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
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