NAD, Hype Or Miracle Molecule?

[JPB]

If one feels the need to address age-related conversion issues as part of their NAD+ strategy, this article may be of interest:

Flavonoid apigenin is an inhibitor of the NAD+ ase CD38: implications for cellular NAD+ metabolism, protein acetylation, and treatment of metabolic syndrome.

Abstract
Metabolic syndrome is a growing health problem worldwide. It is therefore imperative to develop new strategies to treat this pathology. In the past years, the manipulation of NAD(+) metabolism has emerged as a plausible strategy to ameliorate metabolic syndrome. In particular, an increase in cellular NAD(+) levels has beneficial effects, likely because of the activation of sirtuins. Previously, we reported that CD38 is the primary NAD(+)ase in mammals. Moreover, CD38 knockout mice have higher NAD(+) levels and are protected against obesity and metabolic syndrome. Here, we show that CD38 regulates global protein acetylation through changes in NAD(+) levels and sirtuin activity. In addition, we characterize two CD38 inhibitors: quercetin and apigenin. We show that pharmacological inhibition of CD38 results in higher intracellular NAD(+) levels and that treatment of cell cultures with apigenin decreases global acetylation as well as the acetylation of p53 and RelA-p65. Finally, apigenin administration to obese mice increases NAD(+) levels, decreases global protein acetylation, and improves several aspects of glucose and lipid homeostasis. Our results show that CD38 is a novel pharmacological target to treat metabolic diseases via NAD(+)-dependent pathways.

 

[Will Brink]

You started with an informative article, but infer fundamentally misleading conclusions.

False. There's nothing miseasding in that article nor anything posted here.

That things like NMN, NR, or NAD infusions are worthy of consideration. Yes you keep bringing up the issue of conversion like somehow this make NR or NMN superior. My point is the issue of conversion applies to all of these molecules in essentially the same manner. So it is a mute point.

False, and paper supplied showing such. You're looking less and less informed on this topic with each post now.

All these molecules must be converted. Age related changes in conversion applies to all of them, given no or very little oral NMN or NR makes it past the liver before being converted to NAM. What NR or NMN gets past the liver must still be converted. The issue of conversion, and related affected pathways, is partially why I advocate cyclical circadian dosing patterns. And the infusion method is clearly not practical as a long-term strategy, although there may be interventional upside for those with specific disease states.

Again, false, and data supplied. It's interesting to note (which you'd understand if you read/understood the papers supplied...) that CD38 degrades NAD and NMN, but apparantly not NR. That's bodes well for NR as a tharapy over NMN. That's a most interesting finding, and may lead, as data suggests to higher NAD+ levels via NR vs NMN or even NAD+ itself.

So far, other than "it works for me" and repeatedly demonstrating you're not as well informed as you think you are, you have supplied jack chit for your opinions. While I agree 100% more data is needed, per the article, the bulk of the data supports what I'm saying.

Supply some actual data that counters anything I am saying, vs repeating incorrect statements shown false.

 

[Will Brink]

If one feels the need to address age-related conversion issues as part of their NAD+ strategy, this article may be of interest:

Flavonoid apigenin is an inhibitor of the NAD+ ase CD38: implications for cellular NAD+ metabolism, protein acetylation, and treatment of metabolic syndrome.

Abstract
Metabolic syndrome is a growing health problem worldwide. It is therefore imperative to develop new strategies to treat this pathology. In the past years, the manipulation of NAD(+) metabolism has emerged as a plausible strategy to ameliorate metabolic syndrome. In particular, an increase in cellular NAD(+) levels has beneficial effects, likely because of the activation of sirtuins. Previously, we reported that CD38 is the primary NAD(+)ase in mammals. Moreover, CD38 knockout mice have higher NAD(+) levels and are protected against obesity and metabolic syndrome. Here, we show that CD38 regulates global protein acetylation through changes in NAD(+) levels and sirtuin activity. In addition, we characterize two CD38 inhibitors: quercetin and apigenin. We show that pharmacological inhibition of CD38 results in higher intracellular NAD(+) levels and that treatment of cell cultures with apigenin decreases global acetylation as well as the acetylation of p53 and RelA-p65. Finally, apigenin administration to obese mice increases NAD(+) levels, decreases global protein acetylation, and improves several aspects of glucose and lipid homeostasis. Our results show that CD38 is a novel pharmacological target to treat metabolic diseases via NAD(+)-dependent pathways.

And that may be one approach to increasing NAD+ levels, but adding quercetin and apigenin comes with far more potential negatives than adding NR to an invivo system. I'm not against the concept, but if one is concerned with a hammer approach to a large number of enzymes, adding quercetin and apigenin is potentially problematic as a major inhiibitor of P450 enzymes as well as others.

 

[JPB]

I am not personally advocating apigenin or quercetin as NAD+ agents, there are indeed absorption issues and other effects, but I thought since you were arguing the importance of addressing conversion issues, then you may consider my posting as informative. But you are committed to taking a contrary perspective vs myself.

CD38 degrades NAD and NMN, but apparently not NR. That's bodes well for NR as a therapy over NMN.

Which does not matter one iota since no NR or NMN makes it past the liver before being converted to NAM.

You continue arguing about superiority of NR or NMN when I have clearly cited research demonstrating none of it makes it past the liver before being converted to NAM. Which implies cleary that downstream conversion of NAM is what leads to increases in NAD+. Intermediaries are NMN and NR. If NR or NMN made it past the liver this discussion might make sense, but since delivering these agents at therapeutic levels orally or otherwise (ie. sublingually) would be at a cost factor up to 10x of NAM, NAM is still the most practical approach.

This debate illustrates why I did not want to jump down the research article rabbit hole. The interpretation of research is commonly manipulated and/or misapplied based on the educational shortcomings or interpretational objectives of those involved.

What is needed is head-to-head studies comparing the molecules affects on NAD+. And comparisons on equivalent dose. Since NAM is a factor of 10 or so less expensive, and NMN and NR are converted to NAM in the liver (making them nothing more than very expensive forms of NAM) I stand by my recommendations. Because of the vested interests of the major players involved and their influence, the head-to-head comparisons have not been made. There is little money to be made with NAM.

 

[Guided_by_Voices]

I'll stick to Rapamycin for the time being , however I agree that this looks like it has potential. I recently listened to Ben Greenfield's interview with Dr. Craig Koniver on this topic and it sounds like the infusions can be self-administered, so potentially more practical that the word infusion implies. Once this is available on a wider scale it can be evaluated in a crowd-sourced way, just like TRT, and people will figure out what's real.

 

[Nelson Vergel]

The debate will continue until there are more studies. My real-world results with niacinamide tell me all I need to know for now. Pay attention to what I say about circadian pattern matching AM to early afternoon dosing so converting enzymes and pathways are replenished nightly. The cost factor with NAM is about 80-90% less than going with NR or NMN. Keep in mind leading researchers in the field, ie Brenner and Sinclair, have vested interests.

When you say "pay attention to circadian pattern matching AM to early afternoon dosing", what exactly do you mean? Thanks for this interesting discussion. @JPB

 

[Will Brink]

I'll stick to Rapamycin for the time being , however I agree that this looks like it has potential. I recently listened to Ben Greenfield's interview with Dr. Craig Koniver on this topic and it sounds like the infusions can be self-administered, so potentially more practical that the word infusion implies. Once this is available on a wider scale it can be evaluated in a crowd-sourced way, just like TRT, and people will figure out what's real.

Maybe I'm missing the connection, but NAD+ and Rapamycin are sorta apples and oranges thing. What's your dose/schedule on the Rapamycin? Schedule most do is 3-5mg 1X per week. That's also a very interesting and promising area. You may find this site useful on Rapamycin and other anti aging "cutting edge" protocols:

Age Reversal Network

 

[Guided_by_Voices]

Wow! That's an interesting looking forum. Thanks for that. That looks like what I've been looking for more of.

I wasn't implying that NAD+ and Rapa have similar MOEs, but rather that they both address anti-aging and age reversal, and Rapa is fairly easily accessable and has a decent number of positive reports with low to no sides and decent understanding of its oral effectiveness. I take 2mg every other week (slightly magnified with grapefruit juice.) I know that that is on the very low end of the dosage spectrum but I'm being careful until there is a bit more data on it.

 

[Will Brink]

Wow! That's an interesting looking forum. Thanks for that. That looks like what I've been looking for more of.

Owned by a friend of mine who also owns Life Extension. He's all about furthering the science of anti aging and we are now making real progress in that area.

I wasn't implying that NAD+ and Rapa have similar MOEs, but rather that they both address anti-aging and age reversal, and Rapa is fairly easily accessable and has a decent number of positive reports with low to no sides and decent understanding of its oral effectiveness. I take 2mg every other week (slightly magnified with grapefruit juice.) I know that that is on the very low end of the dosage spectrum but I'm being careful until there is a bit more data on it.

That's something I may add in as data continues to come in. I'm much more comfortable with NAD and NAD precusors from a data and potential toxiciy side than I am for Rapa, but those I know really pushing the envelope are doing both and others from that site. Knowing what Rapa is used for, as an organ rejection drug and immuno suppressant, it took me a while to make the mental adjustment to see the value in it as an anti aging drug. When I first heard about that one, I thought they were crazy. But as with anything, the dose makes the poison and used correctly, apprears to be a legit anti aging drug.[/QUOTE]

 

[JPB]

When you say "pay attention to circadian pattern matching AM to early afternoon dosing", what exactly do you mean? Thanks for this interesting discussion. @JPB

What I am essentially saying is that when you raise your NAM levels the NAD+ and sirtuin related pathways may and likely are temporarily suppressed. This is not a big deal when you coincide this with your bodies natural autonomic functions and keep your NAM supplementation cyclical. Think flight or fight during the day, rest and repair at night. The NAM will feed the energy expenditure cycle which is naturally catabolic, but "coil the spring" such that later in the day (and post-workout) the NAD+ and sirtuin pathways will rebound back into play, strongly. To coincide and support repair and anabolism. These are fairly advanced concepts and the research backup would take forever so I really don't want to debate these matters with those that may be so inclined, so I will just parlay this as my informed philosophy. Besides the essence of what I am saying regarding circadian cycles, more fundamentally this also allows overloaded channels to recycle (the conversion factors, etc). I would not advocate keeping NAM levels high 24x7, and believe it could certainly be counter-productive. The specific timing is to a degree conjecture.

 

[DragonBits]

I'd say read article and decide for yourself. Jury is still out for me, but I did get an NAD infusion and it clearly holds promise. How much, for who, etc is unclear until some human trials get published.

So how do i measure the current serum level of nad+?

How do you know how much you can use? Did it make you feel any different, and are any other blood test levels affected by your increased level of NAD+

 

[JPB]

There is no practical way that I am aware of to measure NAD+ levels and a serum level test would not tell you much since what is important is intracellular levels. NAD+ interplays with mitochondrial function.

 

[DragonBits]

There is no practical way that I am aware of to measure NAD+ levels and a serum level test would not tell you much since what is important is intracellular levels. NAD+ interplays with mitochondrial function.

There must be some way to test for NAD+ because I see ads that say things like TRU NIAGEN is clinically proven to increase NAD+ by 60%, while NIH says NAD+ declines XX with age.

Then the NIH says our results demonstrate that 6 weeks of NR supplementation at this dose is well-tolerated in humans and effectively increases blood cellular NAD+ concentrations.

So it's possible this to be measured, however ...

It's likely the case that to test cellular levels of NAD+ is possible but not commonly available, which makes me wonder why take the "therapy" if you don't know if it is either effective or needed?

It's anti-aging, so does this affect the length of telomeres?

Just some general questions if anyone knows the answers.

 

[Will Brink]

So how do i measure the current serum level of nad+?

How do you know how much you can use? Did it make you feel any different, and are any other blood test levels affected by your increased level of NAD+

Tissue levels are what matter, and testing tissue levels difficult to impossible depending on the tissue. It's well established that tissue levels decline predictably with age and various disease, etc, and that low levels are associated with all manner of age related stuff best avoided. The real Q left, which is truly the only one that matters at the end of the day is: does restoring tissue levels (and there's tissue specific metabolism of NAD to consider...) help prevent/reverse age related negative outcomes.

In animals and in vitro, results suggest the answer is yes

Early human clinical studies looked promising, but far from conclusive.

A ton of studies are in the works so hopefully the all important Qs start to get answered in the near future.

Many report feeling better, as in more energy, better sleep etc, but that's subjective and of limited value.

What to track for blood work in terms of looking for impact on objective measures is being done by some docs and those interested in seeing what, if anything is happening, but most don't simply due to costs and being unclear just what to test for.

Articles linked in my article linked in the OP go into far more details.

Also discussed at length on Super Human Radio as of yesterday:

SHR # 2330 :: Are The Anti-aging Promises of Nicotinimide Riboside (NAD) Worth The Money?

 

[DragonBits]

Tissue levels are what matter, and testing tissue levels difficult to impossible depending on the tissue. It's well established that tissue levels decline predictably with age and various disease, etc, and that low levels are associated with all manner of age related stuff best avoided. The real Q left, which is truly the only one that matters at the end of the day is: does restoring tissue levels (and there's tissue specific metabolism of NAD to consider...) help prevent/reverse age related negative outcomes.

In animals and in vitro, results suggest the answer is yes

Early human clinical studies looked promising, but far from conclusive.

A ton of studies are in the works so hopefully the all important Qs start to get answered in the near future.

Many report feeling better, as in more energy, better sleep etc, but that's subjective and of limited value.

What to track for blood work in terms of looking for impact on objective measures is being done by some docs and those interested in seeing what, if anything is happening, but most don't simply due to costs and being unclear just what to test for.

Articles linked in my article linked in the OP go into far more details.

Also discussed at length on Super Human Radio as of yesterday:

SHR # 2330 :: Are The Anti-aging Promises of Nicotinimide Riboside (NAD) Worth The Money?

From what I have read, exercise increases NAD+ and that supplementation to some degree does the same thing without exercise. Calories restriction may or may not be needed to get the full benefits.

So I guess one question is if one does a lot of exercise and calorie restriction, is NAD+ supplementation, (either by infusion / or nicotinimide riboside) add much benefit?

 

[Will Brink]

From what I have read, exercise increases NAD+ and that supplementation to some degree does the same thing without exercise. Calories restriction may or may not be needed to get the full benefits.

So I guess one question is if one does a lot of exercise and calorie restriction, is NAD+ supplementation, (either by infusion / or nicotinimide riboside) add much benefit?

My instincts say yes, the data however does not exist at this time. Per article and posts in this thread, will depend on factors such as age, health etc. I'd expect someone who is active and practices CR would benefit less, but we can say that for a lot of things. I'd also expect if they match healthy active 70 year olds to in active less healthy 70 year olds, the former would have higher NAD levels, but would they be similar to levels of a younger person? Like T, probably not is my educated guess.

NR is under the "might be worth a try" category until more data exists, but I'm leaning toward recommending it for those who don't want to wait until all studies are in to do so.

I also tend to think creatine would raise NAD+, but so far, have not found data to show it.

 

[Will Brink]

Chris Masterjohn covers it.

Niacin in any form, in excess consume methyl groups etc.

Then you may need to listen to that show again. I commented on it in another thread, and no place does he recommend not using NR because it consumers methyl groups per se, but he does recommend some nutrients to take as methyl doners, and recommends what I have for decades: taking creatine to reduce need for methyl groups.

 

[JPB]

The issue with methyl groups has to do with dosage as well as flux and status of methyl donors. Masterjohn likes TMG as a methyl donor, and said he only takes 150mg NR daily.

 

[Will Brink]

The issue with methyl groups has to do with dosage as well as flux and status of methyl donors. Masterjohn likes TMG as a methyl donor, and said he only takes 150mg NR daily.

Does that mean you're intellectually honest enough person to admit you were wrong? Or, will you only use him as a reference here as it pertains to methyl donors but not as it applies to your prior claims which he outlined were incorrect?

 

[Will Brink]

Then you may need to listen to that show again. I commented on it in another thread, and no place does he recommend not using NR because it consumers methyl groups per se, but he does recommend some nutrients to take as methyl doners, and recommends what I have for decades: taking creatine to reduce methyl group demand.