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Recipe for NAD (and ATP)

Discussion in 'General ME/CFS Discussion' started by Kimsie, Nov 22, 2014.

  1. Kimsie

    Kimsie Senior Member

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    There have been a couple of threads in the past about how to raise NAD levels. This is something that I have been giving a lot of thought lately and I would like to share what I have come up with.

    Often people with CFS and other chronic illnesses find that something helps them quite a lot...for a short while, and then it stops working. For instance, one person took NADH and stopped crashing for 10 days, and then it stopped working.

    I would like to suggest that when that happens it is because the person actually needs more of several things, or ingredients. Lets take a recipe. suppose we want to make cookies, and we need 3 cups of item A, 1 cup of item B, and 1 tablespoon of item C. If we have 1 cup of item B but only 1 cup of item A, we can only make 1/3rd of the recipe because we have run out of one of the items.

    When a person takes something that helps, they have more of item A, but when they run out of item B that they also need to make the product, they can't make it any more and the supplement they are taking appears to no longer be working, but if they took item B in sufficient amounts to go with item A, then they could keep making the product.

    So what is the recipe for NAD?

    niacin (or niacinamide) + ATP = NAD

    So you see that when we make NAD, we use up a molecule of ATP for every molecule of NAD that we make. So we need to make a lot of ATP (new or de novo synthesis, not recycling) to make our NAD. So what do we need to make ATP?

    Glycine + aspartate + glutamine + D-ribose + folate = ATP (these ingredients are for the Adenosine synthesis, the A part)

    Folate isn't actually an ingredient, it is part of the mixer.

    Aspartate and glutamine can be either taken as a supplement or made indirectly through TCA cycle intermediates by taking L-malic acid. This process requires P5P (B6) for the aminotransferases. If you might be low on B6, then taking aspartate and glutamine might work better, but glutamine and glycine are ingredients for glutathione, so taking glutamine with the glycine can trigger detox.

    So if a person takes D-ribose as a supplement, they can still only make as much ATP and NAD as they have enough glycine and glutamine, etc. The D-ribose is no longer the limiting factor. In order to make lots of ATP and NAD (and FAD and coenzyme A, which also consume ATP for synthesis), you have to have lots of all the ingredients at the same time. And of course for NAD you need the addition of lots of niacin or niacinamide.

    You also have to have enough of other supporting parts (enzyme cofactors) of the mixer, such as folate, B12, magnesium, B6, etc.

    So besides needing more ATP, why do we need so much NAD? Some parts of the following are my hypothesis, they haven't been scientifically proven.

    Because when the NAD/NADH ratio gets too low several key enzymes in the TCA cycle are inhibited, especially alpha-ketoglutarate dehydrogenase.

    And why would the NAD/NADH ratio be too low? Because the electron transport chain is inhibited. When the electron transport chain (ETC) is inhibited, the NADH levels have to build up high enough to "push" the ETC reactions, so if there isn't enough NADH to "push" the ETC, then you don't have enough energy.

    And if you don't have enough NAD to be changed into NADH and still have enough left to keep the NAD/NADH ratio high enough to not inhibit the TCA cycle enzymes, you are in trouble and your body can slip into using 2 ADP to produce one ATP and one AMP for energy production and for each time that happens you have to produce a new ATP de novo, as per Sarah Myhill's article.

    So in order to make lots of de novo ATP, and lots of NAD, you have to take glycine, D-ribose, either malate (and enough P5P) or glutamine and aspartate, niacin or niacinamide, and folate and all the other supplements like magnesium that I think most of you already take. The thing is, you have to have enough of all of them, not just D-ribose.

    Any increase in the amount of niacin or niacinamide would probably bring an improvement if a person is taking the other items, but in our experience, the amount really needed (to overcome the inhibition of the TCA cycle) is far above what people here at Phoenix Rising are accustomed to taking. And with the niacin more folate and B12 is needed because niacin is metabolized by methylation. I know taking large amounts of niacin or niacinamide goes against what a lot of people believe here, but give it some thought; if you need lots of NAD, you will have to take a lot of niacin or niacinamide.

    This post only addresses ATP de novo and NAD synthesis. Other parts of the TCA cycle need support for the best energy production results, such as carnitine or coconut oil to help produce acetyl CoA, etc. If you don't have the NAD production in place any efforts to increase acetyl CoA will only have temporary results.

    Just something to think about!

    Yes, there have been cases of niacin, especially slow-release niacin, causing liver damage at high doses, so I am mentioning that here, but I think that the safety of niacin or niacinamide could be covered in another post if anyone is interested in the subject. This post is long enough already.

    Kim
     
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  2. alex3619

    alex3619 Senior Member

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    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.
     
    Last edited: Nov 22, 2014
  3. alex3619

    alex3619 Senior Member

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  4. alex3619

    alex3619 Senior Member

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    Let me sum up the first post this way, to see if I got it right. This is about addressing an ATP problem by increasing the size of the AMP and NAD pools. AMP is also needed to make NAD (via ATP) but is returned when NAD is catabolized.

    My questions are these: what processes regulate these pools? In other words what feedback loops exist? What factors are not being taken into account? What are the potential downsides? This last I understand will be discussed in a further post.
     
  5. alex3619

    alex3619 Senior Member

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    Does anyone know of any reliable measures of the ADP pool in ME patients?
     
  6. alex3619

    alex3619 Senior Member

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    One of the things that worries me is that many ME patients have elevated urinary uric acid. This can arise due to AMP breakdown. Is our AMP pool depleted? How would we know? I am not convinced it is, however if this is due to lots of energy going to new AMP synthesis then this would have its own problems.

    To me the AMP pool is important as with energy and inorganic phosphate this leads to ADP and ATP, and ATP is used for NAD synthesis.

    In case anyone is unaware, when NAD is broken down it can release AMP.

    One way to boost AMP would be to decrease its degradation.
     
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  7. Gingergrrl

    Gingergrrl Senior Member

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    This has not only been true for me but one step beyond. A medication or treatment can work great the first time and then nearly kill me in subsequent tries (like over-methylation or fluid overload from saline.) I have always wondered why and wish I had the scientific background to understand the rest of this thread but it is light years above my grasp!
     
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  8. Kimsie

    Kimsie Senior Member

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    I am going to put my comments in the quote in bold to make it easier to follow.

     
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  9. Kimsie

    Kimsie Senior Member

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  10. Kimsie

    Kimsie Senior Member

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  11. alex3619

    alex3619 Senior Member

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    Correct, my bad. However the AMP pool and the ADP pool appear to have a strong correspondence. What I am unsure of is the kinetics involved. Myhil also postulates that when pushed we destroy ADP if I recall correctly. I have AMP on my brain at the moment because its important in other things I have been investigating.

    Yes, but my point was: why? We are still trying to figure that out. I do not think there is much doubt we cannot make enough ATP, but this is only really clear when our body is challenged. When we try to make more ATP to meet increased demand we appear to crash, though the process is so far not well understood and complex.

    NAD, AMP and ADP are subject to multiple regulatory loops in the mitochondria. The ratios and amounts appear to be regulated. I am not aware of the full details. It may be difficult to alter this reliably.

    I understand there is anecdotal evidence of improvement from B3, NAD, CoQ10, Ribose, etc. What we lack is solid research evidence. That doesn't mean people shouldn't try things, it means we should be cautious.

    This is too vague. It could be that the nerves are not regulated right, leading to poor circulation, leading to low aerobic capacity in the mitochondria, at least in a subset. I acknowledge we cannot increase ATP production beyond a low threshold (and this is probably what causes PEM when we push) but we still don't know why, or if its the same why in everyone. It probably isn't the same for everyone.

    I have no problems with people trying things, I just want everyone to approach it with caution. Here is my lemon rule:

    http://forums.phoenixrising.me/index.php?entries/28-rules-of-thumb.941/
    22. Most treatments for ME are lemons, they don't suit everyone - but you often wont know if it suits you until you suck it and see. If you see a soured look on my face you will know why.

    A big reason I am cautious is that supra-physiological doses of anything can have unpredictable or dangerous results. This may only show up when large numbers of people have been doing it for a while.

    I am aware of this, which is why I commented on the principle. I am also aware this often does not work. Its one thing to do this in a test tube, another to do it in a living system. The system has set points and fights back, and there are often unintended consequences. Hence my suggestion of caution. Sometimes this might not show up until after prolonged use - it can be delayed. While regular chemical reactions, in isolation, follow Le Chateliers Principle, biological systems with enzyme driven reactions can violate the rule to some extent.

    One of the issues is that many of these kinds of treatments do work in varying degrees, but only for subsets. It was suggested, I think, that alpha ketoglutarate might be a marker. It would be interesting to see if responders versus non responders can be predicted from alpha ketoglutarate levels.

    The improvement we often get from more CoQ10, which in some cases is dramatic, suggests the problem might not be entirely with NADH, though its also possible it can also drive improved NADH metabolism in the electron transport chain. I just do not know. I suspect that adding CoQ10 to the mix might improve the response, at least in a subset. There are a few studies now that have indicated we might have a CoQ10 deficiency which is entirely consistent with the larger picture.

    Cross comparison of groups with disorders other than ME can be useful, but also might be misleading.

    Unless an improvement is dramatic and in almost everyone then we do need clinical research tests. It was once the case that we couldn't get funding for things like this, but Rich van Konyenburg managed (a folate clinical trial using the simplified methylation protocol), and we now have crowd sourcing as a possible financial mechanism. The funding model needs to change, and natural therapies need to have research funded by patients. Also if some indications are right the FDA and other regulatory agencies in many countries might ban many natural supplements. They have been trying for years, and in some cases succeeded. If that happens then research would be mandatory to gain acceptance.

    One thing we could do is establish a dosage that is generally recognized as safe and run a small research pilot study. If improvements are seen and established reliably then follow-up studies can be done.

    Please don't misunderstand me, if it can be shown, even anecdotally, that a high percentage of patients make dramatic improvements under this model then I think quite a lot of us will try it, and good luck to them.

    For the record I used a protocol similar to this but missing ribose, back in the late 90s. My energy was restored but two weeks later severe side effects set in. It did nothing for fatigue though - but I will take restored energy if I can get it safely.

    One of the most important things that needs to be monitored is who, if any, get severe adverse results. Even drug companies fail at this and we don't have anything like their resources.
     
    Last edited: Nov 23, 2014
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  12. alex3619

    alex3619 Senior Member

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    This is what Myhil suggests. Its not contradictory because the 2ADP pathway is an emergency energy pathway, with the mitochondria destroying ADP to make more energy so you don't die. I do not know the kinetics, or rate, at which AMP is converted to ADP. This might be a rate limited step. I suspect it is.
     
  13. alex3619

    alex3619 Senior Member

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    That is indeed helpful. :) Its not just energy and time that is a problem for an investigator with ME, its concentration and memory - I keep having to relearn my biochemistry. I used to be able to draw the Krebs cycle and electron transport chain, now I can't remember anything but vague details and need to look it up.

    I used to debate this stuff all the time back when I had a better understanding of the topic. I have lost most of that.
     
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  14. alex3619

    alex3619 Senior Member

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  15. heapsreal

    heapsreal iherb 10% discount code OPA989,

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    Nadh can stimulate dopamine and noradrenaline release, so should have an increase in energy through this mechanism but could also be improving pots/oi symptoms.
    just a thought?
     
  16. alex3619

    alex3619 Senior Member

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    Yes, which might indicate that at least some of the improvement might be related to blood flow not mitochondria.
     
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  17. Kimsie

    Kimsie Senior Member

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    I will respond to the rest of your comments later today, but I wanted to comment on this quickly before I leave. If you didn't take ribose then it wasn't the same protocol. Also, I doubt that you were taking the amount of B3, but that is a moot point without the ribose.

    If you have records, I would like to know what the protocol was and what the side effects were because this is exactly the type of information I am looking for. This is what helps me figure the puzzle out and I need more data like this.

    I hope you don't think that because we don't agree about everything I don't like your comments. I can see that you have studied these things a lot and I like having a conversation with you because of that.
     
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  18. alex3619

    alex3619 Senior Member

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    The issues about protocols was why I commented specifically on ribose.

    I titrated B3 to maximum effect, but I did not need a lot.

    I appreciate that people disagree, and that this should even be expected. I consider we are all looking for answers, and one way to approach that is to question everything. Things that survive hard questions tend to be more reliable. I have also done this before, more than once. Indeed I first got involved in debating theories in the late 90s. I have debunked a few theories, had one of my own debunked, and participated in the very early days of what became the simplified methylation protocol years later.

    We are all looking for answers. WE as patients and caregivers, have a much greater vested interest in finding answers than most doctors.

    I am looking up my old protocols, but they are a mismash .. I had brainfog when I wrote them. I do have something I wrote in a paper for a conference in 1999. I will send it via messaging if I locate it.
     
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  19. alex3619

    alex3619 Senior Member

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    This is a link to an abstract of my presentation, which is debunked as a cause, but in one variation I still think might describe important pathophysiology involving the mitochondria but this was never published:

    http://www.ahmf.org/99access/99young.html
     
  20. alex3619

    alex3619 Senior Member

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    I have found a text file version of my old paper. The treatment section is here, but first I will post a comment. Please note the hypercitricemia theory is disproved as a cause, but not as part of pathophysiology (despite rather poor research claiming otherwise).

     

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