 fat that is found in large quantities in the healthy brain. In the diet, it is available mainly from cold water fish, but eggs and dairy are also good sources. Trans fats are generated by a high-heat process that hydrolyzes polyunsaturated fats into a more stable configuration, which increases their shelf life but makes them so unnatural they almost can no longer be called a food. Trans fats are extremely damaging both to heart and brain health. A high consumption of trans fats has recently been shown to increase the risk of Alzheimer's [41]. Trans fats are especially prevalent in highly processed foods -- particularly when fats are converted to a powdered form.

We are told to avoid saturated fats, mainly because they have appeared, from empirical evidence, to be more likely to raise LDL levels than unsaturated fats. Yet these fats are less susceptible to oxidation, and this may be why they show up in LDL -- because they are of higher quality and therefore should preferentially be delivered to the tissues for functional roles rather than as fuel (i.e., free fatty acids). Coconut oil, a saturated fat, has been shown to benefit Alzheimer's patients [42]. And high-fat dairy (also highly saturated) has been shown to be beneficial both to fertility among women [10] and, remarkably, to heart disease [37][22].

Despite the widespread belief that fats (particularly saturated fats) are unhealthy, an article that appeared in the American Journal of Clinical Nutrition in 2004 [37] claims that, for a group of post-menopausal women, a high-fat, high-saturated-fat diet affords better protection from coronary artery disease than a low-fat (25% of calories from fats) diet. The subjects in the study were obese women with coronary artery disease. Most of them had high blood pressure, and many had diabetes. They fit the profile for metabolic syndrome that I have previously argued is a direct consequence of a prolonged low-fat high-carb diet. I am gratified to see that my hypothesis that an increase in fat intake would decrease their risk of heart disease has been verified by a carefully controlled study.

Another investigation where fats were shown to afford protection against heart disease has just been completed. It involved a long-term study of a large number of Swedish men [22]. The authors looked at low- vs high-fat dairy, as well as consumption of fruits and vegetables, meats, grains, etc. The only statistically significant result that afforded protection from heart disease was a combination of high-fat dairy and lots of fruits and vegetables. Fruits and vegetables with low-fat dairy afforded no protection.

I suspect one of the critical nutrients the fruits and vegetables provide is antioxidants that help prolong the life of the fats. Other excellent sources of antioxidants include richly colored fruits like berries and tomatoes, coffee, green tea, and dark chocolate, and several spices, most especially cinnamon and turmeric (a major ingredient of curry). These should be consumed in abundance along with fats for optimal results.

Polyunsaturated fats such as corn oil and canola oil are unhealthy for the brain precisely because they are unsaturated. There are two major problems: (1) they have a low melting point, which means that, if they are used for frying they will be converted to trans fats, which are extremely unhealthy, and (2) they are much more susceptible to becoming rancid (oxidized) at room temperature than saturated fats, i.e., they have a shorter shelf life.

Researchers in Germany recently conducted an ingenious experiment designed to determine how the degree of freshness of polyunsaturated fats affects the metabolism of those fats in female lactating rats [43]. They divided female rats into two groups, and the only difference between the test group and the controls was that the test group was given fats that had been left in a relatively warm place for 25 days, which caused considerable oxidative damage, whereas the controls were fed fresh fats instead. The rats' unusual diet was begun on the day that they gave birth to a litter. The researchers examined the mammary glands and the milk produced by the two groups for apparent differences. They found that the test group's milk was markedly reduced in the amount of fat it contained, and their mammary glands correspondingly took up less fat from the blood supply. One might surmise that the rats' metabolic mechanisms were able to detect oxidative damage to the fats, and therefore rejected them, prefering to do without rather than to risk the consequences of feeding their pups oxidized fats. Consequently, the pups of the test group gained significantly less weight than the control group's pups.

Boxed items like cookies and crackers that contain processed polyunsaturated fats are doctored with antioxidants and even antibiotics to protect them from spoiling. Once they're consumed, however, they still have to be protected from going rancid. Biochemical laws work the same way whether inside or outside the body. There are plenty of bacteria throughout the body that would be eager to take up house-keeping in rancid fats. The body has devised all kinds of strategies for protecting fats from oxidation (becoming rancid) and from attack by bacteria. But its task is rendered much easier for saturated rather than unsaturated fats, and for fresh rather than stale fats.

If we stop trying to get by on as few fats as possible in the diet, then we don't have to become so preoccupied with getting the "right" kinds of fats. If the body is supplied with an overabundance of fats, it can pick and choose to find the perfect fat to match each particular need; excess or defective fats can just be used as fuel, where it's not very important which fat it is, as long as it can be broken down to release energy.

15. Summary of Alzheimer's Essay

2009-12-17T05:45:00.000-08:00

This is an exciting time for Alzheimer's research, as new and surprising discoveries are coming out at a rapid pace, and evidence is mounting to support the notion that Alzheimer's is a nutritional deficiency disease. It is an indication of how much progress has been made in recent years to note that 42% of the references in this essay were published in 2008 or 2009. A popular new theory is that Alzheimer's may grow out of an impaired ability to metabolize glucose in the brain. The term "type-3 diabetes" has been coined to describe this defect, which often appears long before any symptoms of Alzheimer's. A shift from aerobic towards anaerobic glucose metabolism in the brain seems to be a harbinger of Alzheimer's later in life, but I argue that the reason for this shift is both to provide a basic ingredient (pyruvate) from which to synthesize fatty acids, while simultaneously protecting them from potentially damaging oxidation. The ApoE-4 allele, which is associated with increased risk to Alzheimer's, clearly implicates defects in fat and cholesterol transport, and the remarkable 6-fold reduction in the amount of fatty acids present in the cerebrospinal fluid of Alzheimer's patients [38] speaks loudly the message that fat insufficiency is a key part of the picture. The observation that the myelin is degraded in the frontal lobes of the brains of people possessing the apoE-4 allele further substantiates the theory that the myelin repair mechanism is defective.

Cholesterol obviously plays a vital role in brain function. A whopping 25% of the total cholesterol in the body is found in the brain, and it is present in abundance both in the synapses and in the myelin sheath. The cholesterol in both of these places has been shown to play an absolutely essential role in signal transport and in growth and repair.

Given the strong positive role played by cholesterol, it can only be assumed that statin drugs would increase the risk of developing Alzheimer's. However, the statin industry has been remarkably successful thus far in hiding this painful fact. They have managed to make much of the observation that high cholesterol much earlier in life is associated with an increased risk to Alzheimer's thirty years later. Yet they offer not a single study, not even a retrospective study, to substantiate any claim that actively reducing cholesterol through statin therapy would improve the situation for these people. In fact, most damningly, the statin usage evidence that would answer the question was "unavailable" to the researchers who conducted the seminal study.

Beatrice Golomb is an M.D. Ph.D. who heads up the UCSD Statin Study group, a research team who are actively investigating the risk-benefit balance of statin drugs. She is increasingly becoming convinced that statin drugs should not be recommended for the elderly: that in their case the risks clearly outweigh the benefits. She makes a strong case for this position in an on-line article available here [15]. The section on Alzheimer's is particularly compelling, and it points out the pitfalls in relying on previous studies done by the statin industry, where often those who have memory problems as side-effects of the statin drugs are excluded from the study, so that the results end up inappropriately biased in favor of statins. In summary, she wrote: "It must be emphasized that the randomized trial evidence has, to date, uniformly failed to show cognitive benefits by statins and has supported no effect or frank and significant harm to cognitive function."

In addition to refusing to take statin therapy, another way in which an individual can improve their odds against Alzheimer's is to consume plenty of dietary fats. It seems odd to suddenly switch from a "healthy" low-fat diet to an extremely high fat ketogenic diet, once a diagnosis of Alzheimer's is made. A ketogenic diet consists, ideally, of 88% fat, 10% protein, and 2% carbohydrate [11]. That is to say, it is absurdly high in fat content. It seems much more reasonable to aim for something like 50% fat, 30% protein, and 20% carbohydrate, so as to pro-actively defend against Alzheimer's.

I highly recommend a recent book written by the pediatric brain surgeon, Larry McCleary, M.D., called The Brain Trust Program [33]. This book gives a wealth of fascinating information about the brain, as well as specific recommendations for ways to improve cognitive function and avert later Alzheimer's. Most significantly, he recommends a diet that is high in cholesterol and animal fats, including an abundance of fish, seafood, meat, and eggs. He also recommends coconuts, almonds, avocados and cheese, all foods that contain a significant amount of fat, while encouraging the avoidance of "empty carbs." His knowledge on this subject grew out of his interest in helping his young patients heal more rapidly after brain trauma.

Our nation is currently bracing itself for an onslaught of Alzheimer's, at a time when baby boomers are approaching retirement, and our health care system is already in a crisis of escalating costs and shrinking funds. We can not afford the high cost of caring for the swelling population of Alzheimer's patients that our current practices of low-fat diet and ever expanding statin usage are promoting.

Appendix of Alzheimer's Essay

2009-12-17T05:43:00.000-08:00

In this appendix, I include the full abstract of two papers that are relevant to the theory presented here. The first is the abstract of reference [19] in [46], which is reference [44] here [see the section on statin drugs above for context]:

Abstract, "Epidemiological and clinical trials evidence about a preventive role for statins in Alzheimer's disease:"

"This paper reviews epidemiological and clinical trials data about whether statin use reduces the risk of Alzheimer's disease (AD). The available information has come in three waves. The initial, mostly cross-sectional observational reports suggested that statins might prevent dementia. Next, two large clinical trials with cognitive add-on studies showed no benefit and neither did the third wave, again with observational studies. The latter were mostly longitudinal, and were critical of the first studies for not adequately addressing confounding by indication (i.e. that patients with dementia would be denied statins). Most recently, new data from the Canadian Study of Health and Aging have produced a mixed result. While methodological considerations are clearly important in understanding why the reports are so variable, there might also be merit in differentiating between statins, based on their presumed - and variable - mechanisms of action in dementia prevention, before concluding that the initial reports are entirely artefactual. Still, the first reports appear to have overestimated the extent of protection, so that unless there are important effects achievable with specific statins, a more than a modest role for statins in preventing AD seems unlikely."

The second abstract is taken from reference [28], on the "alternative hypothesis" that amyloid-beta is protective rather than detrimental to Alzheimer's, i.e., that it is a "protective response to neuronal insult:"

Abstract, "Amyloid-beta in Alzheimer disease: the null versus the alternate hypotheses:"

"For nearly 20 years, the primary focus for researchers studying Alzheimer disease has been centered on amyloid-beta, such that the amyloid cascade hypothesis has become the "null hypothesis." Indeed, amyloid-beta is, by the current definition of the disease, an obligate player in pathophysiology, is toxic to neurons in vitro, and, perhaps most compelling, is increased by all of the human genetic influences on the disease. Therefore, targeting amyloid-beta is the focus of considerable basic and therapeutic interest. However, an increasingly vocal group of investigators are arriving at an "alternate hypothesis" stating that amyloid-beta, while certainly involved in the disease, is not an initiating event but rather is secondary to other pathogenic events. Furthermore and perhaps most contrary to current thinking, the alternate hypothesis proposes that the role of amyloid-beta is not as a harbinger of death but rather a protective response to neuronal insult. To determine which hypothesis relates best to Alzheimer disease requires a broader view of disease pathogenesis and is discussed herein."

References for Alzheimer's Article

2009-12-17T05:38:00.000-08:00

[1] H. Akiyama, S. Barger, S. Barnum, B. Bradt, J.Bauer, G.M. Cole, N.R. Cooper, P. Eikelenboom, M. Emmerling, B.L. Fiebich, C.E. Finch, S. Frautschy, W.S. Griffin, H. Hampel, M. Hull, G. Landreth, L. Lue, R. Mrak, I.R. Mackenzie, P.L. McGeer, M.K. O'Banion, J. Pachter, G. Pasinetti, C. Plata-Salaman, J. Rogers, R.Rydel, Y. Shen, W. Streit, R. Strohmeyer, I. Tooyoma, F.L. Van Muiswinkel, R. Veerhuis, D. Walker, S. Webster, B. Wegrzyniak, G. Wenk, and T. Wyss-Coray, "Inflammation and Alzheimer's disease." Neurobiol Aging (2000) May-Jun;21(3):383-421,

[2] Alzheimer's Association, "Alzheimer's Disease Facts and Figures," Alzheimer's and Dementia (2009) Vol. 5, Issue 3.

[3] K.J. Anstey, D.M. Lipnicki and L.F. Low, "Cholesterol as a risk factor for dementia and cognitive decline: a systematic review of prospective studies with meta-analysis." Am J Geriatr Psychiatry (2008) May, Vol. 16, No. 5, pp. 343-54.

[4] G. Arendash, A. Cox, T. Mori, J. Cracchiolo, K. Hensley, J. Roberts 2nd, "Oxygen treatment triggers cognitive impairment in Alzheimer's transgenic mice," Neuroreport. (2009) Jun 18.

[5] B.J. Balin, C.S. Little, C.J. Hammond, D.M. Appelt, J.A. Whittum-Hudson, H.C. Gerard, A.P. Hudson, "Chlamydophila pneumoniae and the etiology of late-onset Alzheimer's disease." J. Alz. Dis. (2008) Vol. 13, pp. 371-380.

[6] G. Bartzokis, MD; P.H. Lu, Psy, D.H. Geschwind, MD, N.Edwards, MA, J. Mintz, PhD, and J.L. Cummings, MD, "Apolipoprotein E Genotype and Age-Related Myelin Breakdown in Healthy Individuals: Implications for Cognitive Decline and Dementia," Arch Gen Psychiatry (2006) Vol. 63, pp. 63-72.

[7] N. Bernoud, L. Fenart, C. Bénistant, J. F. Pageaux, M. P. Dehouck, P. Molière, M. Lagarde, R. Cecchelli,d, and J. Lecerf, "Astrocytes are mainly responsible for the polyunsaturated fatty acid enrichment in blood-brain barrier endothelial cells in vitro" Journal of Lipid Research (1998) Sept., Vol. 39, pp. 1816-1824.

[8] M. S. Brown and J. L. Goldstein, "A Receptor-Mediated Pathway for Cholesterol Homeostasis," Nobel Lecture, December 9, 1985.

[9] N. Cartier, C. Sevin, A. Benraiss, P. DeDeyn, D. Bonnin, M-T Vanier, M. Philippe, V. Gieselmann and P. Aubourg, "AAV5-Mediated Delivery of Human Aryl Sulfatase A (hARSA) Prevents Sufatide Storage and Neuropathological Phenotype in Metachromatic Leukodystrophy (MLD) Mice," Molecular Therapy (2005) 11, S166-S167; doi: 10.1016/j.ymthe.2005.06.431

[10] J. Chavarro, W.C. Willett, and P.J. Skerrett, The Fertility Diet, (2008) McGraw Hill.

[11] L.C. Costantini, L.J. Barr, J.L. Vogel and S.T. Henderson, "Hypometabolism as a therapeutic target in Alzheimer's disease" BMC Neurosci (2008) Vol. 9, Suppl. 2, S16. doi: 10.1186/1471-2202-9-S2-S16.

[12] V. Demarin, S.S. Podobnik, D. Storga-Tomic and G. Kay, "Treatment of Alzheimer's disease with stabilized oral nicotinamide adenine dinucleotide: A randomized, double-blind study" Drugs Exp Clin Res. (2004) Vol. 30, No. 1, pp. 27-33.

[13] R.B. DeMattos, R.P. Brendza, J.E. Heuser, M.Kierson, J.R. Cirrito, J. Fryer, P.M. Sullivan, A.M. Fagan, X. Han and D.M. Holtzman, "Purification and characterization of astrocyte-secreted apolipoprotein E and J-containing lipoproteins from wild-type and human apoE transgenic mice," Neurochem Int. (2001) Nov-Dec;39(5-6):415-25. doi:10.1016/S0197-0186(01)00049-3.

[14] M. Dezfulian, M.A. ShokrgozarA, S. Sardari, K. Parivar and G. Javadi, "Can phages cause Alzheimer's disease?" Med Hypotheses (2008) Nov;71(5):651-6.

[15] B.A. Golomb, M.D., Ph.D., "Statin Adverse Effects: Implications for the Elderly," Geriatric Times (2004) May/June, Vol. V, Issue 3

[16] W.R. Grant, Ph.D., "Does Vitamin D Reduce the Risk of Dementia?" Journal of Alzheimer's Disease (2009) May, Vol. 17, No. 1., pp. 151-9.

[17] Dr. Duane Graveline, Lipitor: Thief of Memory, Statin Drugs and the Misguided War on Cholesterol, (2004) www.buybooksontheweb.com.

[18] X. Han, "Potential mechanisms contributing to sulfatide depletion at the earliest clinically recognizable stage of Alzheimer's disease: a tale of shotgun lipidomics," J. Neurochem (2007) November, Vol. 103, Suppl. 1. pp. 171-179. doi: 10.1111/j.1471-4159.2007.04708.x.

[19] X. Han, H. Cheng, J.D. Fryer, A.M. Fagan and D.M. Holtzman, "Novel Role for Apolipoprotein E in the Central Nervous System: Modulation of Sulfatide Content" Journal of Biological Chemistry, March 7, 2003, Vol. 278, pp. 8043-8051, DOI 10.1074/jbc.M212340200.

[20] K. Heininger, "A unifying hypothesis of Alzheimer's disease. IV. Causation and sequence of events," Rev Neurosci. (2000) Vol. 11, Spec No, pp.213-328.

[21] S.T. Henderson, "Ketone Bodies as a Therapeutic for Alzheimer's Disease," NeuroTherapeutics,, (2008) Jul;5(3):470-80, doi:10.1016/j.nurt.2008.05.004

[22] S. Holmberg, A. Thelin and E.-L. StiernstrNvm, "Food Choices and Coronary Heart Disease: A Population Based Cohort Study of Rural Swedish Men with 12 Years of Follow-up," Int. J. Environ. Res. Public Health (2009) Vol. 6, pp. 2626-2638;

[23] K. Honjo, R. van Reekum, and N.P. Verhoeff, "Alzheimer's disease and infection: do infectious agents contribute to progression of Alzheimer's disease?" Alzheimers Dement. (2009) Jul;5(4):348-60.

[24] S.M. Innis and R.A. Dyer, "Brain astrocyte synthesis of docosahexaenoic acid from n-3 fatty acids is limited at the elongation of docosapentaenoic acid," (2002) Sept. Journal of Lipid Research, Vol. 43, pp. 1529-1536.

[25] L. Jeng, A.V. Yamshchikov, S.E. Judd, H.M. Blumberg, G.S. Martin, T.R. Ziegler and V. Tangpricha, "Alterations in Vitamin D Status and Anti-microbial Peptide Levels in Patients in the Intensive Care Unit with Sepsis," Journal of translational Medicine," (2009) Vol. 7, No. 28.

[26] J. Kountouras, M. Boziki, E. Gavalas, C. Zavos, G. Deretzi, N. Grigoriadis, M. Tsolaki, D. Chatzopoulos, P. Katsinelos, D. Tzilves, A. Zabouri, I. Michailidou, "Increased cerebrospinal fluid Helicobacter pylori antibody in Alzheimer's disease," Int J Neurosci. (2009) 119(6):765-77.

[27] J. Kountouras, M. Boziki, E. Gavalas, C. Zavos, N. Grigoriadis, G. Deretzi, D. Tzilves, P. Katsinelos, M. Tsolaki, D. Chatzopoulos, and I. Venizelos, "Eradication of Helicobacter pylori may be beneficial in the management of Alzheimer's disease," J Neurol. (2009) May;256(5):758-67. Epub 2009 Feb 25.

[28] H.G. Lee, X. Zhu, R.J. Castellani, A. Nunomura, G. Perry, and M.A. Smith, "Amyloid-beta in Alzheimer disease: the null versus the alternate hypotheses," J Pharmacol Exp Ther. (2007) June, Vol. 321 No. 3, pp. 823-9. doi:10.3390/ijerph6102626.

[29] J. Marcus, S. Honigbaum, S. Shroff, K. Honke, J. Rosenbluth and J.L. Dupree, "Sulfatide is essential for the maintenance of CNS myelin and axon structure," Glia (2006), Vol. 53, pp. 372-381.

[30] R.T. Matthews, L. Yang, S. Browne, M. Baik and M.F. Beal, "Coenzyme Q10 administration increases brain mitochondrial concentrations and exerts neuroprotective effects," Proc Natl Acad Sci U S A. (1998) Jul 21, Vol. 95, No. 15, pp.8892-7.

[31] D. Lutjohann and K. von Bergmann, "24S-hydroxycholesterol: a marker of brain cholesterol metabolism" Pharmacopsychiatry (2003) January 10, Vol. 36 Suppl 2, pp. S102-6, DOI: 10.1055/s-2003-43053.

[32] J. C. McCann and B.N. Ames, "Is there convincing biological or behavioral evidence linking vitamin D deficiency to brain dysfunction?", (2008) FASEB J. Vol. 22, pp. 982-1001. doi: 10.1096/fj.07-9326rev.

[33] Larry McCleary, M.D., The Brain Trust Program (2007) September, The Penguin Group, New York, New York.

[34] B. McGuinness et al., "Statins for the prevention of dementia," Cochrane Database of Systematic Reviews, (2009) No. 2.

[35] M.M. Mielke, P.P. Zandi, M. Sjogren, et al. "High total cholesterol levels in late life associated with a reduced risk of dementia," Neurology (2005) Vol. 64, pp. 1689-1695.

[36] S.A. Moore, "Polyunsaturated Fatty Acid Synthesis and Release by Brain-Derived Cells in Vitro," Journal of Molecular Neuroscience (2001), Vol. 16, pp. 195ff.

[37] D. Mozaffarian, E.B. Rimm, D.M. Herrington, "Dietary fats, carbohydrate, and progression of coronary atherosclerosis in postmenopausal women," Am J Clin Nutr (2004) Vol. 80, pp. 1175-84.

[38] M. Mulder, R. Ravid, D.F. Swaab, E.R. de Kloet, E.D. Haasdijk, J. Julk, J.J. van der Boom and L.M. Havekes, "Reduced levels of cholesterol, phospholipids, and fatty acids in cerebrospinal fluid of Alzheimer disease patients are not related to apolipoprotein E4," Alzheimer Dis Assoc Disord. (1998) Sep, Vol. 12, No. 3, pp. 198-203.

[39] I.L. Notkola, R. Sulkava, J. Pekkanen, T. Erkinjuntti, C. Ehnholm, P. Kivinen, J. Tuomilehto, and A. Nissinen, "Serum total cholesterol, apolipoprotein E epsilon 4 allele, and Alzheimer's disease," Neuroepidemiology (1998) Vol. 17, No. 1, pp. 14-20.

[40] F.W. Pfrieger, "Outsourcing in the brain: Do neurons depend on cholesterol delivery by astrocytes?", BioEssays (2003) Vol. 25 Issue 1, pp.72-78.

[41] A. Phivilay, C. Julien, C. Tremblay, L. Berthiaume, P. Julien, Y. Giguère and F. Calon, "High dietary consumption of trans fatty acids decreases brain docosahexaenoic acid but does not alter amyloid-beta and tau pathologies in the 3xTg-AD model of Alzheimer's disease." Neuroscience (2009) Mar 3, Vol. 159, No. 1, pp. 296-307. Epub 2008 Dec 14.

[42] M.A. Reger, S. T. Henderson, C. Hale, B. Cholerton, L.D. Baker, G.S. Watson, K. Hyde, D. Chapman and S. Craft, "Effects of Beta-hydroxybutyrate on cognition in memory-impaired adults," Neurobiology of Aging (2004) Vol. 25, No. 3, March, pp. 311-314,

[43] R. Ringseis, C. Dathe, A. Muschick, C. Brandsch and K. Eder, "Nutrient Physiology, Metabolism, and Nutrient-Nutrient Interactions Oxidized Fat Reduces Milk Triacylglycerol Concentrations by Inhibiting Gene Expression of Lipoprotein Lipase and Fatty Acid Transporters in the Mammary Gland of Rats," American Society for Nutrition J. Nutr. (2007) Sept., Vol. 137, pp. 2056-2061.

[44] K. Rockwood, "Epidemiological and clinical trials evidence about a preventive role for statins in Alzheimer's disease." Acta Neurol Scand Suppl. (2006) Vol. 185, pp. 71-7.

[45] G. Saher, B. Brugger, C. Lappe-Siefke, W. Mobius, R. Tozawa, M.C. Wehr, F. Wieland, S. Ishibashi, and K.A. Nave, "High cholesterol level is essential for myelin membrane growth." Nat Neurosci (2005) Apr, Vol. 8, No. 4, pp. 468-75. Epub 2005 Mar 27.

[46] A. Solomon, M. Kivipelto, B. Wolozin, J. Zhou, and R.A. Whitmer, "Midlife Serum Cholesterol and Increased Risk of Alzheimer's and Vascular Dementia Three Decades Later," Dementia and Geriatric Cognitive Disorders (2009) Vol. 28, pp. 75-80, DOI: 10:1159/000231980.

[47] M. Simons, MD, P. Keller, PhD, J. Dichgans, MD and J.B. Schulz, MD, "Cholesterol and Alzheimer's disease: Is there a link?" Neurology (2001) Vol. 57, pp. 1089-1093.

[48] L.L. Smith, "Another cholesterol hypothesis: cholesterol as antioxidant," Free Radic Biol Med. (1991) Vol. 11, No. 1, pp. 47-61.

[49] J. Tong, P.P. Borbat, J.H. Freed and Y-K Shin, "A scissors mechanism for stimulation of SNARE-mediated lipid mixing by cholesterol," PNAS (2009) March 31 Vol. 106, No. 13, pp. 5141-5146.

[50] M-C Vohl, T. A.-M. Neville, R. Kumarathasan, S. Braschi, and D.L. Sparks, "A Novel Lecithin-Cholesterol Acyltransferase Antioxidant Activity Prevents the Formation of Oxidized Lipids during Lipoprotein Oxidation," Biochemistry (1999) Vol. 38 No. 19, pp. 5976-5981. DOI: 10.1021/bi982258w.

[51] M. Waldman, MD,, 9th International Conference on Alzheimer's and Parkinson's Diseases (2009) Abstract 90, Presented March 12-13.

[52] R. West, M.A., M. Schnaider Beeri, Ph.D., J. Schmeidler, Ph.D., C. M. Hannigan, B.S., G. Angelo, M.S., H.T. Grossman, M.D., C. Rosendorff, M.D., Ph.D., and J.M. Silverman, Ph.D., "Better memory functioning associated with higher total and LDL cholesterol levels in very elderly subjects without the APOE4 allele," Am J Geriatr Psychiatry (2008) September; Vol. 16, No. 9, pp. 781-785. doi: 10.1097/JGP.0b013e3181812790.

[53] A.W.E. Weverling-Rijnsburger, G.J. Blauw, A.M. Lagaay, D.L. Knook, A.E. Meinders, and R.G.J. Westendorp, "Total cholesterol and risk of mortality in the oldest old," The Lancet, (1997) Vol. 350, No. 9085, pp. 1119-1123,

[54] R.F. Wilson, J.F. Barletta and J.G. Tyburski, "Hypocholesterolemia in Sepsis and Critically Ill or Injured Patients" Critical Care (2003), Vol. 7, pp. 413-414.

[55] S.-C. Zhang and S. Fedoroff, "Neuron-microglia Interactions in Vitro," Acta Neuropathol (1996) Vol. 91, pp. 385-395.

APOE-4: The Clue to Why Low Fat Diet and Statins may Cause Alzheimer's by Stephanie Seneff is licensed under a Creative Commons Attribution 3.0 United States License.

Is ADHD Caused by Insufficient Dietary Fat?

2009-11-21T14:24:00.002-08:00

Over the last few decades, there has been an alarming increase in the incidence of several syndromes that affect both the physical and mental health of children and adults, especially in the United States. These include the obesity epidemic and metabolic syndrome, the alarming rise in the incidence of autism, the steady increase in food allergies among children, and the rise in the new brain disease termed "attention deficit hyperactivity disorder." To understand what might be causing these conditions, we need to look for substantial changes in lifestyle that have occurred between the last forty years and the previous forty years.

Two lifestyle changes that occurred almost simultaneously in the late 1970's are the practices of avoiding dietary fat and avoiding sun exposure. These practices have since gained a persistent strong endorsement by our government and medical experts, which has led to the almost unshakable belief across our population that avoiding dietary fat and sun exposure are healthy choices. I believe that these practices are in fact unhealthy, and are the underlying causes of the above mentioned diseases.

While people mistakenly believe that eating fat will lead to obesity, I have come to believe the exact opposite: that not eating enough fat can lead to obesity. I have elaborated on my arguments in a recent blog post on the obesity epidemic, and associated metabolic syndrome in America, where I claim that nutritional deficiencies in vitamin D, calcium, and dietary fats can account for most of the symptoms associated with metabolic syndrome. Previously, I developed an argument that the alarming rise in the incidence of autism in America may also be attributable to maternal deficiencies in these key nutrients, especially when the pregnant mother is sufficiently disciplined to remain thin despite strong temptations to eat. In this essay, I will develop a theory that Attention Deficit Hyperactivity Disorder (ADHD), a disease that barely existed before the 1970's, but is now steadily increasing in incidence rates in the United States, is also likely caused by inadequate dietary fats, with a possible contributory role played by vitamin D deficiency.

The American medical establishment continues to aggressively promote low fat diet, while Americans continue to grow in size and the autism epidemic keeps getting worse. By avoiding fats, Americans instead tend to eat an excessive amount of high-glycemic index carbs -- highly processed foods that digest very quickly and cause the blood sugar level to spike. This eventually leads to insulin resistance and type-II diabetes. Meanwhile, insufficient fat in the diet results in an unstable supply of fuel to the heart and fat resources to the brain. The brain utilizes only glucose for fuel, but fatty acids are essential to construct its neural connections.

In this essay, I am going to develop a theory that the rise of ADHD in America is a direct consequence of fat avoidance and sun avoidance. My theory explains many observations that have been made about ADHD, including:

-- Why ADHD is much more prevalent in boys than in girls,
-- Why ADHD children tend to have stunted growth,
-- Why ADHD children suffer from sleep disorders,
-- Why ADHD children are hyperactive,
-- Why Ritalin alleviates the symptoms.

I will also explain why I think that the widespread practice of drugging children with Ritalin, while clearly effective in promoting learning in the short term, is leading to a number of looming crises down the road, including drug abuse among non-ADHD children, and serious health issues later in life, such as heart disease and Parkinson's disease.

2. Possible Causes of ADHD

2009-11-21T14:24:00.001-08:00

Although many theories have been investigated, the cause of ADHD remains a mystery. None of the results of the experiments have led to a clear and compelling outcome. A nutritional deficiency of some sort remains high on the list of candidate causes (Dietary Theories for ADHD) . Potential deficiencies in several different vitamins and rare metals, such as zinc, magnesium, iron, and vitamin B6 have been posited, but in controlled studies, supplements have failed to show statistically significant improvements. The fact that ADHD appears to be especially prevalent in America suggests that it has something to do with differences between the American diet and the diet of other countries. To me, the most obvious difference is America's obsession with low fat diet. Today it is practically impossible to find full-fat yogurt at an American grocery store, and non-fat or low-fat products crowd out the full-fat versions of the same things on grocery shelves. Marketing ploys are proud to boast that a given product contains little, or, better yet, no, fat.

The nutritional theory for ADHD that has gained the most traction is that it may be caused by a deficiency or imbalance in essential fatty acids. These are omega-3 and omega-6 fats, which are widely available in meats, fish, and eggs. Humans are unable to manufacture these fats naturally from other dietary sources. While omega-6 fats are also found in vegetable oil, omega-3 fats are only abundant in animal fat, especially cold-water fish. Experiments that provide ADHD children with an omega-3 supplement have shown modest but encouraging results. However, I'm not proposing simply adding an omega-3 pill alongside the Ritalin tablet. I'm proposing that the cheerios and skim milk for breakfast be replaced with bacon and eggs; that the diet coke for lunch be replaced with whole milk, and the lean turkey breast in the sandwich be replaced with dark tuna, peanut butter, or liverwurst (a healthy choice that has all but disappeared from America's grocery shelves).

Another theory suggests that ADHD may be due to too much dietary refined sugar [16]. This theory also makes sense because the near absence of fat, coupled with an overabundance of high glycemic index foods, leads to a wildly unstable food supply in the blood. Glucose levels in the blood skyrocket immediately after a meal, and this triggers a sharp increase in insulin supply, rushed out by the pancreas to process the glucose. However, as long as the insulin concentration in the blood is high, fats that are stored in fat cells remain inaccessible and are not released into the blood. Many of the body's cells can utilize either glucose or fats as fuel. However, the brain can not utilize fats for fuel, but, critically, needs fat as raw material for construction of its network of nerve fibers. This is especially true for a growing child with a maturing brain. The brain needs a simultaneous presence of adequate glucose and adequate fat, something that is very hard to achieve when fats are unavailable from food sources, and high glycemic index foods are abundant.

Previous experiments conducted to test whether too much sugar causes ADHD involve substituting aspartame (a zero-calorie sweetener) for sugar [32]. I am not surprised that these experiments have failed, because aspartame is arguably even more damaging than sugar: the sweet taste on the tongue triggers the release of insulin, but there is no sugar for the insulin to break down. Hence the insulin lingers longer in the blood and fat release from available stores is further suppressed.

There is a strong genetic component to ADHD, i.e., it tends to run in families [8]. But this does not mean that the cause is genetic. Instead, genetic factors predispose individuals to develop alternative strategies for coping with nutritional deficiencies, that lead to different, but perhaps equally damaging, health issues. I would argue that, in the case of ADHD, genetics determine how the body manages homeostasis in the face of excess carbohydrates along with dietary deficiencies in essential fatty acids. (With respect to nutrition, homeostasis refers to the maintenance of a stable supply of glucose and fatty acids in the blood under varying conditions of food supply.) Studies to determine which genes are involved in ADHD have turned up hundreds of genes that play a role, but each gene has only a very small influence, so the relationship to genetics is extremely complex.

3. My Theory for the Cause of ADHD

2009-11-21T14:23:00.002-08:00

It appears to me that at least two complementary coping mechanisms have been developed in different segments of the population to adjust metabolism for dietary fat deficiency. One coping mechanism, which I described in my essay on obesity, involves storing a steadily expanding "silo" of fat reserves on the body. The alternative mechanism, which I now believe is the one adopted by children with ADHD, is to implement a fat conservation mode: to manipulate the body's energy requirements towards favoring glucose over fat, while simultaneously stunting growth and compromising brain development.

While in my essay on obesity I argued that the obese suffer from defective glucose metabolism in the muscles, it appears that children with ADHD suffer from the exact opposite problem: very efficient glucose metabolism. Insulin is critical for the metabolism of glucose. When insulin levels are high, body fat cells are unable to release their fat stores, as shown in the figure at the right [lipolysis = breakdown of fat tissue]. I have proposed that obesity is protective against ADHD because the abundant fat cells can release plenty of triglycerides into the blood early in the morning, before the first meal. This fat supply can tide the person over through the long fatty-acid drought that occurs during the day, while an abundance of high-glycemic index low-fat foods are consumed. A further advantage is that obese people typically have reduced insulin production (due to insufficient calcium, which I explain later), so the levels of insulin in the blood are never excessively high. Their muscle cells have been programmed to prefer fat metabolism, but there is also plenty of fat available from the triglycerides (released before the meal began) to supply the brain's raw materials to enhance communication through neural pathways. Furthermore, the glucose that is not consumed by the muscles is readily available

It seems that ADHD children have adopted an entirely different strategy for coping with insufficient fats in the food sources. Research has shown that many of them suffer from hypoglycemia (low blood sugar), because their insulin is extremely efficient -- the opposite of diabetes [19]. In direct contrast with obese people, the fat cells of ADHD children program the muscles to prefer glucose over fat as a fuel source. This reduces the burden placed on the fat cells to convert glucose to fat, which is a very inefficient process. Furthermore, unlike the obese, ADHD children typically have no shortage of insulin, produced by the pancreas in response to glucose. Insulin enables the muscles to readily consume the glucose, but also unfortunately supresses the ability of the fat cells and the liver to release stored fats. If there is plenty of glucose in the consumed foods, and very little fat, then the muscles and brain consume the glucose, but the brain is deprived of sufficient fats to construct high quality long-distance neural connections. ADHD children have been found to have shrunken white matter in parts of the brain that are involved with focus of attention and learning new knowledge. I believe this is a direct consequence of a lack of a supply of fats, critically, when the neural pathways that make up the white matter are actively being formed.

The body with inadequate fat supply in the food sources is essentially like a car engine running on only two cylinders. While it has been argued that the body can manufacture all the fats it needs from other sources such as glucose, this is not actually true. The body uses fats not only as an energy source, but also, crucially, as a component of cell walls and as the insulation that covers all nerve fibers, i.e., the myelin sheath, not just in the brain but everywhere in the body. Two specific kinds of fats, omega-3 fats and omega-6 fats, are called "essential fatty acids" (EFA's) because the body cannot manufacture them. It is essential to obtain them from food sources such as meat, eggs, and fish.

Furthermore, the body cannot produce fat supply in the blood stream "at will." As I have mentioned previously, when insulin levels are high, the subcutaneous fat cells and the abdominal fat cells, as well as the liver, are suppressed from releasing their stored fats. When glucose is available, the fat cells are otherwise engaged in the task of taking up the glucose and converting it into additional fat supplies. The presence of insulin disables the process of lipolysis that is necessary before the stored fats can be released into the blood stream.

4. Nutritional Deficiency and ADHD

2009-11-21T14:23:00.001-08:00

A husband and wife team of nutrition experts, Fred and Alice Ottoboni, have published an excellent article on the theory that ADHD might be a nutritional deficiency disease [25]. They draw analogies with Beriberi and Pellagra which became endemic in previous centuries as a consequence of significant dietary changes within a large population. The wholesale switch from brown to white rice in Asia in the 1800's led to many deaths from Beriberi, and the switch from meat, eggs, and milk to corn led to widespread Pellagra in western nations at the same time.

They argue that ADHD may be a direct consequence of a large shift in dietary practices that has taken place in America over the last 40 years -- a shift towards increased consumption of processed foods containing an overabundance of sugar and starch, along with a dramatic shift in the sources of fat from meat, fish, and eggs to vegetable fats and oils. They express concern about both the high ratio of omega-6 to omega-3 fats (20:1) in vegetable oils, as well as their propensity to become highly damaging trans fats if overheated. They specifically mention the importance of DHA (docosahexaenic acid), found in meats and eggs, and AA (arachidonic acid), found in cold water fish.

These authors cite a number of different studies that have shown a relationship between fatty acid deficiency and ADHD [15] [34] or a decrease in brain size in ADHD children [22] [26]. They also suggest that the observed difference in IQ between breast fed and bottle fed infants may be due to the higher concentration of DHA and AA in breast milk. This deficiency is now fortunately being aggressively corrected both in America and elsewhere in the world (Recommendations for AA and DHA in Baby Formula) , and we can hope that this will lead to a decrease in the incidence of ADHD looking forward.

A study by Price on the health of isolated racial groups compared those who remained on their indigenous diet with those who transitioned to a western diet [26]. The indigenous diet invariably contained essentially no empty carbs, and included large amounts of meat and fish. The children who switched to the "modern" diet showed symptoms of both physical and mental degeneration.

Ottoboni and Ottoboni conclude with this rather ominous remark: "The choice seems clear. We can either continue to depend on prescription drugs to mask the symptoms of ADHD, or consider preventing ADHD by modifying the American diet, particularly for child bearing women and children. Should we decide to continue to depend on prescription drugs, which do not remedy the underlying causes of nutritional deficiency diseases, we can look forward to a country in which there will be more and more children with undersized brains who cannot learn, use costly prescription drugs, drop out of school, commit crimes, and cause anguish for their parents."

5. Fats and the Brain

2009-11-21T14:22:00.002-08:00

Children are especially vulnerable to inadequate fat suppply due to their rapidly developing brain. The brain does not consume fat as fuel -- this would be problematic because it would lead to a cannibalistic behavior where the brain would feed off of itself. According to the Franklin Institute, as much as two-thirds of the brain's mass consists of fats. The membranes of neurons consist of a thin double layer of fatty acid molecules. The myelin sheath that encases each fiber in the network of nerve fibers that make up the "white matter" consists of 70% fat and 30% protein. A child's brain is constantly laying down new connections and reshaping old connections to incorporate new experiences and knowledge into long term memory. This processing requires a steady and reliable supply of fats.

Through a technique known as "diffusion tensor imaging" (DTI), scientists have been able to examine the brains of children with and without a diagnosis of ADHD (Brain Differences in ADHD) [5]. They found several differences, most notably, in the volume of white matter connecting together the frontal cortex, basal ganglia, brainstem, and cerebellum. These areas are involved in higher level thought and reasoning, attention, impulsive behaviour, inhibition, and motor activity. Never-medicated ADHD children had noticeably smaller volume of white matter in these areas, compared to normal children or to ADHD children who had been treated with medications such as Ritalin.

White matter consists of a massively interconnected network of nerve fibers, each of which is coated with a fatty myelin sheath that keeps the message insulated (i.e, keeps the signal strong) and greatly increases the transmission speed. In order to focus attention, the brain releases the hormone dopamine from centers in the midbrain, and dopamine receptors transmit signals over long distance pathways to the frontal cortex, the basal ganglia, and the cerebellum, as shown in the figure on the left. Dopamine is a crucial hormone that orchestrates the brain's thought processes involved in maintaining attention to a task and subsequently acquiring new knowledge. Defective dopamine utilization is widely suspected to play a role in ADHD [36]. Poor quality white matter on these long-distance connections, as a consequence of insufficient supply of fat from the blood, would have a huge impact on the ability to pay attention and to learn new facts.

A very exciting research direction that has been undertaken recently addresses the question of the rate of maturation of the brain [31]. 223 children with ADHD were compared with 223 non-ADHD controls. The research utilized magnetic resonance scans to estimate the thickness of the cerebral cortex at more than 40,000 sample points at different positions along the brain surface. Typically, the thickness increases during childhood and then decreases during adolescence. From samples taken over a period of several years, researchers can pinpoint the point in time when the cortex is thickest. The results of the experiments were remarkable: children with ADHD reached peak thickness much later (on average at 10 and a half years old) than children without ADHD (on average at 7 and a half years old). The biggest delay showed up in regions of the prefrontal cortex (shown in the figure on the right) that control attention and motor planning.

Such a delay in maturation would be a good conservation strategy if there is insufficient fat in the diet. By slowing down the growth rate of the cortex, less demand is placed to acquire adequate fat supply, needed to grow additional neurons and myelinated nerve fibers. The body's stunted growth (another characteristic of ADHD children) could even be a side effect of the need to delay the rate of maturation of the brain. Decreasing the concentration of growth hormone would likely affect both the brain and the body, leading to a consistent slowing down of maturation rates across the board.

6. Managing Homeostasis without Dietary Fats

2009-11-21T14:22:00.001-08:00

Fats are a much more stable energy source than carbohydrates. Sugars and starches, especially in the form of high glycemic index "empty carbs," are absorbed very quickly into the blood stream, causing a sharp spike in the glucose level. This in turn triggers the pancreas to inject a large amount of insulin into the blood, to promote the uptake of the glucose into the body's cells. Carbohydrates ingested without fats are absorbed much more rapidly than carbohydrates buffered by fat, because fat slows down the digestive process. Fats, being digested much more slowly, will become available as an alternative fuel source just as the carbohydrate supplies are becoming exhausted. But this is true only if sufficient fats are consumed with the meal.

Very little excess glucose can be stored in the body for later use, unless it is first converted to fat. The liver can provide a small buffer of glucose stored in the form of glycogen, amounting to no more than 5% of its total mass. Once that capacity is exceeded, any remaining glucose in the blood must be converted to fat to be stored.

A thin child whose diet consists mainly of empty carbs cycles between feast and famine in terms of glucose supply, but suffers chronically from an inadequate supply of fats. This places a lot of stress on the homeostasis system because of the gross imbalance between glucose and fat in the external fuel supply. A solution to this problem can be achieved by piling fat stores on the body, except that the fat stores themselves introduce additional energy needs and the strategy snowballs into obesity.

For the ADHD person, instead of steadily accumulating fat stores and programming the muscles to preferentially consume fats, I argue that their bodies have adopted a strategy of fat conservation. The muscles are programmed to prefer glucose over fat, and the body size is minimized by reducing fat deposits, slowing down the maturation process, and stunting growth. As a consequence of the body's reduced needs for fats, more fat (but still not enough) is available to the brain to support its need to build myelin sheath for the expanding network of nerve fibers.

7. The Role of Ketone Bodies

2009-11-21T14:21:00.002-08:00

I am becoming increasingly convinced that ketone bodies play an important role in ADHD. Ketone bodies are an alternative fuel source for the brain that becomes critically important when glucose levels in the blood are low [12]. As has been said before, the brain is unable to utilize fatty acids as fuel. However, it can utilize ketone bodies, and thus their presence becomes a protective mechanism for the brain when glucose is in short supply.

Ketone bodies are produced by the liver as a by-product of fat metabolism. In the absence of fats in the diet, significantly fewer ketone bodies are produced; i.e., the body derives more ketone bodies from dietary fat than from internally synthesized fats [38]. Furthermore, and most significantly, certain specialized cells in the brain called astrocytes are also able to scavenge free fatty acids from the blood and manufacture ketone bodies from them. It is hypothesized that ketone bodies in the brain can also act as "cellular substrates, thereby preserving neuronal synaptic function and structural stability." ([12], abstract). I suspect that astrocytes may be able to accumulate stores of ketone bodies that can serve both as fuel for the brain in times of glucose deficiency, and to assure that important signals such as dopamine get transmitted across synaptic junctions. But insufficient dietary fats will significantly reduce the availability of this critical nutritional resource.

8. Explaining the Gender Bias in ADHD

2009-11-21T14:21:00.001-08:00

It is curious that the incidence of ADHD is much higher in boys than in girls. Some estimates claim that the ratio of boys to girls diagnosed with ADHD is as high as 10:1. In the context of a theory that ADHD is caused by fat insufficiency, what are the factors that might afford protection for girls?

First of all, the ratio of fat to muscle in girls is generally much higher than in boys. For the same body weight and size, a girl will have significantly more subcutaneous fat, as contrasted with a much higher muscle-to-fat ratio for a boy. This implies that the supply of bioavailable fats will be significantly higher for girls than for boys.

Secondly, and most importantly, the female hormone estrogen is a powerful weapon for increasing fat metabolism. Exactly how this is accomplished remains somewhat unclear, but it has been hypothesized that estrogen achieves this effect by stimulating an increase in both growth hormone and adrenaline. Growth hormone has been demonstrated to increase mobilization of fatty acids from fat tissue [30], and it is well known that adrenaline does this too [24]. Growth hormone also inhibits insulin production, and reduced insulin at the outset would greatly improve the odds of getting insulin levels sufficiently suppressed to allow fat mobilization.

Several investigators have studied gender differences in plasma free fatty acids in response to exercise, and have shown that females end up with significantly higher levels of fatty acids in the blood after an equivalent amount of exercise than do their male counterparts [2].

Thus, the extra fat cells, the enhanced mobilization of fat from these fat cells in general, and the enhanced effect of exercise on fat release all likely contribute to the significantly reduced likelihood of a girl succumbing to ADHD than a boy.

9. Dopamine

2009-11-21T14:20:00.002-08:00

Dopamine is an incredibly important hormone that is released from the substantia nigra in the midbrain and relayed to other parts of the brain through three principal neural pathways: the nigrostriatal pathway to the cerebellum to control body movement, the mesolimbic tract to the reward center and seat of emotion, and the mesocortical tract to the frontal lobes of the cerebral cortex that control high level planning and reasoning. These pathways are part of the white matter that is shrunken in size in the ADHD child's brain. With poor transmission speeds and an inability to maintain a strong signal, these poorly insulated pathways dissipate the message that the dopamine is trying to send.

A recent study by Dr. Nora Volkow compared the brains of 53 nonmedicated ADHD adults with those of 44 healthy non-ADHD adults over the period from 2001 to 2009, using positron emission tomography (PET) brain imaging [36]. The study focused on dopamine receptors, which propagate the signal to distant parts of the brain, and dopamine transporters, which recycle excess dopamine after the signal is transmitted. The study found that both receptors and transporters were reduced in number in the ADHD brains as compared with the normal controls. The receptor count is likely reduced as a consequence of the slow and inefficient transport across the networks. The transporters are reduced in turn in order to slow down the process that sends the dopamine back into storage. This allows the dopamine to stay in the synapse for a longer period of time. Ritalin achieves a similar effect, and this is believed to be the main reason why it is effective.

Research on rats has shown that dopamine release is severely impaired in the absence of insulin [9]. This may be an intentional design as protection against releasing dopamine when there is insufficient glucose to fuel the resulting brain activities. However,the ADHD child, who has an efficient glucose metabolism, must deplete the excess insulin before fats from fat stores can be released. Meanwhile, the dopamine supply is exhausted while trying to send signals over faulty networks, and the release of fats comes too late to be effective.

The brain needs fats as well as glucose for acquiring new knowledge - to reconfigure and reinforce the neural connections. The ADHD child is trapped in a catch-22, because, in order to get at the fat stores, the insulin levels must be low, but if the insulin levels are low, glucose is also likely low (since the insulin is so efficient) and, as well, the dopamine release will be suppressed. A child who consumes a low-fat diet and has very efficient glucose metabolism will likely never have, simultaneously, sufficient blood levels of dopamine, fats and glucose. As soon as the insulin levels are sufficiently low to allow the fats to be released, the glucose and dopamine are likely already depleted. With little fat in the dietary sources, and with impoverished and insulin-suppressed fat cells, it is difficult to imagine where the fat supply for the brain is going to come from.

10. Stunted Growth and Vitamin D and Calcium Deficiency

2009-11-21T14:20:00.001-08:00

In my article on obesity, I argued that calcium deficiency plays an important role because calcium is necessary for the release of insulin from the pancreas and for the uptake of glucose by the muscles. Obesity is strongly associated with both calcium deficiency and insulin resistance, and I argue that the fat cells compensate by inserting themselves into the energy chain. They take upon themselves the task of converting glucose to fat, and they program the muscles to strongly prefer fat over glucose as an energy source. In the process, they hoard calcium and vitamin D, and cause measurable deficiencies in these important nutrients in the blood serum.

It is likely that some ADHD children may suffer from calcium deficiency as well, mainly as a consequence of vitamin D deficiency, a syndrome that is at epidemic proportions in the U.S (Vitamin D Deficiency Epidmemic). Probably the most significant nutritional role of vitamin D is its ability to promote both the absorption of calcium from the gut and the transport of calcium across membranes, a process that is extremely important in many aspects of metabolism and brain function. ADHD children tend to be stunted in growth, and their levels of growth hormone are abnormally low. Extending the length of a bone requires an enormous amount of calcium. Thus, by keeping the bones short, the calcium that would have gone into bone growth can be diverted to assure an adequate supply of insulin and an efficient glucose uptake mechanism in the muscle and fat cells.

It could be that ADHD children also sacrifice calcium levels in the brain in order to assure enough calcium for the efficient metabolism of glucose, which is extremely essential when the body is relying mainly on glucose as an energy source. Evidence that calcium channels in the brain are important for memory comes from the surprising result from a study involving 1,268 people who were being treated for high blood pressure (Calcium Blockers and Memory). The study found that people who take calcium blockers to lower blood pressure score less well on memory tests than people who use other medicines to lower blood pressure. Studies using Magnetic resonance Imaging (MRI) verified brain damage in the white matter of the brains of the people who used calcium blockers.

If ADHD children are deficient in calcium in their brains, they are also likely less able to utilize ketone bodies as an energy source in the brain. This conclusion comes indirectly from studies involving alzheimer's patients. It has been found that alzheimer's patients' brains are deficient in the ability to utilize glucose for fuel, and, as a result, regulatory control mechanisms have led to an increased supply of calcium in the brain, which plays an essential role in the metabolism of ketone bodies [13]. This allows them to efficiently use ketone bodies instead of glucose as a fuel source. The converse of this observation is that reduced calcium in the brain would interfere with ketone body metabolism, leaving the brain even more vulnerable to situations of reduced blood glucose levels.

Vitamin D itself plays an important role in brain function, in addition to its influence on calcium, as implied by the existence of a wide distribution of vitamin D receptors throughout the brain [20] (Vitamin D and the Brain) . Vitamin D also affects proteins in the brain that are directly involved in learning and memory, as well as motor control. It may be that, for some ADHD children, insufficient vitamin D is even the main cause of their symptoms.

11. ADHD and Anorexia

2009-11-21T14:19:00.003-08:00

Fat cells are part of the endocrine system, and, as I've discussed before, they have the power to influence the degree to which muscle cells prefer glucose versus fats as an energy source. They exercise this control by releasing two signaling peptides: leptin and adiponectin. Adiponectin promotes glucose consumption by the muscles, and it also acts directly on the fat cells to encourage them to take up glucose and convert it to fat. Leptin, on the other hand, stimulates the muscles to prefer fat consumption over glucose consumption.

Statistically, children with ADHD have an abnormally efficient glucose metabolism rate, i.e., for the same amount of insulin, blood sugar levels drop more quickly after a meal than in other children. This observation suggests that their fat cells have arranged a set point of a high adiponectin to leptin ratio, such that the muscles prefer glucose over fats, and fat cells are predisposed to convert glucose to fat. The glucose levels drop more quickly because the muscles and fat cells are using more of it.

Anorexics, children who intentionally starve themselves, are known to have extremely efficient glucose metabolism (tend towards hypoglycemia) and also to have a high ratio of adiponectin to leptin concentrations [21]. This strategy maximizes availability of fatty acids to the heart and brain. It is curious that anorexia is much more common in girls, and ADHD is much more common in boys.

Researchers at Harvard Medical School suspected that there might be an association between anorexia and ADHD. To test this hypothesis, they compared girls with ADHD against a control group to see whether the ones with ADHD were predisposed towards anorexia (ADHD and Anorexia). The results showed that girls with ADHD were 3.6 times more likely than the control group to develop an eating disorder. I have come to believe that anorexia is a technique to combat ADHD that girls are able to adopt, whereas boys do not have enough fat cells to carry out the task of converting glucose to fat. Ritalin is well known to reduce appetite, and long term use can lead to an anorexia-like condition. It may well work, in part, because it achieves this ultra-thin state, thus conserving fats by minimizing the consumption of fat by cells that can get by on glucose.

12. ADHD and Fatty Acid Deficiencies

2009-11-21T14:19:00.001-08:00

The incidence of symptoms associated with deficiencies in fatty acids, such as dry hair and skin, excessive thirst and frequent urination, has been observed to be higher in ADHD children as compared with the general population [33]. It has been proposed by many researchers that ADHD children are deficient in essential fatty acids, and omega-3 fat supplements are often prescribed as part of their treatment program [29].

A study involving 96 boys from schools in Indiana, 53 of which had been diagnosed with ADHD, looked at the concentrations of fatty acids found in blood plasma [4]. It was determined that the ADHD children as a group had significantly lower amounts of essential fatty acids (omega-3 and omega-6 fats) in their blood than did the controls. Furthermore, among the ADHD group, the 21 subjects who also manifested many symptoms of essential fatty acid deficiency had further depleted serum levels than the other 32 subjects with ADHD.

13. ADHD and Sleep Disorders

2009-11-21T14:12:00.000-08:00

A recent study has shown that adolescents diagnosed with ADHD are significantly more likely to suffer from sleep disorders such as insomnia, sleep terrors, nightmares, and snoring, compared to controls. I suspect these problems during sleep stem from insufficent fats. The brain is unable to properly integrate the newly acquired knowledge and experiences of the day before into long term memory stores, due to the insufficient supply of fats to build the myelin sheaths surrounding newly constructed nerve fibers and reinforcements. These deficiencies in resources critical to the goals of sleeping may be the source of extreme restlessness, wakefulness, and night terrors.

14. The Beneficial Effects of Hyperactivity

2009-11-21T14:10:00.000-08:00

One of the well-known characteristics of ADHD children is that they are fidgety. Whenever they are trying hard to concentrate, they are in constant motion, unable to sit still, and it has been hypothesized that such kinesthetics actually help them think. One way random movements could be effective is through activating dopamine release. Dopamine plays a critical role in body movement: people with Parkinson's disease are unable to initiate movement and appear paralyzed unless treated with the dopamine precursor, L-dopa. I hypothesize that, through random movements of their limbs, ADHD children are able to stimulate the release of dopamine, and thus increase its bioavailability for the important other roles involved in attention and learning.

A further benefit of the random movements is that they involve anaerobic metabolism of glucose, which consumes the glucose stores in the muscles and releases lactic acid into the blood stream. While lactic acid had been generally considered to be a waste product, it has recently been discovered, quite remarkably, that the heart is able to metabolize lactic acid directly as an alternative source of fuel [6]. This has the effect of sparing fatty acids that the heart would otherwise consume. Furthermore, and, most surprisingly, the brain can also utilize lactate as a fuel source [27]. The brain's consumption of glucose falls substantially after extended anaerobic exercise, since it can also exploit the lactic acid that builds up in the blood as a by-product of anaerobic glucose metabolism.

Thirdly, the depletion of glucose in the muscles is followed by replenishment of the muscles' private stores, which will use up insulin in the process. This accomplishes the important goal of driving down the insulin levels so that the fat cells and liver can release more fats into the blood.

Finally, and perhaps most importantly, exercise stimulates the release of adrenaline from the sympathetic nervous system, and adrenaline is the most significant hormone for allowing fat release from the fat cells, even in the presence of excess insulin [24].

Thus, all of these contributions, the production of lactic acid which can be used by the heart for fuel, the depletion of insulin, and the activation of adrenaline, which will actively promote the release of fats, will contribute towards the goal of increasing the fat supply available for the brain.

15. How Ritalin Works

2009-11-21T14:09:00.000-08:00

In the United States, a popular drug to treat ADHD is Ritalin. It is estimated that as many as 10% of the children in the U.S. now take Ritalin or another stimulant [3], and the U.S. consumes 90% of the Ritalin being manufactured worldwide. Since ADHD children suffer from a reduced number of dopamine receptors in the brain [36], it is hypothesized that Ritalin is effective because it prevents the reuptake of dopamine and allows it to stay in the intercellular spaces for a substantially longer time.

Ritalin has a calming effect on ADHD children. This is understandable since Ritalin both increases the bioavailability of dopamine and suppresses insulin's ability to block fat release from storage sites; i.e., it accomplishes the same two goals that random movements try to accomplish. However, children on Ritalin complain that it results in an initial burst of energy with a racing heart, followed by a period of physical exhaustion ([3], p. 112). The energy burst is associated with the adrenaline rush, and the exhaustion is likely a consequence of depleted supplies of both fats and glucose, once the Ritalin has worn off.

Dopamine is a precursor to adrenaline, the "fight or flight" hormone. If dopamine is allowed to linger longer in a bioavailable state through the action of Ritalin, then adrenaline levels will go up. Adrenaline is a very powerful hormone with diverse effects on the body, mainly aimed at increasing fuel supply to the blood in the short term, i.e., to operate in crisis mode.

One crucial effect adrenaline has is to disable insulin's suppressive effect on the fat cells [24]. This allows them to release their fats even while insulin levels are high. Ritalin thus enables the brain to be simultaneously well supplied with glucose for fuel, fat for nerve fiber construction, and dopamine to control execution of the focus and memory consolidation tasks involved with learning new knowledge.

Through its effect of increasing adrenaline levels, Ritalin also suppresses appetite. In the "fight or flight" reaction, the digestive system is shut down, in order to conserve energy, since the digestion process itself consumes energy. Nearly all ADHD children on Ritalin lose weight, and many become dangerously thin over time. A positive effect of reduced appetite is that it likely leads to an increase in the bias towards glucose consumption and fat conservation, as I argued in the section on anorexia. However, in the long term, the depleted fat reserves eventually further aggravate the original problem of insufficient fat supply.

16. The Dangers of Ritalin Use

2009-11-21T14:07:00.000-08:00

It seems to be remarkably easy to pursuade most Americans that popping a designer pill is the answer to nearly all problems. There is great irony, however, in the fact that many children in America are told, on the one hand, to "say 'no' to drugs," and then, on the other hand, to take a drug which is in many ways equivalent to amphetamines like speed and cocaine. Increasingly, friends of ADHD children are obtaining the drug and then snorting it or shooting it like cocaine to achieve an intense high (Ritalin Abuse). And the children are often naive about the dangers of Ritalin, thinking that, if doctors prescribe it for young children, it must be harmless.

Dr. Peter Breggin has become a strong advocate of the idea that widespread Ritalin use in America is causing far more harm than good. His book, Talking back to Ritalin, [3] presents a compelling argument that, despite the assurances from doctors that it is a safe drug, Ritalin is a very close cousin to amphetamines and exhibitis all of the same dangerous properties leading to addiction and abuse. He cites a 1998 study [18] which showed that the use of a childhood stimulant such as Ritalin "is significantly and pervasively implicated in the uptake of regular smoking, in daily smoking in adulthood, in cocaine dependence, and in lifetime use of cocaine and stimulants."

He also points out that Ritalin is classed with amphetamines in terms of its clinical effects. Ritalin is labelled "Schedule II" by both the DEA and the International Narcotics Control Board. Schedule II for a prescription drug indicates the highest possible potential for abuse. A study comparing Ritalin with cocaine claimed that "Methylphenidate [Ritalin], like cocaine, increases synaptic dopamine by inhibiting dopamine reuptake, it has equivalent reinforcing effects to those of cocaine, and its intravenous administration produces a 'high' similar to that of cocaine" [37].

Aside from its potential for abuse, and its potential to lead to abuse of other drugs later in life, long term Ritalin use, as prescribed, leads to several other adverse health issues. The shutting down of the digestive system suppresses appetite, with subsequent weight loss and stunted growth. By simulating a "fight or flight" reaction, it increases both blood pressure and heart rate [1], and may do other unknown damage to the heart. In March, 2000, a 14-year old boy, Matthew Smith, fell off his skate board and died suddenly. A subsequent autopsy showed severe heart damage, which the coroner suspected was due to the fact that he had been taking Ritalin since he was six years old. This has stirred up considerable discussion among parents of ADHD children regarding the safety of long-term Ritalin use (Matthew Smith Ritalin Discussion). Parents are now urged to screen their children for possible heart conditions if they are considering Ritalin as a treatment option.

More ominously, by overworking the dopamine system, long term Ritalin use may lead to Parkinson's disease much later in life. It has been demonstrated that other drugs that affect the dopamine system can cause Parkinson's disease. Through population studies, amphetamine use many years before was correlated with Parkinson's disease much later in life [10]. Adderall, another popular drug for treating ADHD, is an amphetamine, and Ritalin is a close cousin. In 1983, a defective batch of the street drug, synthetic heroin, also known as "China White", hit the streets of San Francisco, and a number of addicts who were unfortunate victims of this mistake acquired severe irreversible Parkinson's disease after just a single dose, due to the neurotoxin MPTP inadvertently present in the drug. While such a dramatic instantaneous effect would not be expected to occur with Ritalin, it is impossible to predict what will happen long term. I hope I am wrong, but I believe it is likely that we will see a substantial increase in the incidence of Parkinson's disease later in life among today's Ritalin and Adderall users.

17. My Recommendations for Treating ADHD

2009-11-21T14:06:00.000-08:00

In this section, I will present my own ideas on how children with ADHD can, with time, improve their brain function and reduce their dependence on Ritalin. First of all, I want to remind you that I am not an M.D. My doctorate from MIT is in electrical engineering. However, my PhD thesis concerned an auditory model for human speech processing, and thus required extensive reading on neural mechanisms in the brain. My Bachelor's degree from MIT is in biology, with a minor in food and nutrition. I benefit strongly from having been exposed to ideas about nutrition before the low-fat diet craze got its firm grip on our nation's population.

The first step towards healing is to discard the idea that fats are unhealthy. I recommend reading any of the following books, which have covered the subject extensively, Good Calories Bad Calories by the New York Times reporter, Gary Taubes [35], Fat and Cholesterol are Good For You, by Uffe Ravnskov, a Swedish M.D., Ph.D. [28], and Trick and Treat: How 'Healthy Eating' is Making us Ill, by the British researcher and writer, Barry Groves [11].

We have been led by the American medical community to believe that a high-fat diet leads to heart disease, and that increased dietary consumption of fruits and vegetables is a heart-healthy choice. However, a recent (2009) long-term population-based study in Sweden has concluded that fruits and vegetables provide no heart-health benefit at all unless they are consistently eaten with fats [14]. The researchers conducted extensive interviews with several thousand men in rural Sweden about their food practices, and also carefully monitored their heart health status over a 12-year period. Surprisingly, they found no association between coronary disease and the consumption of fish or wholemeal bread, and no association with the consumption of fruits and vegetables, for those who also chose low fat dairy, or consumed little dairy. The only clear benefit they could find was with a combination of lots of fruits and vegetables and high-fat dairy consumption. They hypothesized that the high fat dairy was required to promote the absorption of the vitamins and minerals contained in the fruits and vegetables. However, if they are eating both lots of fat and lots of fruits and vegetables, they are probably also eating few empty carbs. A corollary of this result is that a person who avoids fat is likely deficient in vitamins and minerals, even if they consume a lot of fruits and vegetables.

Once a mother no longer fears fats, she can begin to change her child's diet, with the goal of over-correcting the fatty acid deficit through a high fat, very low carb, diet. An increase in the consumption of meat, fish, and eggs should be balanced with a decrease in the consumption of sugar and starch. Foods containing trans fats should be carefully avoided. Improvements will probably not be dramatic, as it will take a long time for the child to repair all the poorly insulated nerve fibers that are suffering from insufficient fat supply. I can not predict how quickly or how completely a child who has suffered from dietary fat deficiency throughout its life can recover, once the dietary correction is in place.

Of course, the best action would be to avoid the problem in the first place, and this begins with the pregnant mother. It is especially important for her to consume an abundance of omega-3 and omega-6 fats while she is carrying the baby, and to continue to do so once the baby is born, to assure a high-quality milk supply to her child. A recent analysis of data from the Nurses' Health Study, an ambitious long-term study involving over 18,000 nurses, showed that fat in dairy consumption was associated with high fertility. Women who said they ate low-fat diary increased their risk of infertility by 85%, whereas women who consistently ate high-fat dairy decreased their risk by 27% [7]. Fertility is an indicator of the degree to which the body perceives that it is prepared to support a fetus. Breast milk has an extremely high fat content, significantly higher than that of cow's milk. It then seems logical that, once mother's milk is replaced with table foods, these foods should continue to be high in fat content.

I find Ritalin to be a very disturbing drug, particularly because it is a synthetic drug and because it has been on the market for a relatively short time. We have no idea what will happen to children currently taking Ritalin 40 or 50 years hence. Alarm bells have already been raised regarding possible addiction and abuse, appetite loss and subsequent malnutrition and stunted growth, and adverse effects to the heart.

Other stimulants that occur in nature have been used by humans for hundreds of years, and they would likely be safer than Ritalin if they can achieve the same goals. I am thinking of caffeine, chocolate, and even nicotine. It's possible that nicotine is no better than Ritalin, with its known issues regarding the potential for addiction and increased risk for heart disease and lung cancer. But a nicotine patch, which avoids the issue of tar exposure in the lungs leading to lung cancer, is at least an alternative that should be considered instead of Ritalin.

Coffee is a particularly attractive choice -- it has been extremely well studied and appears to have very few if any adverse side effects. It has been shown to improve memory, and it works in part because, in addition to increasing adrenaline levels, it acts directly to disable insulin's suppression of fat release [23], which I consider to be one of the most important goals of an ADHD drug. Chocolate is a stimulant that children will find especially appealing, and chocolate milk (made from whole milk) would be a great way to introduce it.

18. ADHD: Conclusion

2009-11-21T14:04:00.000-08:00

ADHD is a syndrome manifested mainly by hyperactivity and inattentiveness. It affects as many as 10% of boys in the U.S., and perhaps 3% of girls. Children are usually diagnosed during the first few years in school, although it is often believed that they have suffered from the condition since birth. Increasingly, treatment involves a prescription of Ritalin, a drug that has been shown to be effective in calming them down and improving attention span, often leading to higher grades at school. The syndrome was not even listed in the first edition of the DSM (Diagnostic and Statistical Manual of Mental Disorders) issued in 1968, but appeared in the second edition, released in 1980. During the intervening period, the message that dietary fats are harmful to health first made its appearance [17].

I agree with Peter Breggin when he claims in his book Talking back to Ritalin that long term Ritalin use will likely lead to many dire consequences down the road. However, he also claims that ADHD is a fake disease, concocted purely to stuff the pockets of the pharmaceutical industry executives. I try to imagine what it would be like to be a parent of an ADHD child, reading that ADHD is caused purely by social influences -- that the inattentiveness and hyperactivity are due to a dysfunctional family life and/or an unstimulating school environment. I am reminded of the time when autism was blamed on poor parenting. A mother who has done everything she can to create a nurturing environment but has seen no improvement in her child's symptoms must feel very besieged, frustrated, and discouraged.

I believe that ADHD is a real syndrome with a strong genetic component. However, I have argued that the genetic aspect is manifested as a greater susceptibility to brain dysfunction as a consequence of insufficient fats in the diet. This includes the diet of both the child and the mother while she carried the child to term, and while she nursed the child. I believe that symptoms will improve slowly over time if the child's diet is simply adjusted to include more meats, eggs, fish, and high-fat dairy, while minimizing the consumption of empty carbs.

Unfortunately, I doubt that the symptoms will ever go away entirely, especially if the child is already a teenager by the time the change is implemented. I do not know how much of the damage in neural connections in the brain and nervous system can be repaired long after critical developmental milestones have passed. However, children's brains have been shown to be remarkably resilient after brain injury, so we can hope that significant improvement can take place over time. Of course "an ounce of prevention is worth a pound of cure." Anyone who is thinking of starting a family would be wise to change their diet in anticipation of the coming pregnancy -- to stop worrying about the mistaken belief that animal fats are unhealthy, and switch to high-fat dairy, meats, fish, and eggs instead of sugar-laden drinks and starchy foods.

I find it impossible to blame the mother for the problem -- she is only executing on both subliminal and overt messages claiming that dietary fat is unhealthy and will lead to obesity and heart disease. She is trying her best to provide her child with a healthy diet according to strong advice from both the U.S. government and the American medical establishment. I therefore expect ADHD to persist unabated in the U.S. until the authoritarian figures finally recognize and acknowledge their error, and change their tune regarding dietary fat. It is very disturbing to think of how many years it may take for them to own up to the huge mistake they have made by advocating low-fat diet, and the enormous anguish it has caused.

ADHD: References

2009-11-21T13:59:00.000-08:00

[1] J.E. Ballard, R.A. Boileau, E.K. Sleator, B.H. Massey and R.L. Sprague, "Cardiovascular responses of hyperactive children to methylphenidate." JAMA (1976) Dec 20;236(25):2870-4.

[2] F.K. Blatchford, R.G.Knowlton, and D.A. Schneider (1985) "Plasma FFA responses to prolonged walking in untrained men and women," European Journal of Applied Physiology (1985), Vol. 53, pp. 343-347.

[3] P. R. Breggin, M.D., Talking Back to Ritalin: What Doctors aren't Telling you about Stimulants and ADHD , revised edition, Da Capo Press, Cambridge, MA, 2001.

[4] J.R. Burgess et al., "Essential fatty acid metabolism in boys with attention deficit-hyperactivity disorder," American Journal of Clinical Nutrition 1995; 62, pp. 761-68.

[5] F.X. Castellanos et al., "Developmental trajectories of brain volume abnormalities in children and adolescents with attention deficit hyperactivity disorder," JAMA (2002), Vol. 288, NO. 14, pp. 1740--1748.

[6] J. C. Chatham, "Lactate: The Forgotten Fuel," J. Physiol. (2002) Vol 542(2), p. 333.

[7] Jorge Chavarro, Walter C. Willett, and Patrick J. Skerrett, The Fertility Diet, McGraw Hill, 2008.

[8] D. Coghill and T. Banaschewski, "The genetics of attention-deficit/hyperactivity disorder," Expert Rev Neurother (2009) Oct, Vol. 9 No. 10, pp. 1547-65.

[9] B. Garcia, Y. Wei, J.A. Moron, R.Z. Lin, J.A. Javitch and A. Galli, "AKT is essential for insulin modulation of amphetamine- induced human dopamine transporter cell surface redistribution," Molecular Pharmacology (2005); DOI: 10.1124/mol.104.009092

[10] E.R. Garwood, W. Bekele, C.E. McCulloch and C.W. Christine, "Amphetamine Exposure is Elevated in Parkinson's Disease," NeuroToxicology, Vol. 27, No. 6, December 2006, Pages 1003-1006.

[11] Barry Groves, Trick and Treat: How 'Healthy Eating' is Making us Ill, Hammersmith Press, 2008.

[12] M. Guzmán and C. Blázquez, "Ketone body synthesis in the brain: possible neuroprotective effects." Prostaglandins Leukot Essent Fatty Acids (2004) Mar, Vol. 70, No. 3, pp. 287-92.

[13] E. Heininger, "A unifying hypothesis of Alzheimer's disease. IV. Causation and sequence of events," Rev Neurosci. (2000) Vol. 11 Spec No:213-328.

[14] S. Holmberg, A. Thelin and E.-L. Stiernström, "Food Choices and Coronary Heart Disease: A Population Based Cohort Study of Rural Swedish Men with 12 Years of Follow-up," Int. J. Environ. Res. Public Health (2009) Vol. 6, pp. 2626-2638; doi:10.3390/ijerph6102626.

[15] G. Hornstra, "Essential fatty acids in mothers and their neonates," Am. J. Clin Nutr. (2000) Vol 71 (5 suppl), pp. 1262S-1269S.

[16] M. Kinsbourne, "Sugar and the hyperactive child," New England Journal of Medicine, (1994) Feb 3, pp. 355-356.

[17] A. F. La Berge, "How the Ideology of Low Fat Conquered America," Journal of the History of Medicine and Allied Sciences, (2008) Feb. 23, Vol. 63, No. 2, pp. 139-177; doi:10.1093/jhmas/jrn001

[18] N. Lambert and C.S. Hartsough, "Prospective study of tobacco smoking and substance dependence among samples of ADHD and non-ADHD subjects, Journal of Learning Disabilities (1998) Vol. 31, pp. 533-534.

[19] L. Langseth and J. Dowd, "Glucose tolerance and hyperkinesis," (1978) Food Cosmet. Toxicol. Vol. 16, p. 129.

[20] J.C. McCann and B.M.Ames BN, "Review Article: Is there convincing biological or behavioral evidence linking vitamin D deficiency to brain dysfunction," FASEB J. (2008) Vol. 22, pp. 982-1001.

[21] D. Modan-Moses, D. Stein, C. Pariente, A. Yaroslavsky, A. Ram, M. Faigin, R. Loewenthal, E. Yissachar, R. Hemi, and H. Kanety, "Modulation of Adiponectin and Leptin during Refeeding of Female Anorexia Nervosa Patients," The Journal of Clinical Endocrinology & Metabolism, Vol. 92, No. 5, pp. 1843-1847.

[22] S.H. Mostofsky, A.L. Reiss, P. Lockhart and M.B. Denckia, "Evaluation of cerbellar size in attention deficit-hyperactivity disorder," Arch. Gen. Psychiatry, (1996) Vol. 53, No. 7, pp. 607--616.

[23] V. Mougios, S. Ring, A. Petridou, and M.G. Nikolaidis, "Duration of coffee- and exercise-induced changes in the fatty acid profile of human serum," J Appl Physiol (2003) Vol. 94, pp. 476-484. doi:10.1152/japplphysiol.00624.2002

[24] H. Okuda, Y. Saito, N. Matsuoka and S. Fujii, "Mechanism of Adrenaline-induced Lipolysis in Adipose Tissue," J. Biochem, (1974) Vol. 75, No. 1, pp. 131-137.

[25] F. Ottoboni, M.P.H., Ph.D, and A. Ottoboni, Ph.D., "Can Attention Deficit-Hyperactivity Disorder Result from Nutritional Deficiency?", J. American Physicians and Surgeons, Vol. 8, No. 2, Summer, 2003.

[26] W.A. Price, Nutrition and Physical Degeneration, Los Angeles, Calif., Keats Publishing ;1998 (First Edition, 1939).

[27] B. Quistorff, N.H. Secher and J.J. Van Lieshouts, "Lactate fuels the human brain during exercise", The FASEB Journal (2008), Vol. 22, pp. 3443-3449. doi: 10.1096/fj.08-106104.

[28] U. Ravnskov, M.D., PhD, Fat and Cholesterol are Good For You,, G. B. Publishing, Sweden, 2009.

[29] A. Richardson and B. Puri, "Randomized double-blind, placebo-controlled study of the effects of supplementation with highly unsaturated fatty acids on ADHD-related symptoms in children with specific learning difficulties," Prog Neuropsychopharmacol Biol Psychiatry, Vol 26(2), 2002, pp. 233-9.

[30] R.A. Robergs, and S.O. Roberts, Exercise Physiology: Exercise, Performance, & Clinical Applications, (1997) WCB McGraw-Hill, Boston, MA.

[31] P. Shaw, K. Eckstrand,W. Sharp, J. Blumenthal, J.P. Lerch, D. Greenstein, L. Clasen, A. Evans,J. Giedd and J.L. Rapoport, "Attention-deficit/hyperactivity disorder is characterized by a delay in cortical maturation", Proceedings, National Academy of Sciences (2007) December 4,, Vol. 104, No. 49, pp. 19649-19654.

[32] Silver L.B. Attention-Deficit Hyperactivity disorder. Clinical guide to diagnosis and treatment. Washington: American Psychiatric Press Inc, 1992: 129-134.

[33] N. Sinn, "Physical fatty acid deficiency signs in children with ADHD symptoms," Prostaglandins Leukot Essent Fatty Acids (2007) Aug; Vol. 77 No. 2, pp. 109-15. Epub 2007 Sep 6.

[34] L.J. Stevens et al. "Essential fatty acid metabolism in boys with attention-deficit hyperactivity disorder," Am J Clin Nutr (1995) Vol. 26, No. 8, pp. 406--411.

[35] Gary Taubes, Good Calories Bad Calories:Challenging the Conventional Wisdom on Diet, Weight Control, and Disease., Alfred A. Knopf., 2007.

[36] N.D. Volkow, G.J. Wang, S.H. Kollins, T.L. Wigal, J.H. Newcorn, F. Telang, J.s. Fowler, W. Zhu, J. Logan, Y. Ma, K. Pradhan, C. Wong, and J.M. Swanson, "Evaluating dopamine reward pathway in ADHD: clinical implications." JAMA (2009) Sep 9; Vol. 302, No. 10, pp. 1084-91.

[37] N.D. Volkow, Y.-S. Ding, J.S. Fowler, G.-J. Wang, J. Logan, J.S. Gatley, S. Dewey, C. Ashby, J. Lieberman, R. Hitzemann and A.P Wolf, "Is methlphenidate like cocaine?" Archives of General Psychiatry, (1995) Vol. 52, pp. 456--463.

[38] I.T, Yamamoto and M. Sugano, "Effect of dietary fat on lipid secretion and ketone body production in rat liver," J Nutr Sci Vitaminol> (Tokyo) (1984) Apr, Vol. 30 No. 2, pp. 153-62.

The Obesity Epidemic: is the Metabolic Syndrome a Nutritional Deficiency Disease?

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The United States is currently facing an obesity epidemic across its population, affecting children and adults alike. It is now estimated that 30% of Americans are overweight [27], and the problem has been worsening over time.

Why does the US have this problem? Why are we the "leaders" in obesity and related health issues such as heart disease and diabetes, despite our incredibly high dollar investment in health care? What are we doing wrong?

My research, detailed in this essay, shows that in many cases the underlying cause of obesity lies with basic nutritional deficiencies, which can be corrected through simple dietary changes. These deficiencies are likely caused, in large part, by two ill-conceived, yet supposedly "healthy", modern day lifestyle choices: an excessively low-fat diet, and sun phobia. The modern preference of sugar-laden over calcium-rich foods also plays a role.

The solution to our problems, fortunately, is surprisingly simple. It involves making a conscious effort to consume foods rich in vitamin D, calcium and fats, and to spend more time outdoors on sunny days. While many researchers have come to suspect that vitamin D (Details) and calcium (Details) deficiencies play a causative role in obesity [2][4][5][10][19][21][23][33][35][36][39][40], the critical role played by insufficient dietary fats has been largely overlooked. I have previously argued that a deficiency in these three nutrients is a key contributor to the current epidemic in autism in America. I have also made a case for a role played by these deficiencies in increased susceptibility to infectious diseases such as swine flu . Here, I will develop an argument that explains why a person suffering from deficiencies in calcium, vitamin D, and dietary fat is likely to steadily gain weight throughout their life, and develop a host of associated health problems.

Excessive weight is a principal factor associated with what has been termed "the metabolic syndrome." This syndrome is manifested principally by excess fat deposited around the abdomen. It is usually associated with several other risk factors for diabetes and heart disease, including high blood pressure, high levels of triglycerides in the blood, elevated values for LDL (the "bad" cholesterol), reduced values for HDL (the "good" cholesterol), and high blood sugar [40].

The basic problem that a person with severe calcium and vitamin D deficiencies faces is an inability for the heart and muscles to effectively utilize glucose (sugar) for their energy needs [14][17][18]. Even when blood sugar levels are high, the heart and muscles are starved for energy. I am reminded of a ship lost at sea -- water water everywhere and not a drop to drink." However, there is an alternative energy source -- fats -- that would be readily available to them if the body could just maintain an adequate supply.

With a low-fat, high-carb diet, it is sugar rather than fat that is primarily available from food sources. Thus the body's fat cells are recruited to convert the sugar to fat so that the muscles and heart will be able to satisfy their energy needs. The fat cells are overburdened with this monumental task, and, to keep up with demand, they must become more abundant; i.e., the person gains weight.

The heart can never afford to be without energy supply. Hence, I argue that an additional step is taken to assure a private source of fat in very close proximity to the heart. Fat deposits begin to accumulate directly within the walls of the arteries supplying the heart. The familiar name for these fat deposits, placed there to fuel the heart, is "arteriosclerosis." Eventually, fat also accumulates in the body cavity encasing the heart -- i.e., "pericardial fat" [9]. The arterial fat deposits can also provide fuel for bacteria and viruses, which can easily enter the blood stream through the lungs, and I (and others [25][34]) believe that it is infection in the fats lining the coronary arteries that ultimately leads to heart attacks (Details) .

In the following sections, I will first explain why these deficiencies are widespread in America, and then present the argument at a somewhat technical level that explains in detail how the metabolic syndrome evolves. Finally, I will provide recommendations for modest lifestyle changes that will correct these deficiencies.

2. Why are These Deficiencies Present in America?

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Unfortunately, intuitive, yet compelling arguments can be made as to why sun exposure and fat consumption might be unhealthy: the sun's UV rays can cause cancer by introducing errors in DNA transcription; heart disease is strongly associated with fatty deposits in the coronary artieries, fatty acids in the blood, and obesity. It is too easy to imagine that these correlates would likely be related to fat consumption. But does research support these intuitions?

It has been well established that vitamin D and calcium deficiencies are at epidemic proportions in America today. Calcium is known for its role in building strong bones and teeth, but it also plays a critical role in food metabolism. The best source of calcium is milk; however, today people prefer sugar-laden beverages over milk. It has been estimated that 75% of Americans are deficient in calcium. A recent study showed an alarming increase in broken bones in today's children compared to those in the 1970's [16]. Rickets is now reappearing among children [12], and teenagers are being diagnosed with osteoporosis, something that was unheard of in the last two generations.

It has been estimated that 70% of America's children are currently deficient in vitamin D [20] (Details) . This is not surprising, given current medical advice. The sunscreen industry lobby has convinced most Americans, including medical experts, that the sun should be aggressively avoided to prevent skin cancer. This, in spite of the fact that the sun is an excellent source of vitamin D, allowing the skin to manufacture it directly from cholesterol. Moreover, vitamin D is protective against all cancers (Details) a characteristic which, in my view, more than compensates for any extra skin cancer risk incurred by sunbathing. Vitamin D deficiency is also associated with an increased risk of high blood pressure and diabetes [35]. In order to get vitamin D from food, it is necessary to eat animal fats; animals manufacture vitamin D, a fat-soluble vitamin, and store it in their fat cells.

The American medical establishment is heavily entrenched in the idea that dietary fat is unhealthy. People are encouraged to adopt low fat diets, which inevitably lead to an increase in their intake of carbs and sugars, as much of the fat removed in foods is replaced with sugars to make them palatable. Many foods are also often highly processed and easily digested, leading to a rapid rise in blood sugar. At the same time, foods containing vitamin D are avoided, due to their universally high fat content.

Vitamin D is crucial to the absorption of calcium from the gut into the blood stream, and both vitamin D and calcium are important catalysts in crucial biological processes. Fats also promote the vuptake of calcium in the gut, whereas dietary fiber, touted as being healthy, impedes it [38] (Details) . These three nutrients, fats, vitamin D, and calcium, have intricate mutual dependiencies that make it important to consume them together. Americans are deficient in these important nutrients because of their perceived need to pursue a low fat diet and avoid sun exposure.

3. The Basic Problem: Impaired Glucose Uptake

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My research on homeostasis, the process by which the body manages its energy needs, leads me to conclude that a person who suffers from calcium and vitamin D deficiency is operating under an unusual set of rules for energy management. Energy management is a crucial component of all cell metabolism. Any work that a cell does consumes energy, and this energy is supplied by either fatty acids, in the form of triglycerides (derived from dietary fat or supplied by fat cells on the body) or from glucose (derived from carbohydrates and proteins or supplied from temporary stores in the liver). While muscle cells can typically store a small amount of fuel locally, these local stores are quickly depleted during intense exercise. New supplies of nutrients are then extracted from the blood stream. The levels of glucose and triglycerides in the blood are constantly monitored and adjusted based on complex chemical signaling, to maintain sufficient supplies to all the body's cells.

The basic problem that a person with metabolic syndrome faces is an impaired ability for glucose to enter muscle cells [13] (Details) . Critically, this includes the heart muscle. Glucose transport is inhibited because the cell has an inadequate supply of calcium [27] and vitamin D [2][3][28] (Details) . These two nutrients are both critical for the pancreas to release insulin into the blood. Insulin in turn stimulates glucose uptake in the muscle cells [7]. Calcium is also critical for the migration of the catalyst GLUT4 to the membrane of the cell [21][36], where it orchestrates the transfer of glucose across the membrane, providing energy to the cell.

The muscle cell consumes energy when it contracts. The source of this energy is adenosine triphosphate (ATP), which releases energy through a chemical process that converts it to adenosine monophosphate (AMP). The energy that is released when the ATP is converted to AMP fuels muscle contraction. The cell's mitochondria are able to convert AMP back to ATP (to be recycled) by consuming either glucose or fat. When there is not enough fuel to convert AMP back to ATP, the ratio of AMP to ATP builds up. The ratio of AMP to ATP within the cell is a measure of its energy state, and is used by many different types of cells in the body to detect energy shortages and trigger corrective measures.

As the muscle cell exhausts its internal stores of energy, it attempts to draw in more glucose from the blood. An impaired glucose transport mechanism inhibits this process. As a consequence, the ratio of AMP to ATP in the cell steadily rises, activating a powerful regulating peptide secreted by the cell, known as AMPK. AMPK in the muscle cell promotes the movement of GLUT4 to the membrane, even in reduced insulin contexts [33]. With GLUT4 at the cell membrane the cell can now begin to draw upon the glucose and insulin supplies in the blood.

At this point, several things happen to counteract the falling level of blood glucose, which is detected by the pancreas and hypothalamus. They emit hormones and peptides that signal the body to replenish glucose levels in the blood. The alpha cells in the pancreas react by secreting glucagon, a hormone that triggers the liver to convert its stores of glycogen into glucose and release it into the blood stream. Similar glucose-sensing cells in the hypothalamus increase the appetite and stimulate the person to consume food, in order to replenish the supplies being drawn down in the liver.

Both of these glucose sensing mechanisms (in the hypothalamus and in the pancreas) depend on AMPK, and both involve a rush of calcium into the cell as part of their signaling cascade [27] (Details) . I hypothesize that deficiencies in calcium cause these glucose sensing mechanisms to detect low glucose levels internally even when glucose levels in the blood are still reasonably high. This is in fact an intelligent design, to tie their glucose-sensing mechanisms to those of the muscle cells, because, if the muscle cells can't absorb glucose efficiently, it is in some sense equivalent to having low blood glucose.

Thus, due to poor glucose uptake, the set point for the blood levels of glucose is maintained at an artificially high level. This is because poor uptake can be somewhat compensated for by elevating the concentration in the blood. Eating easily processed sugars and starches is the most effective way to quickly satisfy the cravings caused by poor glucose uptake. While the higher levels of glucose help to satisfy the muscles' needs, the glucose is also available to the fat cells, which feed on the excess sugars and store them as fats. Over time, sustained high blood sugar leads to chronic weight gain, diabetes, and heart disease.

Correcting the underlying glucose uptake problem will require long-term dietary changes which I will later describe. But first, I would like to explain some of the biological processes involved in food metabolism and weight, and show how the body tries to compensate for malfunctioning glucose uptake.

4. Fat Cells to the Rescue

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The fat cells play a fascinating role in attempting to compensate for glucose uptake deficiencies. Fat cells are now considered by experts to be an essential part of the endocrine system, in that they can orchestrate energy management by many organs of the body by releasing hormones into the blood [8][11][26]. Fat cells are able to absorb excess sugar from the blood and convert it into fat. The fat will later be released into the blood stream as fatty acids and triglycerides, which offer an alternative energy source to the muscle cells (and most other cells of the body) - an alternative that does not suffer from the problem of membrane transport, which is specific to glucose.

In a situation where glucose transport is defective, the fat cells appear to: (1) program the muscle cells to consume fats rather than sugars, and (2) take upon themselves the task of converting as much of the incoming sugar as possible to stored fats. The fat cells accumulate fat whenever the blood sugar levels are high, and then release it into the blood stream whenever blood sugar levels are low enough. Thus they strive to maintain in the blood stream a steady supply of an alternative and more efficient source of fuel (fats) for the muscles to consume instead of sugar.

Through signaling involving a peptide released into the blood stream by fat cells, called leptin, fat cells are able to redirect the muscle cells to obtain most of their energy needs from fats instead of from glucose. However, as a consequence, the fat cells then become burdened with the task of of converting as much as possible of the incoming glucose to fats.

The fat cells must thus buffer up a reserve store of fats, and release fats into the blood to provide nutrition for the muscle cells during fasting conditions, when glucose is not available. After meals, when glucose levels are high, the fat cells are preoccupied with extracting glucose from the blood, and therefore are unable to release fats. Thus, they must provide additional triglycerides in advance of a meal, so that the muscle cells will continue to have food while the glucose is being taken up by the fat cells and converted to a renewed supply of fat. This safety buffer of triglycerides is what is responsible for the observed high fasting triglyceride levels of the obese.

If more dietary fats were consumed, fat from food sources would be available to the muscles while the fat cells are distracted with taking up glucose, and there would be correspondingly less glucose to convert. But because so much fat is needed to feed the muscles, and because so much excess sugar is going to waste, the fat cells find themselves unable to meet the demand, so they end up proliferating -- and the person becomes obese.

The fat cells also suffer from an impairment of glucose transport, as they rely on the same mechanism involving GLUT4 and insulin to transport sugar across their cell walls (Details) . Fat cells however are able to internally hoard both vitamin D [5] and calcium [40], so that they can improve somewhat their own abilities to transport glucose across their cell membrane. But this also leaves the muscles more vulnerable to glucose uptake inefficiencies, because it further depletes the availability of calcium and vitamin D in the blood. As long as the muscle cells use up fats as their energy source instead of glucose, and as long as the fat cells can maintain a good supply of fats in the blood, all will be well. This is the scheme that the fat cells are trying to perpetuate.

5. How does the Heart Cope?

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The heart is similar to the skeletal muscles in that it too faces glucose deprivation when calcium and vitamin D supplies are inadequate. Like the skeletal muscles, it can utilize both fat and sugar as fuel, and it uses the same GLUT4 peptide to usher the glucose across the cell walls [31]. As long as the fat cells in the rest of the body are able to release a steady stream of triglycerides into the blood stream, the heart can simply use these for most of its energy needs. But it is likely that, especially after a high-carb, low-fat meal, there will be intervals when the heart is fuel deficient.

I propose that the heart adopts two different coping mechanisms: (1) grow bigger, and (2) develop its own "private" supply of nutrients, in the form of fat deposits. By becoming enlarged, the heart is using the strategy of "strength in numbers." Imagine that six children are competing against three adults in a tug-of-war. The children may win, even though they are weaker, simply because there are more of them. Likewise, the heart, by increasing the number of muscle cells, may be able to beat as strongly as a smaller heart, but each independent muscle cell carries a lesser burden, and therefore can get by on a reduced fuel supply.

The second strategy, creating an internal supply of fats, begins with fatty deposits in the linings of the arteries supplying the heart, known familiarly as arteriosclerosis. These deposits, with time, become "hardened," i.e, associated with calcium deposits; calcium that has been hoarded by the fat cells over the years, just as is done in the abdominal fat cells. The calcium is hoarded because it enables the fat cells to absorb glucose and convert it into fats. As a further strategy, the heart develops a layer of "pericardial fat," [9] fatty deposits, typically just outside of the major arteries feeding into the heart. These deposits supply additional fats directly to the heart, to supplement those lining the artery walls.

One problem with encasing the heart with fats is that it becomes susceptible to bacterial infection. The highly oxygenated blood, coming directly from the lungs, may easily become contaminated with bacteria that have entered the body through the lungs. These bacteria may find it attractive to feed off of the fatty deposits lining the arterial walls. As a consequence, cholesterol must infiltrate the artery walls, as a first line of defense in the immune system, to attack the bacteria (Details) . The cholesterol also draws upon white blood cells to assist in the battle. Furthermore, the fat cells encasing the heart, as contrasted with fat cells elsewhere in the body, are especially primed to release cytokines [9], which are also infection-fighting agents. Thus the presence of fat in the heart's arterial walls and encasing the heart is associated with high levels of cholesterol and cytokines in the blood.

6. Hormones and Enzymes that Control Appetite

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The fat cells are able to influence the muscles to preferentially take up fats rather than glucose by releasing certain hormones into the blood, hormones that also have a powerful influence over appetite. One of these hormones is leptin. While leptin influences the muscle cells indirectly through its signaling in the hypothalamus, it also stimulates the muscle cells directly, and influences them to oxidize fatty acids in their mitochondria [26]. Leptin also encourages the fat cells to release their fats through lipolysis [24]. All of these actions work in concert to redirect fuel usage away from glucose. The programming of the muscles to preferentially consume fats aligns well with the fat cells' infusion of fats into the blood and absorption of sugars through their fat-producing factories.

Leptin also has the effect, via the hypothalamus and pituitary gland, of suppressing appetite. Adiponectin is another hormone released by fat cells, and it is generally agreed that adiponectin induces hunger. Leptin and adiponectin levels would ordinarily fluctuate throughout the day, with leptin levels rising at night to encourage a switch from glucose-based to fat-based energy management. However, in the obese person, the leptin levels are typically high all the time, and the adiponectin levels are kept very low [41]. High levels of leptin in the blood signal to the appetite center in the brain a sense of being full [8], whereas high levels of adiponectin are hunger-inducing. This means that the obese are being informed both that they are full, and that they are not hungry. You would think that this would protect them from overeating. However, it is likely that the observed insensitivity to leptin as an appetite suppressant in the obese is also related to calcium depletion, because the signaling mechanisms that respond to leptin in both the hypothalamus (Details) and the pituitary gland (Details) depend on changes in internal calcium concentrations.

So, why does the obese person overeat? I have reached the almost inescapable conclusion that the culprit is over-sensitized AMPK, as is also suggested by several other researchers [15][17][18]. AMPK operates not only in muscle cells, but in just about all cells of the body [15]. In particular, it plays a critical role in sensors in specialized cells in the brain: in the hypothalamus and the pituitary gland. These cells release chemicals into the blood that influence the liver, the pancreas, and the appetite, in terms of turning on or turning off mechanisms that will provide further fuel into the system, in the form of either fats or glucose.

As was said before, whenever the muscles exert themselves for sustained periods, they soon reach a critical point where large amounts of ATP have been converted to AMP, in the process of releasing energy to drive muscle contraction. The AMP:ATP ratio rises sharply. This activates AMPK, which then reprograms the muscle to both increase the levels of calcium inside the cell and consume more sugar [30][32][37], a very bad idea since calcium and insulin are in short supply. Certain GI or "Glucose Inhibited" cells in the hypothalamus, as well as alpha cells in the pancreas, are programmed to respond to low glucose levels by instructing the liver to release more sugars and increasing the appetite for foods with a high glycemic index. They essentially broadcast the urgent message to the brain that more glucose is desperately needed. The person is compelled to consume sugars and carbs that will digest very quickly and further raise the already high blood sugar levels.

7. The Body Grows Larger

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Ironically, the arguments made above suggest that aerobic exercise is ill-advised for those who suffer from this impaired glucose-uptake syndrome. While many have speculated that our more sedentary lifestyle is likely a contributing factor toward obesity, I believe that instead physical fatigue itself is a predictable outcome of defective glucose metabolism, The inability to obtain sufficient fuel from glucose on the part of both the muscles and the heart simply saps us of the energy to move around [22] (Details) .

The effect of sustained aerobic exercise is to switch the muscle back into a glucose-uptake modus operandi for energy acquisition, which, however, is malfunctioning due to calcium and insulin insufficiency. Exercise is able to induce GLUT4 to migrate to the membrane even in the absence of calcium [13] . The insulin/glucose levels fall to possibly dangerously low values, which induces the appetite center in the hypothalamus to sound the alarm bells. The subsequent appetite stimulation induced by AMPK in the hypothalamus overrules all of the other appetite regulating signals and compels the person to overeat the very foods they should be avoiding.

As a consequence of further increases in the already high levels of sugar in the blood, the fat cells are compelled to squirrel away as much of the excess sugar as they can. Particularly susceptible to this urge to make fats will be the abdominal fat, since it is situated in close proximity to both the pancreas and the liver. The higher blood concentrations of both insulin and glucose provide extra impetus to assimilate sugars and manufacture fats. Thus the abdominal fat cells are more efficient in storing food than the peripheral fat cells. They will also tend over time to increase in size and multiply, in order to distribute the task load among their neighbors and reduce the burden carried by each individual cell. The additional fat cells will further deplete the available calcium and vitamin D in the blood, leading to an even poorer ability on the part of the muscle cells to take up glucose.

Alongside the growth of fat cells, other cell types also need to become more abundant, to support the increased burden of a larger body size, combined with reduced energy supply. As already mentioned, the heart becomes enlarged. Muscles must increase in size both to be able to haul around the extra weight and because of their innate inefficiencies in fuel utilization [14]. Bones must grow bigger and stronger to support the excess weight. Blood supplies have to be extended to supply nutrients to all of these proliferating cells. All of this means that the body's overall nutritional needs continue to grow, which puts futher burdens on the fat cells, thus completing the vicious cycle. Over time the person with a severe deficiency in calcium, vitamin D, and fats grows steadily larger, eventually reaching a condition of morbid obesity.

8. The Metabolic Syndrome

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A person with impaired glucose uptake as a consequence of calcium and vitamin D deficiencies ends up in a situation where both glucose and triglyceride levels in the blood are abnormally high. The heart and muscles are very poor at utilizing glucose, and hence they will depend to a large degree on fats (triglycerides) to supply their nutritional needs. The fat cells must release excess amounts of triglycerides during fasting conditions, such as at night, because they will not be able to release triglycerides once they are reassigned to the task of taking up excess glucose. After a meal, when glucose levels are high, the triglycerides will be steadily drawn down by the heart and muscles, while the fat cells absorb the glucose and begin the process of converting it into more fat.

Under conditions of aerobic exercise, the muscles and heart are reprogrammed to consume additional glucose, which causes glucose levels to plummet. This sets off alarm bells in the pancreas, which induces the liver to release more sugar, and in the hypothalamus, which stimulates the appetite for foods with a high glycemic index. The signalling mechanisms in the pancreas and the hypothalamus are likely also defective due to the calcium and insulin deficiencies [6][29] (Details) , and so they maintain a set point for glucose in the blood that is abnormally high. But the high glucose levels are in fact required, in order to compensate for the inefficient transport of glucose across the membrane of the muscle cells. The excess available glucose in the blood is taken up by the fat cells, the fat cells enlargen and multiply and the person becomes obese. Furthermore, the heart, a muscle, enlarges and becomes encased in fatty tissues, and its arteries become laden with fatty deposits, i.e., arteriosclerosis.

I believe the low HDL and high LDL can also be explained as follows. HDL is the carrier for cholesterol that is to be returned to the liver, where it can be disposed of via the gall bladder. It is dispensed by the gall bladder into the gut along with bile, and performs the very useful function of helping digest fats. Anyone who is consuming a low-fat diet requires less cholesterol for digesting the reduced dietary fat, and HDL levels fall. LDL is likely high because it is the carrier that transports cholesterol to the tissues. One of those tissues is the fatty deposits in the artery walls of the heart, that were placed there, according to my interpretation, to supply extra fuel to the heart. But these fatty deposits are also vulnerable to invasion by bacteria and viruses, entering through the lungs. High levels of cholesterol would need to be made available in the blood stream to help keep these invasive microbes under control.

Thus plausible outcomes of the calcium, vitamin D, and dietary fat deficiency are obesity, high blood sugar, arteriosclerosis, high levels of triglycerides, elevated LDL and low HDL, six key aspects of the metabolic syndrome (Details) .