• Log in with Facebook Log in with Twitter Log In with Google      Sign In    
  • Create Account
  LongeCity
              Advocacy & Research for Unlimited Lifespans

Photo
- - - - -

Sinclair’s new paper shows NMN needs to convert to NR before entering cells

nmn

  • This topic is locked This topic is locked
18 replies to this topic

#1 MikeDC

  • Guest
  • 1,478 posts
  • -465
  • Location:Virginia

Posted 11 September 2020 - 08:48 PM


This new paper from Sinclair finally settles the dispute. NMN needs to convert to NR before entering cells.

https://www.biorxiv....9561v1.full.pdf
  • Ill informed x 4
  • Disagree x 2
  • Dangerous, Irresponsible x 1
  • Informative x 1

#2 MikeDC

  • Topic Starter
  • Guest
  • 1,478 posts
  • -465
  • Location:Virginia

Posted 11 September 2020 - 08:54 PM

Only small amount of NMN and NR gets converted to NAD+ directly. But NMN and NR significantly increases endogenous NAD+ synthesis.
  • Dangerous, Irresponsible x 1
  • Ill informed x 1
  • Good Point x 1
  • Disagree x 1

#3 MikeDC

  • Topic Starter
  • Guest
  • 1,478 posts
  • -465
  • Location:Virginia

Posted 12 September 2020 - 09:33 PM

The paper says their data agrees with previous Ling Liu’s Study.
  • Disagree x 2
  • Dangerous, Irresponsible x 1
  • like x 1
  • Ill informed x 1

#4 MikeDC

  • Topic Starter
  • Guest
  • 1,478 posts
  • -465
  • Location:Virginia

Posted 13 September 2020 - 01:45 PM

Here is the data from Ling Liu’s paper. There is small amount of direct NR and NMN in the liver.
NR seems to generate twice as much as NMN. Oral NMN generated more NR than NMN in the blood
After oral supplementation. NR generates twice as much NR in the blood than NMN. Overall, NMN is 50% less
Bioavailable than NR.

Attached Files


  • Disagree x 2
  • Dangerous, Irresponsible x 1
  • Good Point x 1
  • Ill informed x 1

#5 able

  • Guest
  • 811 posts
  • 375
  • Location:austin texas
  • NO

Posted 14 September 2020 - 01:59 AM

It is unfortunate that the moderators here allow you to try and pump up your failing stock price by making such false threads.

 

The title of this thread is not supported at all by the research. 

 

They did not find that NMN has to be converted to NR to enter cells. In their experiments, they did find that most NMN and NR are broken down to NAM. But they also found NMN absolutely intact in tissues:

 

 

"Our results were in close alignment with those findings (Liu et al., 2018), where the ratio of intact M+7 or M+6 to M+0 unlabelled NAD+ was around 2%, whereas  the ratio of M+2 labelled to M+0 unlabelled NAD , presumably as a result of incorporation of free  Nam, was over 10% (Fig. 5c, j, 6c, j). "

 

Meaning, about 15% of the labelled NMN they found was intact, with the rest metabolized to NAM first.

 

They also noted that the extensive isotope labelling applied to the NMN severely limited the time points they could test, and would not capture the fast absoption by the dedicated NMN transporter, SLC12A8.

 
 

 

limited availability of isotope labelled material meant that this study used a single time point, rather than a time course which also encompassed very early timepoints, possibly missing the minute-order kinetics of direct NMN transport, as previously reported (Mills et al., 2016; Yoshino et al., 2011). 

 

 

The real findings of this research are that 

 

1. the gut microbiota play a role in metabolizing NMN and NR.

2. direct incorporation of NMN and NR to NAD+ is not the only method, and they may play a signaling role in triggering endogenous NAD+ production

 

They believe this may be why NMN and NR have such different effect than NAM.  Clearly, its not as straightforward as A + B = C

In the first quote below, they note the increase in unlabeled NAD metabolites is much greater than the labelled NMN supplied, in addition to some labelled NAD+ found in tissues.

 

A surprising aspect of these results was that treatment with 100% labelled NMN led to a striking increase in unlabelled NAD metabolites.

 

 

In contrast to that study, we argue that these counter-intuitive findings run against the classic mass-balance model, whereby it is assumed that exogenous NAD+ precursors raise NAD+ levels through their direct incorporation into the NAD metabolome. Instead, these results raise the idea that treatment with these exogenous precursors could indirectly trigger endogenous NAD+ biosynthesis. The mechanism for this is not yet clear, though given the profound effect of antibiotic treatment, in particular for the overwhelming abundance of NR in the gut (Fig. 5b, 6b, Supp. Fig. 4b, 6b), are likely to involve interplay with the gut microbiome. 

 

Importantly, the increased production of endogenous NAD+ metabolites following exogenous NMN/NR treatment suggests that the benefits of exogenous treatment with NMN or NR could be from indirect signalling, rather than direct incorporation – a finding that has profound importance for therapeutic strategies, in particular the choice of dosing.

 

 


Edited by able, 14 September 2020 - 02:25 AM.

  • Informative x 2
  • Agree x 2
  • like x 2
  • Ill informed x 1
  • WellResearched x 1
  • Good Point x 1

#6 MikeDC

  • Topic Starter
  • Guest
  • 1,478 posts
  • -465
  • Location:Virginia

Posted 14 September 2020 - 11:13 AM

This is from the paper that says NMN absorption in intestine is mostly through NR. Even though they only have one time interval. Liu’s paper showed many time intervals. The initial fast absorption you claim is very small compared to later time intervals if it existed.

“The inability of exogenous NMN to displace the endogenous NMN pool, combined with the surge of labelled NR, suggests that NMN uptake bypasses direct transport, and would instead support the dephosphorylation of NMN into NR to facilitate its intestinal absorption (Supp. Fig. 9). If direct transport of NMN does occur, it is in competition with the microbiome, as even when M+6 or M+7 labelling of NMN was observed at low levels, this only occurred in antibiotic treated animals (Fig. 5b, 6b).”
  • Disagree x 2
  • Ill informed x 2
  • Dangerous, Irresponsible x 1

#7 MikeDC

  • Topic Starter
  • Guest
  • 1,478 posts
  • -465
  • Location:Virginia

Posted 14 September 2020 - 11:19 AM

I believe the study that showed direct absorption showed time intervals upto 35 mins. Liu’s study showed time intervals from 5 minutes to 135 minutes.
You can try to show doubts, but the overwhelming evidence is NMN converts to NR even before absorption into intestine.
  • Disagree x 3
  • Dangerous, Irresponsible x 1
  • Ill informed x 1

#8 MikeDC

  • Topic Starter
  • Guest
  • 1,478 posts
  • -465
  • Location:Virginia

Posted 14 September 2020 - 11:32 AM

“as even when M+6 or M+7 labelling of NMN was observed at low levels, this only occurred in antibiotic treated animals (Fig. 5b, 6b).”

Unless you take antibiotics when you take NMN, direct absorption of NMN through gut can not be detected.
  • Disagree x 3
  • Dangerous, Irresponsible x 1
  • Good Point x 1
  • Ill informed x 1

#9 able

  • Guest
  • 811 posts
  • 375
  • Location:austin texas
  • NO

Posted 15 September 2020 - 03:35 PM

“as even when M+6 or M+7 labelling of NMN was observed at low levels, this only occurred in antibiotic treated animals (Fig. 5b, 6b).”

Unless you take antibiotics when you take NMN, direct absorption of NMN through gut can not be detected.

 

 

They did not detect direct NMN-> NAD+ in the gut except in mice given antibiotics in THIS research.   That is not proof it doesn't happen anywhere in the body in any instance, as you claim in the title.

 

SLC12a8 was shown to transport it directly in other research, as did the Mills research in 2016.

 

Imagine you get up early for breakfast and see some deer in your backyard.  Your wife gets up an hour later, and they are gone.

 

You tell her about the deer.  She tells you it didn't happen because she didn't see them when she got up for breakfast.

 

Then, she goes on facebook to tell everyone you are crazy, and she has proof there were no deer because she took a picture of the backyard when she woke up.

 

To me, that is a good analogy of how you misinterpret research and make statements of fact that are not in the research.


Edited by able, 15 September 2020 - 03:36 PM.

  • Agree x 2
  • like x 2
  • Good Point x 1
  • WellResearched x 1

#10 MikeDC

  • Topic Starter
  • Guest
  • 1,478 posts
  • -465
  • Location:Virginia

Posted 15 September 2020 - 08:56 PM

This study didn’t observe direct NMN absorption. Liu’s paper also showed near zero direct NMN absorption. The NMN transporter study was debunked by Brenner as manipulation of noise.

Sinclair has spoken. NMN doesn’t get absorbed directly in any meaningful way.
  • Disagree x 2
  • Dangerous, Irresponsible x 1
  • Ill informed x 1

#11 able

  • Guest
  • 811 posts
  • 375
  • Location:austin texas
  • NO

Posted 15 September 2020 - 09:07 PM

This study didn’t observe direct NMN absorption. Liu’s paper also showed near zero direct NMN absorption. The NMN transporter study was debunked by Brenner as manipulation of noise.

Sinclair has spoken. NMN doesn’t get absorbed directly in any meaningful way.

 

 

Debunked by Brenner???  Thats funny, and about as meaningful as you interpreting research here.  He is extremely biased, and other researchers don't agree with him about slc12a8.  It is unclear how much - it does seem likely it is small quantities.   But it does transport some NMN direct to NAD+.  For you to claim the opposite, is dishonest.

 

As you know the Mills research in 2016 clearly shows labelled, intact NMN in the blood within 15 minutes and in soleus muscle within 30 minutes. 


Edited by able, 15 September 2020 - 09:07 PM.

  • Agree x 2
  • Well Written x 1
  • Good Point x 1

#12 MikeDC

  • Topic Starter
  • Guest
  • 1,478 posts
  • -465
  • Location:Virginia

Posted 15 September 2020 - 11:35 PM

The Plasma NMN at 15 minutes is not labeled. This could be due to endogenous increase as Sinclair’s paper suggested.
The double labeled NaD+ increase in the muscle could be due to double labeled NR. You can’t tell if the double labeled NAD+ was from NMN or NR since both have the same double label.
  • Dangerous, Irresponsible x 2
  • Ill informed x 1

#13 MikeDC

  • Topic Starter
  • Guest
  • 1,478 posts
  • -465
  • Location:Virginia

Posted 15 September 2020 - 11:43 PM

Brenner mentioned that he never measure plasma NAD+ because of the cell breakage. The measures NAD+ or NMN in the plasma could be from broken cells.
  • Dangerous, Irresponsible x 2
  • Ill informed x 1
  • Disagree x 1

#14 able

  • Guest
  • 811 posts
  • 375
  • Location:austin texas
  • NO

Posted 16 September 2020 - 12:29 AM

Brenner has made excuses for years on various changing reasons why NR is NEVER found in blood plasma.  

 

So, your theory is that NMN given to mice shows up in blood plasma in minutes, due to some broken cells?  But these broken cells never yield NR?  And they have a big spike in NMN and NAD+ from these "broken cells" only after NMN dosage, but not before?

Very strange.

 


Edited by able, 16 September 2020 - 12:34 AM.

  • Agree x 2
  • Good Point x 2
  • Well Written x 1

#15 MikeDC

  • Topic Starter
  • Guest
  • 1,478 posts
  • -465
  • Location:Virginia

Posted 16 September 2020 - 11:06 AM

Brenner has made excuses for years on various changing reasons why NR is NEVER found in blood plasma.

So, your theory is that NMN given to mice shows up in blood plasma in minutes, due to some broken cells? But these broken cells never yield NR? And they have a big spike in NMN and NAD+ from these "broken cells" only after NMN dosage, but not before?
Very strange.


Not big spikes. Just a little change. They only looked at a short time period. If you look over longer period like liu’s data, these spikes are not significant.
  • Dangerous, Irresponsible x 2

#16 longévité

  • Guest
  • 7 posts
  • 9
  • Location:USA

Posted 15 October 2020 - 01:17 PM

Washington Post: Do NAD-boosting supplements fight aging? Not according to current research. https://www.washingt...e8c2_story.html


Edited by longévité, 15 October 2020 - 01:34 PM.


#17 LawrenceW

  • Member
  • 388 posts
  • 329
  • Location:California

Posted 15 October 2020 - 01:47 PM

Washington Post: Do NAD-boosting supplements fight aging? Not according to current research. https://www.washingt...e8c2_story.html

 

 

"Imai said there’s evidence that supplemental NMN behaves differently from NR in the human body, including absorbing in to our tissues faster, which may make NMN more promising. "



#18 MikeDC

  • Topic Starter
  • Guest
  • 1,478 posts
  • -465
  • Location:Virginia

Posted 15 October 2020 - 06:36 PM

"Imai said there’s evidence that supplemental NMN behaves differently from NR in the human body, including absorbing in to our tissues faster, which may make NMN more promising. "

Quoting his own trash study. The new and better studies from Sinclair says otherwise.

Edited by MikeDC, 15 October 2020 - 06:37 PM.

  • Disagree x 1

#19 Gal220

  • Member
  • 298 posts
  • 70
  • Location:United States

Posted Today, 05:06 AM

Does anyone even consider this an issue using liposomal NMN or NAD+?







Also tagged with one or more of these keywords: nmn

0 user(s) are reading this topic

0 members, 0 guests, 0 anonymous users