2255 replies to this topic

[Oakman]

 

I posted months ago about a study showing rats had 35% reduction in exercise performance and my post was basically rejected as not worth much. Tonight I just so happened to read this very sites supplement review of NR and what do I see:
 

 

 

Of course NR will reduce exercise performance. Raising the NAD+/NADH ratio will fission mitochondria and set the QC process in motion. This will naturally result in less ATP production since fissioned mitochondria are less efficient. You have to allow for subsequent fusion and biogenesis to obtain a benefit.

 

 

So, conversely, lowering the NAD+/NADH ratio by supplementing NADH would promote fusion and increased exercise performance... yes?  I wonder if the increase is significant? You'd need to rotate NR/NADH supplementation for best fission / fusion periods. Anyone done this?

[Harkijn]

I posted months ago about a study showing rats had 35% reduction in exercise performance and my post was basically rejected as not worth much. Tonight I just so happened to read this very sites supplement review of NR and what do I see:

"While NR supplementation seems to have multiple benefits in laboratory animals we should notice that research in this area has only started. To the best of our knowledge no human data on the health effects of NR has been published so far. Also the reduced exercise performance in rats fed NR is a warning that we shouldn’t implement NR supplementation in healthy humans as of yet (Kourtzidis et al., 2016). In a few years more data about NR should be available allowing us to make a much more informed decision."

So this very sites is recommending that we not take this stuff yet. But some may say that since this reveiw was written one human study has been published, but did they measure exercise performance? Also there were only16 people in that study.

This stuff is far from proven and my own experience with it was that it did curtail my exercise performance.

Mike,

 

Your post was not rejected. We found it an interesting contribution,  but there were a lot of question marks about the study, neatly summed up by Bryan in post #1044.

NR certainly raised my athletic performance, but more importantly the most recent science indicates that NR raises NAD+levels in the short and midterm. Of course I too am curious about the studies that will be published in june/july. That's when we will have a more definite picture.

[Mike C]

Of course NR will reduce exercise performance. Raising the NAD+/NADH ratio will fission mitochondria and set the QC process in motion. This will naturally result in less ATP production since fissioned mitochondria are less efficient. You have to allow for subsequent fusion and biogenesis to obtain a benefit.

Do you have a source for this theory?

 

 

I posted months ago about a study showing rats had 35% reduction in exercise performance and my post was basically rejected as not worth much. ... [But] this very sites is recommending that we not take this stuff yet. But some may say that since this reveiw was written one human study has been published, but did they measure exercise performance? Also there were only16 people in that study.

This stuff is far from proven and my own experience with it was that it did curtail my exercise performance.

200,000 people are spending money and taking it and getting benefits. The rat study will be proven to be flawed.

 

You mean like snake oil?

Edited by Michael, 07 May 2017 - 11:43 PM.
Fixing quotation markup; trim quote

[aribadabar]

 

 

I decided I was going to try a 1250 mg 7 day test of NR.  On day one I took the NR over the course of the day and in the middle of the night I had stomach aches. In the morning I had a massive (hangover like) headache that lasted for hours.  Needless to say my liver was over taxed which indicates the body does view NR as a toxin to be cleared.

 

Needless to say I did not carry on with the test. The only positive I felt was a day later when I went for a run and felt strong.

 

The dose makes the poison. Needless to say, you overdosed.

NR is clearly not a toxin since it is a NAD+ precursor,an intermediate step in the cell energy metabolism. I am fairly certain you would not have experienced negative effects if you stuck to the recommended 250 mg/d.

 

 

Overdose? So how could Niagen cause hangover like headache?
 

 

 

Every person is different so I can only guess what may cause it so take it as such: Since NR is a methyl sink and if the person is a natural undermethylator/having MTHFR gene mutation it may cause severe undermethylation triggering this headache symptoms.

[ceridwen]

As huge number of people have this mutation. How come it's the 1St time we've herd of this. Is this the same for nmn and niacin also?

[Bryan_S]

I posted months ago about a study showing rats had 35% reduction in exercise performance and my post was basically rejected as not worth much. Tonight I just so happened to read this very sites supplement review of NR and what do I see:

"While NR supplementation seems to have multiple benefits in laboratory animals we should notice that research in this area has only started. To the best of our knowledge no human data on the health effects of NR has been published so far. Also the reduced exercise performance in rats fed NR is a warning that we shouldn’t implement NR supplementation in healthy humans as of yet (Kourtzidis et al., 2016). In a few years more data about NR should be available allowing us to make a much more informed decision."

So this very sites is recommending that we not take this stuff yet. But some may say that since this reveiw was written one human study has been published, but did they measure exercise performance? Also there were only16 people in that study.

This stuff is far from proven and my own experience with it was that it did curtail my exercise performance.

 

This study wasn't a mainstream study and had absolutely no funding. It was conducted at the Department of Physical Education and Sport Science at Serres, Aristotle University of Thessaloniki, Agios Ioannis, Serres, 62110 Greece. The materials used were purchased "NAD+ Cell Regenerator™" containing microcrystalline cellulose, vegetable cellulose (capsule), silica, vegetable stearate administered daily for 21 days via gavage at a dose of 300 mg/kg body weight. This was an off the shelf preparation. The rats in the control group received a saline vehicle "only" not containing the excipients (microcrystalline cellulose, vegetable cellulose (capsule), silica, vegetable stearate). So we have an issue with the NR source anyway with multiple ingredients. 

 

"Evidently, these hypotheses are speculative and are currently being investigated in order to reveal the potential metabolic and redox mechanisms involved in our finding. Further studies are warranted to acquire mechanistic insights on the effect of nicotinamide riboside on exercise performance."

 

All they had to do was ask Chromadex for Nicotinamide Riboside without the excipients and perhaps this would have received some outside review but the experiment was deficient in so many ways. So you are not going to engage anyone on speculation because the authors didn't go deep enough.

 

We do have a full scale human experiment going on at the University of Minnesota. So if you want better data, they are looking at Traumatic Brain Injury with football players but if the subjects suffered an adverse reduction in exercise stamina this should come to light and this is the experiment to watch.

 

Here are some relevant terms used in the football players experiment. "Brain Concussion, Brain Injuries, Brain Diseases, Central Nervous System Diseases, Nervous System Diseases, Craniocerebral Trauma, Trauma, Nervous System, Head Injuries, Closed, Wounds and Injuries, Wounds, Nonpenetrating"

 

As always JMHO

Edited by Bryan_S, 07 May 2017 - 10:02 PM.

[Michael]

I posted months ago about a study showing rats had 35% reduction in exercise performance and my post was basically rejected as not worth much. Tonight I just so happened to read this very sites supplement review of NR and what do I see:

 
Of course NR will reduce exercise performance. Raising the NAD+/NADH ratio will fission mitochondria and set the QC process in motion. This will naturally result in less ATP production since fissioned mitochondria are less efficient. You have to allow for subsequent fusion and biogenesis to obtain a benefit.

To be clear, this is mechanistic speculation, yes? That is, you're assuming that an increase in the NAD+:NADH secondary to NR supplementation will lead to increased mitochondrial fission, based on studies in vitro that do not involve NR that relate the NAD+:NADH to mitochondrial fission, and further assuming that this would interfere with energy production and that this would noticeably affect exercise performance — right? And that exercise performance would actually rebound to levels greater than baseline once an hypothetical post-fission biogenesis occurred — right?
 
You have no actual evidence showing that NR supplementation results in this series of mechanistically-hypothesized events — right?

[Turnbuckle]

 

 

I posted months ago about a study showing rats had 35% reduction in exercise performance and my post was basically rejected as not worth much. Tonight I just so happened to read this very sites supplement review of NR and what do I see:

 
Of course NR will reduce exercise performance. Raising the NAD+/NADH ratio will fission mitochondria and set the QC process in motion. This will naturally result in less ATP production since fissioned mitochondria are less efficient. You have to allow for subsequent fusion and biogenesis to obtain a benefit.

 

To be clear, this is mechanistic speculation, yes? That is, you're assuming that an increase in the NAD+:NADH secondary to NR supplementation will lead to increased mitochondrial fission, based on studies in vitro that do not involve NR that relate the NAD+:NADH to mitochondrial fission, and further assuming that this would interfere with energy production and that this would noticeably affect exercise performance — right? And that exercise performance would actually rebound to levels greater than baseline once an hypothetical post-fission biogenesis occurred — right?
 
You have no actual evidence showing that NR supplementation results in this series of mechanistically-hypothesized events — right?

 

 

 

Right. There is no study I'm aware of the combines all these elements.

[Michael]

 

I posted months ago about a study showing rats had 35% reduction in exercise performance  [...] But some may say that since this reveiw was written one human study has been published, but did they measure exercise performance? Also there were only16 people in that study.

This stuff is far from proven and my own experience with it was that it did curtail my exercise performance.

 
This study wasn't a mainstream study

I have a sense of what politicians mean when they say that a judicial nominee is "outside of the mainstream," and I know what commentators mean when they say that a scientist's views are "outside of the mainstream." I have no idea at all what it means to say that a "study wasn't a mainstream study." Would you clarify?
 

and had absolutely no funding.

Of course, one cannot do a study with absolutely no funding. Are you referring to the statement that the authors had "No funding to declare" in the "Declarations" section? This simply means that they weren't' getting funding from an interested party, such as Chromadex, Life Extension, or one of their competitors, and possibly also that they didn't get any dedicated funding for it, but instead took it out of their lab's internal unallocated funding. The former is a good thing, and the latter is certainly not problematic.
 
Or did you mean something else? And if so, why is the lack of such funding a problem in your view?
 

It was conducted at the Department of Physical Education and Sport Science at Serres, Aristotle University of Thessaloniki, Agios Ioannis, Serres, 62110 Greece.

Indeed: a place with actual expertise in exercise physiology. Nice, huh?
   
Bryan wrote: The materials used were purchased "NAD+ Cell Regenerator™" containing microcrystalline cellulose, vegetable cellulose (capsule), silica, vegetable stearate administered daily for 21 days via gavage at a dose of 300 mg/kg body weight. This was an off the shelf preparation. The rats in the control group received a saline vehicle "only" not containing the excipients (microcrystalline cellulose, vegetable cellulose (capsule), silica, vegetable stearate). So we have an issue with the NR source anyway with multiple ingredients.
 
Well, we don't have a problem with the NR source — it's all Chromadex, yes? (If it was some manufacturer we knew nothing about, you might worry that they or their suppliers were substituting sawdust or plain NAM — but this is Life Extension, and whatever else you think about them, their quality is unimpeachable). And, obviously, the capsule itself would not be included in the gavage administration: while they don't say so, I think we can safely assume that they emptied the capsule out first.
 
However, you do have a point about the excipients not being included as part of the control — but not one that I think should concern one overmuch. MCC is quite inert: if they had fed enormous amounts of it with a meal, you might worry that the MCC might have inhibited their appetite by filling them up, thereby reducing their energy intake and lowering performance, but that isn't a realistic concern at the ratios it's present in LEF's capsules (and even less so when it's delivered via gavage rather than as part of the chow). The effect of the vegetal stearate is a more serious question, but the worst this would do would be to reduce the uptake of NR: that wouldn't explain the supplemented group having poorer performance than the controls.
 
Bryan quoted: "Evidently, these hypotheses are speculative and are currently being investigated in order to reveal the potential metabolic and redox mechanisms involved in our finding. Further studies are warranted to acquire mechanistic insights on the effect of nicotinamide riboside on exercise performance."

I'm not sure why you were quoting this material. Quoted in isolation, a reader (either you, or someone reading your post) might mistakenly think that the authors were suggesting that their findings were somehow speculative and hypothetical, which wouldn't make any sense.
 
Rather, they are offering up a couple of possible hypotheses to explain their findings, and then correctly noting them to be tentative and calling for research to test them:

 
Based on the similar effects of nicotinic acid and nicotinamide riboside on NAD⁺ metabolism, the impairments in exercise performance observed in our study may stem from the same sources as in the studies used nicotinic acid [, namely] ... reduced exercise-induced increases in plasma free fatty acids. Therefore, it is likely that nicotinamide riboside decreased fatty acid oxidation during exercise leading to an earlier fatigue.
 
In addition, the redox properties of NAD⁺ and NADP⁺ could also provide a plausible explanation for the impaired performance observed, namely by disrupting redox homeostasis [10]. In particular, nicotinamide riboside administration may have altered redox homeostasis leading cells to a more reductive (non-optimal) state ... in line with other recent studies stressing the potential detrimental effects of redox-related supplements on exercise capacity [12].
 
Evidently, these hypotheses are speculative and are currently being investigated in order to reveal the potential metabolic and redox mechanisms involved in our finding.

 
I will point out again that there is an additional possible explanation, connected with their hypothesis about the redox coupling of NADP(H). (Nearly?) all NR studies reporting positive effects of megadose NR (on exercise performance, muscle stem cell function, diabetic obesity, etc) have used C57Bl/6J mice, which carry the strain's NNT mutation, leading to inadequate reduction of NADP⁺ in their mitochondria. One possibility is that megadose NR partially offsets this defect by augmenting the cellular level of NAD⁺, facilitating a more normal level of NADP⁺ reduction to NADPH. By contrast, in an animal with an intact NNT gene (such as a rat (as in this study), or the C57BL/6JRcc mice used in this study, or the vast majority of humans) — in such an organism, increasing the level of NAD⁺ via megadose NR might instead disrupt optimal NADP:NADPH redox coupling, leading to functional impairments. (See here, here, and here).
 
Bryan wrote: All they had to do was ask Chromadex for Nicotinamide Riboside without the excipients and perhaps this would have received some outside review but the experiment was deficient in so many ways. So you are not going to engage anyone on speculation because the authors didn't go deep enough.
 
You've pointed out one deficiency (the non-administration of the MCC and vegetal cellulose in the control gavage), which I don't find very troubling for reasons given above; in what other ways would you say it is deficient and did not go deep enough?
 
Bryan wrote: We [Chromadex] do have a full scale human experiment going on at the University of Minnesota. So if you want better data, they are looking at Traumatic Brain Injury with football players but if the subjects suffered an adverse reduction in exercise stamina this should come to light and this is the experiment to watch.
 
Here are some relevant terms used in the football players experiment. "Brain Concussion, Brain Injuries, Brain Diseases, Central Nervous System Diseases, Nervous System Diseases, Craniocerebral Trauma, Trauma, Nervous System, Head Injuries, Closed, Wounds and Injuries, Wounds, Nonpenetrating"

Er ... first, people are taking NR now on the basis of (other) rodent studies. Second: re-read those relevant terms: none of them is "ergogenic aid." The U of M trial's primary outcome is (indirectly-measured) change in brain NAD+ levels, with "physical assessment" as a secondary outcome: it's not clear to me that "physical assessment" would involve testing exercise performance. And even if it did, it's quite different to show that a person with exercise deficits related to TBI recovers following NR supplementation (supposing they were to find that) than to find that exercise performance was improved in uninjured, otherwise-healthy trained or untrained people. So I'd be surprised if this study were all that informative on the issues raised by this study.

Edited by Michael, 08 May 2017 - 03:43 AM.

[Harkijn]

I think we should take the Koutzidis study serious but not be overly impressed by it. They fed NADCell Regenerator to only 9 rats and compared them to 9 rats in a control group. Letting loose statistics on such a small group is like firing a cannon on a musquito. To give the researchers credit: they call the 35% lower performance 'marginally statistically non-significant'.

By contrast this study is far more impressive:

http://www.cell.com/...21?showall=true

Which still does not mean that Koutzidis et. al. should be disregarded. And Michael's point about KO mice is something to keep an eye on in the weeks ahead.

 

[soulprogrammer]

a) the sample size of 9 each in control (placebo) and NR group is too small.

b) look at the data, a lot of outliers. The placebo group has huge variation, same as NR group. The SD is too large for each group. From a min of 56s to a max of 241s (for placebo group). This is like 4 times! Is this normal? Not sure, never conduct any biological experiment.  For NR group, from a min of 21s to max of 188s! Isn't this shows some problems in the data? 

c) the first three authors  "Ioannis A. Kourtzidis†,Andreas T. Stoupas†,Ioannis S. Gioris", I try to Google cannot find their profile. I am trying to look into their credentials and background. (I'm just curios about their background and credentials - also looking into what other papers they published and in what field). Did I done something wrong? I tried Google Scholar, in the search field, I paste "Ioannis Kourtzidis", but nothing come out except the paper we are discussing. How do I find all papers published by him?

 

 

 

    2   Placebo (time in secs) Nicotinamide riboside (time in secs) 3 1 177 188 4 2 170 34 5 3 187 21 6 4 137 63 7 5 161 129 8 6 74 91 9 7 241 72 10 8 100 103 11 9 56 141 12 Average 144.77777777777777 93.55555555555556 13 SD 59.09267674123796 53.30598257023106

 

Sorry, the table data is totally lost its alignment!

Edited by soulprogrammer, 08 May 2017 - 07:56 AM.

[stefan_001]

http://www.jci.org/a...view/83260#SEC1

These data have identified a potentially drug-modifiable SIRT3-dependent program to attenuate the NLRP3 inflammasome and suggest that this pathway may be modulated as a strategy to alleviate/attenuate NLRP3-linked inflammation.

 

(study is older but with non NNT mutated humans)

Edited by stefan_001, 08 May 2017 - 12:12 PM.

[Harkijn]

http://www.jci.org/a...view/83260#SEC1

These data have identified a potentially drug-modifiable SIRT3-dependent program to attenuate the NLRP3 inflammasome and suggest that this pathway may be modulated as a strategy to alleviate/attenuate NLRP3-linked inflammation.

 

(study is older but with non NNT mutated humans)

A very good find Stefan! I hope some posters with specialized knowledge read this study and explain the full ramifications. It seems however that in most respects NR has a very positive role.

[soulprogrammer]

This study is quite interesting

 

B-vitamins and NAD metabolism, or when vitamin B3's bioavailability is not enough

 

Abstract

 

The dietary vitamin B3, which encompasses nicotinamide, nicotinic acid and nicotinamide riboside, is precursor to the coenzyme nicotinamide adenine dinucleotide (NAD+), its phosphorylated parent (NADP+) and their respective reduced forms (NADH and NADPH). Once converted intracellularly to NAD(P)+, it is used as a co-substrate in two types of intracellular modifications, which control numerous essential signalling events (adenosine diphosphate ribosylation and deacetylation), and is a cofactor for over 400 redox enzymes, thus controlling metabolism. Critically, the NAD(P)(H)-cofactor family can promote mitochondrial dysfunction and cellular impairment if present in sub-optimal intracellular concentrations.
Vitamin B3, and other B-vitamins such as thiamine (vitamin B1), riboflavin (vitamin B2) and pyridoxine (vitamin B6) are extracted in their coenzyme forms from food stuff. During digestion, the coenzymes are catabolised to the free circulating vitamins, which are then passively or actively transported across membranes, and salvaged intracellularly to their respective cofactors. Mammals are entirely reliant on a dietary source of vitamin B1 and heavily dependent on the dietary supply of vitamin B3, B2, and B6. Of note, acute deficiencies in vitamin B1 and vitamin B3 effect identical organs, with identical outcomes if left untreated: dementia and death. Conditions such as diabetes and obesity, alcoholism, high fat diet and conditions where therapy impacts nutrition can compromise suitable absorption of these vitamins.
The bulk of intracellular NAD+ is regenerated via the effective salvage of nicotinic acid and nicotinamide (vitamin B3), while de novo NAD+ is obtained from tryptophan. Crucially, these salvage and de novo pathways depend on the functional forms of vitamin B1, B2 and B6 to generate NAD+ via a phosphoriboside pyrophosphate intermediate. Nicotinamide Riboside (NR) is the only form of vitamin B3 from which NAD+ can be generated in a vitamin B1, B2 and B6 independent manner and even though NR is a minor component of vitamin B3, the salvage pathway using NR for the production of NAD+ is expressed in most eukaryotes. While major strides have been made in the field of NAD+ biology and NAD+ metabolism, the role of this later pathway and the importance of the interplay between the bioavailability of vitamin B1, B2 and B6 and the pool of NAD(P)(H)-cofactors remain poorly explored. 
Using our synthetic expertise in nucleotide and stable isotope labelling chemistry, we will generate isotopically labelled vitamin B1 and B3 derivatives. These entities will be used to determine the profile of the vitamin B3 metabolome quantified by mass spectroscopy, under vitamin B1, B2 and B6 depletion conditions, in genetically engineered yeast strains and mammalian (murine and human) hepatocytes. In mammalian cells, these metabolic profiles will be correlated to mitochondrial functions. With this information, we will be able to prioritise the mechanisms cells use to best maintain the NAD(P)(H) pool in time of shortage of vitamin B1, B2 or B6. We predict that the pathway, by which NR is converted to NAD+, provides the means to rapidly yet transiently elevate mitochondrial and cytosolic NAD(P)(H) levels to kick start mitochondrial functions. If demonstrated, this knowledge will help identify new, physiologically relevant, vitamin-B combinations that could better restore mitochondrial function through enhanced bioavailability, in cells and organs where metabolism has been compromised by imbalanced micronutrition. This knowledge will be particularly important in terms of understanding the impacts of a global or partial vitamin B deficiency and vitamin B supplementation on organ functions in relation to malnutrition and over-nutrition.

 

http://gtr.rcuk.ac.u...ef=BB/N001842/1

 

 

[Michael]

I think we should take the Koutzidis study serious but not be overly impressed by it. They fed NADCell Regenerator to only 9 rats and compared them to 9 rats in a control group. Letting loose statistics on such a small group is like firing a cannon on a musquito. To give the researchers credit: they call the 35% lower performance 'marginally statistically non-significant'.
By contrast this study is far more impressive:
http://www.cell.com/...4131(12)00192-1

 
The part of the study you suggest to be far more impressive that looked at the effect of NR on exercise endurance in non-diabetic mice  (a) involved fewer mice, not more (n=8), (b) also observed a small, nonsignificant effect, and © while one should not be superstitious on the subject, had a p-value further from the conventional p<.05 threshold (all (Figure S3A)) than the Greek rat study. Even their substudy in high-fat-and-sugar-fed, diabetic, obese mice used only 10 animals — hardly a dramatic increase in power over n=9.
 

 b) look at the data, a lot of outliers. The placebo group has huge variation, same as NR group. The SD is too large for each group. From a min of 56s to a max of 241s (for placebo group). This is like 4 times! Is this normal? Not sure, never conduct any biological experiment.  For NR group, from a min of 21s to max of 188s! Isn't this shows some problems in the data? 

 

There actually aren't any outliers: I think maybe you mean that there is a lot of spread. And while I agree on the latter, (a) the size of the spread is the same for both groups (≈225 s), (b) the lowest- and highest-endurance animals in the supplemented group were both lower in the NR-supplemented group than the controls.

 

And, again: these were C57Bl/6J mice.

[Harkijn]

 

I think we should take the Koutzidis study serious but not be overly impressed by it. They fed NADCell Regenerator to only 9 rats and compared them to 9 rats in a control group. Letting loose statistics on such a small group is like firing a cannon on a musquito. To give the researchers credit: they call the 35% lower performance 'marginally statistically non-significant'.
By contrast this study is far more impressive:
http://www.cell.com/...4131(12)00192-1

 
The part of the study you suggest to be far more impressive that looked at the effect of NR on exercise endurance in non-diabetic mice  (a) involved fewer mice, not more (n=8), (b) also observed a small, nonsignificant effect, and © while one should not be superstitious on the subject, had a p-value further from the conventional p<.05 threshold (all (Figure S3A)) than the Greek rat study. Even their substudy in high-fat-and-sugar-fed, diabetic, obese mice used only 10 animals — hardly a dramatic increase in power.

 

 

Oops, I inadvertently led you into a dead end road here. I did not mean to start comparing rodent numbers.

I meant to say that the other study in it's wider setup and scope and, as far as I can judge, inner consistency leads to much more specific preliminary conclusions:

 

To further solidify our data, we also wondered whether the enhanced NAD+ levels upon NR treatment could derive from alterations in the NAD+ salvage pathway or PARP activity. However, we could not see any change in Nampt mRNA or protein content in response to NR treatment (Figure 1G). Similarly, PARP activity and PARP-1 content were not affected by NR (Figure 1H). Altogether, these results suggest that NR increases NAD+ by direct NAD+ biosynthesis rather than by indirectly affecting the major NAD+ salvage (Nampt) or consumption (PARPs) pathways. Importantly, this increase in NAD+ was not linked to changes in cellular glycolytic rates or ATP levels (data not shown), which would be expected if NAD+/NADH ratios had been altered to the point of compromising basic cellular functions.

 

It rather points the other way, but, let me repeat, still does not mean that Koutzidis is wrong.

 

(BTW: I checked some online publications on debate or analysis of the Koutzidis study but haven't found anything sofar. Anyone has a clue ahere to look?)

Edited by Harkijn, 08 May 2017 - 04:13 PM.

[Bryan_S]

Er ... first, people are taking NR now on the basis of (other) rodent studies. Second: re-read those relevant terms: none of them is "ergogenic aid." The U of M trial's primary outcome is (indirectly-measured) change in brain NAD+ levels, with "physical assessment" as a secondary outcome: it's not clear to me that "physical assessment" would involve testing exercise performance. And even if it did, it's quite different to show that a person with exercise deficits related to TBI recovers following NR supplementation (supposing they were to find that) than to find that exercise performance was improved in uninjured, otherwise-healthy trained or untrained people. So I'd be surprised if this study were all that informative on the issues raised by this study.

 

 

Thanks Michael I should have taken more time on my meaning, you are precisely the kind of commentary I like here. Also as expressed before thanks for taking some time to help anchor this thread. Your reasoned voice is always welcome.

 

First let me say I did contact ChromaDex in the following weeks after this study to get their thoughts. Now I would to some degree expect them to discount this study. I did expect active NR and NMN researchers to be filtering comments back to them, or their colleagues, even if they didn't publish them, which they had. One comment of note was the preparation this group used, it contained roughly 50% excipients and the University didn't contact ChromaDex for an uncut sample. Also they rolled the experiment up into one defining test, the Incremental swimming performance test and in this test I would have liked to see more data points.

 

Granted that test is used just like the length of treadmill running, frequency of voluntary wheel running and timed hang tests. It is thought to be a more reliable test because there is no starts and stops.

 

I took this questioning a step further and spoke to one noted NR researcher and got the impression this study was largely invisible to the serious researchers because they looked at just one parameter.

 

On the topic of "mainstream" I meant it didn't originate from a University where we've seen NR or NMN research before. They are but a blip on the radar in the NR, NMN and NAD arena. If it had originated from say University of Iowa Carver College of Medicine, University of Washington, University of Colorado, Boulder, Maastricht University Medical Center, Aarhus University Hospital, National Heart, Lung, and Blood Institute (NHLBI), Mayo Clinic, University of Birmingham and The University of Texas Health Science Center at San Antonio to name a few it would have attracted more attention, these are adequately funded institutions looking at NAD metabolism. Of these who has written a review of the Greek study?

 

On funding I should have said "thinly funded." But even so you would think being a University with actual expertise in exercise physiology they would have taken on the questions about the physiology and this is where they speculated. They produced a result without many supporting answers.

 

On the University of Minnesota. Here is a study where healthy athletes are receiving daily NR. I don't have details on all the monitoring parameters but a 35% reduction in performance would make a difference to so many aspects of football where winning is the only result that matters. If this reduction holds true at the human level how long do you suppose a football team would choose to work with this kind of handicap? This is my premiss if performance is indeed reduced this study should shed light in that.

 

I certainly don't have all the answers and you point to some possible reasons these results could be true. However I and many others would liked to have seen oxygen consumption (VO2), or Blood Lactate Concentration levels, so many other parameters could have supported their findings but didn't. You've defended the Greek study but I'll say the data is thin and it needs additional verification.

 

As always JMHO

Edited by Bryan_S, 08 May 2017 - 05:10 PM.

[stefan_001]

 

Er ... first, people are taking NR now on the basis of (other) rodent studies.

 

Hi Michael, I think you are somewhat fixated on this mouse study. The reason why people look at NR is because of its proven ability to raise NAD+ in humans.The reason they do that is because there are many studies linking various age related diseases to a decline in NAD+.

Edited by stefan_001, 08 May 2017 - 05:05 PM.

[stefan_001]

http://www.fasebj.or...nt/602.15.short
NAD+ replacement therapy with nicotinamide riboside does not improve cardiac function in a model of mitochondrial heart disease.

 

lets hope the mouse model is wrong here too as this is about a kids disease

Edited by stefan_001, 08 May 2017 - 07:55 PM.

[Bryan_S]

http://www.fasebj.or...nt/602.15.short
NAD+ replacement therapy with nicotinamide riboside does not improve cardiac function in a model of mitochondrial heart disease.

 

lets hope the mouse model is wrong here too as this is about a kids disease

 

It can be inherited by children. Friedrich’s Ataxia (FRDA) is a rare and poorly understood autosomal recessive disease caused by a pathological deficiency of the mitochondrial protein frataxin. Patients suffer neurodegeneration, ataxia, diabetes, and heart failure. Here is a good overview.

 

They discuss their issues in the study.

 

Discussion In FXN KO hearts, SIRT3 may be irreversibly inactivated, possibly via lipid peroxidation from an increase in reactive oxygen species known to arise secondary to the loss of frataxin. Combining NR therapy with SIRT3 replacement, or trialing longer or larger doses of NR, may be more effective in modifying SIRT3 acetylation targets in the FXN KO heart and warrants further investigation.

 

Conclusion In conclusion, NAD+ supplementation with NR in the FRDA model of mitochondrial heart disease does not alter SIRT3 activity or improve cardiac function.

 

Good find.

Edited by Bryan_S, 09 May 2017 - 12:04 AM.

[Nate-2004]

Cold shock therapy (ice bath) is really good for mitochondrial biogenesis and the lowering of a number of other inflammatory markers. Yet it is also terrible for gains in hypertrophy after exercise and not so good for other fitness gains. However, this is dependent on the timing.

 

So what if NR has a negative effect on exercise performance?  Let's not discount its possible benefits. Let's say the mouse study is repeated on a larger, better conducted scale and proves true. Does that mean NAD+ boosting with NR is out? Depends I guess. Is it a timing issue? Will NMN do the same thing? 

Edited by Nate-2004, 09 May 2017 - 12:44 AM.

[MikeDC]

http://www.fasebj.or...nt/602.15.short
NAD+ replacement therapy with nicotinamide riboside does not improve cardiac function in a model of mitochondrial heart disease.

lets hope the mouse model is wrong here too as this is about a kids disease

It can be inherited by children. Friedrich’s Ataxia (FRDA) is a rare and poorly understood autosomal recessive disease caused by a pathological deficiency of the mitochondrial protein frataxin. Patients suffer neurodegeneration, ataxia, diabetes, and heart failure. Here is a good overview.

They discuss their issues in the study.

Discussion In FXN KO hearts, SIRT3 may be irreversibly inactivated, possibly via lipid peroxidation from an increase in reactive oxygen species known to arise secondary to the loss of frataxin. Combining NR therapy with SIRT3 replacement, or trialing longer or larger doses of NR, may be more effective in modifying SIRT3 acetylation targets in the FXN KO heart and warrants further investigation.

Conclusion In conclusion, NAD+ supplementation with NR in the FRDA model of mitochondrial heart disease does not alter SIRT3 activity or improve cardiac function.

Good find.

Since the Sirt3 gene is permanently disabled, NR obviously has no effect on it. NR can increase NAD+. But in order for this to have health benefit, Sirtuin genes need to normal.

[Michael]

 

 

http://www.fasebj.or...nt/602.15.short
NAD+ replacement therapy with nicotinamide riboside does not improve cardiac function in a model of mitochondrial heart disease.

lets hope the mouse model is wrong here too as this is about a kids disease

Discussion In FXN KO hearts, SIRT3 may be irreversibly inactivated, possibly via lipid peroxidation from an increase in reactive oxygen species known to arise secondary to the loss of frataxin. Combining NR therapy with SIRT3 replacement, or trialing longer or larger doses of NR, may be more effective in modifying SIRT3 acetylation targets in the FXN KO heart and warrants further investigation.

Conclusion In conclusion, NAD+ supplementation with NR in the FRDA model of mitochondrial heart disease does not alter SIRT3 activity or improve cardiac function.

 

Since the Sirt3 gene is permanently disabled, NR obviously has no effect on it. NR can increase NAD+. But in order for this to have health benefit, Sirtuin genes need to normal.

 
To be clear, there is nothing wrong with the SIRT3 gene in these animals: they have a mutation in the gene for the mitochondrial protein frataxin (FXN). As this group had previously reported, mice with these mutations have impaired SIRT3 activity, "caused by an 85-fold decrease in mitochondrial NAD⁺/NADH and direct carbonyl group modification of SIRT3." Because of this inhibited SIRT3 activity, these animals suffer increased mitochondrial protein acetylation (since SIRT3 isn't doing its deacetylation job).
 
The researchers expected that NR supplementation would normalize these animals' heart SIRT3 activity by increasing NAD+ levels in their hearts, just as they had previously found that it could be reversed in vitro by adding extra SIRT3 and NAD+. However, the excess acetylation of SIRT3 targets wasn't affected by NR supplementation as one might expect it to be, and the animals' hearts continued to degenerate.
 
Since SIRT3 protein expression did not differ between groups, they hypothesize that the protein must still be so inactivated  (such as, perhaps, via oxidative damage secondary to loss of frataxin, consistent with the previously-reported carbonylation of the protein)  that raising NAD+ levels could not boost its activity as you would normally expect.
 
However, despite the fact that they say that "In conclusion, NAD⁺ supplementation with NR in the FRDA model of mitochondrial heart disease does not alter SIRT3 activity or improve cardiac function," the meeting abstract doesn't report them actually measuring the effect of NR on NAD+ levels. So it's also possible that NR did not actually elevate NAD+ in their hearts — or, perhaps, that it didn't elevate it in the mitochondrial fraction.
 
And, they don't mention the background strain of mice they use, so the C57Bl/6J NNT mutation may be a potential culprit as well. This may be in the Supplementary Information in their previous report, but I can't get it to download: it seems to be stuck in a Strange Loop ...

Edited by Michael, 09 May 2017 - 03:36 AM.

[Gingerbread Man]

Lately I have only been taking a daily vitamin, b12 sublingual and 100 mg NR/100mg Ubiquinol before bed with my Lantus/victoza shots. I have noticed a leaning of the muscle and fat, but more tone with little if any exercise. I mention this because this mice study with regards to performance has been in my head since i first read about it. A bit ago I was doing curls fairly regularly and I noticed that it felt like I hit a wall earlier than usual. basically at the point where i would normally stop as I was spent. I rested about a minute and continued on, I soon found that after what appeared to be the final wall, I could continue much farther than before. To a point where I was doing way more than I have ever done in one sitting. So I am not sure about the muscle/endurance thing. The other thing about the mice drowning in the study for me, wraps around something else I noticed. There are times I have to dump ash into a galvanized container outside (heating season) and when I dump it I hold my breath. I have noticed for me it seems like I cannot hold my breath anywhere near as long as I could before. So muscle/fat wise it seems the NR helps me quite a bit, but being able to hold my breath it appears adverse. I wonder if the mice drowned because of decreased lung capabilities? Just thinking out loud here.

 

Thanks.

[ambivalent]

I wasn't surprised to learn of the exercise performance of mice. As I reported during the early days of my high-dose experiment, I experienced days of feeling washed out, then energised and alert a day alter.  Weeks later still maintaing the high doses, I had phenomenal endurance during a tough coastal walk. The effects were certainly inconsistent - at the later stages the inconsistency may have been due to the effects of rising levels of histamine spiking but that wasn't the case in the beginning. I believe Fafner55 reported experiencing low energy levels, as well as high levels, for a couple of days during his short high dose experiment, which I believe he put down to mitophagy:

 

The effects of NR are so wide reaching that I can't see that it is possible to assign these observations positively to mitophagy.  However, low energy is consistent with a reduction in mitochondrial mass.

[soulprogrammer]

"NAD is emerging as an important player in neuronal health and survival. Levels of this substance are depleted during stroke, and it has been proposed that increasing NAD levels may be a therapeutic target for treating stroke. "

 

So a stroke patient should take large dose of NR/NMN during/after stroke attack? 

 

 

Edited by soulprogrammer, 09 May 2017 - 12:51 PM.

[Supierce]

"NAD is emerging as an important player in neuronal health and survival. Levels of this substance are depleted during stroke, and it has been proposed that increasing NAD levels may be a therapeutic target for treating stroke. "

 

So a stroke patient should take large dose of NR/NMN during/after stroke attack? 

Unknown yet - it's just worth investigating.

[stefan_001]

http://www.fasebj.or...nt/602.15.short
NAD+ replacement therapy with nicotinamide riboside does not improve cardiac function in a model of mitochondrial heart disease.

lets hope the mouse model is wrong here too as this is about a kids disease

The article talks about (10 ml/kg/day) NR dose. Assuming the ml is a typo and its 10mg/kg/day then thats really low. Other NR studies in mice that attempt to tackle diseases have used 200-500mg/kg/day. Human dose for kids would be 20-30mg/day.


The disease model is also a bit questionable. For me this ones goes to the tbc by another study unless the dosing means something else.

Edited by stefan_001, 09 May 2017 - 04:54 PM.

[Bryan_S]

"NAD is emerging as an important player in neuronal health and survival. Levels of this substance are depleted during stroke, and it has been proposed that increasing NAD levels may be a therapeutic target for treating stroke. "

 

So a stroke patient should take large dose of NR/NMN during/after stroke attack? 

 

 

There is a lot of research on this suggesting B3 can help tissue survival from ischemia.

 

Saving brain cells from stroke

P7C3 compound protects mature and newborn neurons in rats, and also improves physical and cognitive outcomes, following stroke

https://www.scienced...70303082113.htm

 

I think this is the article you referenced above and the source below.

 

https://now.uiowa.ed...in-cells-stroke

"The neuronal protection provided by the P7C3-A20 compound was also associated with a boost in the levels of a substance called nicotinamide adenine dinucleotide (NAD) in the rats’ brains. NAD is emerging as an important player in neuronal health and survival. Levels of this substance are depleted during stroke, and it has been proposed that increasing NAD levels may be a therapeutic target for treating stroke. In this study, P7C3-A20 treatment restored NAD to normal levels in the rats’ cortex after a stroke."

 

We don't have to look far to see research into saving brain cells following traumatic injury or disease.  There have been other articles along the same lines with B3 and this is promoting similar research into NR.

 

Nicotinamide Prevents NAD+ Depletion and Protects Neurons Against Excitotoxicity and Cerebral Ischemia: NAD+ Consumption by SIRT1 may Endanger Energetically Compromised Neurons

https://www.ncbi.nlm...les/PMC2677622/

 

The Use of Nicotinamide as a Treatment for Experimental Traumatic Brain Injury and Stroke: A Review and Evaluation

https://www.omicsgro...5.php?aid=12569

 

Effect of nicotinamide mononucleotide on brain mitochondrial respiratory deficits in an Alzheimer’s disease-relevant murine model https://bmcneurol.bi...2883-015-0272-x

 

Regenerative Neurogenesis After Ischemic Stroke Promoted by Nicotinamide Phosphoribosyltransferase–Nicotinamide Adenine Dinucleotide Cascade http://stroke.ahajou...216.short?rss=1

 

Tied into the Cardiac research of Friedrich’s Ataxia (FRDA) there was a similar article in February:

 

Role of NAD+ and mitochondrial sirtuins in cardiac and renal diseases

https://www.nature.c...eph.2017.5.html

 

Much more has been published.

 

Nicotinamide Mononucleotide, an Intermediate of NAD+ Synthesis, Protects the Heart from Ischemia and Reperfusion

http://journals.plos...al.pone.0098972

 

NAD  and Vitamin B3: From Metabolism to Therapies

http://jpet.aspetjou.../3/883.full.pdf

 

Anthony A. Sauve 

 

I've been following Anthony A. Sauve's work for awhile and long before there was a commercial source for nicotinamide riboside he was talking about NAD precursor therapies so the idea is not new. In fact Dr. Abram Hoffer was ahead of his times and drove interest and study into B3 Niacin. So there are pioneers that came before this recent resurgence into B3. 

 

As always JMHO

 

 

Edited by Bryan_S, 09 May 2017 - 06:09 PM.

[bluemoon]

 

 

There is a lot of research on this suggesting B3 can help tissue survival from ischemia. 

 

I remember reading a paper in 2015 on NAD+ and strokes and that a study might start where recent stroke victims would be given 2000 mg of NR a day for some period of time better haven't seen an actual study announced.

 

From what I know, Mayo Clinic and the U of Minnesota are giving 750 mg of NR to football players who have had one concussion but not more than one so a separate study..