2255 replies to this topic

[Tom Andre F. (ex shinobi)]

yes but the full article make me doubt about lot of things now

[Harkijn]

Im not sure this was already discussed: but NAM seems to have some benefits instead of just NAD+ salvage pathway:

 

from the study : Nicotinamide Overcomes Pluripotency Deficits and Reprogramming Barriers

 

Supplemental NAM, but not other NAD+ precursors, greatly enhances the efficiency and kinetics of hiPSC generation

 

Importantly, among the NAD (because they also used NAD+ directly to show it was not dependent) and NAD+ precursors evaluated, NAM alone remarkably increased the number of AP+ colonies compared to untreated controls

 

Nicotinic acid was better than NAM to increase NAD+

 

We further confirmed that NAM not only increased the reprogramming efficiency but also accelerated the reprogramming time course compared to untreated controls. With NAM supplementation, Nanog+ and Tra-1-60+ clusters were detected after a relatively short period of reprogramming (8-10 days after transduction), whereas their appearance was delayed by 4-5 days in untreated controls (Fig. 4Aa). Increased numbers of Nanog+ and Tra-1- 60+ clusters, up to 3-fold and 8-fold, espectively, were observed at 10 days after
transduction in NAM-treated cells compared to untreated controls

 

Consistently, higher mRNA expression levels of the pluripotency markers Nanog and TERT were detected in NAM-treated cells compared to untreated controls

 

NAM increases the proliferation rate and lowers the apoptosis rate during the reprogramming process

 

NAM alleviates pro-senescence phenotypes triggered by OSKM reprogramming factor

 

NAM potentially down-regulates p53, p16INK4a, and p21CIP1, the active barriers to reprogramming

 

blocking NAMPT activity with the pharmacological inhibitor FK866 induces premature senescence by suppressing SIRT1-mediated p53 degradation (probably due to increased free NAM ?)

 

Any thought ?

Tom, IIRC this study was posted in one of the Niacin or NAD threads. It would be more apt to discuss it there because the study only mentions NR in passing. I don't blame the authors for that because their research predates 3 years of blossoming NR research.

That said, it's an informative study and it's very interesting to learn that simple NAM supplementation (in vitro) not just boosts NAD but also attenuates  PARP hyperactivity. I  look forward to learning more about  'downstream' NAD destruction....

[Tom Andre F. (ex shinobi)]

 

Tom, IIRC this study was posted in one of the Niacin or NAD threads. It would be more apt to discuss it there because the study only mentions NR in passing. I don't blame the authors for that because their research predates 3 years of blossoming NR research.

That said, it's an informative study and it's very interesting to learn that simple NAM supplementation (in vitro) not just boosts NAD but also attenuates  PARP hyperactivity. I  look forward to learning more about  'downstream' NAD destruction....

 

 

Harkijn, do you have the link where it was posted please ?

 

The fact is NAD+ boosting didnt performed significant result on nanog or to boost IP+ colonies. For that we need raw NAM wich is also shown to silent sirtuins.

[Bryan_S]

CD38 Deficiency Protects the Heart from Ischemia/Reperfusion Injury through Activating SIRT1/FOXOs-Mediated Antioxidative Stress Pathway

http://www.hindawi.c...l/2016/7410257/

 

Here is yet another recent study tracking the CD38 NAD+ story. By suppressing CD38 generation it was possible to keep cardiac tissue alive under ischemic conditions. "mice supplied with exogenous NAD were significantly protected from ischemia/reperfusion injury" In 2006 there was an article "Regulation of intracellular levels of NAD: a novel role for CD38" were it was demonstrated that there were extremely high NAD+ levels in many tissues of CD38 knockout mice. In "Emerging therapeutic roles for NAD+ metabolism in mitochondrial and age-related disorders" it was also shown CD38 specific inhibitors have also been shown to induce NAD+ levels that activate sirtuins. So for now it appears Quercetin & Apegenin can slow down the escalating NAD+ consumption by CD38 as we age but how effective are these and by what measure can we verify their effectiveness? http://www.ncbi.nlm....pubmed/23172919

Also see: Bai P, Canto C, Oudart H, Brunyanszki A, Cen Y, Thomas C, Yamamoto H, Huber A, Kiss B, Houtkooper RH et al (2011) PARP-1 inhibition increases mitochondrial metabolism through SIRT1 activation. Cell Metab 13:461–468. doi:10.1016/j.cmet.2011.03.004S1550-4131(11)00091-X

And Barbosa MT, Soares SM, Novak CM, Sinclair D, Levine JA, Aksoy P, Chini EN (2007) The enzyme CD38 (a NAD glycohydrolase, EC 3.2.2.5) is necessary for the development of diet-induced obesity. FASEB J 21:3629–3639. doi:10.1096/fj.07-8290com

 

 

Abstract

 

Ischemia/reperfusion (I/R) injury induces irreversible oxidative stress damage to the cardiac muscle. We previously observed that CD38 deficiency remarkably protects mouse embryonic fibroblasts (MEFs) from oxidative stress-induced injury. However, whether CD38 deficiency protects from I/R injury in the heart is not explored. Here, we showed that the hearts of CD38 deficient mice or wild type mice supplied with exogenous NAD were significantly protected from ischemia/reperfusion injury, seen as reduction of the myocardial infarct sizes when the mice were subjected to 30 min ischemia followed by 24 hours of reperfusion. Consistently, the protection of CD38 deficiency on hypoxia/reoxygenation (H/R) injury was confirmed with a CD38 knockdown H9c2 stable cell line. Furthermore, we observed that knockdown of CD38 remarkably inhibited ROS generation and intracellular Ca2+ overloading induced by H/R in H9c2 cells. The FOXO1 and FOXO3 expressions were significantly elevated by H/R injury in CD38 knockdown cells compared with normal H9c2 cells. The cell immunofluorescence assay showed that FOXO1 nuclear translocation was significantly increased in CD38 knockdown H9c2 cells. In addition, we demonstrated that the increase of FOXO1 nuclear translocation was associated with the increased expressions of antioxidant catalase and SOD2 and the attenuated expression of the ROS generation enzyme NOX4. In conclusion, our results provide new evidence that CD38 deficiency protects the heart from I/R injury through activating SIRT1/FOXOs-mediated antioxidative stress pathway.

 

In conclusion, the results from our present study demonstrated that CD38 deficiency significantly protects the heart from I/R injury in vitro and in vivo, in which the protection is primarily associated with suppressing generation of ROS and overloading of intracellular Ca2+ in myocardial cells through activating Sirt1/FOXOs signaling pathway. The findings of this study will broaden our understanding of the roles of CD38 in physiological and pathological conditions in the heart and provide new insights into the mechanisms of the myocardial ischemia/reperfusion injury.

Edited by Bryan_S, 01 August 2016 - 06:06 PM.

[Nate-2004]

 

CD38 Deficiency Protects the Heart from Ischemia/Reperfusion Injury through Activating SIRT1/FOXOs-Mediated Antioxidative Stress Pathway

http://www.hindawi.c...l/2016/7410257/

 

Here is yet another recent study tracking the CD38 NAD+ story. By suppressing CD38 generation it was possible to keep cardiac tissue alive under ischemic conditions. "mice supplied with exogenous NAD were significantly protected from ischemia/reperfusion injury" In 2006 there was an article "Regulation of intracellular levels of NAD: a novel role for CD38" were it was demonstrated that there were extremely high NAD+ levels in many tissues of CD38 knockout mice. In "Emerging therapeutic roles for NAD+ metabolism in mitochondrial and age-related disorders" it was also shown CD38 specific inhibitors have also been shown to induce NAD+ levels that activate sirtuins. So for now it appears Quercetin & Apegenin can slow down the escalating NAD+ consumption by CD38 as we age but how effective are these and by what measure can we verify their effectiveness? http://www.ncbi.nlm....pubmed/23172919

Also see: Bai P, Canto C, Oudart H, Brunyanszki A, Cen Y, Thomas C, Yamamoto H, Huber A, Kiss B, Houtkooper RH et al (2011) PARP-1 inhibition increases mitochondrial metabolism through SIRT1 activation. Cell Metab 13:461–468. doi:10.1016/j.cmet.2011.03.004S1550-4131(11)00091-X

And Barbosa MT, Soares SM, Novak CM, Sinclair D, Levine JA, Aksoy P, Chini EN (2007) The enzyme CD38 (a NAD glycohydrolase, EC 3.2.2.5) is necessary for the development of diet-induced obesity. FASEB J 21:3629–3639. doi:10.1096/fj.07-8290com

 

 

Abstract

 

Ischemia/reperfusion (I/R) injury induces irreversible oxidative stress damage to the cardiac muscle. We previously observed that CD38 deficiency remarkably protects mouse embryonic fibroblasts (MEFs) from oxidative stress-induced injury. However, whether CD38 deficiency protects from I/R injury in the heart is not explored. Here, we showed that the hearts of CD38 deficient mice or wild type mice supplied with exogenous NAD were significantly protected from ischemia/reperfusion injury, seen as reduction of the myocardial infarct sizes when the mice were subjected to 30 min ischemia followed by 24 hours of reperfusion. Consistently, the protection of CD38 deficiency on hypoxia/reoxygenation (H/R) injury was confirmed with a CD38 knockdown H9c2 stable cell line. Furthermore, we observed that knockdown of CD38 remarkably inhibited ROS generation and intracellular Ca2+ overloading induced by H/R in H9c2 cells. The FOXO1 and FOXO3 expressions were significantly elevated by H/R injury in CD38 knockdown cells compared with normal H9c2 cells. The cell immunofluorescence assay showed that FOXO1 nuclear translocation was significantly increased in CD38 knockdown H9c2 cells. In addition, we demonstrated that the increase of FOXO1 nuclear translocation was associated with the increased expressions of antioxidant catalase and SOD2 and the attenuated expression of the ROS generation enzyme NOX4. In conclusion, our results provide new evidence that CD38 deficiency protects the heart from I/R injury through activating SIRT1/FOXOs-mediated antioxidative stress pathway.

 

In conclusion, the results from our present study demonstrated that CD38 deficiency significantly protects the heart from I/R injury in vitro and in vivo, in which the protection is primarily associated with suppressing generation of ROS and overloading of intracellular Ca2+ in myocardial cells through activating Sirt1/FOXOs signaling pathway. The findings of this study will broaden our understanding of the roles of CD38 in physiological and pathological conditions in the heart and provide new insights into the mechanisms of the myocardial ischemia/reperfusion injury.

 

 

Apigenin and quercetin are available over the counter for human consumption, would it be so difficult for them to study CD38 inhibition and NAD+ in humans, rather than rats, using these? 

Edited by Nate-2004, 05 August 2016 - 04:28 AM.

[Bryan_S]

 

Apigenin and quercetin are available over the counter for human consumption, would it be so difficult for them to study CD38 inhibition and NAD+ in humans, rather than rats, using these? 

 

 

Its a worth wild endeavor. I think we'll see more animal studies first if only from a cost standpoint. They still don't understand what is activating the CD38 with any certainty. Activators are more potent than inhibitors. Here is a quote from one of Leonard Guarente's papers discussing inhibitors and activators;

 

"Either way, there are distinct advantages to pursuing activators over inhibitors. For one, they generally do not have to be as potent as inhibitors to induce cellular and physiological effects, in part because their activity is amplified by downstream signaling pathways. Inhibitors, in contrast, can be rendered ineffective by residual enzymatic activity (1). Another advantage is that activators typically bind to interacting proteins or to regulatory regions outside the conserved catalytic domains and can therefore have greater target specificity within an enzyme family. Lastly, activators—especially those that mimic a natural activation mechanism—may also elicit fewer side effects than do inhibitors."

 

So from this perspective it takes more potent inhibitor than activator to bring about change. Also what ever is triggering higher CD38 levels already has an upstream advantage. So finding whats triggering increased CD38 should be the target. However I'm almost certain we already have a number of people already trying Apigenin and quercetin.

Edited by Bryan_S, 05 August 2016 - 06:08 PM.

[Bryan_S]

NAMPT-Mediated NAD+ Biosynthesis in Adipocytes Regulates Adipose Tissue Function and Multi-organ Insulin Sensitivity in Mice

http://www.cell.com/...(16)30945-7.pdf

 

SUMMARY

Obesity is associated with adipose tissue dysfunction and multi-organ insulin resistance. However, the mechanisms of such obesity-associated systemic metabolic complications are not clear. Here, we char- acterized mice with adipocyte-specific deletion of nicotinamide phosphoribosyltransferase (NAMPT), a rate-limiting NAD+ biosynthetic enzyme known to decrease in adipose tissue of obese and aged ro- dents and people. We found that adipocyte-specific Nampt knockout mice had severe insulin resistance in adipose tissue, liver, and skeletal muscle and adi- pose tissue dysfunction, manifested by increased plasma free fatty acid concentrations and decreased plasma concentrations of a major insulin-sensitizing adipokine, adiponectin. Loss of Nampt increased phosphorylation of CDK5 and PPARg (serine-273) and decreased gene expression of obesity-linked phosphorylated PPARg targets in adipose tissue. These deleterious alterations were normalized by administering rosiglitazone or a key NAD+ intermedi- ate, nicotinamide mononucleotide (NMN). Collec- tively, our results provide important mechanistic and therapeutic insights into obesity-associated systemic metabolic derangements, particularly multi-organ in- sulin resistance.

[Nate-2004]

 

 

Apigenin and quercetin are available over the counter for human consumption, would it be so difficult for them to study CD38 inhibition and NAD+ in humans, rather than rats, using these? 

 

 

Its a worth wild endeavor. I think we'll see more animal studies first if only from a cost standpoint. They still don't understand what is activating the CD38 with any certainty. Activators are more potent than inhibitors. Here is a quote from one of Leonard Guarente's papers discussing inhibitors and activators;

 

"Either way, there are distinct advantages to pursuing activators over inhibitors. For one, they generally do not have to be as potent as inhibitors to induce cellular and physiological effects, in part because their activity is amplified by downstream signaling pathways. Inhibitors, in contrast, can be rendered ineffective by residual enzymatic activity (1). Another advantage is that activators typically bind to interacting proteins or to regulatory regions outside the conserved catalytic domains and can therefore have greater target specificity within an enzyme family. Lastly, activators—especially those that mimic a natural activation mechanism—may also elicit fewer side effects than do inhibitors."

 

So from this perspective it takes more potent inhibitor than activator to bring about change. Also what ever is triggering higher CD38 levels already has an upstream advantage. So finding whats triggering increased CD38 should be the target. However I'm almost certain we already have a number of people already trying Apigenin and quercetin.

 

 

If activators are more potent than inhibitors then that says something about things that activate sirt1 (pterostilbene or resveratrol?) vs things that inhibit it (nicotinamide) does it not? Maybe I'm misunderstanding.

 

I guess it's easier with animals to determine the mechanisms since you can't kill and dissect humans haha.

[Darryl]

Kourtzidis, I.A. et al, 2016. The NAD+ precursor nicotinamide riboside decreases exercise performance in rats. Journal of the International Society of Sports Nutrition, 13(1), p.1.

Eighteen Wistar rats were equally divided in two groups that received either saline vehicle or nicotinamide riboside at a dose of 300 mg/kg body weight/day for 21 days via gavage. At the end of the 21-day administration protocol, both groups performed an incremental swimming performance test. The nicotinamide riboside group showed a tendency towards worse physical performance by 35 % compared to the control group at the final 10 % load (94 ± 53 s for the nicotinamide riboside group and 145 ± 59 s for the control group; P = 0.071). Our results do not confirm the previously reported ergogenic effect of nicotinamide riboside. The potentially negative effect of nicotinamide riboside administration on physical performance may be attributed to the pleiotropic metabolic and redox properties of NAD⁺ and NADP⁺.

[tunt01]

Dose is pretty big on this Kourtzidis study. 3.1 grams on 65 kg HED adult. 9 rats in both groups. IDK. I've not read it, but it just seems a questionable on its face.

[Bryan_S]

Dose is pretty big on this Kourtzidis study. 3.1 grams on 65 kg HED adult. 9 rats in both groups. IDK. I've not read it, but it just seems a questionable on its face.

 

"questionable on its face."

 

My thoughts as well. Let's just say for the moment the data is a little thin. I was just tonight reading the comments in one of the athletic threads on Body Building. I'm trying to weigh the data myself and keep finding myself wanting.

 

First off, its the first study I've seen to go against the other studies. In of itself I like studies that cut across the grain especially if I can find some substance from a new angle. Questioning long accepted results are what open up new areas of understanding. So from that standpoint nothing really made me think wow.

 

They also did this on a shoestring which is OK. I would have liked to see some blood-work. 

 

Next it was published in a less well known publication. Makes me think they took what they could get or we'd have seen this in a more prestigious publication. We will see if it gets any academic review.

 

I looked for some other cross references from their group related to other NR and NAD studies and didn't see any. Appears to be a small group in Greece.

 

I was a bit taken back that they used Life Extension's product which is some 60% filler. I can't say for sure but it appears they just emptied the capsules, made their preparation and force feed it to the animals. That opened up the experiment to some unknowns especially when ChromaDex makes it easy to purchase the pure product.

 

I would have liked to have seen data generated outside of swimming. Seems they could have established a base line initially and shown a progression towards the conclusion of the experiment. This same test group could have had other performance tests to show more than the swimming.

 

I downloaded the Excel data and see some rather large outliers in the P values. They attached a weight to the tails and changed its weight over time and allowed them to swim until exhaustion. "A final load equal to 10 % of the rats’ body weight was used and rats were left to swim until exhaustion. A rat was considered to have reached exhaustion when it exhibited loss of coordinated movements and failure to return to the surface within 10 s three consecutive times." I didn't see a table tracking the weight of each Rat and the weight of the weights attached. I tend to believe once your rat stays submerged 10 s just once the animal is somewhat compromised after filling their lungs with water. I'm not an expert but I see too much room for chance or accumulated error. Maybe some of you could design a better experiment.

 

http://jissn.biomedc...2970-016-0143-x

 

I just got word we'll have some more studies coming out in some of our top tier peer reviewed journals in the next week or so and I'm awaiting those.

[Nate-2004]

I'm guessing it was for budgetary reasons that they didn't use humans? I'm baffled as to why researchers aren't using humans when it is otherwise perfectly safe to do so.

[Harkijn]

 

Dose is pretty big on this Kourtzidis study. 3.1 grams on 65 kg HED adult. 9 rats in both groups. IDK. I've not read it, but it just seems a questionable on its face.

 

"questionable on its face."

 

My thoughts as well. Let's just say for the moment the data is a little thin. I was just tonight reading the comments in one of the athletic threads on Body Building. I'm trying to weigh the data myself and keep finding myself wanting.

 

First off, its the first study I've seen to go against the other studies. In of itself I like studies that cut across the grain especially if I can find some substance from a new angle. Questioning long accepted results are what open up new areas of understanding. So from that standpoint nothing really made me think wow.

 

They also did this on a shoestring which is OK. I would have liked to see some blood-work. 

 

Next it was published in a less well known publication. Makes me think they took what they could get or we'd have seen this in a more prestigious publication. We will see if it gets any academic review.

 

I looked for some other cross references from their group related to other NR and NAD studies and didn't see any. Appears to be a small group in Greece.

 

I was a bit taken back that they used Life Extension's product which is some 60% filler. I can't say for sure but it appears they just emptied the capsules, made their preparation and force feed it to the animals. That opened up the experiment to some unknowns especially when ChromaDex makes it easy to purchase the pure product.

 

I would have liked to have seen data generated outside of swimming. Seems they could have established a base line initially and shown a progression towards the conclusion of the experiment. This same test group could have had other performance tests to show more than the swimming.

 

I downloaded the Excel data and see some rather large outliers in the P values. They attached a weight to the tails and changed its weight over time and allowed them to swim until exhaustion. "A final load equal to 10 % of the rats’ body weight was used and rats were left to swim until exhaustion. A rat was considered to have reached exhaustion when it exhibited loss of coordinated movements and failure to return to the surface within 10 s three consecutive times." I didn't see a table tracking the weight of each Rat and the weight of the weights attached. I tend to believe once your rat stays submerged 10 s just once the animal is somewhat compromised after filling their lungs with water. I'm not an expert but I see too much room for chance or accumulated error. Maybe some of you could design a better experiment.

 

http://jissn.biomedc...2970-016-0143-x

 

I just got word we'll have some more studies coming out in some of our top tier peer reviewed journals in the next week or so and I'm awaiting those.

 

60% filler? I had forgotten about that. I am beginning to feel rattish now.

[Bryan_S]

We can't get around the excipients and fillers for now, from anyone. But what we can do is some inquiry and find a distributer with the cleanest product.

[Harkijn]

We can't get around the excipients and fillers for now, from anyone. But what we can do is some inquiry and find a distributer with the cleanest product.

Yes, your post #342 in this thread is a useful starting point for everyone who wants to reconsider this side of things.

[Nate-2004]

 

We can't get around the excipients and fillers for now, from anyone. But what we can do is some inquiry and find a distributer with the cleanest product.

Yes, your post #342 in this thread is a useful starting point for everyone who wants to reconsider this side of things.

 

 

Regarding fillers or physical performance? I started from 342 and saw a poster about physical performance enhancement and another post about Coffee being a Sirtuin inhibitor which was disconcerting. 

 

I'm now more confused after having read all that lol. Is the attenuation of adaption a good or bad thing? What does that even mean (attenuate training adaption)? I realize your body adapts to training and you hit plateaus but is attenuating that a good or bad thing?

[Harkijn]

 

 

We can't get around the excipients and fillers for now, from anyone. But what we can do is some inquiry and find a distributer with the cleanest product.

Yes, your post #342 in this thread is a useful starting point for everyone who wants to reconsider this side of things.

 

 

Regarding fillers or physical performance? I started from 342 and saw a poster about physical performance enhancement and another post about Coffee being a Sirtuin inhibitor which was disconcerting. 

 

I'm now more confused after having read all that lol. Is the attenuation of adaption a good or bad thing? What does that even mean (attenuate training adaption)? I realize your body adapts to training and you hit plateaus but is attenuating that a good or bad thing?

 

Nate, my mistake. Bryan's post I meant to refer to is in the Experiences thread:

http://www.longecity...-thread/page-12

[Bryan_S]

Nate, my mistake. Bryan's post I meant to refer to is in the Experiences thread:

 

http://www.longecity...-thread/page-12

 

 

Wow after reading that what a blast from the past. Good research guys!

 

You'll also notice I don't write about taking NR sublingually anymore. At this point it doesn't appear to be necessary. The excipients and fillers pose a significant risk with the standard use of powdered silica anyway. Only one distributer changed their formulation to accommodate this concern. Another distributer made the claim they did but wouldn't open themselves up to scrutiny or examination. "Third-Party Tested: With addition to our certified lab, random samples of every product batch are sent to an independent lab for third party testing. This further verifies the quality and effectiveness of our products, creating better transparency and lets our customers know that what’s on our labels are actually what’s in our product."

 

Transparency my &$$. It goes without saying they refused to produce those lab results in any form or fashion. They had claimed 100% Niagen with no Fillers or excitants. We made them at least fess up about their excipients and now they market they use rice bran. Certification . . . what certification, nothing could be obtained from the City or State where this company did business and they refused all requests to see their lab certificate. Several of us approached this marketing lie here on LongeCity, making the request to see those results and we all walked away with nothing, no one was successful. I won't mention this company by name because I don't want to open that can of worms again but when it comes to added ingredients, testing or ingredient handling buyers beware!

 

Also keep in mind not all companies claim a vegetarian, purity or microbial count. Yes microbial count. In the experience thread above this was a factor I later investigated which could have contributed to the stool issue so many people were experiencing.

 

I don't see anyone questioning if the device used to encapsulate our NR. Was it Sterile or not. So how your product is handled and encapsulated once it leaves the ChromaDex factory is as important as the claimed ingredients coupled with claims of third party testing.

 

So first off I'd only do business with those who will open themselves up to scrutiny but most importantly those who will share their testing results upon request. Otherwise you have no recourse.

 

I really have a problem with companies who claim one thing and do another, if they can't generate documents substantiating their claims, they really haven't gone on the record and can't be held accountable. Its the small startup companies who operate out of an apartment claiming they're a certified Lab that I'm concerned with. Those who won't backup what they are marketing are avoiding their public safety responsibilities. So again buyers beware. JMHO

Edited by Bryan_S, 07 August 2016 - 09:11 PM.

[Nate-2004]

I don't mind a can of worms opening so long as I know what company to avoid. I only have ever gotten it from HPN though so if it's them let me know.

[Bryan_S]

You're OK they will produce their third party testing upon request. Sorry for the earlier rant but you'd think anyone marketing to an elite nutritional group concerned with longevity would make themselves beyond reproach and stay completely aboveboard. Especially at the prices they charge for the privilege of access.

Edited by Bryan_S, 07 August 2016 - 09:20 PM.

[Tom Andre F. (ex shinobi)]

 

Dose is pretty big on this Kourtzidis study. 3.1 grams on 65 kg HED adult. 9 rats in both groups. IDK. I've not read it, but it just seems a questionable on its face.

 

"questionable on its face."

 

My thoughts as well. Let's just say for the moment the data is a little thin. I was just tonight reading the comments in one of the athletic threads on Body Building. I'm trying to weigh the data myself and keep finding myself wanting.

 

First off, its the first study I've seen to go against the other studies. In of itself I like studies that cut across the grain especially if I can find some substance from a new angle. Questioning long accepted results are what open up new areas of understanding. So from that standpoint nothing really made me think wow.

 

They also did this on a shoestring which is OK. I would have liked to see some blood-work. 

 

Next it was published in a less well known publication. Makes me think they took what they could get or we'd have seen this in a more prestigious publication. We will see if it gets any academic review.

 

I looked for some other cross references from their group related to other NR and NAD studies and didn't see any. Appears to be a small group in Greece.

 

I was a bit taken back that they used Life Extension's product which is some 60% filler. I can't say for sure but it appears they just emptied the capsules, made their preparation and force feed it to the animals. That opened up the experiment to some unknowns especially when ChromaDex makes it easy to purchase the pure product.

 

I would have liked to have seen data generated outside of swimming. Seems they could have established a base line initially and shown a progression towards the conclusion of the experiment. This same test group could have had other performance tests to show more than the swimming.

 

I downloaded the Excel data and see some rather large outliers in the P values. They attached a weight to the tails and changed its weight over time and allowed them to swim until exhaustion. "A final load equal to 10 % of the rats’ body weight was used and rats were left to swim until exhaustion. A rat was considered to have reached exhaustion when it exhibited loss of coordinated movements and failure to return to the surface within 10 s three consecutive times." I didn't see a table tracking the weight of each Rat and the weight of the weights attached. I tend to believe once your rat stays submerged 10 s just once the animal is somewhat compromised after filling their lungs with water. I'm not an expert but I see too much room for chance or accumulated error. Maybe some of you could design a better experiment.

 

http://jissn.biomedc...2970-016-0143-x

 

I just got word we'll have some more studies coming out in some of our top tier peer reviewed journals in the next week or so and I'm awaiting those.

 

 

Im not sure the fillers was used in the study, they just mention life extension as provider for the raw material. The fillers come only when you have to apply in a capsule, Im not sure they use any capsules there. What I understand is more LE provided the expensive niagen. Why not chromadex directly ? Maybe LE was the one that pushed the experiment and as we seen chromadex seems to like to control the studies published.

 

They also confirm something already noted by users:

 

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 [8, 9]. These studies found that nicotinic acid 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.

 

Indeed many forum members noted that using both NR and NA.. So I dont think we can just give that away

 

and : 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, according to the hormetic theory of reactive oxygen and nitrogen species activity [11]. This is in line with other recent studies stressing the potential detrimental effects of redox-related supplements on exercise capacity [12].

 

but I really cant follow them here.. The full theory they give is based on the redox properties of NAD+ if I understand it well ? Then its wrong since beta lapachone that increase NAD+ strongly actually does the job we all want when we speak about metabolism: it gives more energy !! http://journals.plos...al.pone.0047122

 

More NAD means more energy expendure normally, so maybe just precursor are not best way to increase NAD+ after all.. Im more and more a believer of this theory

 

So more than a lot of speculation, we should rely on the experience thread. Problem is result are mitigated, some mentioned kind of crash under NR If i remember well, it was a concern for me. But no problem for others.. so ?

 

Some longecity niagen users that confirm the study:

 

http://www.longecity...e-9#entry686300

 

or this guy who experienced positive result then the crash:

 

"Then day 4 rolled around. I took the same dose, but hours later I crashed like a lead ballon. It felt like someone took a baseball bat to every muscle in my body. I was lightheaded, dizzy and extremely tired. I was completely incapacitated. The manufacturer had told me that light headedness and fatigue were the first signs of "reaching your limit". I went to bed early and by the next day I felt okay again. I stopped the supplements for a few days and then began again and stayed at a 125 mg. Eventually I had the same effects of coming up for a few days and then a had crash although much less than my previous one. I am going to try 125mg EOD now and see what happens." http://www.longecity...amide-riboside/

 

Edited by Tom Andre F. (ex shinobi), 07 August 2016 - 11:08 PM.

[midas]

Well, I aint a rat or a mouse and I can pretty much guarantee that it has boosted my energy levels and mental capacity...If my stamina has suffered a little in the process then it certainly has not shown in any way......

Also, I am not taking a shit-load of the stuff either...

Like they say, too much of a good thing is probably bad for you anyway....(Hows that for science!)

[Bryan_S]

Tom,

 

Nearly three years taking this stuff for me and its still working. I think you see the problem with the study as we do.

 

I've asked their lead Postgraduate Student a few more questions and haven't heard back yet. So we will see what they gave the rats, the encapsulated product with filler or the pure NR from ChromaDex via Life Extension. Did they buy it or was it donated? The study suggests no funding. I just think their study was a bit thin, don't you? It also appeared the study culminated after the final and only test. I didn't see an initial base line study or any blood work to hint at other factors. It was lacking on many fronts.

 

We've also seen Niacin followers who have gone decades without problems, they also very commonly receive blood tests to keep an eye on the liver enzymes. So for this postgraduate group to make fatty acid oxidation suggestions was at best speculation, without blood samples either side of the experiment. It may be true but it could have been checked and wasn't. Just remember it was a Postgraduate Student study without any funding and they did a great job with what they could afford but it wasn't sufficient to make a lasting statement.

 

So like I said we'll see if this study gets any peer reviews but other than some bodybuilder discussion I haven't seen much chatter elsewhere on the study. Sadly it seems to have been mostly ignored. We'll see what develops, there are some high profile publications coming out that will get peer review in the next weeks that might shed some better light on this athletic performance topic but the big one is in process now.

 

"Thorne Research Announces Clinical Study to Assess Nicotinamide Riboside on Brain NAD+ in College Football Players" So I think this will be a big study on athlete performance and if any of us don't believe this we are fooling ourselves. They are looking for TBI data as the article suggests but with an entire team receiving the NAD precursor, Athletic Performance is still a front and center top factor. Keep in mind this study has already exceeded the length the Rat study.

 

So lets take a step back if your not already aware of US college athletics, just for some perspective. The business of College Football is a big, really big in the US. If the teams Sports Psychologists, Trainers and Coaches suspect any performance issues with their athletes you'll see the plug pulled on this Clinical Trial before the players begin their official season. If the study in Greece was an early preview I think we would have already seen the University of Minnesota withdraw from the study using the 21-day rat study. I'm just saying, no disrespect. I could tell from your tone the study is suspect from an NAD standpoint alone. Let's not read to much into it until the human athletic trials are published.

Edited by Bryan_S, 08 August 2016 - 01:05 AM.

[Tom Andre F. (ex shinobi)]

Well, I aint a rat or a mouse and I can pretty much guarantee that it has boosted my energy levels and mental capacity...If my stamina has suffered a little in the process then it certainly has not shown in any way......

Also, I am not taking a shit-load of the stuff either...

Like they say, too much of a good thing is probably bad for you anyway....(Hows that for science!)

 

What's your dosage please ? and do you make some break such as day off ?

 

Do you use it stand alone or along multi vit for instance ?

 

 

Tom,

 

Nearly three years taking this stuff for me and its still working. I think you see the problem with the study as we do.

 

I've asked their lead Postgraduate Student a few more questions and haven't heard back yet. So we will see what they gave the rats, the encapsulated product with filler or the pure NR from ChromaDex via Life Extension. Did they buy it or was it donated? The study suggests no funding. I just think their study was a bit thin, don't you? It also appeared the study culminated after the final and only test. I didn't see an initial base line study or any blood work to hint at other factors. It was lacking on many fronts.

 

We've also seen Niacin followers who have gone decades without problems, they also very commonly receive blood tests to keep an eye on the liver enzymes. So for this postgraduate group to make fatty acid oxidation suggestions was at best speculation, without blood samples either side of the experiment. It may be true but it could have been checked and wasn't. Just remember it was a Postgraduate Student study without any funding and they did a great job with what they could afford but it wasn't sufficient to make a lasting statement.

 

So like I said we'll see if this study gets any peer reviews but other than some bodybuilder discussion I haven't seen much chatter elsewhere on the study. Sadly it seems to have been mostly ignored. We'll see what develops, there are some high profile publications coming out that will get peer review in the next weeks that might shed some better light on this athletic performance topic but the big one is in process now.

 

"Thorne Research Announces Clinical Study to Assess Nicotinamide Riboside on Brain NAD+ in College Football Players" So I think this will be a big study on athlete performance and if any of us don't believe this we are fooling ourselves. They are looking for TBI data as the article suggests but with an entire team receiving the NAD precursor, Athletic Performance is still a front and center top factor. Keep in mind this study has already exceeded the length the Rat study.

 

So lets take a step back if your not already aware of US college athletics, just for some perspective. The business of College Football is a big, really big in the US. If the teams Sports Psychologists, Trainers and Coaches suspect any performance issues with their athletes you'll see the plug pulled on this Clinical Trial before the players begin their official season. If the study in Greece was an early preview I think we would have already seen the University of Minnesota withdraw from the study using the 21-day rat study. I'm just saying, no disrespect. I could tell from your tone the study is suspect from an NAD standpoint alone. Let's not read to much into it until the human athletic trials are published.

 

I hope this last study will be released soon as it will definitely be the real answer.

 

I think the energy things should have to do with methylation problem if used in large dose maybe.. Means below that high dosage or along a multi vit it can be fine. Else I have really no explanation for now. So lets just wait the US football study, longer and in human.

[works4you2]

While we wait for the Football study, from this article 

 

http://www.ncbi.nlm....pubmed/25361036

 

"Skeletal muscle from aged mice displays higher PARP-1 activity and lower SIRT-1 activity due to decreased intracellular NAD+ content, and as a result reduced muscle performance in response to exercise. Interestingly, injection of PJ34, a PARP-1 inhibitor, in aged mice increased SIRT-1 activity by preserving intracellular NAD+ content, which resulted in higher skeletal muscle mitochondrial biogenesis and performance."

 

Based on the results of this article it seems that preserving your NAD+ and increasing SIRT-1 activity with improve skeletal muscle performance.

 

[Harkijn]

Yes, still no football players yet,but this study on mice will probably assuage concerns about NR and skeletal muscle. Encouraging also that administration was oral.

http://www.cell.com/...4131(16)30350-3

 

Quote:

Mice beginning at age 5.5 months received the treatment continuously for 6 weeks. Intriguingly, this intervention appeared to completely prevent the development of exercise intolerance observed in 7-month-old mNKO mice and reversed lactic acidosis at the point of exhaustion

[Bryan_S]

Yes, still no football players yet,but this study on mice will probably assuage concerns about NR and skeletal muscle. Encouraging also that administration was oral.

http://www.cell.com/...4131(16)30350-3

 

Quote:

Mice beginning at age 5.5 months received the treatment continuously for 6 weeks. Intriguingly, this intervention appeared to completely prevent the development of exercise intolerance observed in 7-month-old mNKO mice and reversed lactic acidosis at the point of exhaustion

 

harken,

 

Thanks, I was running a search every day on their website. This was one of the articles I was waiting for from Cell.com

I find this next paragraph very suggestive. It seems subtle changes in NAD can disproportionately modulate aerobic metabolism. So moving the needle a little bit can have larger downstream benefits. I'll be combing thru this article for days to come.

 fx1_lrg.jpg   178.18KB   4 downloads

"In light of its potent phenotypic effects in mNKO mice, we were surprised to find that NR exerts only a subtle influence on the steady-state concentration of NAD in muscles. Our tracer studies suggest that this is largely attributable to breakdown of orally delivered NR into NAM prior to reaching the muscle. Nonetheless, our results indicate that NR is more effective than NAM for reversing mNKO phenotypes (Figure S5). The correlation between the NAD content and the respiratory capacity of isolated mitochondria, even in cultured myotubes (Figure 4), supports the model that subtle changes in NAD can disproportionately modulate aerobic metabolism. It is important to note that NAD turnover may vary independently from NAD concentration and that small changes in average tissue concentration might reflect larger changes in specific cells or subcellular compartments. It is also possible that intramuscular conversion of NAD into secondary messengers potently influences calcium homeostasis, which is both essential to muscle contraction and can independently modulate mitochondrial respiration (Cárdenas et al., 2010)."

 

Edit: Helper molecule reverses degeneration of muscle in mouse model of tissue aging, wasting Others are picking up on this publication http://medicalxpress...ion-muscle.html

Edited by Bryan_S, 10 August 2016 - 06:19 AM.
medicalxpress.com added

[Harkijn]

 

Yes, still no football players yet,but this study on mice will probably assuage concerns about NR and skeletal muscle. Encouraging also that administration was oral.

http://www.cell.com/...4131(16)30350-3

 

Quote:

Mice beginning at age 5.5 months received the treatment continuously for 6 weeks. Intriguingly, this intervention appeared to completely prevent the development of exercise intolerance observed in 7-month-old mNKO mice and reversed lactic acidosis at the point of exhaustion

 

harken,

 

Thanks, I was running a search every day on their website. This was one of the articles I was waiting for from Cell.com

I find this next paragraph very suggestive. It seems subtle changes in NAD can disproportionately modulate aerobic metabolism. So moving the needle a little bit can have larger downstream benefits. I'll be combing thru this article for days to come.

 

"In light of its potent phenotypic effects in mNKO mice, we were surprised to find that NR exerts only a subtle influence on the steady-state concentration of NAD in muscles. Our tracer studies suggest that this is largely attributable to breakdown of orally delivered NR into NAM prior to reaching the muscle. Nonetheless, our results indicate that NR is more effective than NAM for reversing mNKO phenotypes (Figure S5). The correlation between the NAD content and the respiratory capacity of isolated mitochondria, even in cultured myotubes (Figure 4), supports the model that subtle changes in NAD can disproportionately modulate aerobic metabolism. It is important to note that NAD turnover may vary independently from NAD concentration and that small changes in average tissue concentration might reflect larger changes in specific cells or subcellular compartments. It is also possible that intramuscular conversion of NAD into secondary messengers potently influences calcium homeostasis, which is both essential to muscle contraction and can independently modulate mitochondrial respiration (Cárdenas et al., 2010)."

 

I don't dare to pretend that I fully understand the article, so I refrained from mentioning this paragraph, but I looked at it for a long time........

[Female Scientist]

This study seems really important. I only know just enough of the metabolic science to be able to tell that -- looks like evidence of oral NR making a big impact in exercise performance in older mouse models, even when concentration in the muscle tissue seems lower. There is differential absorption in different tissues, but yet still a strong impact. Intriguing implications for muscular dystrophies, as well. AND Cell is a highly prestigious journal. But I look forward to more insights from the rest of the group so you can help us understand the intricacies of the results.....seems the pace of results is increasing, as was hoped for....very interesting!!

 

Yes, still no football players yet,but this study on mice will probably assuage concerns about NR and skeletal muscle. Encouraging also that administration was oral.

http://www.cell.com/...4131(16)30350-3

 

Quote:

Mice beginning at age 5.5 months received the treatment continuously for 6 weeks. Intriguingly, this intervention appeared to completely prevent the development of exercise intolerance observed in 7-month-old mNKO mice and reversed lactic acidosis at the point of exhaustion

 

harken,

 

Thanks, I was running a search every day on their website. This was one of the articles I was waiting for from Cell.com 

I find this next paragraph very suggestive. It seems subtle changes in NAD can disproportionately modulate aerobic metabolism. So moving the needle a little bit can have larger downstream benefits. I'll be combing thru this article for days to come.

fx1_lrg.jpg

"In light of its potent phenotypic effects in mNKO mice, we were surprised to find that NR exerts only a subtle influence on the steady-state concentration of NAD in muscles. Our tracer studies suggest that this is largely attributable to breakdown of orally delivered NR into NAM prior to reaching the muscle. Nonetheless, our results indicate that NR is more effective than NAM for reversing mNKO phenotypes (Figure S5). The correlation between the NAD content and the respiratory capacity of isolated mitochondria, even in cultured myotubes (Figure 4), supports the model that subtle changes in NAD can disproportionately modulate aerobic metabolism. It is important to note that NAD turnover may vary independently from NAD concentration and that small changes in average tissue concentration might reflect larger changes in specific cells or subcellular compartments. It is also possible that intramuscular conversion of NAD into secondary messengers potently influences calcium homeostasis, which is both essential to muscle contraction and can independently modulate mitochondrial respiration (Cárdenas et al., 2010)."

 

 

 

 

Edited by Female Scientist, 09 August 2016 - 08:34 PM.

[stefan_001]

 

This study seems really important. I only know just enough of the metabolic science to be able to tell that -- looks like evidence of oral NR making a big impact in exercise performance in older mouse models, even when concentration in the muscle tissue seems lower. There is differential absorption in different tissues, but yet still a strong impact. Intriguing implications for muscular dystrophies, as well. AND Cell is a highly prestigious journal. But I look forward to more insights from the rest of the group so you can help us understand the intricacies of the results.....seems the pace of results is increasing, as was hoped for....very interesting!!

 

Yes, still no football players yet,but this study on mice will probably assuage concerns about NR and skeletal muscle. Encouraging also that administration was oral.

http://www.cell.com/...4131(16)30350-3

 

Quote:

Mice beginning at age 5.5 months received the treatment continuously for 6 weeks. Intriguingly, this intervention appeared to completely prevent the development of exercise intolerance observed in 7-month-old mNKO mice and reversed lactic acidosis at the point of exhaustion

 

harken,

 

Thanks, I was running a search every day on their website. This was one of the articles I was waiting for from Cell.com 

I find this next paragraph very suggestive. It seems subtle changes in NAD can disproportionately modulate aerobic metabolism. So moving the needle a little bit can have larger downstream benefits. I'll be combing thru this article for days to come.

fx1_lrg.jpg

"In light of its potent phenotypic effects in mNKO mice, we were surprised to find that NR exerts only a subtle influence on the steady-state concentration of NAD in muscles. Our tracer studies suggest that this is largely attributable to breakdown of orally delivered NR into NAM prior to reaching the muscle. Nonetheless, our results indicate that NR is more effective than NAM for reversing mNKO phenotypes (Figure S5). The correlation between the NAD content and the respiratory capacity of isolated mitochondria, even in cultured myotubes (Figure 4), supports the model that subtle changes in NAD can disproportionately modulate aerobic metabolism. It is important to note that NAD turnover may vary independently from NAD concentration and that small changes in average tissue concentration might reflect larger changes in specific cells or subcellular compartments. It is also possible that intramuscular conversion of NAD into secondary messengers potently influences calcium homeostasis, which is both essential to muscle contraction and can independently modulate mitochondrial respiration (Cárdenas et al., 2010)."

 

 

 

 

 

I think the study shows 3 things:

1) NAD+ boosting recovers muscle

2) NR performs better than nicotinamide

3) The dosing might not need to be high as its not needed to recover NAD+. My own speculation is that the body start off with having an abundance of NAD+ and problems start when a certain threshold low value is achieved. So we may only need to boost till this threshold.