12 replies to this topic

[Michael]

All:
 
Haven't looked beyond the abstract and a glance at the money-shot Figure and table yet:
 

PLoS One. 2017 Dec 6;12(12):e0186459. doi: 10.1371/journal.pone.0186459. eCollection 2017.

An open-label, non-randomized study of the pharmacokinetics of the nutritional supplement nicotinamide riboside (NR) and its effects on blood NAD+ levels in healthy volunteers.

Airhart SE1, Shireman LM2, Risler LJ2, Anderson GD3, Nagana Gowda GA4,5, Raftery D4,5, Tian R5, Shen DD2,3, O'Brien KD1.

... In this non-randomized, open-label PK study of 8 healthy volunteers, 250 mg NR was orally administered on Days 1 and 2, then uptitrated to peak dose of 1000 mg twice daily on Days 7 and 8. On the morning of Day 9, subjects completed a 24-hour PK study after receiving 1000 mg NR at t = 0. Whole-blood levels of NR, clinical blood chemistry, and NAD+ levels were analyzed.

RESULTS:
Oral NR was well tolerated with no adverse events. Significant increases comparing baseline to mean concentrations at steady state (Cave,ss) were observed for both NR (p = 0.03) and NAD+ (p = 0.001); the latter increased by 100%. Absolute changes from baseline to Day 9 in NR and NAD+ levels correlated highly (R2 = 0.72, p = 0.008). ...

PMID: 29211728

DOI: 10.1371/journal.pone.0186459

This constitutes the publication of this trial registered at clinicaltrials.gov .

[Harkijn]

Though it's small scale and short duration this study seems very important to me. The subjects were only 33 years on average and still there were clear increases in blood levels of NR as well as NAD+. (Understandably tissue levels were not measured)

Also interesting to see that NR absorption between individuals seem to vary widely and that there is no lineair relation between NR ingestion and NAD+ levels over time.

Hoping for your informed comment Michael!

[bluemoon]

Why would it be unusual for a group with an average age of 33 to have a rise in NAD+? If they were all 20 year olds, large increases would surprise me.   

[Harkijn]

Why would it be unusual for a group with an average age of 33 to have a rise in NAD+? If they were all 20 year olds, large increases would surprise me.   

 Average is the key word here. 

Additionally, in earlier anecdotal, personal and sometimes scientific reports the consensus seemed to move towards NR being more beneficial for much older people and perhaps those with a medical condition. Now, this small scale study shows that much younger people hit an NAD+ ceiling at 1000mgs. As noted before, too early for definitive conclusions, also about if high NAD+ is always positive and if so in which tissues....

[able]

 

Why would it be unusual for a group with an average age of 33 to have a rise in NAD+? If they were all 20 year olds, large increases would surprise me.   

 Average is the key word here. 

Additionally, in earlier anecdotal, personal and sometimes scientific reports the consensus seemed to move towards NR being more beneficial for much older people and perhaps those with a medical condition. Now, this small scale study shows that much younger people hit an NAD+ ceiling at 1000mgs. As noted before, too early for definitive conclusions, also about if high NAD+ is always positive and if so in which tissues....

 

 

This showed PEAK Nad+ levels maxed out on day 9, but the trough and average NAD+ levels were higher after day  9.

 

Of course, we don't know which is more important for health.

[able]

I find it most interesting that they have solved the problem of detecting NR in the blood cells (not plasma), and find it IS present at baseline, and increased significantly after supplementation.

 

The problem was not as Trammel said, that NR is phosphorylated to NMN too quickly, but in how quickly it degrades in blood (unless chilled, or proteins are removed)

 

To me, it indicates at least SOME NR makes it through the digestive process intact, and does circulate.

 

Which explains why NR has different effects that NAM.

 

But the authors did point out that it’s possible (some?) NR is digested to NAM and then makes its way back to NMN and NAD+

 

“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”

 

One thing I’m still trying to comprehend is, why it shows an increase in NR that corresponds to increase in NAD+, yet no change in NMN? 

 

Does it pass thru NMN so quickly to NAD+ that it doesn’t register an increase?

 

I’m also interested in what others think about any inference we can draw on dosing schedule

 

They found NR peaked at about 3hrs, with a half-life of 2.7 hours, and returning to baseline by 6-8 hours.

 

Yet NAD+ stays elevated pretty much throughout  day 9.

 

If simply elevated  NAD+ is the goal, that implies once daily dosage might be sufficient.

 

But if you’re trying to elevate NR in the blood for longer than 6 hours, it seem 2-3 doses a day is a better bet, imo.

Edited by able, 07 December 2017 - 09:44 PM.

[stefan_001]

http://journals.plos....0186459#sec025

 

I think this study is flawed with its split in 4 very good boosts and 4 minor. Perhaps a testing issue or then  the age range is too big:

 

The remaining eight healthy volunteers (6 female, 2 male, age range 21–50 years) met all inclusion criteria and provided informed consent.

 

I would expect that the 50 year old has the biggest boost in NAD+ and the 21 year old the lowest. Then again the study reports absolute values...... Some speculation, the red curve is likely the oldest participant as that curve has the lowest NAD+ concentration at day 1. So the NR supplementation would give a boost of 50% to the oldest person. That is actually inline with other studies and would point to degradation of other required enzymes as was mentioned by Michael in another thread or presence of other NAD+ consumers e.g. the famous CD38. Nevertheless a good boost for an "oldie". Would be interesting to see whether that boost would improve over longer time.

 

Its waiting for the next study. At least there are now 3 studies indicating NR raising NAD+ so at least there is consistency.

Edited by stefan_001, 31 December 2017 - 07:57 AM.

[able]

http://journals.plos....0186459#sec025

 

I think this study is flawed with its split in 4 very good boosts and 4 minor. Perhaps a testing issue or then  the age range is too big:

 

The remaining eight healthy volunteers (6 female, 2 male, age range 21–50 years) met all inclusion criteria and provided informed consent.

 

I would expect that the 50 year old has the biggest boost in NAD+ and the 21 year old the lowest. Then again the study reports absolute values...... Some speculation, the red curve is likely the oldest participant as that curve has the lowest NAD+ concentration at day 1. So the NR supplementation would give a boost of 50% to the oldest person. That is actually inline with other studies and would point to degradation of other required enzymes as was mentioned by Michael in another thread or presence of other NAD+ consumers e.g. the famous CD38. Nevertheless a good boost for an "oldie". Would be interesting to see whether that boost would improve over longer time.

 

Its waiting for the next study. At least there are now 3 studies indicating NR raising NAD+ so at least there is consistency.

 

Good point.  It would be great to see the ages.  

 

Although if there was some correlation, particularly if the 50 year old showed best response, wouldn't they have published that?   Or is there some confidentiality reason that would not allow that?

[able]

  - below quote copied from personal experience thread, in effort to keep the threads on topic - 

Turnbuckle I agree, that you cannot trust any of the studies financed or conducted by any scientist with a commercial interest in the outcome. NAD precussors are ripe for abuse because they are supplements without regulation. CDX, Bremmer,Guarente or Sinclair. They have all had multiple chances to mention all the other precussors, but have declined to do so. As we all have said, we need an unbaised trial comparing NR, N+R, and NMN. Not sure if we will ever get it.

 

They don't care about the elderly patients that are ageing and dying now.  Sinclair said 3-4 years on NMN, but doesn't say a word about NR or N + R which can be cheaply bought now.

 

Sinclair says 3-4 years for HIS version - some derivative or more bio-available NMN that he can patent.  Although he does say he and his dad take "regular" NMN now, so that seems a recommendation.  And he does mention other precursors much more than the NR fans.

 

The fact that he, a proponent of competitor molecule is editor of this paper makes me trust it a bit more. It does seem to have less of the exaggerated claims than other papers like the trammel thesis.

 

 

Edited by able, 31 December 2017 - 03:52 PM.

[Heisok]

I have an issue. Eight paricipants at baseline had B.G. measured.

 

Glucose mg/dL 93 +- 7 to 97 +- 20       Diff 4        pvalue .51

 

It did go up, and the standard deviation went up to 20 from 7. Is that move of 4 given the much higher standard deviation in such a small group a concern? significant? Indicate that Ribose might be involved in some way?

 

I think that it would be nice to see the raw data. A standard deviation of 20 after even a small rise in B.G. is big. What were the levels of the lowest and highest at baseline, and lowest and highest resulting in a S.D. of 20?

Edited by Heisok, 01 January 2018 - 02:50 AM.

[stefan_001]

I have an issue. Eight paricipants at baseline had B.G. measured.

 

Glucose mg/dL 93 +- 7 to 97 +- 20       Diff 4        pvalue .51

 

It did go up, and the standard deviation went up to 20 from 7. Is that move of 4 given the much higher standard deviation in such a small group a concern? significant? Indicate that Ribose might be involved in some way?

 

I think that it would be nice to see the raw data. A standard deviation of 20 after even a small rise in B.G. is big. What were the levels of the lowest and highest at baseline, and lowest and highest resulting in a S.D. of 20?

 

I thought one the effects of ribose is that it reduces BG as it stimulates insulin release. Levels recover in about 2 hours. I didnt see when they did the measurement.

[Heisok]

Thanks Stefan_001. I think that I should just keep my question focused. To me the  numbers might represent a significant change after only 9 days in light of the Standard Deviation. (I am not saying that it is medically an issue) After looking at the paper again, I see that the blood samples were taken after a 6 hour fast.

 

I think that I am reading too much into this B.G. results. Does a 6 hour fasted B.G. mean of 97 with a standard deviation of 20 indicate that some subjects had much higher than 97 , and much lower than 97.

 

 "Blood samples were obtained to monitor for potential side effects of NR therapy following
6-hour fasts and prior to NR dosing at baseline (Day 1) and on Days 2 and 9. Laboratory
tests on these samples included complete blood count with white blood count differential and
platelets, a serum chemistry panel (sodium, potassium, chloride, glucose, blood urea nitrogen,
and creatinine), creatine kinase, aspartate aminotransferase (AST), alanine aminotransferase
(ALT), uric acid, and lactate dehydrogenase.

 

"Secondary outcomes were to determine the safety and tolerability of NR by assessing adverse event rates and comparisons of laboratory tests, specifically serum levels of potassium, creatine kinase (myositis), glucose (insulin resistance), uric acid and alanine aminotransferase."

[stefan_001]

I tend to agree that the numbers are deviating. But I am not not sure what to do with this study. There are several things that kind of make it harder to interpret. There is the escalating dosing level peaking in the last two days, the large age range and now that you mention 6 hour fast that sounds a bit short. I mean what was the point of going in the last two days to 2 gram a day dosing, perhaps to make sure you will see something in the blood?

Edited by stefan_001, 01 January 2018 - 08:54 PM.