Sulfur: Metabolic Syndrome, Atherosclerosis and Alzheimer’s Disease

Nov• 27•2010

Part III of MIT Computer Science Professor Dr. Stephanie Seneff’s essay on sulfur and health.  For parts and and two see here and here.  For Dr. Seneff’s home page see here.

The Metabolic Syndrome

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.

Fat Cells, Macrophages and Atherosclerosis

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.

Sulfur and Alzheimer’s

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]

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10 Comments

  1. patrons99 says:

    Another fantastic article in the series, Dr Seneff! Bravo!

    Two health paradigms are colliding – allopathic and homeopathic. Recents reports of high Vitamin D levels being associated with pancreatic cancer are troubling. These reports should be carefully scrutinized, as should all medical literature for the last 20 years, for validity.

    “Experimental evidence suggests that vitamin D has anticarcinogenic properties; however, a nested case-control study conducted in a population of male Finnish smokers found that higher 25-hydroxyvitamin D [25(OH)D], the best indicator of vitamin D status as determined by the sun and diet, was associated with a significant 3-fold increased risk for pancreatic cancer. “

    This study begs the question as to what the vaccination status of the case controls and whether there may not have been selection-bias? Was diabetes a controlled variable? Was alcohol consumption a controlled variable? Was obesity a controlled variable? Was hyperlipidemia a controlled variable? Was dietary sulfate a controlled variable? Were cholesterol sulfate and vitamin D3-sulfate levels controlled variables? Real questions.

    “Retrospective case–control studies are more susceptible to selection bias than other epidemiologic studies as by design they require that both cases and controls are representative of the same population.”

    http://www.cancer.gov/newscenter/pressreleases/VitaminDpooling
    http://aje.oxfordjournals.org/content/early/2010/06/18/aje.kwq119.full
    http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2892542/
    http://www.ncbi.nlm.nih.gov/pubmed/19208842
    http://biostatistics.oxfordjournals.org/content/10/1/17.abstract

  2. patrons99 says:

    Here’s an article titled “Schizophrenia Risk Factor Found in Maternal Blood” by Joan Arehart-Treichel.

    http://pn.psychiatryonline.org/content/42/3/22.1.full

    Could the observation of elevated prenatal blood levels of homocysteine relate to dietary sulfur, folic acid, the vaccination schedules, H1N1 vaccine, the methylation cycle, and DNA hypomethylation?

    Why have there been so many miscarriages due to H1N1 vaccines?

    “An elevated prenatal blood level of homocysteine may double the risk of having a child who will develop schizophrenia. But rubella and flu infections during pregnancy seem to be even larger risks.”

    “Vaccination against influenza for women who are of reproductive age and sexually active makes sense. It isn't clear yet whether influenza vaccination during pregnancy could be helpful or harmful,” Brown added.“ One needs to weigh the benefit of protecting the woman and fetus from influenza against the potential risk of a vaccine-induced antibody elevation that could conceivably predispose to schizophrenia.” – Alan Brown

    “CDC Involved in a Cover Up of Miscarriages due to H1N1 Vaccines”

    http://www.politicolnews.com/h1n1-vaccine/

  3. patrons99 says:

    Why have there been so many miscarriages due to H1N1 vaccines?

    From the package inserts of two of this year’s flu vaccines, it states,

    “Pregnancy Category C: Animal reproduction studies have not been conducted with FLUVIRIN. It is also not known whether ________ can cause fetal harm when administered toa pregnant woman or can affect reproductive capacity.” “It is not known whether _______ is excreted in human milk.”

    Here's the link to Appendix I Derived From: ProgressiveConvergence.com's Anecdotal Instances of Miscarriages, Still Births, Premature Births, and Other Health Problems Reported by Women After Their Influenza-Vaccine Inoculations(s) as of 5 February 2010.

    http://www.progressiveconvergence.com/miscarriage-cases.htm

    “Flu Vaccine Caused 3587 US Miscarriages & Stillbirths” on September 22, 2010.

    http://childhealthsafety.wordpress.com/2010/09/22/flu-vaccine-caused-3587-us-miscarriages-%C2%A0stillbirths/

  4. patrons99 says:

    Could it be the 25 micrograms of mercury as thimerosal, present in each dose of the flu vaccine, that is responsible for the miscarriages, still births, premature births, and other health problems reported by women after their influenza vaccine inoculations? Hmmmmmm.

  5. patrons99 says:

    Dr Seneff – You make a very persuasive argument for the importance of dietary sulfur. I begin to understand now why you suspect that "cholesterol and sulfur play an important role in keeping cancer at bay". Of course, vitamin D3-sulfate requires cholesterol, sunlight, and dietary sulfur.

    I'm VERY concerned about potential selection bias in the study by RZ Stolzenberg-Solomon, et al, titled, "Serum vitamin D and risk of pancreatic cancer in the prostate, lung, colorectal, and ovarian screening trial".

    http://www.ncbi.nlm.nih.gov/pubmed/19208842

    My concern has been nagging at me ever since I came across the article. btw – I take daily vitamin D3, in high dosages.

    What was the vaccination status of the study subjects?

    Dr Andrew Moulden has theorized that a common basis of ALL vaccine toxicity involves, in substantial measure, microvascular ischemia, cellular anoxia, and infarctions, which is strongly promoted by lowering of the electrostatic potential ("zeta potential") of our blood. Personally, I strongly believe this theory has merit and will be validated, in time.

    According to an article by Dr Mohammed Ali Al-Bayati, the pancreas is an organ which is VERY vulnerable to microvascular ischemic injury.

    http://www.medicalveritas.com/AB1.pdf

    “Analysis of causes that led to Evyn Vaughn’s respiratory arrest, intracranial and retinal bleeding, and death” by Mohammed Ali Al-Bayati, PhD, DABT, DABVT

    "Evyn received 21 vaccines between the age of 2 and 6 months and developed health problems following receiving these vaccines."

    "Evyn received six vaccines at the age of 12 months while he was suffering from immune depression."

    “The susceptibility of the pancreas to ischemia/reperfusion injury has been demonstrated in experimental studies and in clinical settings such as cardiopulmonary bypass, hemorrhagic shock, and transplantation of the pancreas. Oxygen free radicals, activation of polymorphonuclear leukocytes, failure of microvascular perfusion, cellular acidosis, and disturbance of intracellular homeostasis appear to be important factors/mechanisms in the pathogenesis of ischemia/reperfusioninduced acute pancreatitis [37].”

    “Zhou and Chen stated that ischemia possibly acts as an initiating factor of pancreatic microcirculatory injury in acute pancreatitis, or as an aggravating/continuing mechanism. The end-artery feature of the intralobular arterioles suggests that the pancreatic microcirculation is highly susceptible to ischemia. Various vasoactive mediators, as bradykinin, platelet activating factor, endothelin and nitric oxide participate in the development of microcirculatory failure [38].”

  6. patrons99 says:

    My apologies for the re-post redundancy. Paul, your blogsite, penalizes one for long-winded comments, which I'm often guilty of. As an FYI, I've gotten several auto-generated (?) messages telling me that my comments were too long. So I tried to shorten them and repost, only to later discover that the original long-winded comment was published.

  7. PDM says:

    Hi Patrons,

    Sorry about the auto-generated messages, I greatly value your input on the site. I think the number of references may sometimes trip up the spam filter, I would disable it but there's probably 5 spam comments for every genuine one. Hopefully it won't continue to be a problem and if you ever feel like doing a post, the soap box is yours. BTW, gave Dr. Seneff a heads-up on the comments so if she isn't to busy hopefully she will chime in on the discussion at some point.

  8. patrons99 says:

    Dr Seneff – On a second reading of part III, I picked up on this:

    "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."

    Do you have a link to these articles? They DO INDEED sound fascinating! I'd be VERY interested in knowing whether the same set of experiments have been conducted with vitamin D3-sulfate. Why not measure the effect of various blood levels of cholesterol sulfate and vitamin D3-sulfate on the zeta potential of the blood? Why not use darkfield microscopy of live blood to see what effect, if any, various levels of cholesterol sulfate and vitamin D3 sulfate might have? Finally, why not set up an experiment in nonhuman primates, using the animal as their own control, and study the effect of various blood levels of vitamin D3 sulfate on organ perfusion and organ viability, with functional MRI, SPECT, or PET techniques?

    The time scales for the biochemical events that you describe would seem to be orders of magnitude slower than perfusion related events. Perfusion is closely-linked to tissue viability. Of course, once there is cellular anoxia, infarction soon follows. For a putative anti-carcinogen, e.g. vitamin D3-sulfate, to be effective, it's got to be "delivered" to its site of action, i.e. perfusion must be intact, and the site of action has got to still be viable. Do these putative anti-carcinogens have anti-ischemic properties? Do they have beneficial microvascular hemodynamic and hemorheologic properties? Sorry to keep beating a dead horse. I keep coming back to this question. If the answer is NO, I can move on.

  9. patrons99 says:

    How stable is vitamin D3 sulfate and cholesterol sulfate? Could it be synthesized and administered either orally or parenterally? If so, there are some experiments that suggest themselves.

    Pilot studies of oral or parenteral cholesterol sulfate and vitamin D3 sulfate could be conducted in patients suffering from solid tumors, hematologic malignancies, and acute and chronic ischemic cardiovascular disease. The pharmacokinetics and pharmacodynamic effects would be of great interest. IRB approval might be fairly straight forward, since the molecules are naturally-occurring orthomolecules "designed" by God.

  10. Stephanie says:

    Hi Patrons:

    Wow! You've certainly provided a lot of interesting material to digest! It's a little hard for me to know how to respond to all of this, but I do think you're onto something with the vaccine and heart failure connection. The long list of complaints by pregnant women getting the H1N1 vaccine and then losing their babies was very compelling.

    I believe you were the one who pointed me to the article: Thimerosal Neurotoxicity is Associated with Glutathione Depletion: Protection with Glutathione Precursors, by James et al. in NeuroToxicology, 2005? This article states that mercury binds with sulfhydryl groups, thus depleting the GSH in the cell. This is quite plausible, and it would likely be especially damaging to those who are already deficient to begin with.

    On what I think is a related note, I recommend this article on perlecan:

    Perlecan Maintains the Integrity of Cartilage and Some Basement Membranes, by Costell et al., J. Cell Biol. 1999.

    This article points out that perlecan-deficient mouse embryos die when they are at stage E10.5 due to myocardial defects leading to heart failure. Perlecan is a form of heparan sulfate, and I suspect it may supply sulfate to bind with cholesterol; then cholesterol sulfate can be transported into the cell wall, to deliver sulfate to the muscle cells of the heart. The sulfate would provide sulfur for the synthesis of glutathione.

    Another article that I think is relevant is this one in the Eur. J. Neurosci: Microglial glutamate uptake is coupled to glutathione synthesis and glutamate release. (http://www.ncbi.nlm.nih.gov/pubmed/16925588). It suggests that microglia in the brain protect themselves from H2O2 exposure by converting glutamate to glutathione. I expect muscle cells may do the same.

    I'm struggling with trying to understand the chemistry involved with sulfate & cysteine & glutathione. I just found this full-length article on the web on plant metabolism that might provide some insights:

    Control of sulphate assimilation and glutathione synthesis: interaction with N and C metabolism. Kopriva et al. J. Experimental Botany, 2004.

    You can find the Ma2008 reference on the web at this location: http://ajpendo.physiology.org/content/295/6/E1369.long

    Stephanie