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Slc12a8 transports NMN into cells

nmn nad nad+

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#1 HaplogroupW

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Posted 07 January 2019 - 07:13 PM


Overview:

https://medicine.wus...oute-for-cells/

 

paper:

https://www.nature.c...2255-018-0009-4


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#2 orion22

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Posted 07 January 2019 - 08:06 PM

how to increase 

Slc12a8?

#3 HaplogroupW

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Posted 08 January 2019 - 06:17 AM

Sinclair commentary:

 

https://www.nature.c...2255-018-0015-6

 


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#4 Harkijn

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Posted 08 January 2019 - 07:45 AM

Thanks for posting these publications Haplo. They give strong support for supplementing NMN.

Interesting that Sinclair emphasizes that this is an additional pathway and  also that he hypothesizes about NMN production by the microbiome.


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#5 able

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Posted 08 January 2019 - 09:20 AM

It says Slca18 is unregulated when NAD+ levels are low in aged animals, and is a sort of backup pathway to restore NAD+ independent of the NAMPT salvage pathway.  

 

"expression of the Slc12a8 gene is upregulated in response to NAD+ decline, allowing cells to meet to an urgent demand for NAD+ biosynthesis"

 

And that it is specific for NMN only, not NR or even the very similar NAMN.

 

"We further show that Slc12a8 specifically transports NMN, but not nicotinamide riboside"

 

So not only does this refute the Brenner/Chromadex story that "NMN must convert to NR to enter cells", it shows a pathway where NMN works to restore NAD+ in aged or stressed animals, and it does not work with NR.

 

Most of their test were with small intestine, as that is where Slca18 is most abundant, but is also found in liver, pancreas, and fat cells:

 

"Slc12a8 is highly expressed in the small intestine and pancreas and moderately expressed in the liver and white adipose tissue"

 

So does the NAD+ from intestine reach tissues throughout the body?  NAD+ produced by Slc12a8 in the liver?  They did some testing with liver cells, and they do say this explains the speed (minutes) at which oral NMN reaches muscles and other tissues seen in their prior work, and would explain why it is much faster than has been found with NR.

 

 

"the fast uptake of NMN was completely abrogated in Slc12a8-knockdown (Slc12a8-KD) hepatocytes, whereas no significant reduction in NMN uptake was observed in Nrk1-knockdown (Nrk1-KD) hepatocytes (Fig. 1f), suggesting that Slc12a8 is necessary for the fast uptake of NMN in primary hepatocytes and that the observed increase in intracellular NMN is not due to the conversion of NR or nicotinamide into NMN."

 

Also, mice missing the Slc12a8 gene were disadvantaged in NAD+ synthesis:

 

whole-body Slc12a8-KO mice display significant defects in direct, minute-order NMN transport and NAD+ biosynthesis

 

Lastly, I notice they made a point about flaws in the processing of samples in other research that may account for some discrepency - wonder if that is referring to the Liu study?

 

"plasma samples need to be processed immediately after collection, as we did in this study, because freezing blood or plasma samples causes inaccurate measures of NMN levels."

 

 

 

 


Edited by able, 08 January 2019 - 09:43 AM.

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#6 stefan_001

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Posted 08 January 2019 - 12:06 PM

This an interesting one. You can use expression atlas to see where in the body this could have meaningfull impact:

Slc12a8

https://www.ebi.ac.u...als"]}#baseline

Looks like:Thyroid, small and large intestine.

 

Here the expression for the NR transporters:

NRK1

https://www.ebi.ac.u...als"]}#baseline

You can also find there strong expression in small intestine.

and NRK2

https://www.ebi.ac.u...als"]}#baseline

 

 

I would say that the NRKs are more major transporters but this finding does add to the logic of using both.


Edited by stefan_001, 08 January 2019 - 12:12 PM.

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#7 Harkijn

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Posted 08 January 2019 - 04:29 PM

Thanks for posting these publications Haplo. They give strong support for supplementing NMN.

Interesting that Sinclair emphasizes that this is an additional pathway and  also that he hypothesizes about NMN production by the microbiome.

Taking a second look I now see that it is not Sinclair but the  researchers themselves who draw these  conclusions  ;) .

The mice were fed NMN by  oral  gavage which more or less excludes sublingual absorption. So for this pathway sublingual supplements do not seem necessary?


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#8 able

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Posted 08 January 2019 - 05:46 PM

Taking a second look I now see that it is not Sinclair but the  researchers themselves who draw these  conclusions  ;) .

The mice were fed NMN by  oral  gavage which more or less excludes sublingual absorption. So for this pathway sublingual supplements do not seem necessary?

 

That is what I think also - some NMN supplements can bypass the digestion and quickly convert to NAD+ .  

 

Explains why it is so much faster - can  make it in minutes, vs the  hours for NR that goes thru  stomach and liver before making it to NAD+.

 

 Of course, we don't know what % of a capsule will utilize this pathway to NAD+, and what % will be digested to NAM.

 

I still prefer sublingual, as 30% or so goes direct to bloodstream, and the remainder goes thru the small intestine and some may use Sl12A8 to NAD+.

 

 

It is interesting this pathway is not needed in young animals, but increased in old in response to low NAD+.

 

As Orion22 says - how do we stimulate more Slc12A8?

 

Imai (and likely Sinclair), have already applied for some drugs to go with NMN, but surely there are some lifestyle things we can do also.

 

I'm guessing the same fasting, exercise, sauna and such we do to raise NAD+ levels also signal for increased Slc12A8 and may be why it makes sense to take your NMN with exercise.


Edited by able, 08 January 2019 - 05:48 PM.

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#9 Fredrik

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Posted 08 January 2019 - 07:15 PM

Thanks for posting these publications Haplo. They give strong support for supplementing NMN.

Interesting that Sinclair emphasizes that this is an additional pathway and  also that he hypothesizes about NMN production by the microbiome.

 

I would wait until the first human trials of NMN are published. If oral supplementation of NMN can influence human health in measurable ways THAT would give strong support for supplementing with NMN. NR has not shown any impressive clinical results in human trials as of yet. 


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#10 LawrenceW

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Posted 08 January 2019 - 08:00 PM

I would wait until the first human trials of NMN are published. If oral supplementation of NMN can influence human health in measurable ways THAT would give strong support for supplementing with NMN. NR has not shown any impressive clinical results in human trials as of yet. 

 

Dr. Sinclair has already reported that his trials showed that NMN is safe for human consumption.  Which trials do you suggest we wait for?



#11 Harkijn

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Posted 08 January 2019 - 08:33 PM

I would wait until the first human trials of NMN are published. If oral supplementation of NMN can influence human health in measurable ways THAT would give strong support for supplementing with NMN. NR has not shown any impressive clinical results in human trials as of yet. 

Don't hold your breath for that. I agree with Haplogroup here.



#12 Fredrik

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Posted 08 January 2019 - 09:00 PM

Dr. Sinclair has already reported that his trials showed that NMN is safe for human consumption.  Which trials do you suggest we wait for?

 

Safety is important. I would suggest efficacy is important too. No human trials of NMN have been published so we do not know if it is beneficial, or even safe, in humans.

 

Dr Sinclairs anecdotal evidence of NMN´s safety is encouraging but we need actual published evidence for that. Both he and Dr Charles Brenner is heavily economically invested in their respective compounds and derivatives of them. So the peer-review process is very important. Anecdotes and snippets from interviews is interesting but we also need the actual data.

 

To say that NR or NMN is beneficial to supplement with for humans is a premature conclusion at this stage. There is no data supporting that. 

 

We do not know how much, if any, is needed of NR/NMN in addition to the NAD we synthesise from tryptophan and the broken down NAD from the diet and NMN possibly made from gut bacteria in addition to precursors like nicotinic acid, NR and nicotinamide.

 

I hope for good results both for NR and NMN. But we are not there yet.


Edited by Fredrik, 08 January 2019 - 09:12 PM.

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#13 stefan_001

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Posted 08 January 2019 - 09:28 PM

@able Where does it say in the study that the small intestine releases NAD+ into the bloodstream? I read it more that the small intestine consumed the NMN and raised NAD+ in the small intestine cells. That would mean NAM is released into the blood stream.


Edited by stefan_001, 08 January 2019 - 09:29 PM.

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#14 able

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Posted 08 January 2019 - 10:33 PM

It's possible NAD+ from Slc12a8 in small intestines may be mostly confined and not have any impact on other tissues throughout the body.  But that doesn’t make sense to me.   Slc12a8 is upregulated in response to low NAD+ levels, to protect cells.  Why would intestines be the only tissue that benefits from this unique mechanism?

 

I don’t think they clearly specify what happens to NAD+ from the intestines.

 

I do see these quotes that imply Slc12a8 has a system wide impact:

 

the whole-body Slc12a8-KO mice display significant defects in direct, minute-order NMN transport and NAD+ biosynthesis, particularly in the jejunum and ileum

 

The results from gut-specific Slc12a8-KD mice and whole-body Slc12a8-KO mice demonstrate that the major place where NMN is absorbed is the small intestine

 

(KD=Knockdown, KO=Knockout)

 

They found Slc12a8 is most prevalent in small intestines and is what they tested most.  But it is also found in the liver and may be significant source of NAD+ creation.  But that would be much slower.  

 

They say this pathway explains why prior research show NMN is taken up  and makes it to NAD in tissues throughout the body in minutes.  But I don't know if that implies it is thru the small intestine of not.


Edited by able, 08 January 2019 - 10:37 PM.

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#15 stefan_001

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Posted 08 January 2019 - 11:20 PM

 

It's possible NAD+ from Slc12a8 in small intestines may be mostly confined and not have any impact on other tissues throughout the body.  But that doesn’t make sense to me.   Slc12a8 is upregulated in response to low NAD+ levels, to protect cells.  Why would intestines be the only tissue that benefits from this unique mechanism?

 

I don’t think they clearly specify what happens to NAD+ from the intestines.

 

I do see these quotes that imply Slc12a8 has a system wide impact:

 

the whole-body Slc12a8-KO mice display significant defects in direct, minute-order NMN transport and NAD+ biosynthesis, particularly in the jejunum and ileum

 

The results from gut-specific Slc12a8-KD mice and whole-body Slc12a8-KO mice demonstrate that the major place where NMN is absorbed is the small intestine

 

(KD=Knockdown, KO=Knockout)

 

They found Slc12a8 is most prevalent in small intestines and is what they tested most.  But it is also found in the liver and may be significant source of NAD+ creation.  But that would be much slower.  

 

They say this pathway explains why prior research show NMN is taken up  and makes it to NAD in tissues throughout the body in minutes.  But I don't know if that implies it is thru the small intestine of not.

 

 

Well the transporter does not either transport NMN intact through the small intestine walls into the vessels, it transports it into the small intestine cells. Neither do they write that small intestine cells have some unique function to release NAD+ in the bloodstream. So again I see it more likely that the small intestines consume the NMN and release NAM as product into the bloodstream. And NMN that is not consumed in the small intestines will as you write  end up into the liver and be converted into NAM.

 

So if NAM is released into the bloodstream as distribution mechanism  then I would challenge the large relevance of this transporter pathway beyond getting NAM quickly into circulation and boosting small intestine health (which I already find an exciting finding). As for the Slc12a8 in other tissues you can click the links I posted earlier from the expression atlas.
 


Edited by stefan_001, 08 January 2019 - 11:31 PM.

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#16 able

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Posted 08 January 2019 - 11:50 PM

You write it already yourself if, it is not clear the small intestines release NAD+ in the bloodstream. So then it put some questions around the theory you postulated on fast release of NAD+ into the body. And the transporter does not transport NMN intact through the small intestine walls, it transports it into the cells. I see it more likely that the small intestines consume the NMN and release NAM as product into the bloodstream.

 

So if NAM is released into the bloodstream as distribution mechanism  then I would challenge the large relevance of this transporter pathway beyond getting NAM quickly into circulation. As for the Slc12a8 in other tissues you can click the links I posted earlier from the expression atlas.
 

 

It is not my theory about the fast release of NAD+

 

The Mills/Imai study in 2016 very clearly demonstrated that labelled NMN shows in soleus muscle in minutes and converts to NAD+ within 15 minutes.

 

The question has long been HOW this could be, especially if it had to first convert to NR, since NR has never shown such speed.

 

This pathway shows very fast uptake, and the authors say it explains such  previously found results from their lab.

 

They also did some studies with liver cells that show a 90% reduction of NMN uptake with Slc12a8 Knockout:

 

Lastly, by using primary hepatocytes from control and Slc12a8-KO mice, we again compared the transport of O18-D-NMN and O18-D-NR. When treated with 100 μM O18-D-NMN, Slc12a8-KO hepatocytes showed ~90% reduction in O18-D-NMN uptake compared with control wild-type hepatocytes at 5 min (Fig. 3i)

 

Yes, I know Slc12A8 is not as prevalent as NRK1, and may be limited.  It may indicate a clear advantage over NR, or be inconsequential.

 

But it very clearly has some impact on NMN utilization in mice, and is increased in older animals to compensate for low NAD+.  The authors say it explains the speed of action they find with NMN.

 

It certainly seems Chromadex will have to update their marketing claims.

 


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#17 stefan_001

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Posted 09 January 2019 - 12:04 AM

@able

 

For the fast uptake if you recall this was discussed before. Actually we dont know if the same spike occur also with NR because as far as I can see there has been any study that measured NR in the minutes after supplementation. Typically the measurement has taken place after the time that the NMN NAD+ spike is seen. Given that NRK1 is lso strongly expressed in small intestines I could imagine a same spike is there with NR.

 

not sure how Chromadex factors into this and perhaps its a sign I will stop with the discussion for me as it is driven by this eternal anti-chrmadex bias..


Edited by stefan_001, 09 January 2019 - 12:05 AM.

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#18 able

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Posted 09 January 2019 - 01:04 AM

@able

 

For the fast uptake if you recall this was discussed before. Actually we dont know if the same spike occur also with NR because as far as I can see there has been any study that measured NR in the minutes after supplementation. Typically the measurement has taken place after the time that the NMN NAD+ spike is seen. Given that NRK1 is lso strongly expressed in small intestines I could imagine a same spike is there with NR.

 

not sure how Chromadex factors into this and perhaps its a sign I will stop with the discussion for me as it is driven by this eternal anti-chrmadex bias..

 

Chromadex factors in because they do a lot of advertising with this page, that makes dubious  claims (now proven wrong) like:

 

"2 NR can enter the cell. NMN cannot"

 

" 3. NMN makes NAD in 3 steps. NR requires only 2."

 

" 5. NR is taken orally. NMN is mostly studied by injection"


Edited by able, 09 January 2019 - 01:06 AM.

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#19 stefan_001

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Posted 09 January 2019 - 10:24 AM

Chromadex factors in because they do a lot of advertising with this page, that makes dubious  claims (now proven wrong) like:

 

"2 NR can enter the cell. NMN cannot"

 

" 3. NMN makes NAD in 3 steps. NR requires only 2."

 

" 5. NR is taken orally. NMN is mostly studied by injection"

 

Right should you move those concerns to a supplier chat? I thought this thread was about brand new research that is being vetted.
 


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#20 smithx

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Posted 09 January 2019 - 08:56 PM

Since we don't know whether the NMN remains in the intestine cells or not, sublingual remains the most reasonable way to attempt to raise blood levels of NMN.

 

Once we have pharmacokinetics evaluations of oral NMN we will be in a position to know whether the oral route is adequate or not. In the absence of this information, I'm sticking with sublingual.

 

Taking a second look I now see that it is not Sinclair but the  researchers themselves who draw these  conclusions  ;) .

The mice were fed NMN by  oral  gavage which more or less excludes sublingual absorption. So for this pathway sublingual supplements do not seem necessary?

 


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#21 LawrenceW

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Posted 09 January 2019 - 09:30 PM

Since we don't know whether the NMN remains in the intestine cells or not, sublingual remains the most reasonable way to attempt to raise blood levels of NMN.

 

 

 

 

On the contrary, from the study  "We have previously shown that NMN is absorbed from the gut into blood circulation within 2–3 min and transported into tissues within 10–30 min (refs 5,15). NMN is then immediately utilized for NAD+biosynthesis, significantly increasing NAD+ content in tissues over 60 min."

 

I agree that until we know what % is absorbed from the gut that sublingual is a better way of getting NMN directly into the blood. The only problem is the combination of saturation point and transport time limiting the amount of NMN that can be transported into the blood.sublingually.

 

We have been experimenting with sublingual application of NMN since last spring and our current belief is that the saturation limit is 15 to 25 mgs per application and the transport time is somewhere around 45 minutes. Therefore, we believe that if you took 8 sublinguals during the day you would be getting 120 to 200 mgs of NMN into the blood directly with the rest passing into the gut to be processed at whatever rate that turns out to be. I have now started on what I believe will be my personal maximum benefits for minimum NMN dosing regimen. 400 mg of oral NMN with the activator twice per day interspersed with sublingual NMN 6 times per day.  I will be going in for my full blood test after 3 months of this regimen.  I will post the results when I receive them.


Edited by LawrenceW, 09 January 2019 - 09:34 PM.

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#22 bluemoon

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Posted 09 January 2019 - 09:47 PM

 

To say that NR or NMN is beneficial to supplement with for humans is a premature conclusion at this stage. There is no data supporting that.  

 

The above is not true. Elysium's study showed healthy older adults walked 8% further on a 6 minute walking test and did 8% better on a chair-balance test with 500 mg of NR and 100 mg of pterostilbine than the placebo group. We don't know to what extent NR and pterostilbine played a factor, though.

 

The U of Colorado study showed 1000 mg of NR taken over 6 weeks lowered blood pressure in healthy people with pre-hypertension by 10 points. It is a good guess based on the Elysium study that 500 mg of NR would have a similar effect - less certain about 250 mg. 


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#23 Fredrik

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Posted 09 January 2019 - 10:54 PM

We don't know to what extent NR and pterostilbine played a factor, though.

 

Right. We need human trials of the actual compounds first. Not on supplement combinations put together for commercial reasons.

 

The U of Colorado study showed 1000 mg of NR taken over 6 weeks lowered blood pressure in healthy people with pre-hypertension by 10 points. It is a good guess based on the Elysium study that 500 mg of NR would have a similar effect - less certain about 250 mg. 

 

 

 

That study was done on 24 people and partially funded by Chromadex. Only 13 of the subjects experienced any lowering of blood pressure. These are thoroughly unimpressive results even if they can be replicated in a larger study.

 

We can guess what different doses might do but we need human trials to know. 


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#24 bluemoon

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Posted 09 January 2019 - 11:39 PM

Right. We need human trials of the actual compounds first. Not on supplement combinations put together for commercial reasons.

 

 

That study was done on 24 people and partially funded by Chromadex. Only 13 of the subjects experienced any lowering of blood pressure. These are thoroughly unimpressive results even if they can be replicated in a larger study.

 

We can guess what different doses might do but we need human trials to know. 

 

The Elysium study is a hint that NR is accounting for a good part based on mouse studies, though, since pterostilbine was a small dose.

 

The others disagree with your "thoroughly unimpressive results even if they can be reproduced in a larger study" statement:

" “If this magnitude of systolic blood pressure reduction with NR supplementation is confirmed in a larger clinical trial, such an effect could have broad biomedical implications,” the authors note." (CU Bolder Today, March 28, 2018)

 

With respect to dosage, we have a good idea based on the NAD+ levels with the two different studies. The Elysium study showed 500 mg gave a 55% boost at week 8 and the Colorado study showed a 60% with 1000 mg at 6 weeks. Those are almost identical. 


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#25 Fredrik

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Posted 10 January 2019 - 12:44 AM

What good is increasing NAD levels in certain blood cells if there is no significant clinical benefit to show? NAD is a cofactor in the body, a compound, not a health benefit in and of itself.


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#26 Harkijn

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Posted 10 January 2019 - 07:02 AM

What good is increasing NAD levels in certain blood cells if there is no significant clinical benefit to show? NAD is a cofactor in the body, a compound, not a health benefit in and of itself.

NAD is not just a compound, it is a very essential compound. The longterm positive effects of optimal NAD+modulation are for instance described here.

Attached Files


Edited by Harkijn, 10 January 2019 - 07:03 AM.

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#27 Fredrik

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Posted 10 January 2019 - 12:04 PM

NAD is not just a compound, it is a very essential compound. The longterm positive effects of optimal NAD+modulation are for instance described here.

 

Yes, I know it is essential and I read that paper when it came out (but thank you for providing it here for others). But NAD is synthesised from many sources in the body. It also seems to be very tightly regulated with feedback loops.

 

Where is the proof of your "optimal NAD+ modulation" in humans? Who needs to supplement with precursors other than those in food and what benefits IN HUMANS would such supplementation have?

 

These questions are still unanswered. 


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#28 Harkijn

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Posted 10 January 2019 - 02:59 PM

'My' optimal NAD modulation? I wish I had one!


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#29 MikeDC

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Posted 20 February 2019 - 02:04 AM

I read the paper for the first time. There is no evidence that NMN entered cells intact. The expression of the transporter in the liver is 5000% less in the liver than in the intestine. Since only a few percent of NMN is transported in intestine, 5000% less of a few percent is nothing. This paper doesn’t change previous studies that show NRK1 is required for NMN to increase NAD+. If they really want to prove the NMN transporter works in any meaningful way, they should have knocked down NRK1 and NRK2. To say that since NAD+ is increased quickly in cells, it must be NMN transporter at work is stupid.
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#30 able

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Posted 20 February 2019 - 02:56 AM

I read the paper for the first time. There is no evidence that NMN entered cells intact. The expression of the transporter in the liver is 5000% less in the liver than in the intestine. Since only a few percent of NMN is transported in intestine, 5000% less of a few percent is nothing. This paper doesn’t change previous studies that show NRK1 is required for NMN to increase NAD+. If they really want to prove the NMN transporter works in any meaningful way, they should have knocked down NRK1 and NRK2. To say that since NAD+ is increased quickly in cells, it must be NMN transporter at work is stupid.

 

That is 100% incorrect.

 

This study proved conclusively that NRK1 is NOT required.

 

Now, you can say that NRK1 is still important - which is what Dr Sinclair says in the study.  

 

But it does prove the existence of a transporter that does not require NRK1, and can not transport NR.  

 

It is specific for NMN, and does not involve NR or NRk1 at all.


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