2255 replies to this topic

[Nate-2004]

 

So I finally had my homocysteine levels checked and it was pretty low after 5 months of NR. 7.7 uMols/L

 

Weren't you also taking a multivitamin?

 

Yes I was and have been taking Doctor's Best B-Complex, but not for nearly as long, though I should have mentioned that. The doctor said my B12 was a bit too high actually. This may explain the low value or may not.

[Tom Andre F. (ex shinobi)]

 

 

So I finally had my homocysteine levels checked and it was pretty low after 5 months of NR. 7.7 uMols/L

 

Weren't you also taking a multivitamin?

 

Yes I was and have been taking Doctor's Best B-Complex, but not for nearly as long, though I should have mentioned that. The doctor said my B12 was a bit too high actually. This may explain the low value or may not.

 

 

Yes Nate, this make all the difference. The homocysteine level or the hypermethylation down appear very fast actually. Thats why we recomend to never get a pick of homocysteine and always keep it down. On the other hand someone hypermethylated seems to very fast, almost directly get benefit from niacin supplementation.

 

How was your B12 tested ? wich method test ?
 

[Nate-2004]

Basically I think the suggestion is that if you've already taken 400mcg of methylfolate which is in the B-complex I take, and you take more niacin later on in the day, evening, or whatever, which I sometimes do because I take the NR earlier in the day, you can take B12 which is also a methyl donor. He said my B12 was a bit high and as you can see, my homocysteine is low, but honestly I have no idea where it was before the B-complex.

 

That's my interpretation of the whole methylation thing.

 

Just have it tested randomly once a year I think and you'll at least have the security of knowing you're safe.

Edited by Nate-2004, 07 September 2016 - 06:59 PM.

[Nate-2004]

Yes Nate, this make all the difference. The homocysteine level or the hypermethylation down appear very fast actually. Thats why we recomend to never get a pick of homocysteine and always keep it down. On the other hand someone hypermethylated seems to very fast, almost directly get benefit from niacin supplementation.

 

How was your B12 tested ? wich method test ?
 

 

 

I did not realize it was such a quick change. Almost makes it pointless to get tested but so long as I keep doing the same thing I should be ok.

 

So he tested B12 and Folate and the test result was 1023pg/mL for B12 and said the reference scale was 210 to 950 so it should be at 950 ideally. He said to half the dose I'm taking.

 

The folate result was 18.7 ng/mL with a range of 4.6 to 35.0 as normal.

 

I am trying to find the homocysteine test results and either I threw them away or hid them from myself somewhere, I know it said 7.7 but I don't remember what the scale was.

 

This was all blood test.

[Tom Andre F. (ex shinobi)]

 

Yes Nate, this make all the difference. The homocysteine level or the hypermethylation down appear very fast actually. Thats why we recomend to never get a pick of homocysteine and always keep it down. On the other hand someone hypermethylated seems to very fast, almost directly get benefit from niacin supplementation.

 

How was your B12 tested ? wich method test ?
 

 

 

I did not realize it was such a quick change. Almost makes it pointless to get tested but so long as I keep doing the same thing I should be ok.

 

So he tested B12 and Folate and the test result was 1023pg/mL for B12 and said the reference scale was 210 to 950 so it should be at 950 ideally. He said to half the dose I'm taking.

 

The folate result was 18.7 ng/mL with a range of 4.6 to 35.0 as normal.

 

I am trying to find the homocysteine test results and either I threw them away or hid them from myself somewhere, I know it said 7.7 but I don't remember what the scale was.

 

This was all blood test.

 

 

blood test is not reliable to check B12. Only MMA test it. But you probably have indeed high B12. However high B12 is not that good I read also since it means a certain bad condition too but maybe others expert can help with that ?

 

[Nate-2004]

blood test is not reliable to check B12. Only MMA test it. But you probably have indeed high B12. However high B12 is not that good I read also since it means a certain bad condition too but maybe others expert can help with that ?

 

What is an MMA test?

[Tom Andre F. (ex shinobi)]

The methylmalonic acid (MMA) test

[stefan_001]

blood test is not reliable to check B12. Only MMA test it. But you probably have indeed high B12. However high B12 is not that good I read also since it means a certain bad condition too but maybe others expert can help with that ?

What is an MMA test?

Did the doctor give you an explanation for the high B12? Taking in large amounts of B12 supplements should not lead to raised levels.

[Nate-2004]

 

 

blood test is not reliable to check B12. Only MMA test it. But you probably have indeed high B12. However high B12 is not that good I read also since it means a certain bad condition too but maybe others expert can help with that ?

What is an MMA test?

Did the doctor give you an explanation for the high B12? Taking in large amounts of B12 supplements should not lead to raised levels.

 

 

He didn't give any explanation other than that I should try halving my dose of B12. To quote him "Your B12 was actually a little high, which is not dangerous at that level, but you may consider halving your B12 supplement."

 

Why would it not lead to raised levels?

Edited by Nate-2004, 07 September 2016 - 07:59 PM.

[stefan_001]

blood test is not reliable to check B12. Only MMA test it. But you probably have indeed high B12. However high B12 is not that good I read also since it means a certain bad condition too but maybe others expert can help with that ?

What is an MMA test?

Did the doctor give you an explanation for the high B12? Taking in large amounts of B12 supplements should not lead to raised levels.

He didn't give any explanation other than that I should try halving my dose of B12. To quote him "Your B12 was actually a little high, which is not dangerous at that level, but you may consider halving your B12 supplement."

Why would it not lead to raised levels?

What I understand of B12 is that the reserves of B12 are stored in your liver and should not circulate. Also because Vitamin B12 is water-soluble when you consume more than needed the system can get rid of it.

[Tom Andre F. (ex shinobi)]

thanks stefan, thats what I thought too. Actually the blood test is nothin because does not make any difference between active and non acitve B12. Only the methylmalonic acid (MMA) test is reliable. However, it seems very likely he has high B12.

 

"

Vitamin B12 does not accumulate to toxic levels. Consuming large quantities does not cause side effects or high levels in your system, whether you get it through food or from taking high-dose supplements. High vitamin B12 in the bloodstream is associated with serious diseases. Medical conditions that can increase levels of vitamin B12 include liver disease, kidney failure and a group of blood cancers known as myeloproliferative disorders, which includes myelocytic leukemia and a condition that causes an overgrowth of red blood cells called polycythemia vera. Hypereosinophilic syndrome, a medical condition marked by too many white blood cells, also can cause high vitamin B12.

Warnings

High vitamin B12 is a symptom of an underlying illness that causes the amount in your blood to increase. For example, a damaged liver may release the vitamin out of storage and into the blood. In early stages, illnesses associated with high vitamin B12 often have generic symptoms, such as fatigue and loss of appetite. Considering they’re potentially life-threatening conditions, early diagnosis is vital, so consult your physician when you don’t feel up to par."

 

http://healthyeating...-mean-9057.html

 

I also read it was linked to cancer condition

[rlb373]

I am interested in this  relationship mentioned by Nate:

Is there a way for me to  search a single thread for a keyword...  without resorting to

 

 

looking on every page of the thread ?

 

Yes there is! Google is you friend (as long as it has indexed a page) So, the shortcut (to using "advanced search" - which is hard to find any more but is under "settings" in the lower right corner of you browser window) is to use site:{domain name} e.g.:

 

site:www.longecity.org/forum/topic/82770-nicotinamide-riboside-curated " were surprised by how rapidly NR was able to reactivate dormant mitochondria"

 

Pages from the last few days typically will not be indexed, but everything older than that should be. Try it, you'll like it! 

 

Also, the link to Google's advanced search is: https://www.google.com/advanced_search which I have bookmarked (and you should too)

[Nate-2004]

"Vitamin B12 does not accumulate to toxic levels. Consuming large quantities does not cause side effects or high levels in your system, whether you get it through food or from taking high-dose supplements. High vitamin B12 in the bloodstream is associated with serious diseases. Medical conditions that can increase levels of vitamin B12 include liver disease, kidney failure and a group of blood cancers known as myeloproliferative disorders, which includes myelocytic leukemia and a condition that causes an overgrowth of red blood cells called polycythemia vera. Hypereosinophilic syndrome, a medical condition marked by too many white blood cells, also can cause high vitamin B12."

 

Warnings:

 

"High vitamin B12 is a symptom of an underlying illness that causes the amount in your blood to increase. For example, a damaged liver may release the vitamin out of storage and into the blood. In early stages, illnesses associated with high vitamin B12 often have generic symptoms, such as fatigue and loss of appetite. Considering they’re potentially life-threatening conditions, early diagnosis is vital, so consult your physician when you don’t feel up to par."

 

http://healthyeating...-mean-9057.html

 

I also read it was linked to cancer condition

 

Oh shit. That freaks me out. Is there a test that can determine if there is a problem with my liver? He also provided a large number of other levels of various things.

 

Here are the results in a PDF (personal info removed).

[stefan_001]

So I finally had my homocysteine levels checked and it was pretty low after 5 months of NR. 7.7 uMols/L

The relation ship is that NR is actual niacinamide just linked to a ribose. Means the methyl traping is very likely. Furthermore, these 2 studies just confirm that most of NR will be converted into raw niacinamide, actually only a few seems to stay into the NR form, but still enough to perform effect (do not forget we naturally make NR and NAR..) :

http://www.cell.com/...4131(16)30350-3
http://biochem.uiowa...nts/bogan08.pdf

Both niacin aka nicotinic acid and niacinamide are well known to increase homocysteine IF we do not take others Bs along. NR weight half niacinamide and half ribose. Thats can also make the difference about its effect on homocysteine.

Regarding B12, even if someone have very severe and poor intestinal absorption, he will get the B12 at 500mcg. And sublingual B12 is just not effective, there is no stats difference between group sublingual and oral, so the conclusion is the b12 is only absorbed orally :

http://www.ncbi.nlm....les/PMC1884303/

Finally, I think we have to be careful to methylation anyway, whatever the homocysteine level is because low level is good but can also mean we are hypermethylated as explain this specialist very well in many of his cases:

http://mthfr.net/ove...udy/2012/06/27/

While I havent seen any studies to support this I have not seen either any study contradicting Tom's view on methylation. Therefore I have added a B12 complex to my regimen, its better to avoid the risk.

Edited by stefan_001, 07 September 2016 - 08:46 PM.

[Bryan_S]

 

Something like the NR Bible is now available:

"200 page research work behind several Nicotinamide Ribose PRs published online

This week the thesis work behind the press releases "<a href="http://www.timelessl.../">NicotinamideRiboside increases the Co-enzyme NAD+ in Human Clinical Study</a>" and "<a href="http://investors.chromadex.com/mobile.view?c=212121&v=203&d=1&id=2078994" target="_blank">Unexpected Discovery of Novel Biomarkers of Effective NAD+ Precursor, Nicotinamide Riboside</a>" was published online.

The thesis, "NOVEL NAD+ METABOLOMIC TECHNOLOGIES AND THEIR APPLICATIONS TO NICOTINAMIDE RIBOSIDE INTERVENTIONS", by Samuel A.J. Trammell was done at the Graduate College of The University of Iowa under supervision of Professor Charles Brenner.

......Together, these works performed in human and murine systems prove NR is superior to other B3 vitamins effecting the NAD metabolome and increasing NAD+ in particular......"

http://www.timelessl...blished-online/

Champagne will probably uncorked at Chromadex's, for this one human who had a major surge in NAD+metabolism 2 to 8 hours after ingestion in the morning, took 1000mgs. I have been taking 400mgs per day so far, but now we can assume that more is at least not harmful....

 

 

 

FYI - There is a 150 page thesis by Krista Hawrylyshyn from University of Western Ontario, "Nicotinamide Riboside Delivery Generates NAD+

Reserves to Protect Vascular Cells Against Oxidative Damage."   source

 

It's somewhat interesting, though does not appear to break new scientific ground.  I've not read the whole thing yet.

 

 

I've been surprised the board hasn't been a blaze with comments from this research trove. Where are all the people who were so impatient before? I'm reviewing the 200-page Ph.D. thesis of Samuel A.J. Trammel now and it will take me a few days with all I have on my plate. I've been waiting for much of the Brenner research "as have you all" . . . here it is, so come and get it!

[playground]

 

I am interested in this  relationship mentioned by Nate:

Is there a way for me to  search a single thread for a keyword...  without resorting to

 

 

looking on every page of the thread ?

 

Yes there is! Google is you friend (as long as it has indexed a page) So, the shortcut (to using "advanced search" - which is hard to find any more but is under "settings" in the lower right corner of you browser window) is to use site:{domain name} e.g.:

 

site:www.longecity.org/forum/topic/82770-nicotinamide-riboside-curated " were surprised by how rapidly NR was able to reactivate dormant mitochondria"

 

Pages from the last few days typically will not be indexed, but everything older than that should be. Try it, you'll like it! 

 

Also, the link to Google's advanced search is: https://www.google.com/advanced_search which I have bookmarked (and you should too)

 

 

A+   (Rib373)

 

Excellent reply.  And it works perfectly !

I have bookmarked 'Advanced Search Google'

 

Edited by playground, 08 September 2016 - 02:50 AM.

[Nate-2004]

 

 

Something like the NR Bible is now available:

"200 page research work behind several Nicotinamide Ribose PRs published online

This week the thesis work behind the press releases "<a href="http://www.timelessl.../">NicotinamideRiboside increases the Co-enzyme NAD+ in Human Clinical Study</a>" and "<a href="http://investors.chromadex.com/mobile.view?c=212121&v=203&d=1&id=2078994" target="_blank">Unexpected Discovery of Novel Biomarkers of Effective NAD+ Precursor, Nicotinamide Riboside</a>" was published online.

The thesis, "NOVEL NAD+ METABOLOMIC TECHNOLOGIES AND THEIR APPLICATIONS TO NICOTINAMIDE RIBOSIDE INTERVENTIONS", by Samuel A.J. Trammell was done at the Graduate College of The University of Iowa under supervision of Professor Charles Brenner.

......Together, these works performed in human and murine systems prove NR is superior to other B3 vitamins effecting the NAD metabolome and increasing NAD+ in particular......"

http://www.timelessl...blished-online/

Champagne will probably uncorked at Chromadex's, for this one human who had a major surge in NAD+metabolism 2 to 8 hours after ingestion in the morning, took 1000mgs. I have been taking 400mgs per day so far, but now we can assume that more is at least not harmful....

 

 

 

FYI - There is a 150 page thesis by Krista Hawrylyshyn from University of Western Ontario, "Nicotinamide Riboside Delivery Generates NAD+

Reserves to Protect Vascular Cells Against Oxidative Damage."   source

 

It's somewhat interesting, though does not appear to break new scientific ground.  I've not read the whole thing yet.

 

 

I've been surprised the board hasn't been a blaze with comments from this research trove. Where are all the people who were so impatient before? I'm reviewing the 200-page Ph.D. thesis of Samuel A.J. Trammel now and it will take me a few days with all I have on my plate. I've been waiting for much of the Brenner research "as have you all" . . . here it is, so come and get it!

 

 

Haha I wish I had your time. Looking forward to your comments and thoughts.

[Harkijn]

Nate, perhaps you should take some time to read Trammel's paper after all. It would set your mind at ease about the safety of the NR salvage pathway. That would be much better for you than having yourself freaked out here by the umpteenth rehash about homocysteine and B12.

[Harkijn]

 

Something like the NR Bible is now available:

"200 page research work behind several Nicotinamide Ribose PRs published online

This week the thesis work behind the press releases "<a href="http://www.timelessl.../">NicotinamideRiboside increases the Co-enzyme NAD+ in Human Clinical Study</a>" and "<a href="http://investors.chromadex.com/mobile.view?c=212121&v=203&d=1&id=2078994" target="_blank">Unexpected Discovery of Novel Biomarkers of Effective NAD+ Precursor, Nicotinamide Riboside</a>" was published online.

The thesis, "NOVEL NAD+ METABOLOMIC TECHNOLOGIES AND THEIR APPLICATIONS TO NICOTINAMIDE RIBOSIDE INTERVENTIONS", by Samuel A.J. Trammell was done at the Graduate College of The University of Iowa under supervision of Professor Charles Brenner.

......Together, these works performed in human and murine systems prove NR is superior to other B3 vitamins effecting the NAD metabolome and increasing NAD+ in particular......"

http://www.timelessl...blished-online/

Champagne will probably uncorked at Chromadex's, for this one human who had a major surge in NAD+metabolism 2 to 8 hours after ingestion in the morning, took 1000mgs. I have been taking 400mgs per day so far, but now we can assume that more is at least not harmful....

 

The positive effects of NR supplementation on mice, rats and people in this study are impressive. Indeed, as the author says, NR far surpasses other NAD+precursors and it's effects are 'near miraculous' ! Despite this he says in his conclusion:

Further, despite higher innervation than control, NR causes lower thermal sensitivity in nondiabetic mice (Figure 7.2c). This could indicate that healthy individuals could be negatively impacted by NR supplementation.

[Bryan_S]

At least you went to the section on "8.3 Future Investigations of NR as a Health Promoting Agent" Many here are just waiting for the comments from those who have read it. I'm not alarmed because there is so much more overwhelming evidence of the health benefits.

 

In another passage he says "NR did not oppose hyperglycemia in the type 1 diabetic model but did so in the type 2 diabetic model, suggesting that neuropathy and the positive effect of NR does not depend upon increased glycemic control." So in respects to diabetes there is clearly more to study and that research will be an ongoing to discover where NR fits in and works in one disease model and not another.

 

The author also evaluated the other NAD precursors in some head to head tests by attaching heavy atoms to track the paths. So I think he went a long way towards a fair evaluation. He also revisited the idea that NR is a superior precursor to NMN and that NMN appears to be converted to NR extracellularly. I can see some fight coming from the Sinclair camp down the road. For now price separates the 2 molecules, so its a mute argument either way unless you can afford NMN which many here can not. Ref "I compared the kinetics of NR versus NMN using stable isotope technologies and revealed NR is a superior precursor to NMN and that NMN appears to be converted to NR extracellularly." So I'm glad to see some head to head tests.

 

He references a large increase in NAAD that occurred around the same time as NAD+ elevation. This was a surprise because NAAD was thought to to be synthesized from tryptophan and NA, not from NR. So in this I think the NR to NAD metabolism needs some more study because this was a finding that came clearly from left field.

 

I also found some other reading interesting about where the NAD peak was found in the Human trials:

"In the human subject’s PBMCs at 7.7 and 8.1 hours post ingestion, NAD+ and Me2PY reached peak levels, increasing above baseline concentrations by 2.7-fold and 8.4-fold respectively. At these time points, unexpectedly, NAAD, the substrate of glutamine-dependent NAD+ synthetase (12), which is only expected to be produced in biosynthesis of NAD+ from tryptophan and NA (129), was elevated from less than 20 nM to as high as 0.91 μM. Whereas NAAD lagged the rise in PBMC NAD+ by one time point, the rise in PBMC NAD+ was not as pronounced as the spike in NAAD, which was at least 45-fold above the baseline level. Though contrary to expectations, these data suggested that NR might be incorporated into NAAD after formation of NAD+ and chased back to the NAD+ peak as NAD+ declines."  I'm sure my interpretation is lacking in many ways but it looks like after a peak in NAD is reached NAAD becomes the storehouse place holder and is utilized as NAD levels drop to begin producing NAD again. Someone else can comment.

 

At this point I've read his thesis and a few points stood out but it will be several days before I can seriously comment and see where we can find insights into our regiments. One nagging thing I really wanted answered were half-life questions and the Peak NAD timeframes came later after ingestion than I expected. As always JMHO

 

 

[Harkijn]

I read it twice from A to Z now, though taking the descriptions of research setups at face value. Enjoyed sentences like: Mice were euthanized by live decapitation.... 

At some place the authors conclude that NR goes through first pass metabolism in the liver. In medicine I believe this means that larger doses are more effective than smaller ones. Would this apply to a vitamin as well?

[stefan_001]

 

 

I also found some other reading interesting about where the NAD peak was found in the Human trials:

"In the human subject’s PBMCs at 7.7 and 8.1 hours post ingestion, NAD+ and Me2PY reached peak levels, increasing above baseline concentrations by 2.7-fold and 8.4-fold respectively. At these time points, unexpectedly, NAAD, the substrate of glutamine-dependent NAD+ synthetase (12), which is only expected to be produced in biosynthesis of NAD+ from tryptophan and NA (129), was elevated from less than 20 nM to as high as 0.91 μM. Whereas NAAD lagged the rise in PBMC NAD+ by one time point, the rise in PBMC NAD+ was not as pronounced as the spike in NAAD, which was at least 45-fold above the baseline level. Though contrary to expectations, these data suggested that NR might be incorporated into NAAD after formation of NAD+ and chased back to the NAD+ peak as NAD+ declines."  I'm sure my interpretation is lacking in many ways but it looks like after a peak in NAD is reached NAAD becomes the storehouse place holder and is utilized as NAD levels drop to begin producing NAD again. Someone else can comment.

 

HI Brian, I understood this a bit differently. While indeed NAAD is some form of storage and appearently some form of pre-cursor of NAD+ it is a small, not highly relevant storage and therefore they flag it as biomarker because it nicely correlates and large % increases so probably easier to measure.  

Edited by stefan_001, 09 September 2016 - 12:48 PM.

[trakker]

 

 

 

I also found some other reading interesting about where the NAD peak was found in the Human trials:

"In the human subject’s PBMCs at 7.7 and 8.1 hours post ingestion, NAD+ and Me2PY reached peak levels, increasing above baseline concentrations by 2.7-fold and 8.4-fold respectively. At these time points, unexpectedly, NAAD, the substrate of glutamine-dependent NAD+ synthetase (12), which is only expected to be produced in biosynthesis of NAD+ from tryptophan and NA (129), was elevated from less than 20 nM to as high as 0.91 μM. Whereas NAAD lagged the rise in PBMC NAD+ by one time point, the rise in PBMC NAD+ was not as pronounced as the spike in NAAD, which was at least 45-fold above the baseline level. Though contrary to expectations, these data suggested that NR might be incorporated into NAAD after formation of NAD+ and chased back to the NAD+ peak as NAD+ declines."  I'm sure my interpretation is lacking in many ways but it looks like after a peak in NAD is reached NAAD becomes the storehouse place holder and is utilized as NAD levels drop to begin producing NAD again. Someone else can comment.

 

HI Brian, I understood this a bit differently. While indeed NAAD is some form of storage and appearently some form of pre-cursor of NAD+ it is a small, not highly relevant storage and therefore they flag it as biomarker because it nicely correlates and large % increases so probably easier to measure.  

 

 

 

I also found the huge NAAD increase most interesting.  

 

Is it a “pool” that converts back to NAD+ later?

 

Does the increase in all the other NAD+ metabolites matter?

 

If not, it seems that 1,000 mg a day is probably more than needed.

 

I’ve been taking 500mg a day for over a year (off and on).

 

But reading this post about effects of different quantities it seems like anything over 300 mg a day might not help much, if at all.  

 

Not sure if that is anything more than guesswork tho.  

 

Does anyone else see some good indications of where the upper limit of effectiveness might be from the Trammel paper?

[Bryan_S]

 

I also found the huge NAAD increase most interesting.  

 

Is it a “pool” that converts back to NAD+ later?

 

Does the increase in all the other NAD+ metabolites matter?

 

If not, it seems that 1,000 mg a day is probably more than needed.

 

I’ve been taking 500mg a day for over a year (off and on).

 

But reading this post about effects of different quantities it seems like anything over 300 mg a day might not help much, if at all.  

 

Not sure if that is anything more than guesswork tho.  

 

Does anyone else see some good indications of where the upper limit of effectiveness might be from the Trammel paper?

 

 

Page 167of the 200-page Ph.D. thesis of Samuel A.J. Trammel will answer your questions about what each one-time dosage is expected to produce. It correlates closely to the press release over the human trials. 100 mg bumps NAD by approximately 30%, 300 mg and 1000 mg by approximately 50%. Check the percent changes in the Mean NAD levels from the Pre, 1, 2, 4, 6, 8, & 24 across all three dosages.

 

The PR stated:

"The oral presentation and poster presented data which indicate that single doses of NIAGEN® NR can elevate the co-enzyme NAD+ in the blood by as much as 2.7-fold. In the first-in-humans clinical trial which involved dosing twelve healthy adult subjects, the group showed that blood cell NAD+ increased with single 100 mg, 300 mg and 1 gram doses of NIAGEN® NR. Average maximal increases in blood NAD+ were approximately 30% at the 100 mg dose and approximately 50% at the higher doses. Increases in blood NAD+ tended to be sustained for longer times at higher doses."

 

Using a percent difference calculator I can see where they got those numbers. You can run the | Pre | against the highest peak reached during the monitoring hours 1 thru 24 and you'll see the correlation to the PR.

 

Also see page 85 @ hour 167 a 216 % increase but this individual had reached a 316 % increase at one point. I've looked at the subjects age and I can almost guess who this is from the time of the study but I could be totally wrong. 

 

I wish I had a chart showing the mean NAD levels of the placebo members to see how that tracks as a human circadian reference. 

 

I feel the dosage needs to be spread out a bit more over the day than taken all at once. "A Time-released dose comes to mind." The gavage experiments with the mice are similar to the signal dose human experiments. The ad libitum feeding experiments with the Rats have produced I think the best results because the NR is always available unlike the one time dosages. There is data to suggest you can do better than the NAD rise from the 300 mg experiment but we need more long-term data which you can see is coming by the completed studies. I'm eager to see that data and how the human metabolism adapts to a constant NR supply.

 

As always JMHO

Edited by Bryan_S, 12 September 2016 - 07:52 AM.

[Bryan_S]

Loss of NAD Homeostasis Leads to Progressive and Reversible Degeneration of Skeletal Muscle

http://www.ncbi.nlm....pubmed/27508874

http://www.cell.com/...(16)30350-3.pdf

 

I did a cursory search of the URL and title on our thread and couldn't find anyone posting this. 

 

Highlights

d Mice with $85% NAD depletion in skeletal muscle are grossly normal as young adults

d Reduced NAD content impairs mitochondrial function and fiber integrity over time

d Progressive muscle dysfunction can be reversed by the NAD precursor NR

d Preventing muscle NAD loss during aging partially preserves exercise performance 

 

Authors

David W. Frederick, Emanuele Loro, Ling Liu, ..., Joshua D. Rabinowitz, Tejvir S. Khurana, Joseph A. Baur

Correspondence

baur@mail.med.upenn.edu

 

In Brief

NAD levels decline in multiple tissues with age or in disease. Frederick et al. show that impaired intramuscular NAD synthesis compromises skeletal muscle mass and strength over time but can be quickly restored with an oral NAD precursor. Upregulation of the NAD salvage pathway preserves exercise performance in aged mice. 

 

NAD is an obligate co-factor for the catabolism of metabolic fuels in all cell types. However, the avail- ability of NAD in several tissues can become limited during genotoxic stress and the course of natural aging. The point at which NAD restriction imposes functional limitations on tissue physiology remains unknown. We examined this question in murine skel- etal muscle by specifically depleting Nampt, an essential enzyme in the NAD salvage pathway. Knockout mice exhibited a dramatic 85% decline in intramuscular NAD content, accompanied by fiber degeneration and progressive loss of both muscle strength and treadmill endurance. Administration of the NAD precursor nicotinamide riboside rapidly ameliorated functional deficits and restored muscle mass despite having only a modest effect on the intramuscular NAD pool. Additionally, lifelong over- expression of Nampt preserved muscle NAD levels and exercise capacity in aged mice, supporting a critical role for tissue-autonomous NAD homeostasis in maintaining muscle mass and function. 

 

[Adaptogen]

I have an elderly cat, around 20 years old, who has been experiencing rather severe sarcopenia over the past year or so. I've given him NR noncommittally on several occasions, but would like to start more regular dosing, considering how promising the research is. Based on the studies, could someone provide an (estimated) allometrically scaled dosage?  He probably weighs around 8-10 lbs.

[trakker]

 

 

I also found the huge NAAD increase most interesting.  

 

Is it a “pool” that converts back to NAD+ later?

 

Does the increase in all the other NAD+ metabolites matter?

 

If not, it seems that 1,000 mg a day is probably more than needed.

 

I’ve been taking 500mg a day for over a year (off and on).

 

But reading this post about effects of different quantities it seems like anything over 300 mg a day might not help much, if at all.  

 

Not sure if that is anything more than guesswork tho.  

 

Does anyone else see some good indications of where the upper limit of effectiveness might be from the Trammel paper?

 

 

Page 167of the 200-page Ph.D. thesis of Samuel A.J. Trammel will answer your questions about what each one-time dosage is expected to produce. It correlates closely to the press release over the human trials. 100 mg bumps NAD by approximately 30%, 300 mg and 1000 mg by approximately 50%. Check the percent changes in the Mean NAD levels from the Pre, 1, 2, 4, 6, 8, & 24 across all three dosages.

 

The PR stated:

"The oral presentation and poster presented data which indicate that single doses of NIAGEN® NR can elevate the co-enzyme NAD+ in the blood by as much as 2.7-fold. In the first-in-humans clinical trial which involved dosing twelve healthy adult subjects, the group showed that blood cell NAD+ increased with single 100 mg, 300 mg and 1 gram doses of NIAGEN® NR. Average maximal increases in blood NAD+ were approximately 30% at the 100 mg dose and approximately 50% at the higher doses. Increases in blood NAD+ tended to be sustained for longer times at higher doses."

 

Using a percent difference calculator I can see where they got those numbers. You can run the | Pre | against the highest peak reached during the monitoring hours 1 thru 24 and you'll see the correlation to the PR.

 

Also see page 85 @ hour 167 a 216 % increase but this individual had reached a 316 % increase at one point. I've looked at the subjects age and I can almost guess who this is from the time of the study but I could be totally wrong. 

 

I wish I had a chart showing the mean NAD levels of the placebo members to see how that tracks as a human circadian reference. 

 

I feel the dosage needs to be spread out a bit more over the day than taken all at once. "A Time-released dose comes to mind." The gavage experiments with the mice are similar to the signal dose human experiments. The ad libitum feeding experiments with the Rats have produced I think the best results because the NR is always available unlike the one time dosages. There is data to suggest you can do better than the NAD rise from the 300 mg experiment but we need more long-term data which you can see is coming by the completed studies. I'm eager to see that data and how the human metabolism adapts to a constant NR supply.

 

As always JMHO

 

 

Thanks Brian.

 

I did see the results for the increase in NAD+ levels for each one-time dosage.  

 

And the impact of the 1,000 mg daily dosage  of the one individual.  Both are quite useful. 

 

What I am trying to estimate is what the impact would be of a daily dose or 300mg, which they didn’t show results for.

 

The 1,000 mg dose clearly raised NAD+ more quickly at the 8 hour mark, but as you pointed out it seems the increase “tops out” and repeated daily dosages  of 1,000 mg do not have a cumulative effect.

 

From the data it looks like 300mg eventually reached the same NAD+ increase as 1,000 mg and they were equivalent at 24 hours.

 

Since the NAD+ level is already elevated at 24 hours, perhaps a 300 mg dose on day 2 would raise NAD+ levels to the “max” more quickly on day 2 than what it accomplished on the single dosage testing.  So it might be nearly as effective as the 1,000 mg dose on a daily basis.

 

 

Anyways, as you said we need results from more of the ongoing tests that you linked to before we really  know.

[Bryan_S]

Thanks Brian.

 

I did see the results for the increase in NAD+ levels for each one-time dosage.  

 

And the impact of the 1,000 mg daily dosage  of the one individual.  Both are quite useful. 

 

What I am trying to estimate is what the impact would be of a daily dose or 300mg, which they didn’t show results for.

 

The 1,000 mg dose clearly raised NAD+ more quickly at the 8 hour mark, but as you pointed out it seems the increase “tops out” and repeated daily dosages  of 1,000 mg do not have a cumulative effect.

 

From the data it looks like 300mg eventually reached the same NAD+ increase as 1,000 mg and they were equivalent at 24 hours.

 

Since the NAD+ level is already elevated at 24 hours, perhaps a 300 mg dose on day 2 would raise NAD+ levels to the “max” more quickly on day 2 than what it accomplished on the single dosage testing.  So it might be nearly as effective as the 1,000 mg dose on a daily basis.

 

 

Anyways, as you said we need results from more of the ongoing tests that you linked to before we really  know.

 

 

"What I am trying to estimate is what the impact would be of a daily dose or 300mg, which they didn’t show results for."

On Page 167 the "mid" is the 300 mg NAD data. What we can't see is the data past hour 24 on this chart and we don't have numbers to represent repeated 300mg dosing. However look at hour-167.6 of the chart on page 85. This is the last hour of a 7-day experiment of daily dosing. Now following the dosage schedule outlined this should be the residual from the dose taken 24-hours earlier and the last blood sample taken within the 7-day window. The Pre NAD levels at hour-0 were 12 and at hour-167.6 levels were at 38. The percent difference over day-0 is 216%. So I would call this a cumulative effect or carry over being that at hour 23.8 we only see a 167% increase over hour-0. The difference between 167% and 216% is 29%. Now I don't like to make assumptions from a data set at a higher dosage than your question but the 300mg dosage may display a similar pattern or it may not, we just don't have the data to indicate a similar day-to-day carry over. 

 

"From the data it looks like 300mg eventually reached the same NAD+ increase as 1,000 mg and they were equivalent at 24 hours." Yes this appears so. But in the PR they said; "Increases in blood NAD+ tended to be sustained for longer times at higher doses." The 7-day study seemed to indicate that.

 

"The 1,000 mg dose clearly raised NAD+ more quickly at the 8 hour mark, but as you pointed out it seems the increase “tops out” and repeated daily dosages  of 1,000 mg do not have a cumulative effect." I really do believe there is a feedback mechanism that will only let levels increase so far. In biology the cell does not waste energy resources to produce surpluses beyond its immediate or pending needs. So in this I think there is a maximum set point. Now thats not to say there isn't a adaptive response mechanism that wouldn't kick in if on repeated occasions the cell needed more NAD. Daily exercise comes to mind as one such influence. So I would expect to see a difference in the amount of NAD produced between an active and sedentary individual.

 

As outlined above I think there are signs of a cumulative effect.

 

"Since the NAD+ level is already elevated at 24 hours, perhaps a 300 mg dose on day 2 would raise NAD+ levels to the “max” more quickly on day 2 than what it accomplished on the single dosage testing.  So it might be nearly as effective as the 1,000 mg dose on a daily basis." I can't say anything definitive without more data. I would expect both dosages to have carry over, however with 1000 mg I would expect more NAD sustained for longer times.

 

Personally for me I stopped taking my daily dosage all at one time after ChromaDex shared its 4-Hour-half-life data. We ran some experimental charts for conversation purposes only, you might want to review them. "These are not ChromaDex sanctioned charts." So far they haven't updated this figure to indicate our charting results were very far off. So even if I were taking 250 or 500mg dose's I'd still break it down into 125mg individual dosages throughout the day. If in fact we have a maximum NAD set point as the 2 human studies suggested, I don't want my NR going down the drain because I took to much all at once and my kidneys processed it away before I could utilize it.

 

As always JMHO

Edited by Bryan_S, 13 September 2016 - 06:49 PM.

[midas]

The way I'm seeing it is that the 250mg dose is sufficient for me I'm sure if I could afford to take more I would.  I feel a really noticeable effect from the 250mg, so I'll be sticking with that. And to be honest 125mg seemed to keep me at a good level for a month when I was short of cash.

 

I would just like to take this opportunity to thank Bryan (and others) once again for all the hard work round here on NR, quite a lot of this goes over my head but I get the general gist of what's going on......Cheers guys

[mrkosh1]

I still think that by itself nicotinimide riboside will have relatively weak anti-aging effects even if greater than most other supplements. There are probably thousands of people who have taken this supplement for many months, and I doubt anyone has experienced a significant reversal of their aging process. My guess is that to produce the anti-aging supplement we all really want nicotinimide riboside needs to be combined with other substances that produce similar effects. 

 

My best guess at a combination that could produce potent effects would be R-alpha lipoic acid, acetyl-l-carnitine, and nicontinmide riboside. They all can up regulate NAD+, upregulate the SIRT genes, and thereby increase the production of telomerase. A possible addition would be a supplement that prevents the breakdown of NAD+. Together, they might be able to provide for a much more rapid reversal of the aging process.

 

What I'd love to see is the following:

 

1) An in-vitro test in human cells to determine any synergy of these substances on SIRT, NAD+, telomerase, and population doublings.

 

2) If the above shows synergism, a volunteer trial of people taking these supplements and being tested over time for anti-aging effects.

 

3) If it would take too much effort to test humans, a trial on mice would be interesting.