18 replies to this topic

[MikeDC]

No major findings except it is safe and no NMN was detected in the blood. Lower insulin and higher bilirubin could be due to fasting.

 

Edited by Michael, 08 November 2019 - 03:39 AM.
Removed offending link

[Michael]

MikeDC, others:again, please do not post links to sites providing back doors through paywalls: you're putting Longecity at risk of paratrooping lawyers and takedown bombardment.

 

This was particularly unreasonable, since the paper is available in free full text from the publisher.

 

In terms of the results: you seem to have missed, or chose not to report, an important feature of the study: these results are after a single oral administration of NMN. No matter how optimistic one is, no one would reasonably expect dramatic changes in these outcomes after popping one capsule.

 

"Lower insulin and higher bilirubin could be due to fasting:" no, they couldn't, because they were fasting in the control condition, too. More likely with 10 subjects and one administration, it's noise. But we'll see.

[LawrenceW]

MikeDC.

 

You also took your "no NMN was detected in the blood." statement out of context.

 

Below is the relevant statement from the study.

 

"Unfortunately, we failed to detect NMN in plasma samples

in this study, most likely because freezing plasma

samples before extraction might have caused the degradation

of NMN. The procedure of blood sampling could

have also contributed to the failure of the detection of

NMN, because the recent reports showed that NMN was

degraded very rapidly in blood that was handled above –

80°C [7, 21]."

 

Your NR bias is showing again!

[MikeDC]

MikeDC, others:again, please do not post links to sites providing back doors through paywalls: you're putting Longecity at risk of paratrooping lawyers and takedown bombardment.

This was particularly unreasonable, since the paper is available in free full text from the publisher.

In terms of the results: you seem to have missed, or chose not to report, an important feature of the study: these results are after a single oral administration of NMN. No matter how optimistic one is, no one would reasonably expect dramatic changes in these outcomes after popping one capsule.

"Lower insulin and higher bilirubin could be due to fasting:" no, they couldn't, because they were fasting in the control condition, too. More likely with 10 subjects and one administration, it's noise. But we'll see.

The paper speculated that it is most likely due to fasting because they didn’t have controls. You would also expect blood insulin to go down in a 5 hour period without food.

[MikeDC]

MikeDC.

You also took your "no NMN was detected in the blood." statement out of context.

Below is the relevant statement from the study.

"Unfortunately, we failed to detect NMN in plasma samples
in this study, most likely because freezing plasma
samples before extraction might have caused the degradation
of NMN. The procedure of blood sampling could
have also contributed to the failure of the detection of
NMN, because the recent reports showed that NMN was
degraded very rapidly in blood that was handled above –
80°C [7, 21]."

Your NR bias is showing again!

I just put up a brief summary. There are excuses. But no NMN was detected is the result.

[Fredrik]

I just put up a brief summary. There are excuses. But no NMN was detected is the result.

 

The story won´t end there. Noteworthy is the authors mention in the DISCUSSION on how they will follow up this very small safety trial with a more comprehensive PK study that is ongoing and will look at plasma, and possibly tissue levels of NMN and changes in NAD+ levels:

 

Our next clinical study to evaluate plasma NMN levels and NAD + levels in peripheral blood mononuclear cells is now in progress. If possible, biopsy samples from tissues such as the adipose tissue and skeletal muscle need to be analyzed for tissue NMN and NAD + levels.

 

Edited by Fredrik, 08 November 2019 - 12:05 PM.

[LawrenceW]

I just put up a brief summary. There are excuses. But no NMN was detected is the result.

 

Or, the NMN has already made its way to the cells and was no longer in the blood as per "We have previously demonstrated that the transport of NMN from the gut to the circulation and then to tissues occurred within 10 min (ref. 15). " from this paper https://www.nature.c...2255-018-0009-4

 

We know that you love NR and Chromadex, but, you really should try some NMN and find out what you have been missing all these years!

[MikeDC]

Or, the NMN has already made its way to the cells and was no longer in the blood as per "We have previously demonstrated that the transport of NMN from the gut to the circulation and then to tissues occurred within 10 min (ref. 15). " from this paper https://www.nature.c...2255-018-0009-4

We know that you love NR and Chromadex, but, you really should try some NMN and find out what you have been missing all these years!

Brenner is doing a mice study with all NAD+ precursors. It is funded by Gates Foundation. Once it is published we will know the answer about bioavailability of NMN, NR, etc.

[able]

They say there was a problem measuring NMN. But they say NAD+ was not measured.  That makes no sense to me.

 

It does look promising that the 2 forms of MeNAM were increased throughout, indicating NAD+ usage was increased.

 

Its hard to tell from the graphs, but it seems both 2Py and 4Py increased in less than 60 minutes.   That is  much faster than NR in the first trial that Brenner did on himself, which showed nothing significant at 2.7 hours, with the big jump at 4 hours.

Edited by able, 08 November 2019 - 04:28 PM.

[MikeDC]

They say there was a problem measuring NMN. But they say NAD+ was not measured. That makes no sense to me.

It does look promising that the 2 forms of MeNAM were increased throughout, indicating NAD+ usage was increased.

Its hard to tell from the graphs, but it seems both 2Py and 4Py increased in less than 60 minutes. That is much faster than NR in the first trial that Brenner did on himself, which showed nothing significant at 2.7 hours, with the big jump at 4 hours.

2Py and 4Py can be formed from degraded NAM. So you cannot say it is from NAD+ consumption.

Edited by MikeDC, 08 November 2019 - 05:19 PM.

[able]

So when Dr Brenner says MeNam indicates NR->NAD+ that is  utilized, you believe it.  But if it is NMN, you say it is from NMN that was not metabolized to NAD+, but degraded back to NAM.  

 

Regardless of the path taken from NMN to MeNAM, in this small study, NMN reached the bloodstream and was metabolized to MeNAM 2-4x faster than NR in the Trammel study.

[MikeDC]

So when Dr Brenner says MeNam indicates NR->NAD+ that is utilized, you believe it. But if it is NMN, you say it is from NMN that was not metabolized to NAD+, but degraded back to NAM.

Regardless of the path taken from NMN to MeNAM, in this small study, NMN reached the bloodstream and was metabolized to MeNAM 2-4x faster than NR in the Trammel study.

No, most of NMN and NR are degraded to NAM before reaching blood stream. My current estimate is 20% to 30% NR reach liver. The amount of NR and NMN reaching blood is probably below 5%.

[able]

No, most of NMN and NR are degraded to NAM before reaching blood stream. My current estimate is 20% to 30% NR reach liver. The amount of NR and NMN reaching blood is probably below 5%.

 

I agree that a high % of NR and NMN are likely degraded to NAM in the liver.

 

But why is the increase in MeNAM 2-4x faster than with NR?

 

It seems a significant amount is not taking the 4 hour journey thru intestines and liver as with NR.

[MikeDC]

I agree that a high % of NR and NMN are likely degraded to NAM in the liver.

But why is the increase in MeNAM 2-4x faster than with NR?

It seems a significant amount is not taking the 4 hour journey thru intestines and liver as with NR.

I don’t think MeNAM increases faster than NR. It is a matter of scale. NR seems to be able to increase MeNAM more than NMN.

[able]

I know you've seen this dozens of times, but here again is the chart from Trammel thesis that shows effect of 1,000 mg of NR.  As you know, it was 4 hours before NAD+ and other metabolites including 2py and 4py show a big spike.

 

In contrast, the other image shows results of 100, 250, and 500 mg NMN from this first study.  As you can see, 2py and 4py start increasing after approx 1 hour.  

 

It looks like NMN is far faster to reach the bloodstream than NR.  Why?

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Attached Files

•  nmn.jpg   165.96KB   0 downloads
•  trammell-brenner-NR.jpg   183.12KB   0 downloads

Edited by able, 09 November 2019 - 03:09 AM.

[Fredrik]

So when Dr Brenner says MeNam indicates NR->NAD+ that is  utilized, you believe it.  But if it is NMN, you say it is from NMN that was not metabolized to NAD+, but degraded back to NAM.  

 

Regardless of the path taken from NMN to MeNAM, in this small study, NMN reached the bloodstream and was metabolized to MeNAM 2-4x faster than NR in the Trammel study.

 

 

Just to add to your observation, Dr Brenner and Chromadex writes in their GRAS on page 89:

 

The pharmacokinetic analysis from the first in human clinical study (14NBHC) shows that Methyl-nicotinamide (MeN am), Py 4 and Py 2 are predominant NAD+ related metabolites that appear within hours after ingestion of a single dose of Niagen.

 

The generation of these NR metabolites is consistent with nicotinamide being an intermediate in the metabolism ofNiagen in humans.

 

Methyl-nicotinamide is a biomarker of niacin status and correlates with NAD+ levels in red blood cells in humans. (Jacob et al., 1989; Fu et al., 1989). Moreover MeNam, Py 4 and Py 2 concentrations in urine correlate with the levels of niacin intake and NAD+ levels in humans. (Jacob et al., 1989; Fu et al., 1989; Shibata et al., 1989).

 

Thus, the pharmacokinetic data strongly suggest that NR is metabolized in a similar fashion to nicotinamide in humans. This supports that NR is another form ofVitamin B3 that can function as a NAD+ precursor in cellular energy metabolism. 

 

Edited by Fredrik, 09 November 2019 - 07:01 AM.

[MikeDC]

I know you've seen this dozens of times, but here again is the chart from Trammel thesis that shows effect of 1,000 mg of NR. As you know, it was 4 hours before NAD+ and other metabolites including 2py and 4py show a big spike.

In contrast, the other image shows results of 100, 250, and 500 mg NMN from this first study. As you can see, 2py and 4py start increasing after approx 1 hour.

It looks like NMN is far faster to reach the bloodstream than NR. Why?

Told you to check the scale. NR increased MeNAM 100% in 0.3 hours. While NMN doubles it in 5 hours. NR increases MeNAM 10 folds in 4 hours.

[able]

Told you to check the scale. NR increased MeNAM 100% in 0.3 hours. While NMN doubles it in 5 hours. NR increases MeNAM 10 folds in 4 hours.

 

 

 

MeNAM flucutuates. It is back down at the next check at .6 hours.  Like all the other metabolites, it very clearly shows a big spike at 4.1 hours.  

 

This is comparing 1,000 mg of NR (in 1 human) vs 500 mg NMN.  

 

The only thing you can see in the comparison is that NMN appears to be faster acting.

 

Of course, more data is needed.  Hope to see more complete data from Dr Sinclair soon.

[MikeDC]

MeNAM flucutuates. It is back down at the next check at .6 hours. Like all the other metabolites, it very clearly shows a big spike at 4.1 hours.

This is comparing 1,000 mg of NR (in 1 human) vs 500 mg NMN.

The only thing you can see in the comparison is that NMN appears to be faster acting.

Of course, more data is needed. Hope to see more complete data from Dr Sinclair soon.

NR doubles MeNAM at 0.3 hours. Drops down to increase of 20% at 0.6 hours which is still higher than NMN. At 1 hour NR increased MeNAM 3 fold. It continued to increase up to 10 fold. It does not look like NMN is fast acting at all. NMN produced significantly less MeNAM overall.