A new disease class – Epigenetic Disorders

There are infectious diseases subdivided into bacterial and viral diseases, there is cancer where there are many sorts of cancer, there is heart disease, lung disorders  etc. There could be a new disease class. There could  be epigenetic disorders where there is common origin for a wide range of epigenetic disorders. With epigenetic mechanisms  dysregulated many different diseases can arise as there are many different ways genes and histones can become inappropriately methylated.  My idea is that a dysregulation of aconitase 1 can dysregulate iron metabolism and decrease 2-oxogularate synthesis which will in turn dysregulate TET enzymes, which demethylate DNA,  and dysregulate Jumonji domain-containing proteins, which demethylate histones.   Dysregulation of  TET enzymes and dysregulation of Jumonji domain-containing proteins  can play out many different ways in terms of inappropriate DNA methylation and inappropriate histone methylation whereby many different diseases can arise. Though many different diseases can arise from dysregulations of aconitase 1, iron metabolism and 2-oxoglutarate synthesis prevention of a range of illnesses could be achieved by the same treatment. For example, a treatment than prevents schizophrenia could also prevent Alzheimer’s disease and Parkinson’s disease. The Treatment presented in the Treatment section is not ready for home use, however, a Moon shot would not be necessary to get the treatment to a state where family doctors could prescribe a treatment which would prevent a range of chronic illnesses from schizophrenia, to Alzheimer’s disease, to Parkinson’s disease. What is needed is a launch ten weather balloons into the high atmosphere then collect and analyze data kind of effort.

Manganese, antioxidants and free radical chain reactions

A complete  set of antioxidants, which addresses all links of a free radical chain,  could be the only antioxidant program that could work, where, of course, the toxic antioxidants N-acetyl-l-cysteine and lipoic acid must be religiously avoided.  Superoxide dimutase is at the bottom level of the antioxidant free radical chain reactions.  With manganese deficiencies superoxide dismutase levels will be low whereby no supplemental antioxidants  will work and supplemental antioxidants  could even have negative effects. Strange effects individuals get from antioxidant supplements could be due to manganese deficiencies. Manganese deficiencies can not be logically deduced but rather tests are needed.

Manganese excesses, however,  are associated with a form of Parkinson’s disease. No  one gets manganese levels checked which given individuals have chronic poorly diagnosed illnesses is a misstep and could be a terrible misstep. Anyone taking supplemental manganese basically has to get manganese tests.

Divalent metal transporter 1 (DMT1) which transports iron also transports manganese. DMT1 translation is regulated by iron regulatory protein 1 (IRP1) which is aconitase 1 without a 4Fe-4S iron-sulfur cluster.  Dysregulations in aconitase 1 could also dysregulate manganese metabolism

There could be some improvement in Alzheimer’s disease with appropriate treatment

There could be some improvement in Alzheimer’s disease with appropriate treatment. I am making a logical point. I have no biological evidence that this is the case. Various illnesses that present as dementia’s can be treated. Major depressive disorder can appear to be a dementia, however, the dementia of major depressive disorder is treatable. There could be certain aspects of Alzheimer’s disease that arise from biochemical abnormalities which are not strictly related to  death of neurons. With the biochemical abnormalities addressed various aspect of an Alzheimer’s dementia could be reversed. In my paper A disease-modifying treatment for Alzheimer’s disease: focus on the trans-sulfuration pathway  I argue than Alzheimer’s disease can be prevented and stopped with appropriate Treatment, however, from a logical viewpoint  some symptoms of Alzheimer’s disease could even be reversed especially in the early stages of the disease.

One clinical trial to rule them all

Bill Gates in a recent GatesNotes post talks about how expensive and time consuming  clinical trials for Alzheimer’s disease are. What I have been arguing is that a lot of chronic illnesses are due to dysregulations of epigenetic mechanisms. Aconitase is an iron-sulfur enzyme in the  citric acid cycle which is required to produce 2-oxoglutarate and also regulates iron metabolism. Many enzymes are iron dependent and 2-oxoglutarate dependent enzymes. In terms of epigenetic dyregulations dysregulation of TET enzymes, which demethylate DNA and Jumonji domain-containing proteins, which demethylate histones,  are key.  TET enzymes and  Jumonji domain-containing proteins are iron and 2-oxoglutarate dependent enzymes.    With aconitase dysregulated TET enzymes and Jumonji domain-containing proteins will be dysregulated due to lack of availability of 2-oxoglutarate and dysregulation of iron metabolism. With TET enzymes and Jumonji domain-containing proteins dysregulated there will be epigenetic dysregulations. There, however, can be many different kinds of epigenetic dysregulations whereby many different chronic illnesses can develop. A key point is that all these diseases could  respond to the same treatment.   One six week trial of the supplements in major depressive disorder could open up a pathway for a new treatment for Alzheimer’s disease.  The evidence for dysregulation of aconitase and dysregulation of epigenetic mechanisms in Alzheimer’s disease is strong. I recently published a paper, A disease-modifying treatment for Alzheimer’s disease: focus on the trans-sulfuration pathway on this subject. The treatment has been modified from what is the paper. Please see the Treatment page.

Another simple test of the evils of increased absorption

Bluebonnet sells a natural beta-carotene from d. salina where the softgel fill has glycerin.  With the glycerin there will be heightened absorption of the beta-carotene whereby the Bluebonnet natural beta-carotene from d. salina will have a very depressing effect on mood. In a trial the Bluebonnet softgels should be swallowed. In supplements glycerin is from hell.  The Bluebonnet label is completely accurate. The difficulty is that the beta-carotene in the Bluebonnet softgel  is extremely well absorbed.

Now Foods sells a natural beta-carotene from d. salina where the fill is only olive oil.  Now Foods natural beta-carotene from d. salina is not well absorbed, thank heaven, and is an effective anti-depressant.

The effects of Bluebonnet  natural beta-carotene from d. salina are almost immediate as are the effects of  the Now Foods a natural beta-carotene from d. salina. No more than four days would be needed for the trial, however, if the Bluebonnet natural beta-carotene from d. salina does act as a depressant stop immediately. A trial would consist of one softgel four times a day.  When trying Bluebonnet natural beta-carotene from d. salina one should have in the house Now Foods natural beta-carotene from d. salina so the ‘antidote’ can be quickly taken. If Now Foods natural beta-carotene from d. salina acts as an antidepressant the safety of beta-carotene should be researched. On some grounds on Amazon 90 softgels of Now natural beta-carotene from d. salina costs $10.19 for 90 softgels while 180 softgels costs $9.58. On Amazon 90 softgels of Bluebonnet natural beta-carotene from d. salina,  which is much more than anyone will ever need, costs $18.36. The Solaray dry beta-carotene could work better as it is a powder rather than an oil.

Now Foods, which is the least expensive supplement brand and has ugly bottles, is an excellent supplement brand.  Bluebonnet many years ago sold a capsule formulation of natural beta-carotene from d. salina which was an effective antidepressant. I am not trying to single out Bluebonnet as a particularly egregious supplement manufacturer.    All supplement manufacturers have moved to increased absorption. I think the labels of Bluebonnet are completely  truthful.

That there is oxidant stress in major depression is very believable. All that has to be accepted is than increased absorption of supplements is a disaster in terms supplements working.



Supplements as preventive medicine is a fail

Supplements should have some immediate positive effects. Unless supplements have immediate positive effects there is no way to know whether  supplements are taking  individuals in the right direction.  Taking supplements to prevent diseases of aging is a poor strategy for healthy longevity. There are so many ways to go wrong with supplements that stumbling on a longevity supplement regime that really works is very unlikely, however, if supplements have immediate beneficial effects then one knows one is going the right direction. Taking supplements as preventive medicine is a fail as strategy for taking supplements. Balanced meals, watching the weight and exercise are the best preventive medicine all of which have immediate positive benefits.

Supplemental beta-carotene trials for the prevention of cancer

A meta-analysis indicates that supplemental beta-carotene is not useful for the prevention of cancer and, moreover, that if individuals are smokers or have been exposed to asbestos that supplemental beta-carotene can increase the risk of  lung cancer and stomach cancer. Supplemental beta-carotene in clinical trials is invariably prescribed in softgel formulations. And yet increased dietary intakes of beta-carotene are associated with decreases in all-cause mortality.

There have been thousand of articles that push various sorts of vitamin E or various carotenes as the health promoting tocopherols or the health promoting carotenes.   The goal has been to find out exactly which tocopherols and which carotenes can prevent chronic illnesses. All this searching for the health promoting tocopherols and the health promoting carotenes is largely misguided. Softgel formulations of fat-soluble vitamins simply do not work.  Supplement formulations have to be such that fat-soluble vitamins are available in the intestines whereby supplemental formulations of fat-soluble vitamins must be dry formulations.

The risk of all-cause morality – dietary antioxidants vs. supplementation with softgel antioxidants

High levels of antioxidants obtained from diet significantly reduces the risks of all-cause mortality. The Risk Ratio  for dietary intakes of antioxidants comparing highest to lowest levels were: total carotenoids, 0.76 (95% CI: 0.66, 0.85); total antioxidant capacity, 0.77 (95% CI: 0.73, 0.81); selenium, 0.79 (95% CI: 0.73, 0.85); α-carotene, 0.79 (95% CI: 0.63, 0.94); β-carotene, 0.82 (95% CI: 0.77, 0.86); vitamin C, 0.88 (95% CI: 0.83, 0.94); and total carotenes, 0.89 (95% CI: 0.81, 0.97). The Risk ratio of all-cause mortality for the highest compared with the lowest category of circulating antioxidant concentrations were as follows: total carotenes, 0.60 (95% CI: 0.46, 0.74); vitamin C, 0.61 (95% CI: 0.53, 0.69); selenium, 0.62 (95% CI: 0.45, 0.79); β-carotene, 0.63 (95% CI: 0.57, 0.70); α-carotene, 0.68 (95% CI: 0.58, 0.78); total carotenoids, 0.68 (95% CI: 0.56, 0.80); lycopene, 0.75 (95% CI: 0.54, 0.97); and α-tocopherol, 0.84 (95% CI: 0.77, 0.91).

Studies however have shown that supplemental antioxidants can increase all-cause mortality. Multivariate meta-regression analyses showed that low-bias risk trials (RR, 1.16; 95% CI, 1.04[corrected]-1.29) and selenium (RR, 0.998; 95% CI, 0.997-0.9995) were significantly associated with mortality. In 47 low-bias trials with 180 938 participants, the antioxidant supplements significantly increased mortality (RR, 1.05; 95% CI, 1.02-1.08). In low-bias risk trials, after exclusion of selenium trials, beta carotene (RR, 1.07; 95% CI, 1.02-1.11), vitamin A (RR, 1.16; 95% CI, 1.10-1.24), and vitamin E (RR, 1.04; 95% CI, 1.01-1.07), singly or combined, significantly increased mortality. Vitamin C and selenium had no significant effect on mortality.

Clinical trials of supplemental fat-soluble antioxidants invariably use softgel formulations of fat-soluble antioxidants which greatly increases absorption of fat soluble antioxidants, however, by increasing absorption of fat-soluble antioxidants the enteric system gets by-passed which can increase all-cause mortality.   Incorrect forms of selenium are also used in clinical trials. Se-methylselenocysteine should be used in clinical trials rather than L-selenomethionine.

The moral of the story is only supplement with dry formulations of fat-soluble antioxidants and  only supplement with Se-methylselenocysteine when supplementing with selenium.

Why did the selenium and vitamin E cancer prevention trial (SELECT) fail to show any benefits in the reduction of cancer from supplementing with selenium and vitamin E?

The selenium and vitamin E cancer prevention trial (SELECT) failed to show any benefits in the reductions of cancers from supplementing with selenium and/or vitamin E.  In light of my hypothesis that supplements formulated for increased absorption can have deleterious effects the findings of the SELECT trial are straightforwardly understood.  The SELECT trial prescribed all rac-α-tocopheryl acetate which is a softgel formulation that is very well-absorbed. Had d-α-tocopheryl succinate been prescribed, which is a dry vitamin E formulation that is not well absorbed, I think vitamin E would have been shown to reduce incidences of cancer, for example, prostate cancer.

The SELECT trial also prescribed L-selenomethionine. L-selenomethionine is metabolized by the transsulfuration pathway. In cancer there are elevated homocysteine levels which indicate that the transsulfuration pathway is dysregulated in cancer.  Various illnesses are associated with dysregulation of the transsulfuration pathway.   With the transsulfuration pathway dysregulated in cancer L-selenomethionine can not be appropriately metabolized so selenoproteins can be formed.  Se-methylselenocysteine can be metabolized by enzymes not in the transsulfuration pathway which makes Se-methylselenocysteine the preferred form of selenium to supplement with. Had Se-methylselenocysteine been prescribed rather than L-selenomethionine I think selenium would have shown benefits in the reduction of incidences of cancer.

In sum the SELECT trial failed to show benefits in reductions of incidences of cancer  from supplementing with vitamin E and/or selenium due to the inappropriate formulations of vitamin E and selenium  prescribed. Vitamin E obtained from food reduces risks of developing prostate cancer. The difference between vitamin E obtained from food and vitamin E obtained from softgels  is than vitamin E obtained from foods is available in the enteric system while vitamin E obtained from softgels is not available in the enteric system.  Very unfortunately softgels are highly effective in increasing absorption.