Any reprogramming of youthful methylation patterns in humans would require that TET enzymes be re-regulated first


Sinclair et al. using the eye as a model CNS tissue, showed that ectopic expression of Oct4, Sox2 and Klf4 genes in mouse retinal ganglion cells restores youthful DNA methylation patterns and transcriptomes, promotes axon regeneration after injury, and reverses vision loss in a mouse model of glaucoma and in aged mice. The beneficial effects of OSK-induced reprogramming in axon regeneration and vision require the DNA demethylases TET1 and TET2.

However, I have been arguing in papers (see Treatment-resistant schizophrenia: focus on the transsulfuration pathway and A disease-modifying treatment for Alzheimer’s disease: focus on the transsulfuration pathway) and on this blog that TET enzymes are the very enzymes that are dysregulated in many chronic illnesses, which results in various chronic illnesses possessing a range of phenotypic expressions. Ectopic expression of OCT4, KLF4 and SOX2 alone would not work in aged humans and/or ill humans as TET enzymes are dysregulated in aged and/or ill humans.

TET enzymes are iron and 2-oxoglutarate dependent dioxyegenases. Fixing TET enzymes could be a key part of the treatment of a range of chronic illness and would be a lot simpler and safer than systematic ectopic expression of OCT4, KLF4 and SOX2 in humans. A lot of methylation changes acquired during aging must be beneficial. Systematically turning back the clock to 18 or so would not be desirable .’Just’ fixing TET enzymes would allow desirable methylations to occur but would allow DNA demethylations of undesirable DNA methyations. Clearly fixing TET enzymes would be a required first step prior to any genetic engineering of humans to restore youthfulness given that such genetic engineering was feasible and desirable.

Regulation of iron metabolism by the transsulfuration pathway

top – ACO1; bottom – iron regulatory protein 1 bound to an mRNA

Iron metabolism is regulated by hepicidin, ferroportin and iron regulatory proteins. Aconitase 1 (ACO1) is a dual function protein that serves as an aconitase, which is an enzyme in the TCA cycle, when ACO1 has a 4Fe-4S iron sulfur cluster and as iron regulatory protein 1 when ACO1 looses a 4Fe-4S cluster. The sulfur for iron-sulfur clusters is derived from L-cysteine.

L-cysteine is synthesized from homocyteine via the transsulfuration pathway. Dysregulation of the transsufuration pathway by dysregulating L-cysteine synthesis could dysregulate iron-sulfur cluster formation thereby dyseregulating iron regulatory protein 1 and iron homestasis.

High homocysteine levels are present in a lot of illnesses, for example, schizophrenia, Parkinson’s disease, Alzheimer’s disease and bipolar disorder. A key part of the difficulties that arise from high homocysteine levels could be due to dysregulation of iron homeostasis.

Supplementing with free antioxidants in more than RDA amounts is worse than useless

Many illnesses, such as schizophrenia, Alzheimer’s disease, Parkinson’s disease and bipolar disorder are associated with oxidant stress. Yet, increasing levels of free antioxidants by supplementing with more than RDA amounts of vitamin E, beta-carotene and vitamin C does not treat these illnesses.

Increasing levels of free antioxidants via supplmentation could be much worse than useless. Before iron can be absorbed iron must be reduced from Fe3+ to Fe2+. Antioxidants like vitamin C, vitamin E , beta-carotene and quercetin could one way or other promote the reduction of Fe3+ to Fe2+ in the gastrointestinal tract which would increase absorption. The goal, however, is to delay iron absorption as long as feasible.

There is oxidant stress in lots of illnesses but this could be due to dysregulation of selenoproteins and dysregulation of iron metabolism which would not be fixed by increasing levels of free antioxidants with supplemental vitamin C, vitamin E , beta-carotene, quercetin etc.

Supplementing with free antioxidants could be associated with very subtle but serious mineral dysregulations which would basically be undiagnosable.

For the experimentally inclined

Calcium citrate contains a whole lot of citrate. The formula of calcium citrate is Ca3(C6H5O7)2. Calcium citrate is about 85% citrate. Citric acid can be purchased on Amazon. 4 ounces of food grade citric acid can be purchased on Amazon for $4.99. 4 ounces should be more than enough for the experiment. 600 millgrams of calcium from calcium citrate would have 4000 milligrams of citrate.

A citric acid drink with say 4000 milligrams of citric acid could be drunk 3 or 4 times a day for 3 or 4 days. The drink would only contain water and citric acid. The hypothesis being tested is whether citric acid can befuddle thinking. I am not actually recommending anyone do this experiment but as I stated for the experimentally inclined.

Citric acid should increase iron absorption still I think the adverse effects of citric acid are due to an iron interaction with citric acid in the gut which makes iron unavailable in the gut with very significant negative effects. Iron chelated to citric acid in the gut is not bioavailable in the gut. Iron must be available in the gut as well as systematically. Enhancers of iron absorption can have negative effects on iron metabolism in the gut.

In defense of a calcium citrate calcium supplement but not Mountain Dew the citrate in calcium citrate could largely be be chelated to calcium rather than to iron.

How are Mountain Dew focus groups actually run? Do individuals running the focus groups give indivduals in the focus groups Mountain Dew to drink then riff in ads on postive reactions to Mountain Dew and the individuals who gave those postive reactions?

Iron and Alzheimer’s disease

Iron overload in various regions of the brain has been postulated to be involved in the pathological mechanism of Alzheimer’s disease. Iron overload in the brain may very well be involved in the etiology of Alzheimer’s disease but iron overload in the brain in Alzheimer’s disease would not be due to too much iron in the diet.

A meta-analysis indicates that serum iron levels are significantly lower in Alzheimer’s disease patients than in healthy controls. Another meta-analysis also indicates that serum iron is significantly lower in patients with Alzheimer’s disease than in healthy controls.

Loss of control over iron metabolism rather that just ‘too much iron’ could be why iron can have negative effects in Alzheimer’s disease. Treatment in AD would demand that control be regained over iron metabolism. Iron chelators have been proposed as a treatment for Alzheimer’s disease. Iron chelators, however, would not be useful in terms of regaining control over iron metabolism. Iron chelators could have negative effects in AD.

Adverse affects from polyphenol extracts could appear to be various mysterious allergies or hypersensitivities

Polyphenol extracts are everywhere. Natural flavors are polyphenol extracts. Sodas contain polyphenols from natural flavors. Various plant oils contain concentrated polyphenols. Various supplements are marketed on the very basis that such supplements contain polyphenols, for example quercetin, pycnogenol and resveratrol. Coffee and tea contain polyphenols. Almost all frozen foods will contain natural flavors. Polyphenol extracts are a major difficulty.

This is starting to sound about as bad as ‘electromagnetic hypersensitivity’ in terms of being able to escape the difficulty. Cases of ‘electromagnetic hypersensitivity’ could in fact be adverse reactions to polyphenol extracts and concentrated polyphenols.

Adverse reactions to polyphenols are not immune responses. A difficulty with polyphenols is that polyphenols bind to iron. Polyphenols binding to iron in the gut could lead to inactivation of aconitase 1 in the gut which could have systematic effects.

I have been very strongly stressing the effect of polyphenols on iron absorption, however, there are likely other difficulties with polyphenols for individuals. Polyphenols increase beta-oxidation. If the there are difficulties in fatty acid absorption and fatty acid metabolism increases in beta-oxidation due to polyphenols can not be sustained with difficulties then arising. Even with no difficulties in fatty acid absorption and fatty acid metabolism polyphenol laden drinks should not be drunk throughout the day. Limiting coffee to two cups of coffee drunk in the morning away from iron supplements could be a safe way to drink coffee.

Iron positively regulates other enzymes in the citric acid cycle besides aconitase

Besides aconitase iron positively affects three other citric acid cycle enzymes, the enzymes being citrate synthase, isocitric dehydrogenase synthase and and succinate dehydrogenase.

Iron-dependent changes in cellular energy metabolism: influence on citric acid cycle and oxidative phosphorylation

Horst Oexle, Erich Gnaiger and Gunter Weiss Biochimica et Biophysica Acta (BBA) – Bioenergetics


Iron modulates the expression of the critical citric acid cycle enzyme aconitase via a translational mechanism involving iron regulatory proteins. Thus, the present study was undertaken to investigate the consequences of iron perturbation on citric acid cycle activity, oxidative phosphorylation and mitochondrial respiration in the human cell line K-562. In agreement with previous data iron increases the activity of mitochondrial aconitase while it is reduced upon addition of the iron chelator desferrioxamine (DFO). Interestingly, iron also positively affects three other citric acid cycle enzymes, namely citrate synthase, isocitric dehydrogenase, and succinate dehydrogenase, while DFO decreases the activity of these enzymes. Consequently, iron supplementation results in increased formation of reducing equivalents (NADH) by the citric acid cycle, and thus in increased mitochondrial oxygen consumption and ATP formation via oxidative phosphorylation as shown herein. This in turn leads to downregulation of glucose utilization. In contrast, all these metabolic pathways are reduced upon iron depletion, and thus glycolysis and lactate formation are significantly increased in order to compensate for the decrease in ATP production via oxidative phosphorylation in the presence of DFO. Our results point to a complex interaction between iron homeostasis, oxygen supply and cellular energy metabolism in human cells.

The Major Histocompatibility Complex, HFE and schizophrenia

The Major Histocompatibility Complex (MHC) has been associated with schizophrenia. The hemochromatosis gene, HFE, which regulates iron levels is linked to the MHC on chromosome 6. In cells that express HFE IRP1 and IRP2 binding increases as the labile iron pool decreases with increased HFE expression. IRP1 and IRP2 are regulated by iron levels. Genetic studies that have associated the MHC region with schizophrenia frequently conclude that this is evidence for an infectious etiology to schizophrenia as the MHC is involved in immunity. What genetic associations of the MHC to schizophrenia could be picking up is associations of HFE with schizophrenia where such associations arise due to dysregulations in iron metabolism.

Aconitase 1 and on-off disorders

Aconitase 1 (ACO1) is an enzyme in the citric acid cycle. Aconitase 1 is a dual function protein. Upon loss of an iron-sulfur cluster ACO1  becomes iron regulatory protein 1 (IRP1).  IRP1 affects stability of mRNA transcripts of proteins involved in iron metabolism such as ferritin, DMT1, which is an iron transporter, and ferroportin, which is the only known iron exporter.   Increasing iron levels switches IRP1 to ACO1 as IRP1 gains an iron-sulfur cluster. With a 4Fe-4S iron-sulfur cluster ACO1 can participate in the citric acid cycle and generate ATP.

On-off disorders could be are due to wide swings in ACO1/IRP1 and the TCA cycle. Suddenly the TCA cycle is functioning and then the TCA cycle is not functioning while at the same time there are swings in the regulation of iron regulated proteins. Dietary iron could be associated with swings in on-off symptoms.An added wrinkle is  that high IRP1 levels adversely affects copper absorption, however, copper is needed for iron metabolism.

I very much like answers that answer everything. On-off symptoms are prominent in lots and lots of illnesses. There is, of course, bipolar disorder but a lot of depressions cycle rapidly and are some of the most difficult depressions to treat.  Parkinson’s disease has a very prominent on-off symptoms.  In Parkinson’s disease there are  indications that iron metabolism is  dysregulated. There could be a unitary explanation for cycling disorders.

Iron chelators

Iron chelators are being clinically tested in a number of neurodegenerative illnesses such as Alzheimer’s and Parkinson’s disease . I do not think iron chelation is going to work. In fact I think iron chelators will make Alzheimer’s and Parkinson’s worse. I very much hope I am mistaken. The difficulty isn’t iron per se but rather dysregulation of iron regulated biological processes. Sensible ideas are wrong all the time. Iron chelation is a very sensible approach to treatment of Alzheimer’s and Parkinson’s which I think is going to be disastrous.