Lack Of Methyl Donors, Demethylation, Folic Acid, B12

Zpol

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Haidut's summarization of the article
Protective CO2 and aging
Is...
"methylation can be thought of as a direct measure of aging (or cancer potential) and reversing it is thought to be beneficial both for anti-aging and anti-cancer purposes. Baking soda, bag breathing, sugar (and efficient metabolism for its conversion to CO2), acetazolamide, niacinamide are all methods that are known to directly cause demethylation."

I have a gene variant called MTHFR SNP and am lacking methyl donors an so have severe nutritional deficiencies (despite eating high nutrient diet) and my liver is poor at phase I and phase II detoxification.

The article states... "...Restriction of methyl donors causes demethylation of DNA". And so it correlates (or results from? IDK) with biological youth and prevention of degenerative disease.

I am lacking methyl donors, so shouldn't I be feeling very youthful and healthy?!?

And how do I supplement to improve my health? I would theoretically need methyl forms of folate and B-12 but these are correlated with cancer (sorry I can't find my link for that, but I have a quote from Haidut "Possibly yes, but I think folic acid and B12 have other issues beyond just methylation. Both of them have been linked to cancer in adult and the recent studies seem to be more and more towards causal link. It is one of the reasons I don't have these two vitamins in Energin.")

Been looking at this every which way and cannot understand. Although, one thing I noticed is that when RP writes of demethylation he's referring to DNA, and my lacking methyl donors have to with FAD, which is an electron acceptor. (Sorry can't find my link to this either, I'm on my phone, I will edit to include when i get home).
 
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Zpol

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Here's the link to the thread I mentioned above...

by tyw...

"I state this without proof: Most methylation problems are either due to a lack of Methyl Donors, or insufficient FAD.

I will start with FAD.

FAD is derived from a 2-step enzymatic reaction from Riboflavin / Vit B2. Thiamine balance is implicated here, and again I do not give recommendations on the doses. I will say that both must be present, and supplemented in together for a prolonged period (at least several weeks) for there to be substantial effect."


from the thread...
MTHFR Mutations AND Thiamine-Responsive Megaloblastic Anemia
 

managing

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Here's the link to the thread I mentioned above...

by tyw...

"I state this without proof: Most methylation problems are either due to a lack of Methyl Donors, or insufficient FAD.

I will start with FAD.

FAD is derived from a 2-step enzymatic reaction from Riboflavin / Vit B2. Thiamine balance is implicated here, and again I do not give recommendations on the doses. I will say that both must be present, and supplemented in together for a prolonged period (at least several weeks) for there to be substantial effect."


from the thread...
MTHFR Mutations AND Thiamine-Responsive Megaloblastic Anemia
Bumping this out of personal interest also . . .
 

Mito

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Haidut's summarization of the article
Protective CO2 and aging
Is...
"methylation can be thought of as a direct measure of aging (or cancer potential) and reversing it is thought to be beneficial both for anti-aging and anti-cancer purposes. Baking soda, bag breathing, sugar (and efficient metabolism for its conversion to CO2), acetazolamide, niacinamide are all methods that are known to directly cause demethylation."
That statement makes it seem like MTHFR undermethylation is a good thing, but obviously too little methylation causes problems too (like elevated homocysteine).
 
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Zpol

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The role of vitamin B12 in DNA modulation mechanisms
"Dietary B12 can affect epigenetic mechanisms by regulating DNA methylation status."

Don't know what is meant by "regulating"... does the author mean the end result is demethylation of the DNA?! I wish the author defined this term a bit better.
In this article...
Folate and DNA Methylation: A Review of Molecular Mechanisms and the Evidence for Folate’s Role1,2
the author states "DNA methylation is an epigenetic modification critical to normal genome regulation and development. The vitamin folate is a key source of the one carbon group used to methylate DNA".
... as if methylating of DNA is a good thing!

So yea, still confused.

But I do realize now that methylation of B-vitamins is a very different thing than methylation of DNA. Methylation of B-vitamins (specifically folate and b12) IS required to have "regulated[ing]" DNA methylation... just don't know what this so called "regulated" DNA methylation is. It seems that some research scientists consider methylating of DNA a good thing (going against the logic of RP and his findings) and so I don't know what to make of the conclusions of these articles.

....more research to be done.
 

managing

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The role of vitamin B12 in DNA modulation mechanisms
"Dietary B12 can affect epigenetic mechanisms by regulating DNA methylation status."

Don't know what is meant by "regulating"... does the author mean the end result is demethylation of the DNA?! I wish the author defined this term a bit better.
In this article...
Folate and DNA Methylation: A Review of Molecular Mechanisms and the Evidence for Folate’s Role1,2
the author states "DNA methylation is an epigenetic modification critical to normal genome regulation and development. The vitamin folate is a key source of the one carbon group used to methylate DNA".
... as if methylating of DNA is a good thing!

So yea, still confused.

But I do realize now that methylation of B-vitamins is a very different thing than methylation of DNA. Methylation of B-vitamins (specifically folate and b12) IS required to have "regulated[ing]" DNA methylation... just don't know what this so called "regulated" DNA methylation is. It seems that some research scientists consider methylating of DNA a good thing (going against the logic of RP and his findings) and so I don't know what to make of the conclusions of these articles.

....more research to be done.
This is an interesting and brief explanation of a conventional (receptor) discussion of breast cancer, DNA, and methylation:

The Good and the Bad of DNA Damage DNA Damage and Epigenetic Marks Drive Transcription and Repair

Its obviously necessary to go beyond this in our understanding. I find it interesting that, although they attribute negative effects to methylation of DNA, they are essentially putting it in opposition to estrogen. They describe estrogen as "nicking" and thus damaging DNA. They say that methylation of the damage then "locks" the nick so that it cannot be repaired.

This seems wrong and short-sighted. I have to put a period here, but I am with you "more research to be done ".
 

managing

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Berberine lowers blood glucose levels by increasing insulin sensitivity. The study below (and there are others) showed that it also lowered homocysteine levels (murine). I think this suggests that the dephosphorylation of HMG-CoA reductase eventually results in the production of homocysteine. Interestingly, NADH can limit HMG-CoA reductase.

So, lowered BG or lowered NADH should result in lowered homocysteine. Berberine is a pathway to lowered BG. But only one. A pathway to lowered NADH is through FAD and thiamine/riboflavin. How does niacinamide effect FAD or HMG-CoA reductase . . . .

Regulation of hepatic cholesterol biosynthesis by berberine during hyperhomocysteinemia. - PubMed - NCBI
Regulation of hepatic cholesterol biosynthesis by berberine during hyperhomocysteinemia.
Wu N1, Sarna LK, Siow YL, O K.
Author information

Abstract
Hyperhomocysteinemia, an elevation of blood homocysteine levels, is a metabolic disorder associated with dysfunction of multiple organs. We previously demonstrated that hyperhomocysteinemia stimulated hepatic 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase leading to hepatic lipid accumulation and liver injury. The liver plays an important role in cholesterol biosynthesis and overall homeostasis. HMG-CoA reductase catalyzes the rate-limiting step in cholesterol biosynthesis. Hepatic HMG-CoA reductase is a major target for lowering cholesterol levels in patients with hypercholesterolemia. The aim of the present study was to examine the effect of berberine, a plant-derived alkaloid, on hepatic cholesterol biosynthesis in hyperhomocysteinemic rats and to identify the underlying mechanism. Hyperhomocysteinemia was induced in Sprague-Dawley rats by feeding a high-methionine diet for 4 wk. HMG-CoA reductase activity was markedly elevated in the liver of hyperhomocysteinemic rats, which was accompanied by hepatic lipid accumulation. Activation of HMG-CoA reductase was caused by an increase in its gene expression and a reduction in its phosphorylation (an inactive form of the enzyme). Treatment of hyperhomocysteinemic rats with berberine for 5 days inhibited HMG-CoA reductase activity and reduced hepatic cholesterol content. Such an inhibitory effect was mediated by increased phosphorylation of HMG-CoA reductase. Berberine treatment also improved liver function. These results suggest that berberine regulates hepatic cholesterol biosynthesis via increased phosphorylation of HMG-CoA reductase. Berberine may be therapeutically useful for the management of cholesterol homeostasis.
 

Xisca

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I have the same genética and same liver phase I and II problem.
Metylcobalamin was a great + for me but I don't know if I should go on.
I take co Q10
 
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Zpol

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Really wishing I had an education in biochem right about now!

Thank you managing, Mito, and Xisca. I am going to further into these articles and recommendations )
 

Mito

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I have a gene variant called MTHFR SNP and am lacking methyl donors an so have severe nutritional deficiencies (despite eating high nutrient diet) and my liver is poor at phase I and phase II detoxification. And how do I supplement to improve my health?
Some ideas in this podcast. https://chrismasterjohnphd.com/2017/08/12/living-with-mthfr/

Here is the summary.
A Dietary Strategy for MTHFR Polymorphisms
1) Get the RDA for folate from non-fortified whole foods.
  • For adults and children 14 years and older, the RDA is 400 micrograms, except that it is 600 for pregnant and lactating women, regardless of age.
  • For children, the RDA increases from 65 micrograms in the first six months, to 80 in the second six months, 150 for 1-3-year-olds, 200 for 4-8-year-olds, and 300 for 9-13-year-olds.
  • Feel free to use (as an adult, not for children), 400 or 600 micrograms per day of a methyl-folate supplement, providing you are adding it to a folate-rich diet rather than using it to replace food folate. I recommend Jarrow Methyl Folate based on cost, dose, and the fact that it is otherwise the same high-quality product as sold by other manufacturers in more expensive, higher-dose supplements.
2) Consume at least the RDA for protein.
  • The RDA for protein is 0.36 grams per pound bodyweight.
  • Most people need more than this for other reasons, such as optimizing body composition, preventing loss of lean mass during weight loss, reaching satiety to manage energy intake, or reaching athletic goals. You may need one gram per pound body weight or more, depending on your goals, but the RDA is adequate to support the methylation pathway.
3) Get 3 grams of creatine per day.
  • 1-2 pounds of muscle meat or fish (but not organ meats, eggs, dairy, or plant proteins) will supply on average 3 grams of creatine.
  • Large volumes of muscle protein may be undesirable for someone with an MTHFR mutation because it could exacerbate the loss of glycine.
  • Alternatively, you can supplement with 3 grams of creatine (or 5, if you wish, the standard maintenance dose for athletes). I’m currently using Optimum Nutrition Micronized Creatine Powder.
4) Consume 900-1200 mg/d choline.
  • This can be obtained by eating 4-5 egg yolks per day.
  • You can substitute 100 grams of liver for two egg yolks.
  • You can meet this choline amount by eating a very large volume of low-carbohydrate plant foods. See Meeting the Choline Requirement for more details.
  • You can supplement with phosphatidylcholine, but be careful of the labeling. Usually the supplement lists the phosphatidylcholine, and not the choline yield. A 420 mg capsule of phosphatidylcholine only provides 55 mg of choline, which means you’d have to take 22 capsules per day to get 1200 mg. On the basis of quality, soy-free status, and good feedback from others about the taste, I recommend Micro Ingredients Sunflower Lecithin. Although the choline content is not guaranteed, on the basis of this paper I recommend consuming four to five tablespoons per day to reach the recommended choline yield.
  • If you find that memory loss, poor cognitive function, or weakness are your primary symptoms of concern, consider using alpha-GPCfor your choline at the same dose. This form is more effective at converting to acetylcholine, a neurotransmitter involved in neuromuscular function.
5) Boost your glycine intake.
  • At a minimum, use the skin and bones of the animals you eat. For example, eat chicken with the skin instead of without. Use the bones to make bone broth. If you eat canned fish, get the fish with edible bones.
  • Consider supplementing with glycine. I recommend using between 1/2 serving and 3 servings of Vital Proteins Marine Collagen, on the basis that it has a much higher glycine content than beef hide products made by the same company or others with a similar devotion to quality and cleanness of source.
6) Be careful with SAMe. SAMe supplements support methylation, but MTHFR mutations increase the use of glycine to buffer SAMe levels, even when you don’t have enough. While I do not make a blanket recommendation against supplementing with SAMe, I caution against its use in this context because it could aggravate the loss of glycine. If you use it, be careful, and consider monitoring your glycine levels (see recommended lab tests below).

Lab Tests Recommended for MTHFR Polymorphisms
1) Homocysteine. Available from LabCorp, Quest, and the Genova ION panel, aim to keep your numbers between 6 and 9, rather than the larger range on the report.

2) Plasma or serum folate. Available from Quest or LabCorp, aim to be in the normal range as listed. Avoid RBC folate unless you alsocorroborate it with plasma or serum.

3) Plasma methionine, glycine, and sarcosine. Available on a LapCorp amino acids profile, a Quest amino acids profile, a Genova ION panel, or a NutrEval, methionine and glycine should be toward the middle of the range rather than the bottom and sarcosine is best being as low as you can get it.

4) The HDRI methylation panel. Aim to keep 5-CH3-THF in the normal range. If it is specifically low while other folate forms are normal, this suggests your MTHFR mutation is impacting your methylationpathway negatively. The “extended” panel has methionine and homocysteine, but not glycine or sarcosine.

5) Other tests of interest. Serum creatine from Quest or LabCorp might be a good way of testing whether your MTHFR mutation is affecting your creatine synthesis if you are not supplementing. Aim to be in the normal range. The combination of creatine, creatinine, and guanidinoacetate (the direct precursor to creatine) from the same urine sample can be used to test problems with creatine synthesis. Unfortunately, these are only offered from labs looking for a genetic disorder, such as Mayo Clinic, Greenwood Genetics Center, and Baylor Genetics, and I’m not sure if they are easy to order for someone with no suspicion of a metabolic disorder or whether the reference ranges would be relevant for looking at the impact of an MTHFR mutation.
 
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Zpol

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Seems like a reasonable approach.

I'm not familiar with some of the supp's he mentioned. I'll look them up when I get home to my computer.

I am wondering about glycine. I read somewhere on this forum about people with the MTHFR snp have impaired glycine pathways. I will find it later and link to it.

Thanks!
 

Mito

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The creatine idea is interesting. He claims that supplementing creatine can reduce the demand for Methyl groups. So it seems supplementing creatine could fix undermethylation unless you have the most serve MTHFR polymorphisms.
 

Mito

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I also found it interesting that he says you cannot fix an MTHFR undermethylation problem with Methyl folate and therefore recommends no more than 400-600 mcg per day if you choose to supplement. And I don't recall him even mentioning B12.
 
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Zpol

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The creatine idea is interesting. He claims that supplementing creatine can reduce the demand for Methyl groups. So it seems supplementing creatine could fix undermethylation unless you have the most serve MTHFR polymorphisms.

I also found it interesting that he says you cannot fix an MTHFR undermethylation problem with Methyl folate and therefore recommends no more than 400-600 mcg per day if you choose to supplement. And I don't recall him even mentioning B12.

Ok so I finally got the chance to listen to whole podcast... and, wow, I'm blown away! Things are making a lot more sense to me now.
So glad he addressed the issue of supplementing Methyl folate and how it's basically just a band-aid (it doesn't fix the up-stream problem). And the alternate pathway involving creatine!!... I had not come across this anywhere before! The use of creatine instead of taking methyl donor supp's and risking overmethylation is pretty big news to me :)

I do recall him mentioning B12 but I don't remember the context. I also listen to
Methylate Your Way to Mental Health With Dopamine. It might have been on this podcast that he mentioned it.

Also, he addressed my glycine quandary!
"The note regarding Magnesium in a non glycinate or aspartate form is based on the observation that many people who have such "methylation issues" often come with a dysfunctional Glycine Cleavage System (which itself is NAD+ dependent, and thus requires a high NAD+/NADH ratio) -- Glycine cleavage system - Wikipedia . Usually this comes with an unfavourable GAD SNP, which does affect GABA levels in the brain."
From the thread ...
MTHFR Mutations AND Thiamine-Responsive Megaloblastic Anemia

Basically, he said one must have sufficient choline in order for the Glycine Cleavage System to function properly. That is if I understood correctly. I think I'm going to have listen again to these two podcasts to thoroughly understand everything.

Mito, what do you think about using MitoLipin to provide the needed choline if one could not get enough from food?
Per
haidut...
"In theory, it is a precursor to acetylcholine. However, the studies with PC (and especially saturated PC) did not show any cholinergic effects. See the studies in the brain/mood section of the original thread. The primary benefit of saturated PC is to protect the cell from PUFA toxicity and re-saturate the cardiolipin inside the mitochondria. If it has any cholinergic effets, they are probably seen in multi-gram doses. In the doses found in MitoLipin, it is similar to eating 2 eggs, but without the PUFA that they contain. See this:
Dipalmitoylphosphatidylcholine (dppc) Protects From Pufa Cytotoxicity"


He's saying it would not have a cholinergic effect in the recommended dose, but also that it would be similar to eating 2 eggs in terms of choline effect. I'm confused by this. Perhaps he meant that the recommended dose would not provide ALL the choline one would need per day. I'm thinking if I ate 2 eggs, plus took one dose of MitoLipin, I should be getting pretty close to the total recommended amount. (Can't eat liver, gives me GERD symptoms.) I do realize that MitoLipin is not intended as a choline supp but I have been considering taking this for other reasons and so it'd be great if it would have dual effects for me.
The other supp's Masterjohn recommends don't seem too appealing; have you tried any of them?

Can't thank you enough pointing me in the direction of Chris Masterjohn :)
 
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Zpol

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The creatine idea is interesting. He claims that supplementing creatine can reduce the demand for Methyl groups. So it seems supplementing creatine could fix undermethylation unless you have the most serve MTHFR polymorphisms.

I also found it interesting that he says you cannot fix an MTHFR undermethylation problem with Methyl folate and therefore recommends no more than 400-600 mcg per day if you choose to supplement. And I don't recall him even mentioning B12.

Ok so I finally got the chance to listen to whole podcast... and, wow, I'm blown away! Things are making a lot more sense to me now.
So glad he addressed the issue of supplementing Methyl folate and how it's basically just a band-aid (it doesn't fix the up-stream problem). And the alternate pathway involving creatine!!... I had not come across this anywhere before! The use of creatine instead of taking methyl donor supp's and risking overmethylation is pretty big news to me :)

I do recall him mentioning B12 but I don't remember the context. I also listen to
Methylate Your Way to Mental Health With Dopamine. It might have been on this podcast that he mentioned it.

Also, he addressed my glycine quandary!
"The note regarding Magnesium in a non glycinate or aspartate form is based on the observation that many people who have such "methylation issues" often come with a dysfunctional Glycine Cleavage System (which itself is NAD+ dependent, and thus requires a high NAD+/NADH ratio) -- Glycine cleavage system - Wikipedia . Usually this comes with an unfavourable GAD SNP, which does affect GABA levels in the brain."
From the thread ...
MTHFR Mutations AND Thiamine-Responsive Megaloblastic Anemia

Basically, he said one must have sufficient choline in order for the Glycine Cleavage System to function properly. That is if I understood correctly. I think I'm going to have listen again to these two podcasts to thoroughly understand everything.

Mito, what do you think about using MitoLipin to provide the needed choline if one could not get enough from food?
Per
haidut...
"In theory, it is a precursor to acetylcholine. However, the studies with PC (and especially saturated PC) did not show any cholinergic effects. See the studies in the brain/mood section of the original thread. The primary benefit of saturated PC is to protect the cell from PUFA toxicity and re-saturate the cardiolipin inside the mitochondria. If it has any cholinergic effets, they are probably seen in multi-gram doses. In the doses found in MitoLipin, it is similar to eating 2 eggs, but without the PUFA that they contain. See this:
Dipalmitoylphosphatidylcholine (dppc) Protects From Pufa Cytotoxicity"


He's saying it would not have a cholinergic effect in the recommended dose, but also that it would be similar to eating 2 eggs in terms of choline effect. I'm confused by this. Perhaps he meant that the recommended dose would not provide ALL the choline one would need per day. I'm thinking if I ate 2 eggs, plus took one dose of MitoLipin, I should be getting pretty close to the total recommended amount. (Can't eat liver, gives me GERD symptoms.) I do realize that MitoLipin is not intended as a choline supp but I have been considering taking this for other reasons and so it'd be great if it would have dual effects for me.
The other supp's Masterjohn recommends don't seem too appealing; have you tried any of them?

Can't thank you enough pointing me in the direction of Chris Masterjohn :)
 

Pet Peeve

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Someone posted a link to a page about Walsh and how he treats schizophrenia regulating methylation. Many Mentally Ill Have Histamine-methylation Ratio Imbalance

Undermethylators shouldn't take b9 or b12 but methionine. After reading this I took some methionine I had laying around and my face looked noticeably less tired and worn after a few days. I had looked this tired and run down for months and it was affecting my self esteem, methionine fixed it.

I do have low creatinine. Need to listen to that podcast.

Seems to me Peats advice is mainly geared towards overmethylators (?)
 

Mito

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Mito, what do you think about using MitoLipin to provide the needed choline if one could not get enough from food?
Maybe it's possible that supplementing phosphatidylcholine could provide a little choline and reduce the need for choline to go down the phosphocholine path so more of it goes down the Betaine BHMT path to methionine.
IMG_0763.jpg
 

Mito

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The other supp's Masterjohn recommends don't seem too appealing; have you tried any of them?
None of his specific recommendations. I supplement 400 mcg methylfolate three days per week but I use Pure Encapsulations. I also use Great Lakes hydrolized collagen for extra glycine. I might try creatine but I want to test homocysteine again first.
 
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Zpol

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"From supplementation studies, you would think on this basis that a gram and a half of creatine would be sufficient to cut your methylation demand maximally, but there are some studies suggesting that 5 grams of creatine per day is the dose that you might need to really cut your homocysteine down if you have an MTHFR mutation that’s leading to high homocysteine. So I would say I think a gram to—between one and a half and 5 grams of creatine is potentially useful for supporting the methylation system."
.... this is from the
Methylate Your Way to Mental Health With Dopamine podcast transcript.
Alrighty then... and now to find how to properly use this supp. I'm thinking with meals, and specifically breakfast and lunch as apparently it can cause insomnia.

 

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