192 replies to this topic

[MikeDC]

Achieving the same NAD+ levels with different precursors don’t get the same results. I also posted on the NMN thread that NMN is the least effective NAD+ precursor. Nicotinamide and Niacin are effective NAD+ precursors, but they are not effective at activating longevity genes including Sirt1. This is demonstrated by the fact that high doses of both induce insulin resistance while NR increases insulin sensitivity. NMN has the same properties as NR and NAD+, but it is not very effective at increasing NAD+ in cells.

[able]

Achieving the same NAD+ levels with different precursors don’t get the same results. I also posted on the NMN thread that NMN is the least effective NAD+ precursor. Nicotinamide and Niacin are effective NAD+ precursors, but they are not effective at activating longevity genes including Sirt1. This is demonstrated by the fact that high doses of both induce insulin resistance while NR increases insulin sensitivity. NMN has the same properties as NR and NAD+, but it is not very effective at increasing NAD+ in cells.

 

 

Can you point to any research showing effectiveness of NR vs NMN raising NAD+ in cells, or are you simply referring the the Trammel/Brenner paper showing NAD+ in the liver?

[MikeDC]

Achieving the same NAD+ levels with different precursors don’t get the same results. I also posted on the NMN thread that NMN is the least effective NAD+ precursor. Nicotinamide and Niacin are effective NAD+ precursors, but they are not effective at activating longevity genes including Sirt1. This is demonstrated by the fact that high doses of both induce insulin resistance while NR increases insulin sensitivity. NMN has the same properties as NR and NAD+, but it is not very effective at increasing NAD+ in cells.

Can you point to any research showing effectiveness of NR vs NMN raising NAD+ in cells, or are you simply referring the the Trammel/Brenner paper showing NAD+ in the liver?

That paper and another NMN paper. Check out the image I posted on the NMN thread.

The NMN paper showed 300mg/kg only increased NAD+ in the liver and muscle by less than 20%. Brenner paper showed 100% increase in the liver with only 185mg/kg.

http://www.sciencedi...550413116304958

[able]

 

 

Achieving the same NAD+ levels with different precursors don’t get the same results. I also posted on the NMN thread that NMN is the least effective NAD+ precursor. Nicotinamide and Niacin are effective NAD+ precursors, but they are not effective at activating longevity genes including Sirt1. This is demonstrated by the fact that high doses of both induce insulin resistance while NR increases insulin sensitivity. NMN has the same properties as NR and NAD+, but it is not very effective at increasing NAD+ in cells.

Can you point to any research showing effectiveness of NR vs NMN raising NAD+ in cells, or are you simply referring the the Trammel/Brenner paper showing NAD+ in the liver?

That paper and another NMN paper. Check out the image I posted on the NMN thread.

The NMN paper showed 300mg/kg only increased NAD+ in the liver and muscle by less than 20%. Brenner paper showed 100% increase in the liver with only 185mg/kg.

http://www.sciencedi...550413116304958

 

 

So for NR, you are still referring only to the increase of NAD+ in Liver, as reported in Brenner/Trammel?

 

If you are saying NR is superior because NMN only raised NAD+ by 20% in muscle in a 12 MONTH LONG study, you should point to research with NR showing the increase in muscle over long term.

[MikeDC]

It is unfortunate we don’t have all the information we need. But existing data indicate NMN is less effective than NR.

[MikeDC]

This is a paper that studied Oral intake of NMN in mice.

 

1. long term intake of NMN could cause very little increase in steady state levels of NAD+ in plasma and tissues.

 

2. 300mg/kg dose decreased sirt1 activity in the brain.

 

https://www.ncbi.nlm...les/PMC5668137/

 

"This long-term oral administration regimen could cause very small increases in the steady-state levels of plasma or tissue NMN and NAD+ when mice take a sip of NMN-containing water. However, it is technically very difficult to detect such small fluctuations of plasma or tissue NMN and NAD+ levels. Nonetheless, we observed a tendency of dose-dependent NAD+ increase over time in the liver and BAT, but not in other tissues including skeletal muscle and WAT"

 

"we found that expression of Ox2r and Prdm13, two downstream genes in the SIRT1-mediated signaling pathway in the hypothalamus, exhibited significant decreases in the hypothalami of 300 mg/kg/day NMN-treated mice"

 

[MikeDC]

hypothalamus is the central regulator of aging. 300mg/kg NMN reduced Sirt1 activity in hypothalamus which will translate to accelerated aging in both hypothalamus and other tissues. So the side effects of high dose NMN is accelerated aging. 

 

This may explain a NMN user here who took huge amount of NMN and reported excellent results. But after pausing for a few months, his body aged a lot. High dose NMN didn't slow down aging, it accelerated aging. You are worse than before taking NMN. You get a high while you take NMN. But your body is being destroyed.

Edited by MikeDC, 20 February 2018 - 07:59 PM.

[able]

You are ignoring the fact that the mice in the 12 month study showed dramatic improvement in many measures of metabolic health.

 

There were healthy mice, that were not deficient in NAD+, so it's not surprising that the muscle shows a slight increase in NAD+.  

 

Very different than all the studies using mice with some disease model or knockout genes that very low NAD+.

 

There is NO study of NR for 12 months.  I believe the longest is 3 months?  

 

Look at those and compare the improvement in metabolic health of the animals vs those in the 12 month NMN study.

 

I haven't spent hours comparing them, but a casual review seems to me the NMN study showed more improvement.  

 

In fact, that is the reason I started really examining the science behind NMN, and doubting some of the spin in the Brenner/Trammel study.

Edited by able, 20 February 2018 - 09:26 PM.

[able]

From that study - a single dose of NMN by oral gavage clearly raises NAD+ in tissues throughout the body, much quicker than NR.   

 

 

“Interestingly, in the liver, after administering C13-D-NMN by oral gavage, we clearly detected doubly-labeled NAD+ (C13-D-NAD+) at 10 min, and the level of C13-D-NAD+ further increased at 30 min (Figures 1C and S1D). In the soleus muscle, we detected C13-D-NAD+ at 30 min, but not at 10 min (Figures 1C and S1D). These results suggest that orally administered NMN is quickly absorbed, efficiently transported into blood circulation, and immediately converted to NAD+ in major metabolic tissues.”

 

As you know, the studies with double label NR show very little, if any, make it to muscle, and certainly not that quick.

 

Long term, its probably not important for NMN or NR to elevate NAD+ above baseline in any tissue, unless it is low from age or disease.  It’s important for NMN or NR to elevate NAD+ in tissues that are deficient.

 

The 12 month study focused more on long term health benefits and found:

 

NMN-administered mice exhibit suppression of age-associated body weight gain

 

NMN-administered mice show enhancement of energy metabolism and higher physical activity during the dark time

 

NMN-administered mice show improved insulin sensitivity and plasma lipid profile

 

Long-term NMN administration reverses age-associated gene expression changes in peripheral tissues and enhances mitochondrial respiratory capacity in skeletal muscle

 

Long-term NMN administration significantly improves eye function, bone density, and myeloid-lymphoid composition in aged mice

 

 

 

 

 

[MikeDC]

I agree NMN helps health in low doses. But high dose NMN causes more aging. NMN seems to cause a quick spike in NAD+ and goes back down the baseline. NR causes elevated NAD+ for much longer.

[MikeDC]

The personal experience of someone who claimed he went through a NMN trial indicate NMN can cause very severe negative feed back loop. Long term administration of NMN will desensitize your NAD+ synthesis pathways and you will need more and more NMN to get the same effects. It is like a drug addiction. If you stop taking it, you NAD+ levels will crash and you will age much faster.

[LawrenceW]

MikeDC

 

One of these days you will get your facts straight.  Unfortunately you are not even close on this one.  The "severe negative feed back loop" as you put it was that the body was simply excreting the excess NMN and in the high dose (3,700 mg twice per day) case excreting pretty well all that was taken. In other words your "severe negative feed back loop" was very expensive urine! From September through December last year I dropped down to 1,800 mg twice per day and my December blood work came back identical to my high dose blood work.   I am currently on a 750 mg twice per day dosage and physically everything feels the same it was with  the other 2 dosing regimens.  I will be going in at the end of March for my full blood panels and that will tell the story what is going on inside.

 

As far as your theory of desensitizing the NAD+ synthesis pathway, that is exactly what it is, a theory.  In the real world, I have been significantly reducing my dosages with no drop off in NMN benefits. 

 

 

[able]

The personal experience of someone who claimed he went through a NMN trial indicate NMN can cause very severe negative feed back loop. Long term administration of NMN will desensitize your NAD+ synthesis pathways and you will need more and more NMN to get the same effects. It is like a drug addiction. If you stop taking it, you NAD+ levels will crash and you will age much faster.

 

 

 

You vociferously denied the good test results from Lawrence as being not trustworthy.

 

Then you turn around and claim some little nugget from those same results prove how bad NMN is.

 

I don't see any proof that NMN "desensitize your NAD+ synthesis pathways and you will need more and more NMN to get the same effects"

 

Also, if NMN does  "desensitize your NAD+ synthesis pathways and you will need more and more NMN to get the same effects",   there is no reason to believe NR would be any different.

 

But since we don't have any results from long term testing of NR (over 3 months),  we don't really know.

Edited by able, 22 February 2018 - 04:50 PM.

[Turnbuckle]

From that study - a single dose of NMN by oral gavage clearly raises NAD+ in tissues throughout the body, much quicker than NR.   

 

 

“Interestingly, in the liver, after administering C13-D-NMN by oral gavage, we clearly detected doubly-labeled NAD+ (C13-D-NAD+) at 10 min, and the level of C13-D-NAD+ further increased at 30 min (Figures 1C and S1D). In the soleus muscle, we detected C13-D-NAD+ at 30 min, but not at 10 min (Figures 1C and S1D). These results suggest that orally administered NMN is quickly absorbed, efficiently transported into blood circulation, and immediately converted to NAD+ in major metabolic tissues.”

 

As you know, the studies with double label NR show very little, if any, make it to muscle, and certainly not that quick.

 

 

 

 

Both are substantially broken down in the small intestines, though it appears that NMN is being absorbed gastrically, as 10 minutes is less than the emptying time of the stomach. If so you can improve that by dissolving it in a little water, drinking it down on an empty stomach and lying on your left side. I've had good results with glutathione doing this--

 

The human stomach is capable of absorbing most acidic drugs and the very weakly basic drugs. Salicylic acid, aspirin, thiopental, secobarbital and antipyrine, which are undissociated in the acidic gastric contents, were readily absorbed. Phenol red, quinine, ephedrine and aminopyrine, which are almost completely ionized in acid solution were not absorbed. These results are compatible with the hypothesis that drugs are absorbed by passive diffusion of their lipid soluble undissociated form. Many drugs may be absorbed by the human stomach as rapidly or more rapidly than ethyl alcohol.

http://jpet.aspetjou...ntent/120/4/540

 

[MikeDC]

The personal experience of someone who claimed he went through a NMN trial indicate NMN can cause very severe negative feed back loop. Long term administration of NMN will desensitize your NAD+ synthesis pathways and you will need more and more NMN to get the same effects. It is like a drug addiction. If you stop taking it, you NAD+ levels will crash and you will age much faster.

You stated that after stopping NMN for a while your age markers were older than before taking NMN. That is prove that your body has been trained to waste NMN instead of converting to NAD+.
We may not have long term mice studies with NR, we have hundreds of thousands of people taking it over 3 years.



You vociferously denied the good test results from Lawrence as being not trustworthy.

Then you turn around and claim some little nugget from those same results prove how bad NMN is.

I don't see any proof that NMN "desensitize your NAD+ synthesis pathways and you will need more and more NMN to get the same effects"

Also, if NMN does "desensitize your NAD+ synthesis pathways and you will need more and more NMN to get the same effects", there is no reason to believe NR would be any different.

But since we don't have any results from long term testing of NR (over 3 months), we don't really know.

[stefan_001]

 

 

Both are substantially broken down in the small intestines, though it appears that NMN is being absorbed gastrically, as 10 minutes is less than the emptying time of the stomach. If so you can improve that by dissolving it in a little water, drinking it down on an empty stomach and lying on your left side. I've had good results with glutathione doing this--

 

The human stomach is capable of absorbing most acidic drugs and the very weakly basic drugs. Salicylic acid, aspirin, thiopental, secobarbital and antipyrine, which are undissociated in the acidic gastric contents, were readily absorbed. Phenol red, quinine, ephedrine and aminopyrine, which are almost completely ionized in acid solution were not absorbed. These results are compatible with the hypothesis that drugs are absorbed by passive diffusion of their lipid soluble undissociated form. Many drugs may be absorbed by the human stomach as rapidly or more rapidly than ethyl alcohol.

http://jpet.aspetjou...ntent/120/4/540

 

 

 

Why not put the powder under your tongue then you dont need to worry about the digestion path?
 

Edited by stefan_001, 22 February 2018 - 07:06 PM.

[Turnbuckle]

 

 

 

Both are substantially broken down in the small intestines, though it appears that NMN is being absorbed gastrically, as 10 minutes is less than the emptying time of the stomach. If so you can improve that by dissolving it in a little water, drinking it down on an empty stomach and lying on your left side. I've had good results with glutathione doing this--

 

The human stomach is capable of absorbing most acidic drugs and the very weakly basic drugs. Salicylic acid, aspirin, thiopental, secobarbital and antipyrine, which are undissociated in the acidic gastric contents, were readily absorbed. Phenol red, quinine, ephedrine and aminopyrine, which are almost completely ionized in acid solution were not absorbed. These results are compatible with the hypothesis that drugs are absorbed by passive diffusion of their lipid soluble undissociated form. Many drugs may be absorbed by the human stomach as rapidly or more rapidly than ethyl alcohol.

http://jpet.aspetjou...ntent/120/4/540

 

 

 

Why not put the powder under your tongue then you dont need to worry about the digestion path?
 

 

 

 

500 mg of acidic glutathione? Don't think so.

[stefan_001]

 

 

 

 

Both are substantially broken down in the small intestines, though it appears that NMN is being absorbed gastrically, as 10 minutes is less than the emptying time of the stomach. If so you can improve that by dissolving it in a little water, drinking it down on an empty stomach and lying on your left side. I've had good results with glutathione doing this--

 

The human stomach is capable of absorbing most acidic drugs and the very weakly basic drugs. Salicylic acid, aspirin, thiopental, secobarbital and antipyrine, which are undissociated in the acidic gastric contents, were readily absorbed. Phenol red, quinine, ephedrine and aminopyrine, which are almost completely ionized in acid solution were not absorbed. These results are compatible with the hypothesis that drugs are absorbed by passive diffusion of their lipid soluble undissociated form. Many drugs may be absorbed by the human stomach as rapidly or more rapidly than ethyl alcohol.

http://jpet.aspetjou...ntent/120/4/540

 

 

 

Why not put the powder under your tongue then you dont need to worry about the digestion path?
 

 

 

 

500 mg of acidic glutathione? Don't think so.

 

 

I meant the NR..

 

[Turnbuckle]

Can't say about NR, stefan. But there was speculation here -- http://www.longecity...for-sublingual/

[stefan_001]

Can't say about NR, stefan. But there was speculation here -- http://www.longecity...for-sublingual/

 

Thanks, personally from trying it (I am doing it with 2 capsules, one at a time) it feels there is a different, more direct effect. But may be placebo
 

[MikeDC]

Big difference between the pharmacodynamics of NMN and NR. NMN peaks in the blood at 15 min and steady state NAD+ in the liver and muscle is close to baseline at 1 hour.

This human study of NR showed NR peaked at 3 hours in the blood. NAD+ concentration remains elevated up to 24 hours.

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[able]

Yes, as the researchers themselves stated:

 

“These results suggest that orally administered NMN is quickly absorbed, efficiently transported into blood circulation, and immediately converted to NAD+in major metabolic tissues “

 

And

 

“Interestingly, in the liver, after administering C13-D-NMN by oral gavage, we clearly detected doubly-labeled NAD+ (C13-D-NAD+) at 10 min, and the level of C13-D-NAD+ further increased at 30 min (Figures 1C and S1D). In the soleus muscle, we detected C13-D-NAD+ at 30 min, but not at 10 min (Figures 1C and S1D). These results suggest that orally administered NMN is quickly absorbed, efficiently transported into blood circulation, and immediately converted to NAD+ in major metabolic tissues.”

 

 

As opposed to NR, which is very slow to be metabolized to NAD+, possibly because most of it is first digested to NAM, and SLOWLY makes its way to NAD+.  As the research you linked to states:

 

 

“It is also possible that NR is degraded to nicotinamide in the gut; nicotinamide is then absorbed and converted to NMN, which can further be converted to NAD+ or dephosphorylated to NR. If true, the degradation of NR to nicotinamide in the gut, which presumably involves purine nucleoside phosphorylase in mammalian and bacterial cells [21] may be a variable step involved in the oral intake of NR.”

 

 

They also found evidence of the “upper limit” of effective dose on average (along with much variability between subjects):

 

 

“the observation that 1000 mg NR given on Day 9 did not further increase NAD+ levels in any subject could imply that the maximal effect of NR on raising the NAD+ pool has been attained.”

 

That aligns with other research that found dosages about a certain level end up as excess NAM that is excreted.

 

Together, I agree these results do indicate a difference in the pharmacodynamics.

 

But I fail to see why you believe that is such a vote in favor of NR.

 

If you want a very fast acting precursor that quickly makes its way into muscle and tissue throughout the body, that would be NMN.

 

If you want a slow, time released precursor that is effective at elevating NAD+ in the liver and bloodstream for up to 24 hours, that would be NR (and NAM).  

 

To me, that is further indication that they will prove effective in combination.

 

One last thought -  due to the fast utilization throughout the body, It would seem that NMN might not have the same “upper limit” dosage as NR.  

 

In fact, that reasoning, along with Lawrences anecdotal evidence, persuaded me to up my sublingual NMN dosage.  I had been sticking to 750Mg or less. For the last 2 weeks I decided to boost that to 1500 Mg.   

[MikeDC]

You are wrong on your reasoning. Since NMN causes a spike, you should reduce the dose so your cells don’t have excess NMN that is becomes toxic at high doses.
Why does NAD+ come down to baseline so quickly when NMN is used? Where is the recycling of NAM? My suspecision is the spike in NMN in cells causes negative feed back loop that wastes NMN or NAM. Will long term supplementation of NMN cause permanent leaky NAD+ synthesis pathways?

The down regulation of Sirt1 in the brain at 300mg/kg daily dose is concerning because mice took it in drinking water throughout the day and it is equivalent to slow release.

Edited by MikeDC, 24 February 2018 - 11:39 PM.

[Turnbuckle]

 

 

 

 

 

“Interestingly, in the liver, after administering C13-D-NMN by oral gavage, we clearly detected doubly-labeled NAD+ (C13-D-NAD+) at 10 min, and the level of C13-D-NAD+ further increased at 30 min (Figures 1C and S1D). In the soleus muscle, we detected C13-D-NAD+ at 30 min, but not at 10 min (Figures 1C and S1D). These results suggest that orally administered NMN is quickly absorbed, efficiently transported into blood circulation, and immediately converted to NAD+ in major metabolic tissues.”

 

 

As opposed to NR, which is very slow to be metabolized to NAD+, possibly because most of it is first digested to NAM, and SLOWLY makes its way to NAD+.  As the research you linked to states:

 

 

 

 

 

 

The researchers didn't show the full results over time in Fig 1C, did they? Previous studies with mice showed that NMN breaks down into NR in the intestines and NR breaks down into NAM. That some NMN quickly got into the bloodstream in minutes points to gastric absorption, but you can expect that the bulk of it will be broken down once the stomach empties.

[able]

You are wrong on your reasoning. Since NMN causes a spike, you should reduce the dose so your cells don’t have excess NMN that is becomes toxic at high doses.
Why does NAD+ come down to baseline so quickly when NMN is used? Where is the recycling of NAM? My suspecision is the spike in NMN in cells causes negative feed back loop that wastes NMN or NAM. Will long term supplementation of NMN cause permanent leaky NAD+ synthesis pathways?

 

 

 

NMN "causes a spike" because it is quickly metabolized and utilized directly into NAD+ in muscle and tissue.

 

You somehow believe too much is toxic?   very strange.

 

It doesn't show the same recycling to NAM because it makes its way so quickly into tissues - not floating around the liver.   

 

 

 

 

 

 

 

 

 

“Interestingly, in the liver, after administering C13-D-NMN by oral gavage, we clearly detected doubly-labeled NAD+ (C13-D-NAD+) at 10 min, and the level of C13-D-NAD+ further increased at 30 min (Figures 1C and S1D). In the soleus muscle, we detected C13-D-NAD+ at 30 min, but not at 10 min (Figures 1C and S1D). These results suggest that orally administered NMN is quickly absorbed, efficiently transported into blood circulation, and immediately converted to NAD+ in major metabolic tissues.”

 

 

As opposed to NR, which is very slow to be metabolized to NAD+, possibly because most of it is first digested to NAM, and SLOWLY makes its way to NAD+.  As the research you linked to states:

 

 

 

 

 

 

The researchers didn't show the full results over time in Fig 1C, did they? Previous studies with mice showed that NMN breaks down into NR in the intestines and NR breaks down into NAM. That some NMN quickly got into the bloodstream in minutes points to gastric absorption, but you can expect that the bulk of it will be broken down once the stomach empties.

 

 

 

Yes, it seems some NMN breaks down to NR and then NAM.  We don't really know how much, do we?   

 

Some is quickly utilized in tissue.    The remainder that ends up as NR/NAM should continue cycling thru the system.   

 

That NMN tends to result in much lower levels of NAD+ in the liver seems to indicate that most of it was utilized by tissue, else it would elevate NAD+ in liver much more, wouldn't it?

 

If sublingual NMN increases the percentage that makes its way to tissues, and avoids the breakdown to NR/NAM, wouldn't that be a good thing?  It seems to me that would allow a much higher dosage of NMN to be effective, and not end up getting pissed away as NAM.

[MikeDC]

There are a few papers demonstrate that high NMN in cells is toxic to axons. This has been mentioned many times. Something is different with the brain cells since high dose low release NMN also damage brain cells by Sirt1 down regulation.
You might have younger body parts from using NMN, but your brain might have aged faster.

[MikeDC]

Yes, it seems some NMN breaks down to NR and then NAM. We don't really know how much, do we?

Some is quickly utilized in tissue. The remainder that ends up as NR/NAM should continue cycling thru the system.

That NMN tends to result in much lower levels of NAD+ in the liver seems to indicate that most of it was utilized by tissue, else it would elevate NAD+ in liver much more, wouldn't it?

If sublingual NMN increases the percentage that makes its way to tissues, and avoids the breakdown to NR/NAM, wouldn't that be a good thing? It seems to me that would allow a much higher dosage of NMN to be effective, and not end up getting pissed away as NAM.

Even if NMN is quickly utilized in the tissue such as muscles, the NAD+ will become NAM and you should see a prolonged NAD+ Elevation from NAM recycling. The lack of NAM recycling means either most of NMN are wasted or NAM recycling is down regulated.

Edited by Michael, 25 February 2018 - 06:10 PM.
trim quotes

[LawrenceW]

MIikeDC.

 

I really need to ask the question of how much Chromadex pays you to troll anything to do with NMN?

[MikeDC]

MIikeDC.

I really need to ask the question of how much Chromadex pays you to troll anything to do with NMN?

I am not paid by anyone. How much are you paid to promote NMN? You keep promoting NMN even after your health was hurt by taking it. I am just comparing the pharmacodynamics of NMN and NR.

[tunt01]

Even if NMN is quickly utilized in the tissue such as muscles, the NAD+ will become NAM and you should see a prolonged NAD+ Elevation from NAM recycling. The lack of NAM recycling means either most of NMN are wasted or NAM recycling is down regulated.

 

 

I think this is why there should be renewed focus on NAMPT regulation in this forum.  Google Calico is pursuing P7C3 drugs which regulate NAMPT activity and NAM/NAD+ recycling.  Exercise upregulates NAMPT.  I think NAMPT regulation may ultimately prove to be a better risk/reward approach.