471 replies to this topic

[midas]

Tom, Bryan.....do you think maybe this should be moved to its own thread....I keep being brought back to this and have I no real interest in it...and this is an Nicotinamide Riboside thread???......Whatcha think?

[Bryan_S]

Point well taken

 

Guys β-lapachone has a thread http://www.longecity...beta-lacaphone/

 

Oxaloacetate http://www.longecity...te-supplements/

 

Glycine  http://www.longecity...e-be-taking-it/

[Bryan_S]

NIAGEN® NR Age Defense

 

Looks like CVS pharmacy is getting into the NAD boosting game.

http://investors.chr...icle&ID=2086302

http://globenewswire...Supplement.html

[Bryan_S]

NNMT: A Bad Actor in Fat Makes Good in Liver.

 

Samuel A.J. Trammell1,2and Charles Brenner1,2,3,4,* 1Department of Biochemistry 2Program in Genetics 3Department of Internal Medicine 4Obesity Research & Education Initiative Carver College of Medicine, University of Iowa, Iowa City, IA 52242 *Correspondence: charles-brenner@uiowa.edu http://dx.doi.org/10...met.2015.07.017

 

Dr. Charles Brenner hasn't been idle, here is an excerpt "Because NAD+ is required for fuel oxidation and is consumed by sirtuins, the competition between NNMT and NAD+salvage suggests that NNMT could be a ‘‘bad actor’’ that might limit fuel oxidation and promote the storage of fat. If NNMT is highly expressed, then Nam might not be salvageable such that NAD+ dependent processes would be limited. This is exactly what was reported for adipose expression of NNMT (Kraus et al., 2014)."

 

http://www.researchg...s_Good_in_Liver

[docmaas]

So maybe plain old glycine supplementation is effective, after all. But I really think it's inefficient at fasting glucose reduction as compared to a 100 mg to 1 g of oxaloacetate per day. While I recommend watching the entire video, definitely check out the graph at 14:21 if you have glucose management problems.

 

 

Have you had similar results?  This study is so old and obscure it's hard to know what to make of it.  Cash's conspiracy allusion about not patentable because it's natural doesn't help either.  I wonder if he has tried to duplicate the results himself and if so what the results were.  If it were really that great one would expect someone else to have followed up with new tests.  That data distribution looks like it might be reflective of specific genotype as well though the original researchers would never have known that.

 

If Cash/Terra want to test it I'm sure there are lots of people like me, currently controlling glucose with diet and exercise that would be willing subjects.  If it is true it would be great news for those of us who suffer from type 2 diabetes.

 

I'm skeptical and I've said why over on the Wow Benegene thread.  Below is the most recent post copied here.  I suggest that additional conversation on oxaloacetate should either go to the older oxaloacetate thread or the newer "Wow benigene" thread.  Him showing up on bulletproof makes me even more skeptical.

 

Here's my post:

NIH test of benagene led to no increase in life span of mice.  In one of Cash's youtube presentations ( at 12:57) he alludes to the fact that "we", probably his company, asked the NIH to send them a sample of the chow containing oxaloacetate and they had it tested and found no oxaloacetate and he then concludes the test was a comparison of two controls against one another.  However the NIH results say nothing about this event here:  http://www.ncbi.nlm....les/PMC3598361/ where they do say it had no impact at all on lifespan and also go into significant detail about the preparation and testing of the chow to which the oxaloacetate was added.

 

There should be a corrective from the NIH if what Cash says is true.  Where is it?

 

In the absence of significant results from both the NIH and from Spindler why is anyone even seriously considering this drug right now? 

 

Mike

[BigLabRat]

Point well taken

 

Guys β-lapachone has a thread http://www.longecity...beta-lacaphone/

 

Oxaloacetate http://www.longecity...te-supplements/

 

Glycine  http://www.longecity...e-be-taking-it/

 

I agree this thread is drifting, but unlike some others I'm finding it quite interesting and useful.

 

Of the three threads mentioned above, only the Glycine thread is worth anything (it's quite good in fact). The Oxaloacetate thread is quite dead and has less substantive content on it than the recent discussion here.

 

My hat's off to you for even finding the beta-lapachone thread, since it is entitled with the misspelling "beta-lacaphone" (even in the link you pasted). No wonder it only has one post.  
 

Edited by BigLabRat, 11 September 2015 - 06:34 AM.

[Bryan_S]

Resveratrol and pterostilbene epigenetically restore PTEN expression by targeting oncomiRs of the miR-17 family in prostate cancer

 

Swati Dhar1, Avinash Kumar1, Agnes M. Rimando2, Xu Zhang3, Anait S. Levenson1,4 1

Cancer Institute, University of Mississippi Medical Center, Jackson, Mississippi, USA 2 United States Department of Agriculture, Agricultural Research Service, Natural Products Utilization Research Unit, University, Mississippi, USA 3 Center of Biostatistics and Bioinformatics, University of Mississippi Medical Center, Jackson, Mississippi, USA 4 Department of Pathology, University of Mississippi Medical Center, Jackson, Mississippi, USA Correspondence to: Anait S. Levenson, e-mail: alevenson@umc.edu Keywords: oncomiRs, prostate cancer epigenetics, PTEN, pterostilbene, resveratrol Received: July 07, 2015 Accepted: July 24, 2015 Published: August 06, 2015

 

 

Sorry guys but as sirtuin activators contained in our quest for NAD boosting both Resveratrol and Pterostilbene developments are under the umbrella of this thread. There are also a number of NR users on this thread who are taking these, who will be interested in any epigenetic side benefits they may be gaining.

 

http://www.impactjou...ubmed-linkout=1

 

http://www.impactjou...77&path[]=12736

 

"In recent years, not only has the role of miRNAs in cancer become increasingly clear but also their utilization as potential biomarkers and therapeutic targets has gained ground. Although the importance of dietary stilbenes such as resveratrol and pterostilbene as anti-cancer agents is well recognized, our understanding of their miRNA-targeting capabilities is still limited. In our previous study, we reported that resveratrol downregulates PTEN-targeting members of the oncogenic miR-17 family, which are overexpressed in prostate cancer. This study investigates the resveratrol and pterostilbene induced miRNA-mediated regulation of PTEN in prostate cancer. Here, we show that both compounds decrease the levels of endogenous as well as exogenously expressed miR-17, miR-20a and miR-106b thereby upregulating their target PTEN. Using functional luciferase reporter assays, we demonstrate that ectopically expressed miR-17, miR-20a and miR-106b directly target PTEN 3’UTR to reduce its expression, an effect rescued upon treatment with resveratrol and pterostilbene. Moreover, while stable lentiviral expression of miR-17/106a significantly decreased PTEN mRNA and protein levels and conferred survival advantage to the cells, resveratrol and more so pterostilbene was able to dramatically suppress these effects. Further, pterostilbene through downregulation of miR-17-5p and miR-106a-5p expression both in tumors and systemic circulation, rescued PTEN mRNA and protein levels leading to reduced tumor growth in vivo. Our findings implicate dietary stilbenes as an attractive miRNA-mediated chemopreventive and therapeutic strategy, and circulating miRNAs as potential chemopreventive and predictive biomarkers for clinical development in prostate cancer."

[stefan_001]

Sirtuin activation mentioned again. Next week my order of 3 months Honikiol arrives, let's see do I notice something over time (will take in combination with NR and pterostilbene)

http://www.livescien...rs-disease.html

"It's showing us a new mechanism, or a new pathway, towards Alzheimer's treatments," Turner said. "This is targeting amyloid in an indirect way," he said. Researchers think that resveratrol activates proteins called sirtuins, which are also activated by calorie restriction, and may have anti-aging effects.

[Bryan_S]

Sirtuin activation mentioned again. Next week my order of 3 months Honikiol arrives, let's see do I notice something over time (will take in combination with NR and pterostilbene)

http://www.livescien...rs-disease.html

"It's showing us a new mechanism, or a new pathway, towards Alzheimer's treatments," Turner said. "This is targeting amyloid in an indirect way," he said. Researchers think that resveratrol activates proteins called sirtuins, which are also activated by calorie restriction, and may have anti-aging effects.

 

Good find stefan_001 there is more than one reason to take this sirtuin activator. There was no mention of pterostilbene in that study and the last I heard support for Resveratrol was waning in favor of the more potent pterostilbene. So do we wait for a pterostilbene study to clear the air and can we assume since the molecules are so similar and pterostilbene is more bioactive, that if you take it your covered? Or should we take a Pterostilbene & Resveratrol combination which is already on the market? Interesting course of events, which is better.

 

I think we recently read an article to shed some light on this question. See full-text link "Low-dose pterostilbene, but not resveratrol, is a potent neuromodulator in aging and Alzheimer’s disease" credit to APBT for finding this text. So you be the Judge but I think if this comparative study had been published before the Georgetown study commenced in 2012 they would have looked at pterostilbene over Resveratrol.

 

Also our other sirtuin activator Honikiol (SIRT3) made the press again this last week. "Honokiol, a Lignan Biphenol Derived from the Magnolia Tree, Inhibits Dengue VirusType 2 Infection" However since we are talking about the 2 aforementioned sirtuin activators in an Alzheimer's context, Honikiol also made similar headlines. "Magnolol and honokiol inhibited the amyloid formation of human calcitonin" Now I am still evaluating Honikiol from an anti-inflammatory standpoint and hands down it's racking up headlines as an inhibitor of inflammation, study after study. "Article The Japanese traditional therapy, honokiol, blocks key protein in inflammatory brain damage" and it specifically mentions "Microglial inflammation is also observed in several neurodegenerative diseases including Alzheimer's disease, Parkinson's disease, and multiple sclerosis." So Honikiol is very relevant as a sirtuin activator and in neurological disease and the research continues to verify this.

 

I've long felt prevention is as important as a cure. However a cure won't bring back whats lost if neurons have died!

 

 

Resveratrol impacts Alzheimer's disease biomarker September 11, 2015

 

 

http://medicalxpress...-biomarker.html

http://www.sciencene...1203560006.html

 

 

Previously 

 

Georgetown physician leads national resveratrol study for Alzheimer's disease May 14, 2012

 

http://medicalxpress...-alzheimer.html

http://www.medstarge...eimers-disease/

Edited by Bryan_S, 12 September 2015 - 06:16 PM.

[Tom Andre F. (ex shinobi)]

Bryan

 

thanks a lot for your previous post. Still, we need to understand the whole process: why PARP activity is increased with aging ?

 

For the pterostilbene, i think there is no more way to use resveratrol in my opinion. Pterostilbene is just a methylated resveratrol wich even give the body some methyl that we clearly need, for exemple for the glutathion production. All studies seems to confirm that pterostilbene is far better than resveratrol and do a better job. I will post a new article soon on my blog to show again some comparison on oxidativ stress protection capacity and as a cognitiv enhancer. For me its clear, we do not need resveratrol if we use pterotilbene. Best combo summary for now to fight aging seems to be: pterostilbene / NR / Honokiol and maybe beta-lapachone, oxaloacetate and C60oo. This is the real basis updated

 

 

EDIT: does anyone have access to this : http://ursca.whittie...ammatory-status

 

"Spermidine is a naturally occurring polyamine that may have beneficial characteristics to one’s health when supplemented into daily nutrition. This particular nutraceutical is known to be an inducer of autophagy and DNA methylation. Increased autophagy activity correlates to an increased lifespan. Therefore, if spermidine is able to significantly increase autophagy activity, supplementation of exogenous spermidine into a daily diet may be beneficial to one’s health in regard to aging. To test our hypothesis we used as our model system an immortal T cell line called Jurkat cells. Jurkat cell cultures were treated with spermidine at 50, 100 and 500 mg/ml concentrations.Treatments resulted in an 18% increase of growth when treated with 100 mg/ml relative to our control culture at time points of 0 hrs and 24 hrs. In addition, we analyze spermidine’s effect on longevity genes of our cultured cells, specifically the expression of NF-kB, MAPK, DNA methyltransferase and Sirtuin1-7 genes. Expression of our targeted gene was analyzed by using RT-PCR. Our results indicate that there were changes in the gene expression due to spermidine treatment."

Edited by Tom Andre F. (ex shinobi), 12 September 2015 - 11:47 PM.

[albedo]

 

NIAGEN® NR Age Defense

 

Looks like CVS pharmacy is getting into the NAD boosting game.

http://investors.chr...icle&ID=2086302

http://globenewswire...Supplement.html

 

Informative. Do we know which dose they will be offering?

[Bryan_S]

 

 

NIAGEN® NR Age Defense

 

Looks like CVS pharmacy is getting into the NAD boosting game.

http://investors.chr...icle&ID=2086302

http://globenewswire...Supplement.html

 

Informative. Do we know which dose they will be offering?

 

 

Nothing was given on a roll out date or possible dosage. I think this move signals market acceptance. I'd like to see this in everyones multi-vitamin regiment and see the price come down. As much as I can make out the product will be named "NIAGEN® NR Age Defense."

[Bryan_S]

Bryan

 

thanks a lot for your previous post. Still, we need to understand the whole process: why PARP activity is increased with aging ?

 

All studies seems to confirm that pterostilbene is far better than resveratrol and do a better job.

 

Tom,

 

I think from a research standpoint the mechanisms are pretty straight forward. With declining NAD levels we might expect oxidative stress, which in turn could increase PARP activity in response to oxidative DNA damage. So I would view this topic as Age-related alteration of poly(ADP-ribose) polymerase activity from a declining NAD standpoint. From a oversimplified perspective I see cause and effect here where declining NAD supports oxidative stress and the resulting damage requires PARP activity, which is very simplified. So I'll be carful when saying "PARP1 activity is linked to the aging process" but I don't see it as a cause.

 

I also look at this topic thru the Nicotinamide Riboside lens which is the charter of this thread and want to give my DNA maintenance workers every advantage. If you want to read up on the correlation of PARP activity and NAD levels thru aging here is a good study to round out your understanding.

 

I also feel pterostilbene is better than resveratrol.

 

Also a general board comment; Guys let's keep our comments as closely tied to Nicotinamide Riboside, NAD boosting and its supporting topics as much as possible. From a News and Updates standpoint we as an audience want to see the most recent supporting evidence on this topic. If it doesn't fit or correlate to this discussion it likely should find a home on another thread.

Edited by Bryan_S, 13 September 2015 - 03:04 PM.

[midas]

Lack of Transferrin Receptor 1 in the Heart Causes Lethal Cardiomyopathy and Disruption of Mitophagy in Mice

 

http://dukespace.lib...dle/10161/10522

 

"Mice lacking Tfr1 in the heart died in the second week of life, with cardiomegaly, poor cardiac function, failure of mitochondrial respiration and ineffective mitophagy. The phenotype could only be rescued by aggressive and ongoing iron therapy, but it was ameliorated by either a mutant Tfr1 allele that does not bind transferrin or administration of nicotinamide riboside, an NAD precursor."

[Bryan_S]

Lack of Transferrin Receptor 1 in the Heart Causes Lethal Cardiomyopathy and Disruption of Mitophagy in Mice

 

http://dukespace.lib...dle/10161/10522

 

Hadn't seen that one, thanks. Here is another one to slip thru the cracks.

 

Emerging concepts in the therapy of mitochondrial disease

http://www.sciencedi...00527281500050X

 

"Notably, NAD⁺ exerts a substrate-dependent activation of Sirt1, which has homeostatic significance, setting up mitochondrial biogenesis to NAD⁺availability. We recently showed that the NAD⁺ pool can be increased by diet supplementation with its natural precursor nicotinamide riboside (NR) or by genetic or pharmacological inhibition of poly(ADP) ribosyl-polymerase 1 (Parp1), a NAD⁺ consumer and Sirt1 competitor."

[docmaas]

I posted a writeup of a short experiment with blood glucose and glycine in the glycine thread.

 

http://www.longecity...e-3#entry744026

 

Mike

I posted a writeup of a short experiment with blood glucose and glycine in the glycine thread.

 

http://www.longecity...e-3#entry744026

 

Mike

[Bryan_S]

NAD⁺-dependent enzymes at the endoplasmic reticulum.

 

 

Looks like the function of the endoplasmic reticulum is also tied to the NAD pool.

 

http://www.ncbi.nlm....pubmed/24171768

 

"The post-translational modifications of proteins by mono- and poly-ADP-ribosylation involve the cleavage of βNAD⁺, with the release of its nicotinamide moiety, accompanied by the transfer of a single (mono) or several (poly) ADP-ribose molecules from βNAD⁺ to a specific amino-acid residue of various cellular proteins. Thus, both mono- and poly-ADP-ribosylation are NAD⁺-consuming reactions. ADP-ribosylation reactions have been reported to have important roles in the nucleus, and in mitochondrial activity. Distinct subcellular NAD⁺ pools have been identified, not only in the nucleus and the mitochondria, but also in the endoplasmic reticulum and peroxisomes. Recent reports have shed new light on the correlation between NAD⁺-dependent ADP-ribosylation reactions and the endoplasmic reticulum. We have demonstrated that ARTD15/PARP16 is a novel mono-ADP-ribosyltransferase with a new intracellular location, as it is associated with the endoplasmic reticulum. The endoplasmic reticulum is a membranous network of tubules, vesicles, and cisternae that are interconnected in the cytoplasm of eukaryotic cells. This intracellular compartment is responsible for many cellular functions, including facilitation of protein folding and assembly, biosynthesis of lipids, storage of intracellular Ca²⁺, and transport of proteins. ARTD15 might have a role in both the nucleo-cytoplasmic shuttling, through importinβ1 mono-ADP-ribosylation, and in the unfolded protein response through its ability to ADP-ribosylate two components of this pathway: PERK and IRE1. This review summarizes our present knowledge of the enzymes and targets involved in ADP-ribosylation reactions, with special regard to the novel regulatory reactions that occurs at the level of the endoplasmic reticulum, and that can affect the function of this organelle."

[Tom Andre F. (ex shinobi)]

 

Bryan

 

thanks a lot for your previous post. Still, we need to understand the whole process: why PARP activity is increased with aging ?

 

All studies seems to confirm that pterostilbene is far better than resveratrol and do a better job.

 

Tom,

 

I think from a research standpoint the mechanisms are pretty straight forward. With declining NAD levels we might expect oxidative stress, which in turn could increase PARP activity in response to oxidative DNA damage. So I would view this topic as Age-related alteration of poly(ADP-ribose) polymerase activity from a declining NAD standpoint. From a oversimplified perspective I see cause and effect here where declining NAD supports oxidative stress and the resulting damage requires PARP activity, which is very simplified. So I'll be carful when saying "PARP1 activity is linked to the aging process" but I don't see it as a cause.

 

I also look at this topic thru the Nicotinamide Riboside lens which is the charter of this thread and want to give my DNA maintenance workers every advantage. If you want to read up on the correlation of PARP activity and NAD levels thru aging here is a good study to round out your understanding.

 

I also feel pterostilbene is better than resveratrol.

 

Also a general board comment; Guys let's keep our comments as closely tied to Nicotinamide Riboside, NAD boosting and its supporting topics as much as possible. From a News and Updates standpoint we as an audience want to see the most recent supporting evidence on this topic. If it doesn't fit or correlate to this discussion it likely should find a home on another thread.

 

 

Bryan,

 

very helpeful !! thanks.

 

Here is a good summary and I think its THE key to understand really the process:

 

"The removal of oxidative DNA damage through repair of DNA single strand breaks by DNA base excision repair, is facilitated by Poly(ADP-ribose) polymerase-1 (PARP) [12], [13], [14]. PARP is an abundant protein modifying nuclear enzyme involved in DNA repair. The enzymatic activity of PARP is strongly activated in cells in response to treatment with ROS such as H₂O₂ [15]. Activation of PARP leads to the transfer of ADP-ribose moieties from NAD⁺, to the target protein [16]. Since PARP uses NAD⁺ as the only endogenous substrate for poly-ADP-ribosylation, PARP activity is dependent on the amount of NAD⁺ available, and may act as a nuclear energy sensor. Under physiological conditions, mild activation of PARP can regulate several cellular processes, including DNA repair, cell cycle progression, cell survival, chromatin remodeling, and genomic stability [13], [17]. However, overactivation of PARP can repress genomic transcription and reduce cell survival. NAD⁺, in addition to being a substrate for PARP, also serves as an important redox carrier to power oxidative phosphorylation and ATP production [18]. Depletion of NAD⁺ following PARP hyperactivation has been shown to deplete intracellular ATP stores leading to the release of apoptosis-inducing factors (AIF) and consequent cell death due to energy restriction [19]. PARP activation has been implicated in the pathogenesis of hypertension, atherosclerosis, lung injury, haemorrhagic shock, and diabetic cardiovascular and kidney complications [20], [21], [22], [23], [24]. In these diseases, the oxidant-mediated endothelial cell injury is dependent on PARP activation, and can be attenuated by pharmacological PARP inhibitors [25], [26]. Therefore, tight regulation of PARP activity is crucial to prevent the development of several age-related pathological disorders."

 

So, another safe way to reduce PARP activity is by increasing our endogenous antioxidant via probably some NRF2 activator such as pterostilbene http://www.pterostil...ivator-of-nrf2/

 

Btw Bryan, why did you speculate that beta lapachone decrease parp activity in healthy cells ?
 

Edited by Tom Andre F. (ex shinobi), 16 September 2015 - 10:59 PM.

[Bryan_S]

NAD+-Metabolizing Ectoenzymes in Remodeling Tumor–Host Interactions: The Human Myeloma Model

 

The first part of this review provides an excellent overview of the role played by NAD+ in human models. See Biogenesis of NAD+

 

 

http://www.mdpi.com/...409/4/3/520/htm

[Bryan_S]

Stimulation of the Fibrillar Collagen and Heat Shock Proteins by Nicotinamide or Its Derivatives in Non-Irradiated or UVA Radiated Fibroblasts, and Direct Anti-Oxidant Activity of Nicotinamide Derivatives

 

Pretty good article on aging skin and mitigating damage with Nicotinamide or its derivatives as told thru a Cosmetics perspective. This article is not associated with the "Nicotinamide Reduces Nonmelanoma Skin Cancer Formation" study we reviewed back in May but it does add to the body of evidence to further support the concept of supplementation for skin health.

 

http://www.mdpi.com/...284/2/2/146/htm

[Bryan_S]

Anticancer Activity of Nicotinamide on Lung Cancer

 

Noticed another study, this one to investigate (Nam) on Lung Cancer since Nicotinamide was found to be effective in several animal cancer models including lung, bladder, liver, etc.

 

https://clinicaltria...tinamide&rank=5

 

 

Edited by Bryan_S, 17 September 2015 - 05:50 PM.

[Asor]

 

Lack of Transferrin Receptor 1 in the Heart Causes Lethal Cardiomyopathy and Disruption of Mitophagy in Mice

 

http://dukespace.lib...dle/10161/10522

 

Hadn't seen that one, thanks. Here is another one to slip thru the cracks.

 

Emerging concepts in the therapy of mitochondrial disease

http://www.sciencedi...00527281500050X

 

"Notably, NAD⁺ exerts a substrate-dependent activation of Sirt1, which has homeostatic significance, setting up mitochondrial biogenesis to NAD⁺availability. We recently showed that the NAD⁺ pool can be increased by diet supplementation with its natural precursor nicotinamide riboside (NR) or by genetic or pharmacological inhibition of poly(ADP) ribosyl-polymerase 1 (Parp1), a NAD⁺ consumer and Sirt1 competitor."

 

 

Nice... Viscomi is my guy , we exchange several emails and he's very interested in my case.

[Bryan_S]

In vivo Monitoring of Transcriptional Dynamics After Lower-Limb Muscle Injury Enables Quantitative Classification of Healing

 

http://www.nature.co...icles/srep13885

 

 

It obvious there were a lot of things going on to promote tissue repair. I think the gene expression of Nicotinamide Riboside Kinase 2 after injury signals what these injured tissues were using as an energy substrate, at least in part. 

 

"The time point-weighted signatures method assigns normalized weights to the magnitude of the fold change between the injured and control samples and used the calculated weights to match gene profiles between training and blinded samples (see Methods). Using this approach, specific genes whose changes in expression are useful for classifying a blinded time point could be determined. Examples of the representative genes include TCDD-Inducible Poly(ADP-Ribose) Polymerase-Tiparp (fold change = 3, P-value = 0.011) at 3 h, FOS-Like Antigen 1-Fosl1 (fold change = 13.06, P-value = 0.0166) at 10 h, Nicotinamide Riboside Kinase 2-Nmrk2 (fold change = 3.01,P-value = 7.05e-5) at 24 h, Insulin-like Growth Factor 2 Receptor-Igf2r (fold change = 3.18, P-value = 2.34e-4) at 48 h, Interferon-Induced Protein 35-Ifi35 (fold change = 4.31, P-value = 1.44e-4) at 72 h, Phosphoglucomutase 5-Pgm5 (fold change = 2.90, P-value = 1.88e-3) at 168 h, Collagen Type VI Alpha 6-Col6a6 (fold change = 8.02, P-value = 4.95e-5) at 336 h, and Myosin Light Chain 10-Myl10 (fold change = −3.68, P-value = 1.72e-2) at 672 h. These genes had a high fold change for a single time point, and low fold changes of injured versus control for each of the other time points. Genes such as these were then selected to differentiate between time points because pairwise profile comparisons at adjacent time points are of greater interest than the global expression profile of a gene across multiple time points."

[Supierce]

Does the current research lead to any consensus on optimal dosage levels, timing, or single vs. split dosage?

[BigLabRat]

Does the current research lead to any consensus on optimal dosage levels, timing, or single vs. split dosage?

 

Of what?

[Supierce]

Does the current research lead to any consensus on optimal dosage levels, timing, or single vs. split dosage?

 
Of what?

Nicotinamide Riboside

[Bryan_S]

The released study info suggested a NAD+ ceiling was reached @ 300mg and higher. To me this would suggest taking two 125mg capsules or 250mg (our typical dosage) would be as high as we could reasonably raise our NAD levels approximately 50%. You could take more but at some point you'll be excreting and wasting some portion of it but it will keep NAD+ levels elevated longer at higher dosages.

 

Then we have to consider the time component, the (terminal half-life) of NR, the rate at which it will be metabolized and or excreted. "The biological half-life or terminal half-life of a substance is the time it takes for a substance (for example a metabolite, drug, signaling molecule, radioactive nuclide, or other substance) to lose half of its pharmacologic, physiologic, or radiologic activity, as per the MeSH definition." This was to be answered in the aforementioned study "Primary Outcome Measures: t1/2 (terminal half-life) [ Time Frame: 24 hours ] [ Designated as safety issue: No ] 24 hour dosing period; 3 dosing periods each separated by 7 day washout" I'm a little disappointed they have not released this latest data but earlier ChromaDex said;

 

"Thank you for your email. The half-life of Nicotinamide Riboside Chloride is 4 hours.

Kind regards,

Collene Villalobos

Sales Manager - Ingredients"

Credit APBT

 

We can also make some other assumptions, we know intracellular NAD+ levels drop fairly fast, with the short half-life of NAD+, which is estimated around 1 to 2 h. So its consumed pretty fast but NR lingers long enough in the blood stream to replenish the demand because we know our blood plasma concentrations drop 50% every 4 hours. (when we get better data we will update this)

 

So after an initial dose the question becomes "what is the maintenance regiment to maintain consistently elevated NAD+ levels thru the day?" That question also invokes yet another which is "elevated to what percent?" And that question is best answered by your wallet and how much of your monetary resources your willing to commit. Its sad but true.

 

Knowing the approximate t1/2 (terminal half-life) maybe one of our Math Majors can work up some graphs on different dosing schemes.

 

I'm sure we'll debate the ideal dosing for maximum sustainable NAD levels until Charles Brenner, PhD publishes his accurate terminal half-life data but right now if I was taking 250mg per day I'd split the dose 12 hrs apart, pretty simple decision with 125mg capsules. If I was taking 500mg/per/day I'd likely break it down into 4 dosages or two dosages 12 hrs apart. At 1000mg/per/day you can even out the dose thru the day and smooth out the NAD+ peaks and valleys. I'm on this 1000mg regiment and take 250mg followed by 125mg every 2 hours.

 

The next studies are to shine a finer light on long term supplementation and what happens to your NAD+ levels over the course of many weeks taking NR. 

 

Here is what they released in the last study:

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

 

That's the best I can interpret from the data so far. Overall I think we need more complete data and I await the long term studies but it appears beyond a certain dosage we are wasting our money and under a certain dosage the benefits might be slim and fade fast.

 

JMHO Hope that helps.

Edited by Bryan_S, 19 September 2015 - 10:33 AM.

[Supierce]

That's exactly what I was looking for. Thank you, Bryan.

[albedo]

More (podcast) on Cash and Oxaloacetate:

https://thequantifie...(Episode Title)

 

 "We can essentially “bio-hack” our systems by tricking the cells into thinking that the NAD to NADH ratio is high so that fat production is reduced (12:50)."

"Oxaloacetate is used in the Kreb’s cycle to oxidize NADH to NAD (17:09)."

"Alan Cash spent years proving to the FDA that there do not seem to be any negative effects found with taking large doses of oxaloacetate (38:35)."

"Recently, clinical trials have begun to study oxaloacetate as a treatment for different conditions such as mitochondrial dysfunction, Parkinson’s disease, and Alzheimer’s disease (30:13)."

"When trying your own experiment, take a daily fasting glucose level for a couple weeks to see the normal variability and then follow with oxaloacetate supplementation along with daily reading of your glucose levels (48:06)."

"Long term potentiation, the restoration of the ability to learn, may improve for patients after a stroke or closed head injury if oxaloacetate is used in combination with acetyl-l-carnitine (36:18)."

 

See also here for the mechanisms:

 

Oxaloacetate supplementation increases lifespan in Caenorhabditis elegans through an AMPK/FOXO-dependent pathway

http://www.ncbi.nlm....les/PMC2988682/

[Bryan_S]

Generation, release and uptake of the NAD precursor nicotinic acid riboside by human cells

Received May 12, 2015. Accepted September 18, 2015.

http://www.jbc.org/c...8.full.pdf html

 

"Capsule Background: Nicotinamide riboside (NR) and nicotinic acid riboside (NAR) can serve as precursors of NAD in human cells. Results: Human cells generate and release NR and NAR. Conclusion: NR and NAR are authentic intermediates of human NAD metabolism. Significance: Different cell populations might support each other's NAD pools by providing ribosides as NAD precursors.

 

Abstract NAD is essential for cellular metabolism and has also a key role in various signaling pathways in human cells. To ensure proper control of vital reactions, NAD must be permanently resynthesized. Nicotinamide (Nam) and nicotinic acid (NA) as well as nicotinamide riboside (NR) and nicotinic acid riboside (NAR) are the major precursors for NAD biosynthesis in humans. In this study we explored whether the ribosides NR and NAR can be generated in human cells. We demonstrate that purified, recombinant human cytosolic 5'-nucleotidases (5'-NTs) CN-II and CN-III, but not CN-IA, can dephosphorylate the mononucleotides NMN and NAMN and thus catalyze NR and NAR formation in vitro. Similar to their counterpart from yeast, Sdt1, the human 5'-NTs require high (millimolar) concentrations of NMN or NAMN for efficient catalysis. Overexpression of FLAG-tagged CN-II and CN-III in HEK293 and HepG2 cells resulted in the formation and release of NAR. However, NAR accumulation in the culture medium of these cells was only detectable under conditions that led to increased NAMN production from NA. The amount of NAR released from cells engineered for increased NAMN production was sufficient to maintain viability of surrounding cells unable to use any other NAD precursor. Moreover, we found that untransfected HeLa cells produce and release sufficient amounts of NAR and NR under normal culture conditions. Collectively, our results indicate that cytosolic 5'-NTs participate in the conversion of NAD precursors and establish NR and NAR as integral constituents of human NAD metabolism. In addition, they point to the possibility that different cell types might facilitate each other's NAD supply by providing alternative precursors."

Edited by Bryan_S, 19 September 2015 - 05:04 PM.