2255 replies to this topic

[Mike C]

https://www.scienced...61027122047.htm

[Bryan_S]

 

 

He touched on the heart 3 times I believe. Mostly he was describing NRK2 in the context of gene expression. "For some reason" many researchers are looking into why this enzyme, which is used to convert NR to NAD is expressed exponentially during times of stress and injury in muscle, cardiac and nerve tissue. The heart is one area he touched on.

 

If you give me the time code I can give you an idea of what exactly he was trying to embrace. I'm correcting the Closed Captioning in a few select areas, what is the timecode number?

 

Charles Brenner, PhD discusses Nicotinamide Riboside Back to the point. "He didn't flat out say NR is good for the heart, right?" Many are asking why this tissue would express NRK2 at these times of stress. So its a question with an implied unproven answer since we know what the cell uses NRK2 for . . . only animal research will prove or disprove this hypothesis.  

 

 

I was referring to the discussion at the end starting at around 39:00 but going back realize he also discussed the heart ten minutes earlier. 

 

Brenner said that NR was the least stressful way for the heart to get NAD+ (I think) but wasn't clear to me if NR helped the heart. Anyway, great interview!

 

 

That is the reasoning and why they are investigating this path.

 

39:25 that's one of the reasons we think that

when a heart cell is in a failure mode

it induces expression of NRK2

because conversion of NR to NAD would

stress the heart the least. So a

failing heart has low phosphorylcreatine and

low ATP and so it potentially quote "wants"

if a heart cell wants anything. We're

anthropomorphizing there.

You would want the NAD precursor that

would allow it to restore its NAD with

the least amount of ATP and such and

that's through the NRK pathway.

 

I fixed the Closed Captioning in that section so this might help. Much like I outlined before he's describing elevated expression of NRK2 (NMRK2) in failing heart tissue and why expression of this pathway might be in the best interest of the stressed heart cell, "in this instance." So you are in a sense seeing the bread crumbs researchers are following. Fascinating process, I think.

 

I'll fix more of the Closed Captioning in the interview as time allows.

 

As always JMHO

Edited by Bryan_S, 28 October 2016 - 10:19 AM.
added transcription

[midas]

 

 

I was referring to the discussion at the end starting at around 39:00 but going back realize he also discussed the heart ten minutes earlier. 

 

Brenner said that NR was the least stressful way for the heart to get NAD+ (I think) but wasn't clear to me if NR helped the heart. Anyway, great interview!

 

 

 

Bluemoon

 

If you look in the article linked to below in Mike C's post about NMN you will find this quote......I see no reason for this being any different with NR supplementation....

 

""Even though NAD synthesis was stopped only in the fat tissue, we saw metabolic dysfunction throughout the body, including the skeletal muscle, the heart muscle, the liver and in measures of the blood lipids," Yoshino said. "When we gave NMN to these mice, these dysfunctions were reversed. That means NAD in adipose tissue is a critical regulator of whole body metabolism.""

 

 

 

https://www.scienced...61027122047.htm

 

Edited by midas, 28 October 2016 - 04:21 PM.

[warner]

Another interesting thing from the Imai paper was their speculation about dosage in humans:

 

It should be noted that NMN administration did not generate any obvious toxicity, serious side effects, or increased mortality rate throughout the 12-month-long intervention period, suggesting the long-term safety of NMN. Nonetheless, an optimal dose of NMN to maximize its efficacy appears to differ depending on physiological functions. For example, whereas the effects of NMN on body weight gain, insulin sensitivity, tear production, and bone mineral density were dose-dependent, 100 mg/kg/day of NMN improved oxygen consumption, energy expenditure, and physical activity better than 300 mg/kg/day. For rod and cone photoreceptor function, both doses had similar effects.  Indeed, we found that expression of Ox2r and Prdm13, two downstream genes in the SIRT1-mediated signaling pathway in the hypothalamus, exhibited significant decreases in the hypothalami of 300 mg/kg/day NMN-treated mice (our preliminary finding), which could partly explain some of the observed differences in the effects of NMN, particularly those on physical activity, between two tested doses. Additionally, the extent of agedependent NAD+ decline or NMN uptake in each tissue or organ might determine an optimal dose of NMN to restore each physiological function. Given that 100 mg/kg/day of NMN was able to mitigate most age-associated physiological declines in mice, an equivalent surface area dose for humans would be 8 mg/kg/day (Freireich et al., 1966), providing hope to translate our findings to humans.

 

Given MWs for NR (as NR Cl) of 290.70 and for NMN of 334.22, and a body weight between 60 and 80 kg, the 8 mg/kg/day would work out to be roughly 500 to 650 mg/d NMN, or 400 to 550 mg/d NR (as NR Cl = Niagen) --- assuming that NR and NMN are equally effective on a molar basis.

 

That's also the first solid evidence I recall seeing that may suggest that dosing in the neighborhood of 1000 mg/d NR or higher may have a negative impact on certain parts of the body.  Interestingly, when recently reviewing the GRAS document for NR,

 

http://www.fda.gov/d...y/ucm505226.pdf

 

I was impressed by how all of the metabolites produced by NR rise dramatically with the 1000 mg/d dosage (see plots at end of that document), as compared to the 300 and 100 mg/d levels, where the latter tend to stay within more normal levels.  Combined with the observation by Brenner's group et al. that 1000 mg is no better than 300 mg at raising NR levels, it seems prudent now to stay with NR doses at or below 500 mg/d.  (I'm currently taking 3 x 125 = 375 mg/d.)

Edited by warner, 28 October 2016 - 07:22 PM.

[Bryan_S]

In the Imai (Mills et al.) paper ( http://www.cell.com/...4131(16)30495-8 ) the only cancer-related observation made was wrt causes of death:  "No obvious differences were observed for the causes of death, which included urinary tract obstruction, thrombosis, and myocardial infarction, between control and NMN-administered mice."  So Imai's verbal comment simply meant they were happy to not see a lot of new cancer in the NMN mice, but the study was not really designed to answer the broader question of cancer prevention/promotion by NMN.

 

causes of death.jpg

 

This new paper was published yesterday guys and this is what everyone is commenting on. So this is all new stuff Warner is talking about.

 

Long-Term Administration of Nicotinamide Mononucleotide Mitigates Age-Associated Physiological Decline in Mice

http://www.cell.com/...4131(16)30495-8

 

Kathryn F. Mills, Shohei Yoshida, Liana R. Stein7, Alessia Grozio, Shunsuke Kubota, Yo Sasaki, Philip Redpath, Marie E. Migaud, Rajendra S. Apte, Koji Uchida, Jun YoshinocorrespondencePress enter key for correspondence informationemailPress enter key to Email the author, Shin-ichiro Imai8,correspondencePress enter key for correspondence informationemailPress enter key to Email the author

7Present address: Gladstone Institute of Neurological Disease and Department of Neurology, University of California, San Francisco, San Francisco, CA 94158, USA

8Lead Contact

Publication stage: In Press Corrected Proof

DOI: http://dx.doi.org/10...met.2016.09.013

hideArticle Info

 

Publication History

Published: October 27, 2016

Accepted: September 24, 2016

Received in revised form: July 5, 2016

Received: December 4, 2015

Edited by Bryan_S, 28 October 2016 - 07:31 PM.

[stefan_001]

I have some skepticism wrt to the cancer risk link theory because NAD falls as we age and supplementation doesnt recover it to old levels so compared to when we were younger that would mean we are at less risk for getting cancer and obviously that is not the case. What I understand of it is that certain cancer cells have a higher sensitivity to NAD availability. So if you have cancer one way to kill cancer is to strip the body of NAD. The cancers cells which are more sensitive to NAD availability should then die first before the normal cells are impacted. So taking NR may counter act certain cancer drugs which aim to inhibit it. But as we talk cancer here let me add this is JMHO

Edited by stefan_001, 28 October 2016 - 08:32 PM.

[Daniscience]

I am 30 years old and this is my first day on NR.

 

Am I supposed to feel anything? I took this pill containing 150mg NR chloride, 125mg quercetin, 75mg Trans-resveratrol and 25mg betaine. But I don't perceive anything, at least consciously.

 

Should I double the dosage or is this enough to get the NR longevity and energy benefits?

Edited by Daniscience, 28 October 2016 - 08:12 PM.

[stefan_001]

I am 30 years old and this is my first day on NR.

 

Am I supposed to feel anything? I took this pill containing 150mg NR chloride, 125mg quercetin, 75mg Trans-resveratrol and 25mg betaine. But I don't perceive anything, at least consciously.

 

Should I double the dosage or is this enough to get the NR longevity and energy benefits?

 

That's probably good news you dont feel anything. It just means you are a normal healthy 30 year old with NAD levels that are still high.

[Nate-2004]

 

I am 30 years old and this is my first day on NR.

 

Am I supposed to feel anything? I took this pill containing 150mg NR chloride, 125mg quercetin, 75mg Trans-resveratrol and 25mg betaine. But I don't perceive anything, at least consciously.

 

Should I double the dosage or is this enough to get the NR longevity and energy benefits?

 

That's probably good news you dont feel anything. It just means you are a normal healthy 30 year old with NAD levels that are still high.

 

 

I agree. 125mg of HPN NR would be ideal over the next 7 years or so before even contemplating upping the dosage. It'd be relatively cheap for a year's worth on that dosage, assuming the shelf-life is good.

[whileitravel]

I am 30 years old and this is my first day on NR.

 

Am I supposed to feel anything? I took this pill containing 150mg NR chloride, 125mg quercetin, 75mg Trans-resveratrol and 25mg betaine. But I don't perceive anything, at least consciously.

 

Should I double the dosage or is this enough to get the NR longevity and energy benefits?

 

Hell dude, I'm nearly 50 (March) and I don't feel anything. Mind you I've been jogging/exercising most of my adult life, eating well and keep within my ideal body weight. I work in health care, so I'm interested in what keeps me healthy. Not to brag, but most of my colleagues and people I meet for the first time think I'm in my late 30's. So too did my gf!

 

I was taking two 125 mg, but after watching a recent video here, essentially stating that if you're already in good shape, you probably don't need 250mg. Right or wrong, that's the way I interpreted the video.

 

Good luck. I personally think 30 is too young to start this, but then again it's your body and money!!!

Edited by whileitravel, 28 October 2016 - 10:27 PM.

[Nate-2004]

I disagree that 30 is too young, NAD begins to drop at 25 and it may be more of an aging prevention than anything. You're unlikely to feel anything at all though, it's preventative, not therapeutic. Most people wouldn't feel anything drastic unless they're over 55 or 60.

[whileitravel]

I disagree that 30 is too young, NAD begins to drop at 25 and it may be more of an aging prevention than anything. You're unlikely to feel anything at all though, it's preventative, not therapeutic. Most people wouldn't feel anything drastic unless they're over 55 or 60.

 

Fair enough. It takes place at the cellular level and I've yet to notice after nearing 3 months any changes. I read of someone taking NR having some difficulty running 2km's, but after NR being able to run 10k no sweat.

 

I haven't noticed a change. I'm combining NR (Thorne) with 50 mg pterostilbene (Jarrow) and a few other things.

 

G.

Edited by whileitravel, 28 October 2016 - 11:03 PM.

[Nate-2004]

This may belong in the personal experience thread but I think it'd be important to know what brands people are using. I realize it's all supposed to come from the same source but quality is important and so is the filler they use. I use HPN.

 

I'm 6 months in now. Changes are probably subtle and long term and dosage dependent. If you're 50 you should probably be around 375mg a day or more.

[whileitravel]

 

What I understand of it is that certain cancer cells have a higher sensitivity to NAD availability. So if you have cancer one way to kill cancer is to strip the body of NAD. The cancers cells which are more sensitive to NAD availability should then die first before the normal cells are impacted. So taking NR may counter act certain cancer drugs which aim to inhibit it.

Yup, that's the concern - that however much good NR may do in the absence of cancer, there may be risks to taking it in the presence of certain cancers, and we may not be aware of the existence of such cancers when first taking NR.  Even in that case, it might still make sense to take NR as a calculated risk, but the calculation is not possible without knowing a lot more about how various cancers interact with NR supplementation.

 

Personally, I'm taking the risk that the benefits of NR will outweigh such cancer risks (if any), but, as with the researchers in the latest study, we anxiously await further data. 

 

I fast regularly and take 250mg Metformin daily. Hopefully the two offsets my threat of Ca. My NR fix is Thorne.

Edited by whileitravel, 28 October 2016 - 10:55 PM.

[bluemoon]

Thanks to Bryan and midas for their posts on NR and the heart. Oh, I started taking 125 mg of NR through HPN a few days ago and am 47. Also started 500 mg of resveratrol (Biotivia) after not taking since 2010. I have 100mg of pterostilbine and might add that but now it seems too much. 

[whileitravel]

I was taking 250mg/day for 2 months, but didn't see any effects and after watching a video recently posted here, I tapered it down to 125mg. Not a monetary issue, but one which I deemed again from the video pragmatic.

Edited by whileitravel, 28 October 2016 - 11:28 PM.

[warner]

wrt the question of dosage based on age, the mice in the recent study we've been discussing,

https://www.scienced...61027122047.htm

http://www.cell.com/...4131(16)30495-8

were continually supplemented, throughout most of their adult lives (5 to 17 months of age), with NMN roughly equivalent to a human dose of about 500 mg/d NR and higher (see my previous post about equivalent dose levels).  Several of the measures across this time period showed a continuously increasing advantage for the NMN-supplemented mice compared to controls.  Here's the plot for body weight, for example, which was associated with other positive changes,

 weight change.jpg   20.3KB   2 downloads

So that seems to indicate that fixed dosing of NMN sets the mice on a different, more healthy trajectory from the controls, and that this trajectory is established from the earliest dosing.  Which raises the question as to whether it will turn out to make sense to try to finesse NR dosage as a function of age, or whether there is a more limited range of optimal doses that are best started at a relatively young age (presumably to address parts of your system that become NAD depleted at an earlier age).

Edited by warner, 29 October 2016 - 01:42 AM.

[Bryan_S]

Just completed the paper and it appeared there was an optimal dosage which worked out to 8 mg per kg in humans. "Given that 100 mg/kg/day of NMN was able to mitigate most age-associated physiological declines in mice, an equivalent surface area dose for humans would be 8 mg/kg/ day (Freireich et al., 1966), providing hope to translate our find- ings to humans." I was taken by how fast the NMN was absorbed into the cells from oral introduction. So I'm scratching my head on that. First read, I'll re-read it tomorrow for clarification.

Edited by Bryan_S, 29 October 2016 - 08:05 AM.

[Harkijn]

Just completed the paper and it appeared there was an optimal dosage which worked out to 8 mg per kg in humans. "Given that 100 mg/kg/day of NMN was able to mitigate most age-associated physiological declines in mice, an equivalent surface area dose for humans would be 8 mg/kg/ day (Freireich et al., 1966), providing hope to translate our find- ings to humans." I was taken by how fast the NMN was absorbed into the cells from oral introduction. So I'm scratching my head on that. First read, I'll re-read it tomorrow for clarification.

The full text mentions that the effects of NMN are dose-dependent and also tissue specific. The authors twice mention that NR's effects will be similar to  that of NMN. This makes me wonder if it would be effective to combine small amounts( because of the price) of NMN as well as NR in our supplementation to achieve a broad effect. Long term supplementation of 300 to 400 mg NR/day has not prevented my eyes from deteriorating while these mice fared better on NMN!

[Daniscience]

 

I disagree that 30 is too young, NAD begins to drop at 25 and it may be more of an aging prevention than anything. You're unlikely to feel anything at all though, it's preventative, not therapeutic. Most people wouldn't feel anything drastic unless they're over 55 or 60.

 

Fair enough. It takes place at the cellular level and I've yet to notice after nearing 3 months any changes. I read of someone taking NR having some difficulty running 2km's, but after NR being able to run 10k no sweat.

 

I haven't noticed a change. I'm combining NR (Thorne) with 50 mg pterostilbene (Jarrow) and a few other things.

 

G.

 

 

Great, I am taking this new product from Thorne called Resveracel, as it combines Resveratrol and NR, someone in this forum said it was a neat combination. The suggested dosage is 2 pills but I think I will take just 1 a day to save some money, as this is not cheap stuff.

 

I lift weights and usually follow a low carb approach, intermittent fasting, turmeric and red wine are also common things in my life ^^

 

 

[warner]

Just completed the paper and it appeared there was an optimal dosage which worked out to 8 mg per kg in humans.

See my earlier post in which I fully quote that section of the paper and calculated what that means for human dosing of NMN and NR, based on molar equivalence.  I concluded that NR doses above 500 mg/d may be unwise, given this study's results (and other info).

[stefan_001]

Just completed the paper and it appeared there was an optimal dosage which worked out to 8 mg per kg in humans.

See my earlier post in which I fully quote that section of the paper and calculated what that means for human dosing of NMN and NR, based on molar equivalence. I concluded that NR doses above 500 mg/d may be unwise, given this study's results (and other info).

I have not yet read the full report but regardless I am not convinced by the conclusion. For a couple of reasons:
1) first off NMN seems to very be fery quickly absorbed as compared to NR. So the transcient is entirely different.
2) we are not continuously feeding ourself with NR, its a slow up down curve. I would think that means optimum dose windows for different tissues will therefore occur during the transcient.

Edited by stefan_001, 29 October 2016 - 02:59 PM.

[mrkosh1]

Is the NMN being provided in their water? If so, could this enhance absorption?

 

This is the only reason I can think why NMN would be absorbed faster than NR, because NMN has to be converted to NR to be absorbed into cells.

[Thell]

I didn't see this already listed and it seemed pertinent...

 

Metabolic Response to NAD Depletion across Cell Lines Is Highly Variable.

 

Nicotinamideadenine dinucleotide (NAD) is a cofactor involved in a wide range of cellular metabolic processes and is a key metabolite required for tumor growth. NAMPT, nicotinamide phosphoribosyltransferase, which converts nicotinamide (NAM) to nicotinamide mononucleotide (NMN), the immediate precursor of NAD, is an attractive therapeutic target as inhibition of NAMPT reduces cellular NAD levels and inhibits tumor growth in vivo. However, there is limited understanding of the metabolic response to NAD depletion across cancer cell lines and whether all cell lines respond in a uniform manner. To explore this we selected two non-small cell lung carcinoma cell lines that are sensitive to the NAMPT inhibitor GNE-617 (A549, NCI-H1334), one that shows intermediate sensitivity (NCI-H441), and one that is insensitive (LC-KJ). Even though NAD was reduced in all cell lines there was surprising heterogeneity in their metabolic response. Both sensitive cell lines reduced glycolysis and levels of di- and tri-nucleotides and modestly increased oxidative phosphorylation, but they differed in their ability to combat oxidative stress. H1334 cells activated the stress kinase AMPK, whereas A549 cells were unable to activate AMPK as they contain a mutation in LKB1, which prevents activation of AMPK. However, A549 cells increased utilization of the Pentose Phosphate pathway (PPP) and had lower reactive oxygen species (ROS) levels than H1334 cells, indicating that A549 cells are better able to modulate an increase in oxidative stress. Inherent resistance of LC-KJ cells is associated with higher baseline levels of NADPH and a delayed reduction of NAD upon NAMPT inhibition. Our data reveals that cell lines show heterogeneous response to NAD depletion and that the underlying molecular and genetic framework in cells can influence the metabolic response to NAMPT inhibition.

→ source (external link)

 

I was not able to locate a non-paywall link.

[warner]

 

 

Just completed the paper and it appeared there was an optimal dosage which worked out to 8 mg per kg in humans.

See my earlier post in which I fully quote that section of the paper and calculated what that means for human dosing of NMN and NR, based on molar equivalence. I concluded that NR doses above 500 mg/d may be unwise, given this study's results (and other info).

I have not yet read the full report but regardless I am not convinced by the conclusion. For a couple of reasons:
1) first off NMN seems to very be fery quickly absorbed as compared to NR. So the transcient is entirely different.
2) we are not continuously feeding ourself with NR, its a slow up down curve. I would think that means optimum dose windows for different tissues will therefore occur during the transcient.

I'm not "convinced" about much of the NR-related stuff we think we know at this time. 

 

Since we don't yet know much about the differences in rates/paths of absorption between NR vs NMN, I chose to set that aside until more info becomes available.  What we do know is that both NR and NMN are quite stable in aqueous solution, are readily absorbed when taken orally, and that, by Brenner's latest work, the NMN (very likely) must be converted to NR before entering cells:

 

NRK1 controls nicotinamide mononucleotide and nicotinamide riboside metabolism in mammalian cells

http://www.nature.co...les/ncomms13103

 

So it seems reasonable to assume that if one is dosing oneself with excess NR or NMN, that a lot of each will be absorbed, and that, without further info, the first best guess (working hypothesis) is that molar equivalents will give roughly the same results.  On that crude basis, I concluded that 500 mg/d NR is as high as I would want to go in order to avoid (1) the negative effects of higher equivalent NMN doses documented in the Imai study, (2) the fact that Brenner's group et al. has shown that 1000 mg/d is no better than 300 mg/d NR in raising blood levels, and (3) the fact that 1000 mg/d produces dramatically more NR metabolites than 300 mg/d as shown in the GRAS approval documents.  In fact, those 3 observations could well be just 3 different aspects of overloading one's system with NR and its metabolites.  (jmho at this time)

[stefan_001]

..

Edited by stefan_001, 30 October 2016 - 11:26 AM.

[stefan_001]

 

 

 

Just completed the paper and it appeared there was an optimal dosage which worked out to 8 mg per kg in humans.

See my earlier post in which I fully quote that section of the paper and calculated what that means for human dosing of NMN and NR, based on molar equivalence. I concluded that NR doses above 500 mg/d may be unwise, given this study's results (and other info).

I have not yet read the full report but regardless I am not convinced by the conclusion. For a couple of reasons:
1) first off NMN seems to very be fery quickly absorbed as compared to NR. So the transcient is entirely different.
2) we are not continuously feeding ourself with NR, its a slow up down curve. I would think that means optimum dose windows for different tissues will therefore occur during the transcient.

I'm not "convinced" about much of the NR-related stuff we think we know at this time. 

 

Since we don't yet know much about the differences in rates/paths of absorption between NR vs NMN, I chose to set that aside until more info becomes available.  What we do know is that both NR and NMN are quite stable in aqueous solution, are readily absorbed when taken orally, and that, by Brenner's latest work, the NMN (very likely) must be converted to NR before entering cells:

 

NRK1 controls nicotinamide mononucleotide and nicotinamide riboside metabolism in mammalian cells

http://www.nature.co...les/ncomms13103

 

So it seems reasonable to assume that if one is dosing oneself with excess NR or NMN, that a lot of each will be absorbed, and that, without further info, the first best guess (working hypothesis) is that molar equivalents will give roughly the same results.  On that crude basis, I concluded that 500 mg/d NR is as high as I would want to go in order to avoid (1) the negative effects of higher equivalent NMN doses documented in the Imai study, (2) the fact that Brenner's group et al. has shown that 1000 mg/d is no better than 300 mg/d NR in raising blood levels, and (3) the fact that 1000 mg/d produces dramatically more NR metabolites than 300 mg/d as shown in the GRAS approval documents.  In fact, those 3 observations could well be just 3 different aspects of overloading one's system with NR and its metabolites.  (jmho at this time)

 

 

In the NMN study the plasma NMN peaks in 5-10 minutes and drops after 15 minutes, NAD+ peaks within the first 30 minutes versus the Trammel / Brenner study where the NMN plasma peak occured after 5-6 hours and the NAD+ after 6-8 hours (in that case where the mouse got a human equivalent dosing of 15mgkg or about 1gram for a 70 kg person). Also because the mice got NMN through there drinking water I would assume they much more frequently dosed resulting in an entirely different NAD+ supplementation pattern.

 

So I dont think you can make direct dose comparisons. There is a long path in the body till cell entry. Its interesting however that NMN seems to be able to cause almost instant high peaks. That could make it a medication for cases like acute heart problems.

 

(disclosure I dont use high amounts of NR so its nothing personal...at 500mg a day here)

 

Edit: also it is somewhat contradictory that the highest NMN dosed mice have the lowest body weight while consuming the most despite the authors stating energy expenditure is higher at the lower dose during dark. Could there be a behavior change at play?

Edited by stefan_001, 30 October 2016 - 02:26 PM.

[warner]

I think Stefan made a good point about it being difficult to compare NMN and NR dosing at this time, but I just want to see more studies directly comparing NMN and NR absorption and pathways (into the cell, not just in plasma) before adding those details to the mix.  (From Brenner's interview, and his recent papers, I also get the impression that his group thinks that NMN supplementation is probably a waste of time, since it is more expensive and just ends up being converted to NR anyway before entering the cell.)

 

Anyway, a couple of other reasons to not use more than 500 mg/d NR might be...

 

(4) As described in previous posts, we haven't a clue yet as to whether NR supplementation will result in promoting some existing cancers, so why use what we have some reason to believe may be an excessive amount?

 

(5) When returning to this forum about a week ago to update my NR knowledge, the continuing positive NR research led my wife and I to increase our (HPN) NR dose from 250 to 375 mg/d.  This consisted of 250 mg in the morning and 125 mg at dinner.  From the Brenner interview, he noted that NAD+ peaks in humans sometime during the afternoon, and then again in the middle of the night, and that one could optionally take a dose of NR at dinner to augment the nightly NAD+ peak (i.e., so both NAD+ peaks would be augmented, although he wasn't himself doing that).  Now, for various reasons (positional apnea control, etc.), my wife and I have an alarm set at 2:30 AM to get us up to pee, and we rarely have any trouble getting back to sleep after that.  However, after upping the NR dose to 375 mg/d, we're both having trouble getting back to sleep at that time.  There is no pain, etc.  We're just wide awake, thinking about stuff, taking much longer to fall back to sleep.  Some others have also noted that taking NR before bed makes sleeping more difficult.  I wouldn't have made much of this, but the fact that it's happening to both of us, under similar conditions, after upping the NR dose, with others reporting similar effects, makes me think its the NR.  So, after a week at 375, we're going back to 250 mg/d and we'll see what happens.  (It may be the case that the body would adapt to the new dose over time, but given the importance of getting good sleep, and with the little we know about long-term NR dosing effects, it seems prudent to reduce the dosage.)

 

So that's another potential problem with higher doses - they may keep you awake at night if you try to spread the higher dose across the day.  Anyway, a good example of how personal experience needs to be mixed into the decision-making.

[warner]

Edit: also it is somewhat contradictory that the highest NMN dosed mice have the lowest body weight while consuming the most despite the authors stating energy expenditure is higher at the lower dose during dark. Could there be a behavior change at play?

 

Lower weight can also be a sign of toxicity - something negative at play - like maybe way too much NMN.  May be another reason to be suspicious of the higher doses (as were the researchers when choosing the lower dose as optimal).

[Iporuru]

Berberine increases the NAD⁺/NADH ratio and activates SIRT1:

https://www.ncbi.nlm...les/PMC3366688/

 

After observing that the effects of BBR on mitochondrial function and biogenesis were dependent on SIRT1, we sought to elucidate the mechanism by which BBR activates SIRT1. BBR did not directly activate SIRT1 as evaluated with an in vitro activity assay (data not shown), indicating that it likely does not function in the same manner as the commonly used Sirtuin Activating Compounds (STACs) [49]. Given that SIRT1 is known to be regulated by NAD⁺ and the NAD⁺/NADH ratio, we measured their abundance in cells treated with BBR. Interestingly, BBR prevented the decrease in the NAD⁺/NADH ratio caused by hyperglycemia (Fig. 6A) in C2C12 myotubes. To explain the increase in NAD⁺/NADH induced by BBR, we evaluated the expression of nicotinamide phosphoribosyltransferase (NAMPT), the rate-limiting factor in NAD⁺ biosynthesis. A decrease in NAMPT expression and consequent depletion of cellular NAD⁺ has been shown as a mechanism linking high glucose and FFAs with SIRT1 downregulation [50]. Therefore, we tested whether BBR modulates NAMPT expression in C2C12 cells. Gene expression of NAMPT markedly increased after 6 h of BBR exposure (Fig. 6C), which was paralleled by an increase in the NAD⁺/NADH ratio (Fig. 6B). Moreover, FK866, an inhibitor of NAMPT, blocked the induction of genes that regulate mitochondrial biogenesis and also in nuclear-encoded and mitochondrial-encoded mitochondrial genes by BBR (Fig. 6D).