A fundamental rule of nutrition

Supplements or drinks with tricarboxylic acid cycle intermediates should be avoided though supplements with alpha ketoglutarate could be helpful. TET enzymes are 2-oxoglutarate dependent.enzymes that demethylate DNA. JmjC domain-containing proteins are 2-oxoglutarate dependent.enzymes that demethylate histones .Fumarate and succinate inhibit TET and JmjC domain-containing proteins. This could lead to DNA hypermethylation and histone hypermethylation. Malic acid could inhibit fumarate dehydratase by end product inhibition and lead to a build up of fumarate.

Accumulation of succinate and fumarate are associated with cancer due the inhibition of 2-oxoglutarate-dependent dioxygenases, such as TET and JmjC-domain containing proteins. Citrate is a competitive inhibitor of oxaloacetate for citrate synthase. Citrate synthase also produces coenzyme A which is needed by the 2-oxoglutarate complex. Citric acid from soft drinks could dysregulate the the 2-oxoglutarate complex. There is a lot of circumstantial evidence that citric acid has goofy effects on individuals witness Mountain Dew ads.

A lot of supplements contain tricarboxylic acid cycle intermediates. Calcium citrate contains citrate. Magnesium succinate contains succincate. Carnitine fumarate contains. fumarate. Citruline malate contains malate, TCA intermediates are everywhere is supplements.

But as always the key selling point of supplements is ‘better absorption’ and minerals, for example, minerals bound to citrate, can be well absorbed. A huge and very frequently deleterious factor not usually considered is what supplements are bound to. ‘Better absorption’ is the siren call of supplements. Chelated minerals are also avoided.

Can deleterious epigenetic changes be reversed by supplemental alpha ketoglutarate?


TET enzymes are 2-oxoglutarate dependent.enzymes that are instrumental in DNA demethylation. JmjC domain-containing proteins, which are 2-oxoglutarate dependent.enzymes, demethylate histones.

Research indicates that 2-oxoglutarate by affecting TET and Jmjc domain-containing proteins can have epigenetic effects reversing epigenetic changes arising from dysregulation of the tricarboxylic acid (TCA) cycle. The TCA cycle synthesizes 2-oxoglutarate.

I have been stressing in this blog that with a dysregulation of iron-sulfur cluster formation there is a dysregulation of aconitase which is an iron-sulfur protein early in the TCA cycle With aconitase dysregulated the TCA cycle is dysregulated. Another enzyme in the TCA cycle, succinate dehydrogenase, also has iron-sulfur clusters.

Could deleterious epigenetic changes in humans, due to dysregulation of the TCA cycle, be reversed by supplemental alpha-ketoglutarate? That has not yet been established.

2-oxoglutarate-dependent dioxygenases are involved in aging, 2-oxoglutarate could be a longevity supplement. A rule of thumb in regards to longevity supplements is never take a longevity supplement for longevity that does not have immediate positive benefits as absent immediate positive benefits knowing whether one is going in the correct direction is unknowable . If 2-oxoglutarate proves to be useful in the treatment of various neurological illnesses but also increases longevity so much the better.

DNA methylation of genes which code for proteins in protein pathways that have fallen into disuse

Could there be epigenetics changes to genes when protein pathways become non-fuctional? Say there is decreased activity in a rate limting enzyme in a protein pathway. Do other genes coding for proteins is the pathway keep producing proteins in the pathway even though those proteins now no longer serve any purpose?’

The Central Dogma of Biology according to James Watson – DNA makes RNA makes protein.

The Central Dogma of biology is at the same time a non-sequitur, strictly false and though simple is simpler than possible. What genes are transcribed matters a very great deal and what genes are transcribed is due to epigenetic changes on those genes so the Central Dogma is a non-sequitur is terms of activites of protein pathways and behaviors of organisms. The Central Dogma is strictly false as RNA viruses can change DNA. The Central Dogma is also simpler than possible. Very many genes code for proteins that are splice variants. The production of splice variants of genes is regulated by a system of trans-acting proteins that bind to cis-acting sites on primary transcripts.

Why bring up the the Central Dogma? The Central Dogma of biology is so 1960’s. The genetic determinism of the Central Dogma of biology is still an undercurrent that gets in the way of appreciating the epigenetic basis of many chronic illnesses.

If transcription of genes for proteins in protein pathways in specific organs can fall together this could give rise to unique illnesses where the basis of such illnesses would be due to epigenetic changes, which at first could be isolated to specific organs but which could spread over time worsening such illnesses in relatively predictable ways. With epigenetics, protein pathways falling into disuse can affect only specific organs though over time there could be a spreading effect which fits with how chronic diseases develop.

Another implication of genes becoming hypermethylated when proteins that those genes code for become unused is that optimum nutrition could result in increased numbers of healthy years lived. I would say that as of now there is very, very litttle useful information on what opimum nutrition is in terms of increasing number of healthy years lived. Preventive medicine in terms of nutrition has been one mistep after another. Huge errors have been made. For example, increasing free antioxidants by taking vitamin E, vitamin C and beta-carotene in more than RDA amounts has been a terrible disaster. The only path in terms discovering what optimum nutrition is would be to work back from nutrional strategies than cure diseases rather than are speculations on diet as to how to prevent diseases developing decades and decades later. Pilot studies are very, very frequently misleading. Supplements are now a minefield.

Homocysteine and epigenetics

High levels of homocysteine are associated with increased risks for a number of illnesses. Hyperhomocysteinemia is a risk factor far osteoporosis, Alzheimer’s disease, Parkinson’s disease, stroke, cardiovascular disease, cancer, aortic aneurysm, hypothyroidism and end renal stage disease among other illnesses. I would add schizophrenia and bipolar disorder.

I have been arguing that high homocysteine levels point to the transsulfuration pathway being dysregulated. That there are so many illnesses associated with high homocysteine combined with the ineffectiveness of folic acid in reducing risk ratios for various illnesses point to high homocysteine levels being a proxy for other dysregulated biological processes. I have been arguing than high homocysteine levels are associated with increased risks for epigenetic dysregulations.

Folic acid supplementation, which reduces homocysteine levels, does not decrease risk ratios for the various illnesses that high homocysteine levels are associated with, for example, cardiovascular illnesses. Folic acid is ineffective as homocysteine must be metabolized through the transsulfuration pathway. Increasing remethylation of homocysteine to L-methionine does not fix the transsulfuration pathway leaving folic acid ineffective in decreasing risk ratios for various illnesses. Very unfortunately increasing levels of L-cysteine through supplementation with N-acetyl-L-cysteine, cysteine, cystine or lipoic acid also does not work where such supplementation can be very dangerous.

Blood tests and false negatives

With epigenetic dysregulations dysregulated transcription does not have to be body wide. With hypermethylated genes and histones isolated to only a few organs blood tests may be normal even though there are definite difficulties. MDs in a all probability would agree that blood tests would not pick up a lot epigenetic dysregulations but then MDs would say ‘what can we do about that?’ and continue to draw blood and do tests on blood.

Genes and histones in the gut as sites of DNA and histone hypermethylation

Genes and histones in the gut are more exposed to the environment than are genes and histones in other internal organs. Given factors in the environment that can result in DNA and histone hypermethylation genes and histones in the gut, compared to genes and histones in other internal organs, would have the highest probability of becoming hypermethylated due to a very high exposure to the environment. The gut is a logical starting point when investigating how environmental factors result epigenetic dysregulations due to DNA and histone hypermethylation.

Histone acetylation and schizophrenia

Histone acetylation, which adds acetyl groups to lysine residues of histones, relaxes chromatin, which is composed of histones.  Histone acetylation increases transcription of genes. Acetyl groups are transferred to histones from acetyl-coenzyme A. Appropriate synthesis of coenzyme A and acetyl-coenzyme A are required for appropriate histone acetylation. With the pyruvate dehydrogenase complex, which synthesizes acetyl-coenzyme A,  dysregulated in schizophrenia there will not be appropriate histone acetylation in schizophrenia.   With histone acetylation dysregulated in schizophrenia epigenetic mechanisms are dysregulated in yet another way in schizophrenia.

Increasing histone acetylation by re-regulating the pyruvate dehydrogenase complex could have the same effect as  histone deacetylase inhibitors which improve learning. Improving abilities to learn in individuals with schizophrenia would clearly be going in the right direction.

Increasing histone acetylation could also improve learning in Alzheimer’s disease.  In Alzheimer’s disease synthesis of L-cysteine is decreased as evidenced by high homocysteine levels. See my paper A disease-modifying treatment for Alzheimer’s disease: focus on the trans-sulfuration pathway, which was published in Reviews in the Neurosciences.   With  synthesis of L-cysteine decreased synthesis of coenzyme A and acetyl-coenzyme A are decreased in Alzheimer’s disease which would lead to decreases in histone acetylation and difficulties in learning.

The treatment, presented on the Treatment page,  which would be effective for schizophrenia could also prevent and treat Alzheimer’s disease. Schizophrenia differs from Alzheimer’s disease as there are different epigenetic dysregulations, however, the headwaters of the schizophrenia and Alzheimer’s disease are the same which allows for identical treatments.

Physicists have a notion of symmetry breaking where at higher energy levels different particles are identical but upon symmetry breakings particles diverge from each other and become different particles.

Different epigenetic dysregulations are different symmetry breakings but at the headwaters of both illnesses schizophrenia and Alzheimer’s disease are identical.

Mutations of genes for enzymes in the TCA cycle can inhibit TET enzymes

TET enzymes, which demethylate DNA, are 2-oxoglutarate dependent enzymes. 2-oxoglutarate is synthesized by the citric acid cycle. Mutation of genes for enzymes in the citric acid cycle can inhibit TET enzymes, thereby dysregulating epigenetic mechanisms.

Iron regulates enzymes is the TCA cycle. Dysregulation of iron metabolism could dysregulate the TCA cycle resulting in epigenetic dysregulations.

Given there was a helpful answer on the biological basis of schizophrenia what kind of answer would that answer have to be?

Given there was a helpful answer to what was the biological cause of schizophrenia what kind of answer would that answer have to be?

Holding that 1000’s of common alleles each of which have an only miniscule impact lead to schizophrenia is a kind of answer that has absolutely no treatment implications.  Focusing on an allele of this or that gene in isolation has absolutely no treatment implications. Epigenetic changes that affect a gene in isolation from other genes have no treatment implications. Focusing on this or that biological anomaly has absolutely no treatment implications. There are hundreds of biologically anomalies in schizophrenia apparently all disconnected from each other.

A helpful answer must point to the headwaters of genetic or epigenetic dysregulations. A transcription factor could affect translation of many genes and at times various researchers have pointed to various transcription factors as being implicated in schizophrenia. Funding research on transcription factors in connection to schizophrenia makes sense in terms of translational medicine.

Another answer that would be helpful in terms of treatment is an answer that pointed to a biological pathway  that could widely dysregulate epigenetic mechanisms. Dysregulation of the TCA cycle via dysregulation of aconitase 1 and the 2-oxogultarate dehydrogenase complex could  widely  dysregulate epigenetic mechanisms.