September 15th 2010
Is The Skin a Solar-Powered Battery for the Heart?
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.
Sulfur Deficiency and Muscle Wasting Diseases
In browsing the Web, I recently came upon a remarkable article [Drge1997] 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.
[Drge1997] 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 [Drge1997] 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.
10. Summary
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 protecting 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.
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