Hi dbkita!
What do you consider to be a high level?
Thanks for mentioning these keywords. DNA methylation and silencing gene expression brought me to a wondrous world I didn’t know. I must say, after googling I’m feeling less worried. Although I did not succeed in doing years of study in one single day, so it could well be I’m missing vital information.
I agree methylation has an impact, but I have difficulty relating massive impacts solely to high intakes of mfolate, mb12 and cofactors. Yes, sure, high intakes have an impact if you have a shortage. But shortage itself may often lead to local or even global hypermethylation. (Hahaha! Hear me, how I sound! Forgive me, just think: the more ignorant, the more arrogant.
)
Compared to global hypermethylation global hypomethylation seems to be more risky to me; “genomic instability and loss of heterozygosity” increase the risk of cancer, and genomic demethylation (demethylating drugs) “can have serious side effects and even promote malignant transformations of genes”.
What I learned: global hypomethylation (of the entire genome) often is accompanied by local hypermethylation. And I think (but it could well be I’m confusing things ATM) there’s no such thing as a simple ‘I’m overmethylating’ or ‘I’m undermethylating’ (not alluding to anyone in particular).
When having cancer for instance, there’s often (always?) localised hypermethylation and genome-wide hypomethylation.
Here are some quotes I gathered:
“Undermethylation of the entire genome is referred to as global hypomethylation. Global hypomethylation combined with over methylation of highly select repeated regions of the gene is associated with both aging and cancer. Both undermethylation of tumor-causing genes, where the genes are not turned off, and overmethylation of tumor-suppressing genes, where the genes are turned off, contribute to cancer development.”
“Folate deficiency has been shown to result in both hypo- and hyper–gene-specific methylation. (…) However, with continued folate deficiency, an increase in both p53 and genome-wide methylation was seen.”
“Selenium deficiency decreased DNA methylation in Caco-2 cells and in rat liver and colon. In contrast, vitamin C deficiency has been associated with DNA hypermethylation in lung cancer cells.”
“Retinoic acid [excess] leads to global hypomethylation but region-specific hypermethylation”
What’s causing changes in methylation? Well, IMHO it definitely isn’t just a matter of taking different amounts of B12, methylfolate and cofactors.
“Different nutrients can have different effects on methylation.” Diets high in fat, for instance, negatively affect methylation. I have read that nutrients can also have local effects on DNA methylation different from their global effects.
It’s not just nutrients, or the lack of them, there are more agents leading to abnormal methylation (in certain tissues).
Heredity (it seems epigenetic changes can be inherited), polymorphisms of course, toxins (e.g. cadmium “initially induces DNA hypomethylation, prolonged exposure results in DNA hypermethylation and enhanced DNA MeTase activity”), disease and stress may all change one’s methylation in specific tissues, in specific cells, in specific regions of a gene.
Please correct me if I’m wrong.
I can see that when there’s a need for methylation and one of the factors (mB12, mfolate, etc) is not present in sufficient quantities you’ll have trouble somewhere in your body (resulting in either hypo- or hypermethylation).
As to high levels…
Like B12, methylfolate is rapidly excreted via the kidneys, AFAIK. I have read L-methylfolate is naturally stored in RBC and used by the body when needed.
So will an excess of these two substances lead to methylation problems somewhere? Just having a huge supply does not necessarily mean that things go wrong, does it? Having lots of sugar in the cupboard does not mean you’ll take more than what’s needed when baking a cake.
If an excess does lead to methylation problems: how much is too much, at what dose will these substances become problematic, in what situation can’t the body get rid of them fast enough?
Also, are there any breaks, are there any counteractions the body takes? I surely can imagine that when my kitchen is flooded with sugar, I’ll arrange a relief squad that gets rid of the excess, instead of putting way too much sugar in my cake or baking more cakes than needed…
Rhetorical questions, but if anyone has an answer that would be nice.
You said:
“For some at high levels this [gene silencing] is an essential characteristic. For others there can be too much suppression.”
For some, for others… - yes, I guess it’s difficult to predict how the individual body will response to any level having so many variables (diseases, sensitivities, deficiencies, disorders, genetics, environment).
In short. Based on what I have read thus far about DNA methylation and silencing genes, I am not convinced a high intake of B12 and mfolate has a massive secondary impact, per se. I think it’s rather the opposite that’s true: low intake has massive impact.
(I have not looked into the impact on the production of carnitine, conversion of histidine etc. yet.)
One thing is clear to me though: when it comes to methylation there are many questions unanswered, a lot is unknown.
So I guess a certain well-known local cynic is right:
“In this casino royale of health you place your money and make your bets...”
Or to put it differently, using your words, dbkita:
“You have to find what works for you.”
A higher intake seems to work for me, without creating additional potassium problems; I haven’t changed that K intake one bit since increasing mB12, aB12 and methylfolate.
My sleep’s shorter, but I am rested. Yesterday for the first time since a year or so, I took a 30 minutes’ walk, it turned out to be a bit too much after twenty minutes, then I got so tired and my leg + hip started to hurt. But I turned to my usual self in the evening, so no extra fatigue on top of what I normally experience, a bit tense in the muscles.
Thanks. I’ll do that.
You’re older than adreno?