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?

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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.

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.

Epigenetics changes everything

Each cell has the same DNA.  As this is the case there must be ways for cells to differentiate from other cells while all cells have the same DNA. In different cell types different genes are translated which is achieved by genes in different cell types having different epigenetic marks.  Epigenetic marks on genes can increase or decrease transcription of genes. DNA methylation and histone methylation are two ways genes can be epigenetically marked and thereby transcription of genes affected. There are various other ways that genes can be epigenetically marked. Environment can affect what epigenetic marks are on genes.

With genetic diseases there is systematic evidence of  genetic anomalies. Take any cell from the body and genes in that cell will show the genetic anomaly.  For example, blood tests can be used to detect genetic anomalies   With epigenetic diseases, however, there is no genetic evidence of the disease and dysregulations do not have to be systematic whereby bloods tests might not be revealing.

Vitamin D is now suspected to play a part in lots of illnesses and I think this is correct  but with epigenetic anomalies there need not be any genetic anomalies though there is still disease.  The last step in the formation of calcitriol, which is active vitamin D, by CYP27B1 requires an iron-sulfur protein called adrenodoxin. Due to difficulties in forming iron-sulfur clusters there will be low levels of adrenodoxin  whereby there are low levels of calcitriol. Giving calcitriol alone, however, is not sufficient to treat many illnesses where there is evidence of calcitriol deficiencies.  With iron-sulfur proteins dysregulated a lot of processes besides the formation of calcitriol will also be adversely affected.

There not being diseases associated with aberrant epigenetic marks is basically impossible given the large part that epigenetics plays in regulations of cells.   I think schizophrenia is  an illness associated with epigenetic dysgulations, an illness in which there are deficiencies of vitamin D but which is basically non-responsive to calcitriol.