MTHFR Mutations AND Thiamine-Responsive Megaloblastic Anemia

OP
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A 50mcg tablet gives me a terrible headache too, apparently it's very common. Now I bite a bit off the tablet each day, about 10mcgs-worth, and I don't have headaches
That is great info. Thanks @Mango . Do you know if your's has silica? I've found silica is a problem for some and not for others. But I will definitely take it slowly with this info.

@tyw or anybody else have an idea why that would be, or attach any significance to it?

EDIT: I just googled riboflavin and headache and apparently it somewhat successful in preventing migraines . . .
 
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OP
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Took a "mere" 40mg last night. Slept like a baby, no headache. Of course the question remains whether it was the reduction in riboflavin or reduction in silica that did it? Still looking for a silica free version but will continue low dose of the other.
 

tyw

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That is great info. Thanks @Mango . Do you know if your's has silica? I've found silica is a problem for some and not for others. But I will definitely take it slowly with this info.

@tyw or anybody else have an idea why that would be, or attach any significance to it?

EDIT: I just googled riboflavin and headache and apparently it somewhat successful in preventing migraines . . .
Took a "mere" 40mg last night. Slept like a baby, no headache. Of course the question remains whether it was the reduction in riboflavin or reduction in silica that did it? Still looking for a silica free version but will continue low dose of the other.

Personally, I do not think it is the silica, but I can't say for sure.

It is true that all the studies I found, using 400mg of riboflavin a day, were showed to improved migraines in general. The fact that you experienced something else obviously is a counter example.

I cannot say for sure if it the riboflavin is causing the issues, or downstream metabolism and methylation related processes that is causing issues. For example, both nicotine and caffeine can cause migraines in people. Some people report nicotine migraines when eating carbs, and prefer to have either nothing, or a fattier meal. Some people report caffeine migraines when drinking too much without food intake. There is obviously a significant interaction between different states of the body and reaction to these substances.

I cannot say much from a clinical perspective in this case, because all the cases I know of where Riboflavin was used, also included the use of Manganese, Molybdenum, 5-MTHF, and sometimes Lithium. This suite of supplements usually fixes all the issues I described above with nicotine and caffeine, and because riboflavin was used in this context of this supplement suite with no ill effects, it may resolve the issues that you have.

As usual, I can't make recommendations, and what I described was done under practitioner supervision.

....
 
OP
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I've been taking a much smaller dose of riboflavin for several days now--30-50mg with lunch. Each day I've noticed a little bit of lethargy afterwards and leading up to dinner time. Not dramatic. And each night I've woken up restless and a little anxious after about 6-7 hrs of sleep. I can kind of fade in and out of sleep for the last hour or two, but not restful.

Seems like classic low blood sugar. I'm curious if @tyw attaches any significance to this?
 

MB50

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Traditionally, the idea was that Oxygen was needed as an electron acceptor for higher-energy derivatives of FAD, in order to regenerate FAD. Based on the clinical models that I've seen, those with SNPs that produce excess SOD (superoxide dismutase) have more "methylation problems". ie: These people have chronically low superoxide (which is the case in diabetes BTW -- Hyperlipid: The Crabtree Effect and superoxide in diabetes).

I have hypothesised therefore that superoxide production is a key ingredient to maintaining fast and efficient FAD regeneration (in addition to ample O2 of course). This article is complex, but does describe the various redox states of FAD, and how transfers can occur -- Cryptochrome and Magnetic Sensing

I do not know if this is true, but it may explain why those who are capable of producing physiologically relevant levels of superoxide, while maintaining good cell level oxygenation, are able to stave of methylation-type issues despite having "poor methylation SNPs".


Any clue if these people with SOD SNP's do better on high-fat diets? I am thinking of Petro's low-level mechanics here. Couldn't generating more superoxide through reverse transport be a good way to create more superoxide and create the oxidizing environment needed to regenerate FAD?
 
OP
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I've been taking a much smaller dose of riboflavin for several days now--30-50mg with lunch. Each day I've noticed a little bit of lethargy afterwards and leading up to dinner time. Not dramatic. And each night I've woken up restless and a little anxious after about 6-7 hrs of sleep. I can kind of fade in and out of sleep for the last hour or two, but not restful.

Seems like classic low blood sugar. I'm curious if @tyw attaches any significance to this?
FWIW, I ordered some Riboflavin-5-phosphate from Purebulk last night.
 
OP
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By way of update, I added NAD+ 25mg lozenge and lysine (500mg at bedtime). Both are great.

NAD is interesting to me. I've always been one of those who couldn't use niacinamide at all. Even a tiny dose (yes, with sugar) just put me right to sleep. House could be on fire and I would curl up on sofa and sleep.

NAD definitely had a calming effect. But did not put me to sleep at all. Slowed my heartrate (5-10bpm) and made me feel cooler, or at least less hot, on a relatively warm day.

Lysine I have taken before and always helps with sleep. Not sure why @tyw suggested it in this specific situation, but its definitely good.

I am curious on NAD. What I bought is labeled "Coenzymated B-3" and subtitled NAD. Label reveals 25mg of niacin "as inositol hexanicotinate" and 25mg of NAD. At least that is how I read it. Does all NAD list this way?
http://www.sourcenaturals.com/products/GP1318
 
OP
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OK, so this is weird. I got the R5P today. I didn't mention this before because I thought it was the cruddy quality of the previous riboflavin supplement. But the riboflavin (with silica and Mg Stearate) gave me significant endotoxin symptoms. Mainly skin, but also headache in higher doses.

So I took about 20mg of R5P today and about 4 hours later . . . even worse endotoxin symptoms than before. My skin was crawling so bad I was looking for spiders in my clothing.

Riboflavin should have opposite effect. WTF? I'll try again tomorrow to make sure it is the R5P but kind of dreading it right now. . .
 
OP
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It did occur to me this morning that perhaps the riboflavin and other things @tyw listed are "reordering" the gut biota. Which will, especially if gut permeability is higher than desirable, result in some symptoms. The symptoms I've had recently with the ribo are categorically different than what I experienced before. Before was burning ears and bumps on back of skull/neck. Now is mostly red itchy blotches on torso. Hopefully it will wane with continued use. Other ideas?
 
OP
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That speculation may have been right. Last two days the effects have dropped progressively.
 

tyw

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Any clue if these people with SOD SNP's do better on high-fat diets? I am thinking of Petro's low-level mechanics here. Couldn't generating more superoxide through reverse transport be a good way to create more superoxide and create the oxidizing environment needed to regenerate FAD?

TBH, I have no clue. I know only of 3 people who are both:

- are known to have the combination of SNPs that could potentially over-express all of SOD1, SOD2, and SOD3
- whom actually roughly track what they are eating
- whom have enough intervention data to confirm that adding more superoxide quenching ability is counter-productive

All of them do not do well with low fat, and habitually eat >30% fat, and one has to be ketogenic due to other complications. That said, I have no clue if this is a case of SOD SNPs bubbling up to affect dietary intake, or some other factor. I will not rush to conclude that the SNP has anything to do with their dietary intake.

Most people have the opposite problem, whereby you get SOD2 a16v GG, and the excess mitochondrial superoxide production that results.

....
 

Koveras

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TBH, I have no clue. I know only of 3 people who are both:

- are known to have the combination of SNPs that could potentially over-express all of SOD1, SOD2, and SOD3
- whom actually roughly track what they are eating
- whom have enough intervention data to confirm that adding more superoxide quenching ability is counter-productive

All of them do not do well with low fat, and habitually eat >30% fat, and one has to be ketogenic due to other complications. That said, I have no clue if this is a case of SOD SNPs bubbling up to affect dietary intake, or some other factor. I will not rush to conclude that the SNP has anything to do with their dietary intake.

Most people have the opposite problem, whereby you get SOD2 a16v GG, and the excess mitochondrial superoxide production that results.

....

Any general thoughts/recommendations for the SOD2 a16v GG?
 

tyw

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Any general thoughts/recommendations for the SOD2 a16v GG?

No particular recommendations, and personally, I do not think that this SNP is significant beyond other existing conditions. Which is to say, if someone has this SNP, and has no other defects, they have zero problems.

This is such a low level mechanic, and TBH, I've never seen a pattern where I can say any particular supplements worked (example list: https://selfhacked.com/2015/10/03/t...or-sod2/#Supplements_That_Decrease_Superoxide), nor have I came across anyone who can explain a method to measure their progress at dealing with this particular SNP. It's always some fuzzy anecdote like "I feel better!", which most likely had absolutely nothing to do with the SNP in the first place. The supplements in that article may be tried, but again, I personally think it is going to be hit or miss, with no way to tell hit from miss.

If we work on the basis of theory, too little SOD2, and thus too much superoxide, will make a person more likely to trigger the signal for metabolic overload. That is to say, that such people with the GG SNP deal with energetic overload more poorly than those without this SNP.

Literally, they may be the type of person to not be able to deal with large meals very well, get wrecked by high fructose, are prone to "food comas", can't use the Intermittent Fasting eating strategy well, etc ....

SIDENOTE: I never had any such issues, even when I was much fatter, and could always do intermittent fasting well (which I do to this day). I have the AA SNP / normal to high SOD2 capacity, but have no clue whether or not this has any effect.​

In theory (I need to emphasise that this is all in theory), overload is signalled when mitochondria-derived superoxide levels accumulate to a significant degree in the cell, and we see reduced both cell membrane potential and reduced cellular insulin sensitivity.

Such a case can be achieved physiologically and safely, through working on a largely fat-based metabolism. This is where Peter @ Hyperlipid's "Protons Hypothesis" comes in, and while I have a major qualm with an aspect of that theory, the practical result is the same -- a highly reduced CoQ pool, which can be a consequence of operating on a lot of fatty acids, can cause Complex 1 backflow and production of superoxide.

SIDENOTE: for those who know Peter's mechanics, my objection is that he claims FADH2 "enters at Complex 2". This is false. Succinate dehydrogenase is a flavoprotein, and its FAD+ moiety is bound to the protein. Any free FADH2 production during beta oxidation has to be re-oxidised to FAD+ using molecular oxygen. His calculations still remain true because of the excessive reducing pressure (relative to carbohydrate metabolism) on the CoQ pool produced through beta oxidation via ETFdh. This is ultimately best approximated using the FADH2:NADH ratio of beta oxidation, despite the fact that Peter's explanation is wrong.​

The above is a healthy case (during endogenous controlled physiologic high fatty acid use), but those with the SOD2 a16v GG SNP would in theory, have the opposite problem, where forward flow / state 3.5 metabolism induces too much superoxide production at Complex 3, which has the eventual consequence of cytochrome c release from the mitochondria, and thus loss of mitochondrial function, excessive mitochondrial cycling, reduction in eagerness of the cell to take on more nutrients, and in the case of sufficient mitochondria loss, the cell dies / kills itself.

SIDENOTE: I am hesitant to use the word "apoptosis" here, because this is as good as a case of "necrosis". In any case, we have a sick cell that is no longer able to respond to further energetic input, and can choose the path of death, or de-differentiated immortality (cancer).​


I am generally not a supporter of trying to eat to "increase metabolism", and I am even more of an opponent in the context of people with mitochondrial defects like this. Overloading the system is not good.

....
 
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misery guts

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I think that's wrong. Homocysteine is either shunted downwards to cysteine (using B6 as cofactor) or recycled back to methionine (using folate, betaine and choline as cofactor). As far as I know there's no pathway going from cysteine back to homocysteine. See here: http://lpi.oregonstate.edu/infocenter/v ... 6diag.html

There's no doubt that elevated homocysteine is really bad news, even in "conservative" circles it's implicated in many diseases. I think its clear that avoiding homocysteine buildup is an important goal. However how should we achieve that?

  • Restrict methionine (the precursor)
  • Watch out for good B6 status to transform homocysteine down to cysteine (which RP says is bad for thyroid)
  • Watch out for good Folate, betaine, choline status to recycle it back to methionine (which RP says is bad)

And how does glycine play into all this? Is there any new information on Ray's stance on this topic?

No particular recommendations, and personally, I do not think that this SNP is significant beyond other existing conditions. Which is to say, if someone has this SNP, and has no other defects, they have zero problems.

This is such a low level mechanic, and TBH, I've never seen a pattern where I can say any particular supplements worked (example list: https://selfhacked.com/2015/10/03/t...or-sod2/#Supplements_That_Decrease_Superoxide), nor have I came across anyone who can explain a method to measure their progress at dealing with this particular SNP. It's always some fuzzy anecdote like "I feel better!", which most likely had absolutely nothing to do with the SNP in the first place. The supplements in that article may be tried, but again, I personally think it is going to be hit or miss, with no way to tell hit from miss.

If we work on the basis of theory, too little SOD2, and thus too much superoxide, will make a person more likely to trigger the signal for metabolic overload. That is to say, that such people with the GG SNP deal with energetic overload more poorly than those without this SNP.

Literally, they may be the type of person to not be able to deal with large meals very well, get wrecked by high fructose, are prone to "food comas", can't use the Intermittent Fasting eating strategy well, etc ....

SIDENOTE: I never had any such issues, even when I was much fatter, and could always do intermittent fasting well (which I do to this day). I have the AA SNP / normal to high SOD2 capacity, but have no clue whether or not this has any effect.​

In theory (I need to emphasise that this is all in theory), overload is signalled when mitochondria-derived superoxide levels accumulate to a significant degree in the cell, and we see reduced both cell membrane potential and reduced cellular insulin sensitivity.

Such a case can be achieved physiologically and safely, through working on a largely fat-based metabolism. This is where Peter @ Hyperlipid's "Protons Hypothesis" comes in, and while I have a major qualm with an aspect of that theory, the practical result is the same -- a highly reduced CoQ pool, which can be a consequence of operating on a lot of fatty acids, can cause Complex 1 backflow and production of superoxide.

SIDENOTE: for those who know Peter's mechanics, my objection is that he claims FADH2 "enters at Complex 2". This is false. Succinate dehydrogenase is a flavoprotein, and its FAD+ moiety is bound to the protein. Any free FADH2 production during beta oxidation has to be re-oxidised to FAD+ using molecular oxygen. His calculations still remain true because of the excessive reducing pressure (relative to carbohydrate metabolism) on the CoQ pool produced through beta oxidation via ETFdh. This is ultimately best approximated using the FADH2:NADH ratio of beta oxidation, despite the fact that Peter's explanation is wrong.​

The above is a healthy case (during endogenous controlled physiologic high fatty acid use), but those with the SOD2 a16v GG SNP would in theory, have the opposite problem, where forward flow / state 3.5 metabolism induces too much superoxide production at Complex 3, which has the eventual consequence of cytochrome c release from the mitochondria, and thus loss of mitochondrial function, excessive mitochondrial cycling, reduction in eagerness of the cell to take on more nutrients, and in the case of sufficient mitochondria loss, the cell dies / kills itself.

SIDENOTE: I am hesitant to use the word "apoptosis" here, because this is as good as a case of "necrosis". In any case, we have a sick cell that is no longer able to respond to further energetic input, and can choose the path of death, or de-differentiated immortality (cancer).​


I am generally not a supporter of trying to eat to "increase metabolism", and I am even more of an opponent in the context of people with mitochondrial defects like this. Overloading the system is not good.

....

Thanks for these posts, I've been looking forward to you talking more about methylation!

Can I please ask for your take on the MAO-A gene? I've attached my nutrahacker .pdf (the gene is on page 4/5) - stated as "T: 1/1". I was pleased to see I had a mutation in something relating to neurotransmitters (as I have depression, and it's a plausible link), and the suggested intervention from nutrahacker is to use a Peat friendly substance - progesterone. I've since been browsing the Wooo/progesterone thread and am now a little less than eager to start trying it. Do you have any thoughts about addressing this mutation beyond supplements already mentioned? Do you see any other glaring issues in those result? Thanks :3
 

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tyw

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Gene in question is rs6323, MAOA R297R, TT variant. This variant is supposed to reduce MAO-A enzyme activity -- Monoamine oxidase A - Wikipedia

MAO-A is often discussed concurrently with COMT function, since both address breakdown of the same products. You can search for the many articles that address both together. It hard to say what a correct balance is though, given that each person is going to have their own unique set of conditions and habits.

The required MAO-A activity is still going to depend on the amount of norepinephrine floating around, and thus if we want to address excess input concerns, then preventing excess sympathetic activation is going to be key.

Avoiding the substances listed in the 'What To Do If You Have High MAO-A' section of this article may also be helpful (including stuff like coffee and methylene blue, and maybe even too much tyramine) -- https://selfhacked.com/2014/12/07/about-mao-a-and-what-to-do-if-you-have-the-warrior-gene/

COMT activity always needs to be fast enough to ensure that the burden on MAO-A is not too great. This is where sufficient methyl donors and Amy Yasko's lithium protocol is probably suitable, and again, needs to be tweaked to the individual's context.

All the interventions listed in the initial post may apply here, though I would highlight B2 / riboflavin use, since MAO-A is a flavin-based enzyme. This would only work if B2 is in deficiency in the first place.

I do not like the idea of using progesterone in this case. I do not see any mechanism by which it addresses the core issue of low MAO-A activity. It seems to be aimed at reducing the symptoms of aggression and/or depression, through some other pathway, rather than enhancing the activity of MAO-A itself. Especially in males, I view this sort of strategy as one with many unknown side effects.

....
 

Mito

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Avoiding the substances listed in the 'What To Do If You Have High MAO-A' section of this article may also be helpful (including stuff like coffee and methylene blue, and maybe even too much tyramine) -- https://selfhacked.com/2014/12/07/about-mao-a-and-what-to-do-if-you-have-the-warrior-gene/....
That article lists 5HT2A blockers as an advanced method to increase MAO-A enzyme activity. Do you think that is a viable strategy (after verifying adequate Riboflavin)?
 

tyw

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That article lists 5HT2A blockers as an advanced method to increase MAO-A enzyme activity. Do you think that is a viable strategy (after verifying adequate Riboflavin)?

No. I don't like playing with receptor modulators, especially not a case like 5-HT2A.

First, I don't believe in the traditional idea of receptors, and see the protein activation of so-called "receptors" as being a side effect of reactive compound activity, instead of the main driver of activity.

The correct way of thinking about receptors is:

Compound X reacted with Cell Y and cause side effects A, B, and C. Side effect C happened to be "receptor protein activity".​


I do not agree at all with the statement from the selfhacked article:
The reference cited was a study titled 'Ginkgo biloba abolishes aggression in mice lacking MAO A', which validated that Ginkgo extract did reduce 5-HT2A protein activity in MAO A Knockout mice that were specifically designed for serotonin and norepinephrine overexpression.

This doesn't say anything at all about 5-HT2A increasing MAO-A activity.

It says that:
- a natural compound (Ginkgo)
- had some side effects, which is not limited to 5-HT2A (look at all the potential effects of ginkgo -- Ginkgo Biloba - The Neutral Nootropic - Brain Health)
- and prevented specifically the aggressive behaviour seen in mice

Note how we don't even know if the muted aggressive behaviour was due to normalisation of serotonin and norepinephrine levels, or if it was some other effect of the Ginkgo that worked despite high serotonin and norepinephrine ....

Saying that "5-HT2A blockers" produced this effect is wrong. Saying that "Ginkgo Biloba extract helps" may or may not be accurate, and may or may not have anything to do with the MAO-A enzyme.

Focusing on 5-HT2A modulation is unproductive, and can potentially lead to massive side effects. It has crosstalk with all the other serotonin receptors (and probably a whole bunch of other G-coupled protein receptors), as well as dopamine homeostasis, to which one can find both dopamine suppressive and enhancing properties concurrent with varying levels of 5-HT2A activity.

This is complex-as ..... I'd rather not play in this receptor mess and risk making it worse.

Hence, the philosophy is to support whatever level of MAO-A activity a person has, while bolstering other enzymes systems (COMT) that also work on the target metabolites of MAO-A.

.....
 

Wagner83

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Good topic to address. The TL;DR is that:

- theoretically niacinamide / nicotinamide is not an appropriate choice at night
- SIRT1 suppression is dose dependent.
- for the purposes of B-vitamin support, doses of 100mg Niacin seem to be sufficient
- at such doses, form of NAD+ precursor may not matter, but experimentation is needed

Addressing topics separately.

---
SIRT1 in circadian regulation

This is clearly an important factor. SIRT1 should be high at night, as per the "WT" (wild-type, aka: normal phenotype) line in the chart below. Note that "BTSG" refers to a transgenic mice that had 10-times SIRT1 activity, and "BSKO" referred to mice with complete SIRT1 knockout. Once again, we see that both too much and too little SIRT1 cause major disruptions to circadian protein expression.

This chart was taken from paper, see full paper for more effects based on this SIRT1 disruption -- http://www.cell.com/cell/fulltext/S0092-8674(13)00594-1

View attachment 4800


In a similar study (mouse model), brain SIRT1 knockout basically destroys all circadian signalling, and SIRT1 depletion leads to major disruptions -- SIRT1 mediates central circadian control in the SCN by a mechanism that decays with aging

See Figure 5 for the reduction in all circadian signalling proteins after SIRT1 depletion, we're basically looking at 30-50% losses in protein expression -- SIRT1 mediates central circadian control in the SCN by a mechanism that decays with aging

The reader can get into the detailed mechanics in their own time. The important thing to note is that SIRT1 expression must be elevated during the darkness hours for proper subsequent expression of all circadian related proteins.

SIRT1 acts in an NAD+ dependent manner, and NAD+ depletion can reduce its effects. Ensuring a good NAD+ pool is required for SIRT1 function, and this is clearly regulated in various tissues.

Two examples, liver studies, whereby circadian NAMPT expression regulates amount of NAD+ available to the liver at different times of the day -- Circadian Clock Feedback Cycle Through NAMPT-Mediated NAD+ Biosynthesis

Note that NAMPT is the rate-limiting step for NAD+ biosynthesis in mammals, and there is clearly a very large difference from day and night. (Fig 1 reproduced below)

View attachment 4802

As an aside, once again we see that it syncing up both food intake and drug delivery during daylight hours has a very significant effect. See this paper for details, which is a good overview of how the Central Clock (dominated by light signalling) synchronises the peripheral clocks -- Circadian timing of metabolism in animal models and humans

This is also a good paper on why peripheral clock mismatch is a bad idea. The entire paper is recommended ;) , though the most important major sections are:

- Circadian coordination of metabolism
- Circadian clock and human metabolic diseases

While section 'Architecture of the circadian timing system: central and peripheral oscillators' explains how the Central Clock entrainment is a dominant factor.

With reference to NAD+ and SIRT1, see the commentary on NAD+ decline and drop in SIRT1 oscillations as a pre-condition for chronic circadian rhythm disruption (especially in the elderly).

SIDENOTE: SIRT1 is obviously very important. For example, it is needed for the acute inflammatory response and subsequent healing -- http://www.anti-agingfirewalls.com/2015/05/01/part-4-of-the-nad-world-the-nq1-gene-the-warburg-effect-sirt-1-and-inflammation-and-possible-interventions/

Also see section number (5) on Niacinamide in this post -- 30 Major Factors that Control SIRT1 Expression, SIRT1 Activity, and SIRT1-mediated Aging. Part 3 of the series NAD+ an emerging framework for health and life extension | AGINGSCIENCES™ – Anti-Aging Firewalls™

All 5 parts are worth reading for those who really want to understand the state of research regarding NAD+ and SIRT1. All parts are linked to from the front matter of the blog post.​

Now, with regards to supplementation of NAD+, we do not want to disrupt this normal rise in SIRT1 at about Zeitgeiber time (ZT) +12 (12 hours after waking). This will affect the choice of precusor

----
NAD+ precursor choice

First, in practical terms, we are dealing with either the choice of:

(1) Niacin
(2) Nicotiamide Riboside (NR)
(3) Niacinamide (NAM)

Only number (3), niacinamide has been observed to decrease SIRT1 activity, and quite significantly as well. The reader can look up the research themselves, but it is fair to say that Niacinamide suppresses SIRT1 activity, while the observed SIRT1 affect in either Niacin or Nicotinamide Riboside supplementation is either neutral, or increased.

For those who are interested, I have made similar commentary on the differing effects of these 3 NAD+ precursors here -- Tobacco Smoke And It's Effect On PUFA

Again, Vince Giuliano did some good comparisons between Niacin and Niacinamide here -- http://www.anti-agingfirewalls.com/2010/03/30/niacin-or-niacinamide-supplementation-–-good-or-bad-idea/

The half life of Niacinamide seems to be dose dependent. Any dose is likely to suppress SIRT1 to some extent, but we do not know for how long, if the dose-to-SIRT1-suppression relationship is linear or not, and if half-life times are any indicator of SIRT1 expression activity.

The half-life of Niacinamide according to -- nicotinamide | C6H6N2O - PubChem

The mean half life values were 2.7 hr, 5.9 hr, and 8.1 hr after taking 1, 3, or 6 g of Niacinamide, respectively.​

That is a high dose of niacinamide. In any case, I think that taking at dinner may have anywhere from small to very significant effects on SIRT1.

Whether or not this can lead to circadian disruption, is again, going to be dose dependent. If we follow the considerations seen in the research however, it is clear that Niacinamide is a "day-time supplement", with night time use potentially being disruptive, and hence not recommended.

A mix of niacinamide in the day and then niacin at night can also be used of course.

Clinically speaking in the context of the B-vitamin balancing and methylation support, all it seems to take to get B-vitamins to balance out is about 100mg niacin a day. This is the lower dose protocol that I would recommend. Higher doses have potential side effects.

Personally, I never do well with niacinamide at night, and if we look to other anti-ageing forums, we find a very mixed response (eg: one person will say that it puts them to sleep, another will say that it keeps them up).

Again, we need to ask, "What are we using an NAD+ precursor for?". The topic of this thread is very specific -- to support proper methylation reactions via B-vitamin balancing. Toward that goal, only low doses of NAD+ precursors are needed, and timed to transiently elevate NAD+ when a specific mixture of other nutrients are added.

As a final commentary, all NAD+ supplementation should be viewed as transient elevators of NAD+ status, with little impact on chronic NAD+ status (this is referring to NAD+ precursor supplementation alone). I will not elaborate on this point here, interested readers can look to the recommended 5-part series of NAD+ on anti-aging-firewalls.com

.....
For those who use niacinamide this is worth a read.

See also:
People With The Lowest Overall Mortality Are Overweight
Is There Any Reason For Me To Take Aspirin?
 
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Markus

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If we work on the basis of theory, too little SOD2, and thus too much superoxide, will make a person more likely to trigger the signal for metabolic overload. That is to say, that such people with the GG SNP deal with energetic overload more poorly than those without this SNP.

In theory (I need to emphasise that this is all in theory), overload is signalled when mitochondria-derived superoxide levels accumulate to a significant degree in the cell, and we see reduced both cell membrane potential and reduced cellular insulin sensitivity.

Such a case can be achieved physiologically and safely, through working on a largely fat-based metabolism. This is where Peter @ Hyperlipid's "Protons Hypothesis" comes in, and while I have a major qualm with an aspect of that theory, the practical result is the same -- a highly reduced CoQ pool, which can be a consequence of operating on a lot of fatty acids, can cause Complex 1 backflow and production of superoxide.

So someone with the GG SNP would not do well on a high-fat diet?
 

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