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Recipe for NAD (and ATP)

Learner1

Senior Member
Messages
6,305
Location
Pacific Northwest
Some will, yes. Last time I calculated (you might wanna do your own calculations) 3g Niacinamide could theoretically soak up about 1g TMG if dedicated to methylation. But it's circumstantial. Ideally you want to promote the NAMPT pathway over it. I can't remember if specific ways were already discussed (more threads like http://forums.phoenixrising.me/index.php?posts/558297/), but regularizing the cycles should contribute. For smaller doses with high protein (high methionine) and carbs and daily choline covered I don't worry about it. There was a similar concern with Glycine (+ retinoic acid).
Thanks for the link. I followed it and was left with the same question.

In that thread it says most PWME under methylate, and as little as 100mg niacinamide can negatively impact methylation.

I'm taking vast amounts of methyl12 and P5P as my body sucks up every bit I can give it. I also take 1mg TMG and 1g methionine. All if this keeps me functioning at my current level.

I also take 500mg niacinamide. I'm very interested in making more ATP, but would going to 1.5g niacinamide caus me to need to triple my B12 dose, too, which would then be 30mg a day?

I doubt it, but suspect it could upset the apple cart. Would the benefits of more niacinamide be worth it?

For what it's worth, I've found taking Enada NADH to help when I need more energy quickly, but have tried Niacel (Nicotinamide riboside) which has done absolutely nothing...

Then, from all the P5P I'm taking, might some of it be converting to niacinamide anyway? I had a NutrEval a few years back that showed B6 and B3 in the red and suggested that my B3 problem stemmed from my B6 problem.

Thanks, just trying to put this to practical use....
 
Messages
516
I've never seen a concrete reason to suggest extra niacinamide requires a triple of B12 or other vitamins (except: in CFS/ME you can make a case for high dose B1). If it affects methylation it should pull the bulk of methyl indirectly from TMG/choline in liver (one unknown is the gut absorption of TMG/choline itself due to gut bacteria), and I think it's enough to not be deficient in B12 and others. The niacinamide is/was used as therapy on its own in other diseases.

I don't really believe 1.5g doses are worth it as they probably keep the blood level high too long, but you could just try it for a couple days. I never read any known serious risks to trying it other than it making you extremely tired if your body can't handle it.

But along those lines it might be worth considering cycling the supplements and protocol itself. Like taking a couple days off per week. When you say 500mg, if that's total daily it's not too bad, but if you meant 500mg in single doses, I wouldn't do that daily perpetually personally.
 

Learner1

Senior Member
Messages
6,305
Location
Pacific Northwest
I've never seen a concrete reason to suggest extra niacinamide requires a triple of B12 or other vitamins (except: in CFS/ME you can make a case for high dose B1). If it affects methylation it should pull the bulk of methyl indirectly from TMG/choline in liver (one unknown is the gut absorption of TMG/choline itself due to gut bacteria), and I think it's enough to not be deficient in B12 and others. The niacinamide is/was used as therapy on its own in other diseases.

I don't really believe 1.5g doses are worth it as they probably keep the blood level high too long, but you could just try it for a couple days. I never read any known serious risks to trying it other than it making you extremely tired if your body can't handle it.

But along those lines it might be worth considering cycling the supplements and protocol itself. Like taking a couple days off per week. When you say 500mg, if that's total daily it's not too bad, but if you meant 500mg in single doses, I wouldn't do that daily perpetually personally.
Yes, it is 500mg in a single dose, but it's actually a small dose compared to everything else.

Thanks for your thoughts.
 

frozenborderline

Senior Member
Messages
4,405
Here is one flaw in the argument. I have read, and suspect its true, that we make more weight of ATP in a day than we actually weigh. Mostly that is recycled from AMP, so technically it cannot be counted the myriad times, as this converts back and forth to ATP. The problem is that in straight production terms we make oodles of ATP. Its more complicated than that.

Now increasing AMP might be useful ... more substrate for the whole process to work on. Increasing B3 somewhat is probably a good idea, as it provides more NAD. Having a balanced approach is probably a good idea.

We possibly have enough Acetyl CoA due to our increased glycolysis, but this is an assumption on my behalf. Does anyone know if this is right?

Any argument on these things has to take into account two issues. The first is feedback loops. The second is empirical evidence. Most theoretical ideas sound good but are then later proven wrong. Of course some are found to be sound, or at least useful. Caution is warranted, but that doesn't mean that a new idea should be dismissed.

NAD is also recycled. Some B3 would be good. A lot is probably unnecessary. Its about making the recycling to make ATP operate faster.

Here is one more problem. We do not yet know why we have a problem making ATP. Everything needs to be considered experimental. Some of the research (e.g. Myhil) suggests we may have transporter problems. Now more substrate might well increase the amount transported ... or not.

We might have microvascular problems, particular regulation, so the cells are oxygen deprived. If that is the case then pushing this system might do a lot of damage.

We might have cytokine issues. The wrong push might increase cytokine production. Might, not will.

We might have different subsets with different issues. Some might benefit, some might not, and some might get worse.

Biological systems have multiple feedback loops. We do not know what impact this might have. One of those I worry about is that the wrong method of increasing energy might increase negative hormonal feedback on ATP production.

One thing I would like to see more focus on is how to recycle AMP and NAD faster, and this is not just about the obvious biochemical equations. There is certainly a principle in chemistry, called Le Chateliers Principle, in which adding more substrate increase the rate of reaction. (It says more than that, but that is the message that applies here.) Under that principle, and ignoring the possible effects of the entire biological matrix, then adding more substrate such as AMP and NAD might indeed help.

It might also shut things down due to feedback effects. Deficiency states are not the only thing that can shut reactions down in a biological system. Enzymatic regulation and gene regulation might play a part here.

One risk that always lurks at the back of my thinking is that a sudden increase in burst energy production can induce massive damage to mitochondria. As always, caution should rule.

Ribose really is a special case. Our bodies can process and even make many things needed, but the ribose sugar is a rate limiting substrate. Its a potential bottleneck. Most of these processes are not bottlenecks. So the ribose needs to be in the diet to make more AMP faster.

The mineral I think would be most involved is magnesium. Its needed at multiple steps.

I am not saying this model is wrong. I am not saying don't try to treat our deficits. I am saying we need some caution.

I would really like a lot of our ideas on PR tested on things like the muscle test beds used in UK research (i.e. Newton). It would be nice if we could get a pilot study to test a lot of these ideas. With that behind us we could then organize bigger and more focused studies.

I will write more later if I can get around to it, I am going to be busy the next few days.

this is something that has been concerning me--overfeeding the cycle to the point where it would /could burn us out a
nd damage us worse--OR doing the wrong thing in a redox reaction. some evidence suggests that CFS is due to oxidative stress--but I think it's possible that it could be due to reductive stress--in which case the reducing forms of any given compound could make things a lot worse potentially.

Here's where my hope lies (because I may do some bioassays): are the kreb's cycle/pyruvate oxidation/etc. rate-limited reactions to some extent? I know that messing with these willy-nilly seems dangerous, but there are processes, some synthesis pathways, etc... in the body that are rate-limited. I would like more info on this just because even if we can't guess what will be effective, if we knew what was rate-limited, we could guess what was safe.
 

alex3619

Senior Member
Messages
13,810
Location
Logan, Queensland, Australia
Here's where my hope lies (because I may do some bioassays): are the kreb's cycle/pyruvate oxidation/etc. rate-limited reactions to some extent?
Yes, its very rate limited. No amount of supplemental ATP will increase the rate much.

Indeed it looks like the problem with ME is that it has too severe a rate limitation. This is most probably not a mitochondrial problem, but some kind of metabolic or immune signalling problem. It might even be an autoantibody issue. Current focus is on a suppression of pyruvate dehydrogenase.

What supplemental ATP might do is trigger free ATP signal effects. That might be bad, and might even cause ME under some theories.

It will temporarily increase the AMP+ADP pool. If the problem lies there for an individual it may help.

I sense the science might be close to partial answers. A blood test might be just a few years away. Of course such predictions have been made for decades, and have been wrong, but eventually a prediction will be right.
 

frozenborderline

Senior Member
Messages
4,405
Yes, its very rate limited. No amount of supplemental ATP will increase the rate much.

Indeed it looks like the problem with ME is that it has too severe a rate limitation. This is most probably not a mitochondrial problem, but some kind of metabolic or immune signalling problem. It might even be an autoantibody issue. Current focus is on a suppression of pyruvate dehydrogenase.

What supplemental ATP might do is trigger free ATP signal effects. That might be bad, and might even cause ME under some theories.

It will temporarily increase the AMP+ADP pool. If the problem lies there for an individual it may help.

I sense the science might be close to partial answers. A blood test might be just a few years away. Of course such predictions have been made for decades, and have been wrong, but eventually a prediction will be right.
I'm more interested in supplementing substrates for certain pathways. Supplementing ATP sounds way more like pouring high octane diesel fuel in my old Honda civic or something. Maybe that's not the best analogy? Maybe more like shooting a high pressure .308 round in a barrel made for the lower pressure 7.62?? lol.

ATP isn't orally bioavailable which is great news for the people who have been taking it indiscriminately but ATP injections seem like they do some weird shit to the cardiovascular system.
 

frozenborderline

Senior Member
Messages
4,405
Looks like I need to spend a few days learning about enzyme kinetics. Are there any good books or diagrams on this you can recommend?
I feel safer experimenting with stuff that feeds the Kreb's cycle if I know about enzyme kinetics and what is rate-limited etc
 

anni66

mum to ME daughter
Messages
563
Location
scotland
Here is one flaw in the argument. I have read, and suspect its true, that we make more weight of ATP in a day than we actually weigh. Mostly that is recycled from AMP, so technically it cannot be counted the myriad times, as this converts back and forth to ATP. The problem is that in straight production terms we make oodles of ATP. Its more complicated than that.

Now increasing AMP might be useful ... more substrate for the whole process to work on. Increasing B3 somewhat is probably a good idea, as it provides more NAD. Having a balanced approach is probably a good idea.

We possibly have enough Acetyl CoA due to our increased glycolysis, but this is an assumption on my behalf. Does anyone know if this is right?

Any argument on these things has to take into account two issues. The first is feedback loops. The second is empirical evidence. Most theoretical ideas sound good but are then later proven wrong. Of course some are found to be sound, or at least useful. Caution is warranted, but that doesn't mean that a new idea should be dismissed.

NAD is also recycled. Some B3 would be good. A lot is probably unnecessary. Its about making the recycling to make ATP operate faster.

Here is one more problem. We do not yet know why we have a problem making ATP. Everything needs to be considered experimental. Some of the research (e.g. Myhil) suggests we may have transporter problems. Now more substrate might well increase the amount transported ... or not.

We might have microvascular problems, particular regulation, so the cells are oxygen deprived. If that is the case then pushing this system might do a lot of damage.

We might have cytokine issues. The wrong push might increase cytokine production. Might, not will.

We might have different subsets with different issues. Some might benefit, some might not, and some might get worse.

Biological systems have multiple feedback loops. We do not know what impact this might have. One of those I worry about is that the wrong method of increasing energy might increase negative hormonal feedback on ATP production.

One thing I would like to see more focus on is how to recycle AMP and NAD faster, and this is not just about the obvious biochemical equations. There is certainly a principle in chemistry, called Le Chateliers Principle, in which adding more substrate increase the rate of reaction. (It says more than that, but that is the message that applies here.) Under that principle, and ignoring the possible effects of the entire biological matrix, then adding more substrate such as AMP and NAD might indeed help.

It might also shut things down due to feedback effects. Deficiency states are not the only thing that can shut reactions down in a biological system. Enzymatic regulation and gene regulation might play a part here.

One risk that always lurks at the back of my thinking is that a sudden increase in burst energy production can induce massive damage to mitochondria. As always, caution should rule.

Ribose really is a special case. Our bodies can process and even make many things needed, but the ribose sugar is a rate limiting substrate. Its a potential bottleneck. Most of these processes are not bottlenecks. So the ribose needs to be in the diet to make more AMP faster.

The mineral I think would be most involved is magnesium. Its needed at multiple steps.

I am not saying this model is wrong. I am not saying don't try to treat our deficits. I am saying we need some caution.

I would really like a lot of our ideas on PR tested on things like the muscle test beds used in UK research (i.e. Newton). It would be nice if we could get a pilot study to test a lot of these ideas. With that behind us we could then organize bigger and more focused studies.

I will write more later if I can get around to it, I am going to be busy the next few days.
Thanks for this explanation. I had thought that the preferred loop was ATP-ADP-ATP and that AMP was difficult to recycle?
 

alex3619

Senior Member
Messages
13,810
Location
Logan, Queensland, Australia
I had thought that the preferred loop was ATP-ADP-ATP and that AMP was difficult to recycle?
Yes, that is right. However its the AMP pool that provides the substrate for ADP. It kick starts the process.
AMP->ADP->ATP->ADP ... etc ...

Phosphorylation essentially adds a phosphate bond, which is a high energy bond. That stores the energy that other processes get out of ATP. AMP has very little energy, ADP more, and ATP has enough to be the main powerhouse molecule for the body.

In this quoted post I mis-stated things a bit, and corrected it in a later post.

However it has been proposed that in PEM we get the destruction of ADP to make AMP and yield energy. This is not confirmed to my knowledge, just proposed. The equation is 2 ADP -> ATP + AMP

It was proposed, irrc, in a paper by Myhill, as energy substrate catabolism as an emergency source of ATP when there is excessive energy demand. The process is known, but we do not know for sure it occurs excessively in PEM.