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Nicotinamide, NAD(P)(H), and Methyl-Group Homeostasis

adreno

PR activist
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4,841
I found the following study interesting. It describes how the balance of B3 and methyl groups ultimately determine health status and aging.

Curr Gerontol Geriatr Res. 2012;2012:302875. Epub 2012 Mar 21.

Nicotinamide, NAD(P)(H), and Methyl-Group Homeostasis Evolved and Became a Determinant of Ageing Diseases: Hypotheses and Lessons from Pellagra.

Williams AC, Hill LJ, Ramsden DB.

Source
Neuropharmacology and Neurobiology, School of Clinical and Experimental Medicine, University of Birmingham, Edgbaston, Birmingham B15 2TT, UK.

Abstract
Compartmentalized redox faults are common to ageing diseases. Dietary constituents are catabolized to NAD(H) donating electrons producing proton-based bioenergy in coevolved, cross-species and cross-organ networks. Nicotinamide and NAD deficiency from poor diet or high expenditure causes pellagra, an ageing and dementing disorder with lost robustness to infection and stress. Nicotinamide and stress induce Nicotinamide-N-methyltransferase (NNMT) improving choline retention but consume methyl groups. High NNMT activity is linked to Parkinson's, cancers, and diseases of affluence. Optimising nicotinamide and choline/methyl group availability is important for brain development and increased during our evolution raising metabolic and methylome ceilings through dietary/metabolic symbiotic means but strict energy constraints remain and life-history tradeoffs are the rule. An optimal energy, NAD and methyl group supply, avoiding hypo and hyper-vitaminoses nicotinamide and choline, is important to healthy ageing and avoids utilising double-edged symbionts or uncontrolled autophagy or reversions to fermentation reactions in inflammatory and cancerous tissue that all redistribute NAD(P)(H), but incur high allostatic costs.

PMID:22536229

An illustration from the study:
CGGR2012-302875.003.jpg

I must admit that I really don't have the knowledge to understand the implications of the article in depth. I'm hoping someone more knowledgeable than me will chime in.

But as I understand it, both under- or overdosing B3 and methyl groups will lead to serious health problems. The question is, how do we find the right balance? From the full text:

Here we suggest the possibility that a hypervitaminosis B3 state, with both nicotinamide and N-methylnicotinamide having an optimal range, resulting from a western diet overrich in meat and vitamin supplements working alongside calorific excesses may be implicated in other modern disease phenomena. Meat eating is preferred where it is available, though during pregnancy it is a common dietary aversion, suggesting that it can be toxic in early development as does the presence of the detoxification enzyme, NNMT and evidence of acute toxicity with nicotinamide overdose and worries about red meat being a risk factor for some cancers [252254]. Nicotinamide exposure can be high, in excess of five times the recommended daily amount (15
x2009.gif
mg/day) where diet has both cereals and “high energy” drinks supplemented with the vitamin and where there is an abundance of cheap meat and milk. This chronic overload can be envisioned as working through unbalancing NAD(H)-dependent systems, including SIRTs and PARPs or dehydrogenase pathways (for instance in cortisol metabolism), and through the direct effects of nicotinamide or N-methylated metabolites. NAD+ is the substrate for SIRTs and nicotinamide is an inhibitor, so dietary levels of NAD(H) precursors could act as both positive and negative influences on such systems. In the case of nicotinamide, dietary inputs are modulated in part by genetic determination of NNMT levels, with 24% of the population being high expressors. Nongenetic factors also modulate expression of the enzyme. These include nicotinamide itself, stress and the demands imposed on NAD(H) availability by growth, tissue repair and exercise. Interestingly, NNMT and other components of NAD(H) pathways are markedly induced in a variety of currently common cancers as well as in the metabolic syndrome, obesity, PD and autism [255262].

So what does this tell the many of us who are essentially megadosing on B vitamins and methyl donors? Is it safe at all? Or should we not supplement them? Are the problems related to ratio, dose or both? How would supplementing NAD or NADH change the picture?

If I seem confused, it's because I am.
 

adreno

PR activist
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4,841
Here is another study showing that high NNMT activity is linked with Parkinson's:

QJM. 2005 Mar;98(3):215-26.

Parkinson's disease: the first common neurological disease due to auto-intoxication?

Williams AC, Cartwright LS, Ramsden DB.
Source
Division of Neurosciences, University of Birmingham, Edgbaston, Birmingham. D.B.Ramsden@bham.ac.uk

Abstract
Parkinson's disease may be a disease of autointoxication. N-methylated pyridines (e.g. MPP+) are well-established dopaminergic toxins, and the xenobiotic enzyme nicotinamide N-methyltransferase (NNMT) can convert pyridines such as 4-phenylpyridine into MPP+, using S-adenosyl methionine (SAM) as the methyl donor. NNMT has recently been shown to be present in the human brain, a necessity for neurotoxicity, because charged compounds cannot cross the blood-brain barrier. Moreover, it is present in increased concentration in parkinsonian brain. This increase may be part genetic predisposition, and part induction, by excessive exposure to its substrates (particularly nicotinamide) or stress. Elevated enzymic activity would increase MPP+-like compounds such as N-methyl nicotinamide at the same time as decreasing intraneuronal nicotinamide, a neuroprotectant at several levels, creating multiple hits, because Complex 1 would be poisoned and be starved of its major substrate NADH. Developing xenobiotic enzyme inhibitors of NNMT for individuals, or dietary modification for the whole population, could be an important change in thinking on primary and secondary prevention.

PMID:15728403
 

adreno

PR activist
Messages
4,841
Certainly, B3 deficiency is problematic. This article argues that pellagrins (patients with B3 deficiency) suffer from a myriad of infections, because pathogens apparently supply NAD. PWCs are often found to have multiple infections, and are low in NADPH, which could point in that direction. Oversupplying methyl groups would then further deplete B3. Is this why so many of us feel rotten on high doses of methylcobalamin and methylfolate?

Med Hypotheses. 2007;69(3):618-28. Epub 2007 Mar 8.

Pellagra: A clue as to why energy failure causes diseases?

Williams AC, Ramsden DB.
Source
Divisions of Neurosciences, University of Birmingham, Birmingham B15 2TT, UK. Adrian.Williams@uhb.nhs.uk

Abstract
Pellagra is a curable dietary illness that unchecked leads to dementia, diarrhoea, dermatitis and death due to lack of the precursors for NAD(H). In addition it caused a wide range of monosyndromic degenerative and functional neurological disorders as well as profound developmental, premature aging and metabolic syndromes. Pellagrins harbour many chronic infections including tuberculosis, yeasts and malaria, that may be symbionts supplying nicotinamide adenine dinucleotide {NAD(H)} when the diet is poor. Many common diseases and aging may be caused by electrogenic energy mismatches from lack of a timely supply of NAD(H) creating disturbed metabolic fields and "protonopathies". Initially these may present in compartments fronted by homeostatic corrections from chronic symbiotic infections to inflammatory disease, cancer and degenerative/autophagic diseases that can all release NAD(H).

PMID:17349750
 

adreno

PR activist
Messages
4,841
This study found that NAD deficiency leads to excess DNA methylation of the BDNF promoter:

Nicotinamide adenine dinucleotide (NAD)-regulated DNA methylation alters CCCTC-binding factor (CTCF)/cohesin binding and transcription at the BDNF locus.
Here, we found that lowering NAD levels in mouse primary cortical neurons led to decreased activity-dependent BDNF expression. The altered BDNF transcription occurred independently of Sirt or Parp activities; instead, low NAD levels promoted increased DNA methylation of the activity-dependent BDNF promoter.

This is obviously not a good thing. Decreased BDNF expression is associated with dementia, depression, bipolar disorder and suicidal behaviour.
 

bertiedog

Senior Member
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Location
South East England, UK
I do terribly on high dose MB12 and methylfolates but do very well when taken daily but only in relatively low amounts such as in 3 Thorne's Basic Nutrients (500 and 400 respectively). I have added in about 33 mg B3 and 20 mg B2, 100 mg B2 plus extra minerals like manganese, moly and selenium without any problems at all. Its the high dose MB12 and high dose methylfolates that are the problem my brain doesn't like it at all and sends me completely hyper.

Pam
 

learner2life

David Pain
Messages
71
Location
Tijuana-San Jose, Ca
Hi Adreno,
My Dad has been reading a book called "Niacin, the real story" which he has been trying to get me to read. From what I read and what he tells me (coming from the book) is that people should be taking 3 gms per day. I do plan on taking it when I feel like I can tolerate a change. It goes into alot of mental disorders, schizophrenia as well as helping people live longer. I really haven't read but only a few pages but it seems very interesting. Just some thoughts.
David
 

Lynn_M

Senior Member
Messages
208
Location
Western Nebraska
Niacin eats up methyl groups. It's recommended for people who are experiencing hyper effects from too much methylfolate and/or methylcobalamin.
 

adreno

PR activist
Messages
4,841
Hi Adreno,
My Dad has been reading a book called "Niacin, the real story" which he has been trying to get me to read. From what I read and what he tells me (coming from the book) is that people should be taking 3 gms per day. I do plan on taking it when I feel like I can tolerate a change. It goes into alot of mental disorders, schizophrenia as well as helping people live longer. I really haven't read but only a few pages but it seems very interesting. Just some thoughts.
David
Yes, I believe psychosis and mania have been associated with hypermethylation, so B3 might help in those cases. There is a danger of liver damage though, when taking high doses of niacin. Perhaps a lower dose of regular B3 combined with NAD would work better.
 

adreno

PR activist
Messages
4,841
Niacin eats up methyl groups. It's recommended for people who are experiencing hyper effects from too much methylfolate and/or methylcobalamin.
Yes, and maybe this is the reason Christine is concerned that methyl supps can deplete B2. Excess methyl groups would deplete NAD, and B2 is needed to synthesize NAD.
 

place

Be Strong!
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341
Location
US
I know I am behind the 8 ball but what are the "methyl groups"? Amino Acids, the B's???
 

adreno

PR activist
Messages
4,841
I know I am behind the 8 ball but what are the "methyl groups"? Amino Acids, the B's???
Methyl groups are the chemicals that methyl donors donate to other compounds. Methyl groups are transferred to other compounds during methylation. It is the "methyl" part of methylcobalamin and methylfolate. Other methyl donors include choline, TMG and SAM-e. All of them donate methyl groups to other compounds.
 

bertiedog

Senior Member
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1,738
Location
South East England, UK
I forgot to say that I have become very well since I was diagnosed with very poor oxygen saturation in my tissues and was advised to breathe oxygen for up to 4 hours daily. In order for me to be very well I have to continue to take physiological doses of steroid so that I am able to tolerate some dessicated thyroid and of course the low dose supplements to aid methylation and essential fatty acids plus lots of antioxidants.

I would never have believed the energy my body now has. I believe it is an enterovirus that has caused all this damage as per Dr Chia's explanation and so a week ago I started on Equilibrant. Time will tell but meanwhile my life has turned around completely and at 64 that is wonderful.

Pam
 

Martial

Senior Member
Messages
1,409
Location
Ventura, CA
Interesting studies thanks for sharing Adreno, one thing that did pique my interest before is from Dr. Lynch. He described the issue of compounding methyl donors and their implications on the rest of the b vitamins, alongside other vitamins and minerals. He mentioned that high dose methyl b12 on its own does not drastically increase methylation but the added methyl folate in higher doses alongside with it.

When they are added together in very high doses then depletion of the other b vitamins gets diminished fairly quickly at first. After the increased demand is met then there is a sort of maintenance phase to upkeep with the extra demand. Here is a quote from him when I asked about adding additional vitamins to the methyl folate/methyl b12 combo. directly.

" B12 and methylfolate increase methylation which puts 'burden' on cells - dividing, replicating, increased mitochondrial function, etc - so in that sense, having sufficient B vitamins, minerals on board - along with fatty acid balance and glutathione, electrolytes - are key. I've learned this the hard way and now I lecture about it ALL the time. Must support all indirect and direct pathways prior to supporting methylation - or some traffic jams will occur ie symptoms/side effects." - Dr. Ben Lynch
 

adreno

PR activist
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4,841
Yes, the golden question is of course what are the correct ratios. Seems hard to find, IME.
 

Martial

Senior Member
Messages
1,409
Location
Ventura, CA
Yes, the golden question is of course what are the correct ratios. Seems hard to find, IME.

The only thing I have gathered so far was that other b vitamins should be in a balanced range between 5-20 mg based on each persons response, though this is a pretty broad range as it stands. Not too minimal as to cause deficiency of other groups and or too high to burden an overload. There are multiple disorders that would require more specific attention to certain co factors though. Pyroluria for one will cause a severe b 6 and zinc deficiency also affecting biotin, magnesium, manganese, and a changing effect on fatty acid ratios.

Seems there are a lot of unique situations for each person that could have a different response to all of this though. This is all only touching the basics as well. From what else I have seen there is also the need for additional Sam E for some, reduction or higher doses of taurine, the removal of certain sulfates as to prevent blockages for CBS up regulation, changes to methylation protocol based on specific SNPs for each person. Keeping in mind of course the changes for each genetic expression results seems highly theoretical right now.
 

Martial

Senior Member
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1,409
Location
Ventura, CA
... and how stable are those ratios over time and between patients? My ratio might not be your ratio, and my ratio today might not be my ratio in a year from now.

That's the part that is really hard to say, there isn't enough known about all of this to give a good estimate. Most researchers right now are trying to formulate exactly that based on individual SNPs and symptoms that appear before, during, and after any treatment. I would hope myself that keeping things in very moderate amounts, having balance would lead to less repercussions. For the most part b vitamins are water soluble after all, the risk of running deficient is mitigated with small to moderate added supplementation. No real toxicities aside from b 6 and perhaps b 3 in mega dosing, keeping other vitamin and mineral levels in balance would solve the other issues. In this sense it seems there is some degree of leeway when it comes to it all.
 

alex3619

Senior Member
Messages
13,810
Location
Logan, Queensland, Australia
The first protocol I designed back in the late 90s was highly successful until rising side effects and cost put the kibosh on it. It was essentially a broad approach, with low doses of everything that might help and was available, with a strong emphasis on B vitamins ... but at the time I was using folic acid, doh. I concur that lower doses and balanced dosage might reduce risk, especially in the long term. A corollary for that though is that lower and broader doses can exert multiple beneficial effects using multiple pathways, and so prevent an excess of a single pathway which will raise the risk of side effects.