142 replies to this topic

[krillin]

Thx Mikey

I assume they were looking at getting the cholesterol improving effect of increasing HDL and lowering LDL?
If so this may still be of interest as a slow release low level niacin source.

 

Here's an IHN pharmacokinetics paper. I also have a cryptic entry in my notes saying Liang, Ma, and Bates (no PMID) had similar results: IHN's half-life was 1.34 h and niacin's appearance half-life was 3.64 h. I can confirm that the stuff lowers cAMP if you take too much, so the nicotinic acid receptor definitely gets activated.

 

Xenobiotica. 2013 Sep;43(9):817-22. 

Biotransformation and pharmacokinetics of inositol hexanicotinate in rats.

Milton SG, Robinson K, Ma J, Wei B, Poon IO, Liang D. 

Abstract 

Inositol hexanicotinate (IHN) is an ester of the anti-hyperlipidemic drug nicotinic acid (NA). This study assessed the hydrolysis rate of IHN in human and rat plasma, and pharmacokinetics of the drug using a rat animal model. IHN (10 or 50 µg/mL) was incubated in plasma at 37 °C for 72 h. Kinetic parameters were determined based on the disappearance of IHN and the appearance of NA. The mean IHN disappearance and NA appearance half-lives were 1.07 and 3.93 h in human plasma, and 0.152 and 2.68 h in rat plasma. Increasing the initial plasma concentration to 50 µg/mL increased the NA appearance half-life in human and rat plasma to 4.66 and 6.47 h, respectively. After single 50 or 100 mg/kg intravenous dose of IHN to Sprague-Dawley rats, the drug showed statistically significant dose-dependent alterations in systemic clearance, suggesting a non-linear saturable elimination of IHN. Dose-normalized mean plasma levels of NA increased by 30% with increasing IHN dose (p < 0.02). The mean metabolic ratio (i.e. NA/IHN AUC ratio) significantly increased with increasing IHN dose (p < 0.05). The results provide first indication of saturable elimination and rapid disappearance of IHN, while niacin was slowly formed. 

PMID:     23347001
 

[Logic]

P7C3 Neuroprotective Chemicals Function by Activating the Rate-Limiting Enzyme in NAD Salvage.
http://www.ncbi.nlm....pubmed/25215490

The Google crowd is financing this stuff
http://www.prnewswir...-274773691.html

Get yours here:
http://www.tocris.co...31#.VEMBd_4cTMw

Is there any way of figuring out which plant? these codenamed molecules come from?

Edited by Logic, 19 October 2014 - 12:12 AM.

[APBT]

FULL TEXT:  P7C3 Neuroprotective Chemicals Function by Activating the Rate-Limiting Enzyme in NAD Salvage

[Bryan_S]

Table 1

NAD Biosynthctic Pathways

http://www.ncbi.nlm....51433/table/T1/

 

Tryptophan (W)                       de novo    Eight-step pathway

Nicotinic acid (NA)                   Salvage    Three-step Preiss-Handler pathway

Nicotinamide (NAM)                 Salvage    Two-step Nampt pathway

Nicotinamide riboside (NAMR) Salvage    Nrk pathway or nucleoside phosphorylated and Nampt pathway

[Logic]

Telmisartan, aka Micardis

http://www.longecity...ndpost&p=441073

Edited by Logic, 21 October 2014 - 10:17 PM.

[Bryan_S]

Logic, been thinking about your theory and the ribose side of the equation. Only I don't think the NR is reduced or cleaved as you suggest. See the conclusions in this 2012 and the following 2014 studies which were based on oral administration. 

The NAD⁺ precursor nicotinamide riboside enhances oxidative metabolism and protects against high-fat diet induced obesity

"Furthermore, NR protects against metabolic dysfunction at lower concentrations than those reported for NMN and we proved that it is effective after oral administration when mixed with food, which is in contrast to NMN which is injected intraperitoneally (Yoshino et al., 2011)." Who would have thought oral administration of (NR) could beat out injection of NMN? Is this what the data is truly saying?

 

Effective treatment of mitochondrial myopathy by nicotinamide riboside, a vitamin B3

"We demonstrate here that oral supplementation with NR, a vitamin B3 form and NAD+ precursor, efficiently prevented development and progression of mitochondrial myopathy in mice. NR delayed the development of morphological hallmarks and ultrastructural changes in mitochondria and resulted in a remarkable induction of mitochondrial biogenesis and oxidative metabolism" 

 

"We administered 400 mg/kg/day of NR, or chow diet (CD), for two groups of male Deletor and control mice (Yang et al, 2007; Canto et al, 2012): “pre-manifestation” (12 months at initiation, 16 months at termination), to test whether early NR treatment can prevent MM, and “post-manifestation” (17 months at initiation, 21 months at termination), to test whether NR can affect the progression of an already-manifested disease. The control groups received similar chow diet without NR. The dose and study protocol were exactly as published previously (Canto et al, 2012), because they showed that this dose of NR efficiently increased NAD+ in skeletal muscle."

 

Here are some insights into what may be happening to the ribose in a recently discovered pathway which seems tissue specific. Something has got to be making this pathway more potent than the typical salvage pathway for NMN. The data just doesn't outline it completely maybe there are other studies that do spell it out.

 

http://www.uniprot.org/uniprot/Q9NPI5

 

http://citeseerx.ist...10.1.1.129.1026

 

http://www.pathwayco...d2.do?id=117650

 

"The use of NR as a precursor in mammalian cell types was first demonstrated in DRG neurons, which induce the NRK2 transcript when damaged by axotomy (71). The ubiquitous expression of Nrk1 in mammalian tissues (80) sug- gests utilization of NR and/or NaR (83) in a diverse array of cell types. However, Nrk2 is present in heart, brain, and skeletal muscle, and is notably absent in kidney, liver, lung, pan- creas, and placenta (48, 71). The fact that DRG neurons cannot be protected from damage induced neuropathy by Na or Nam without concurrent gene expression of Na or Nam sal- vage genes suggests that NR is a uniquely use- ful precursor to the nervous system (71) when de novo synthesis of NAD+ from Trp is not sufficient. "http://biochem.uiowa...nts/bogan08.pdf

 

Its widely accepted that the Tryptophan de novo eight-step pathway is a 60 to 1 conversion ratio some studies peg it higher at 67:1 but this may be do to other nutritional factors. So barring huge Tryptophan ingestion which seems to hit all the tissues if you want to feed the tissues Niacin cant NR is up to the job and at higher efficiencies. "utilization of NR by neurons may provide qualitative advantages over niacins in promoting function in the central and peripheral nervous system."

 

So what I'm getting is NR is superior in specific tissues can be taken at higher doses than either of the other 2 Niacins and it does not have the inhibitory effect on sirtuins like NAM. "the specific utilization of NR by neurons may provide qualitative advantages over niacins in promoting function in the central and peripheral nervous system."

 

Call to action:

Is there a chart anywhere comparing all the NAD Precursors? If there isn't we need to put one together outlining oral absorption, tissue specific absorption/bioactivity, sirtuin interaction with an overall ranking at tolerable doses.

[VERITAS INCORRUPTUS]

As a quick look for edification on one point regardubg the first study:

 

400 mg/kg/day of NR (mice) = ~33mg/kg HED = ~2000mg average human (just quick ballpark figures)

 

my thought is no one is taking 2g are they?

[Asor]

Just wanted to relate this to you guys because i think it's rather relevant.

 

This study is about use of Nicotinamide Riboside on Mice with Mitochondrial Disease (to basically improve mitochondrial biogenesis)

 

http://www.cell.com/...4131(14)00164-8

 

The University of Cambridge and some other research institutes are now planning a study on patients.

 

Why i know that? Because i have a mitochondrial disease so i contacted that group, i exchanged some emails with one of the researchers involved and i got some information. Most likely i will be part of that study on patients in the near future ( i fill their requirements regarding mtDNA mutation etc.).

 

Btw im Italian so excuse my English.

 

So, here you are discussing about  NAD precursors, and this is what they told me about that:

 

The study on mouse models was made with NR, but NR was too expensive to use on a large study with humans, so they were considering other NAD precursors. After some weeks they signed an agreement with Chromadex (the company who holds the patent on NR) so after all they will be using NR on this study.

 

Before that, this is what they were considering to use:

 

- the Cambridge group intended to use Nicotinnamide (not Nicotinamide Riboside)

- the Finnish group Nicotinic Acid.

 

I hope i translate the names correctly because i had this conversation in Italian and im not an expert on this field.

 

Both these alternatives have pros and cons: Nicotinic Acid is more toxic, Nicotinnamide less toxic, but in the initial phase it could have an inverse effect compared to what they're trying to do.

The positive side of those two alternatives is that both have been tested already on humans, while NR is something new, never tested on patients.

So they need to figure out dosages etc... plus there is, as we speak, another study going on made by Chromadex itself about the effects of NR on humans (not on patients with mitochondrial disease), and this will help the study regarding dosages for their own research on patients.

 

I still have contacts with this guy so if you have any interesting question i can forward it.

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

As a quick look for edification on one point regardubg the first study:

 

400 mg/kg/day of NR (mice) = ~33mg/kg HED = ~2000mg average human (just quick ballpark figures)

 

my thought is no one is taking 2g are they?

 

Iv been told this is not how they calculate the dosages, not based on weight but other factors as well like body surface and such.

[Logic]

Logic, been thinking about your theory and the ribose side of the equation. Only I don't think the NR is reduced or cleaved as you suggest. See the conclusions in this 2012 and the following 2014 studies which were based on oral administration. 
The NAD⁺ precursor nicotinamide riboside enhances oxidative metabolism and protects against high-fat diet induced obesity
"Furthermore, NR protects against metabolic dysfunction at lower concentrations than those reported for NMN and we proved that it is effective after oral administration when mixed with food, which is in contrast to NMN which is injected intraperitoneally (Yoshino et al., 2011)." Who would have thought oral administration of (NR) could beat out injection of NMN? Is this what the data is truly saying?
 
Effective treatment of mitochondrial myopathy by nicotinamide riboside, a vitamin B3
"We demonstrate here that oral supplementation with NR, a vitamin B3 form and NAD+ precursor, efficiently prevented development and progression of mitochondrial myopathy in mice. NR delayed the development of morphological hallmarks and ultrastructural changes in mitochondria and resulted in a remarkable induction of mitochondrial biogenesis and oxidative metabolism" 
 
"We administered 400 mg/kg/day of NR, or chow diet (CD), for two groups of male Deletor and control mice (Yang et al, 2007; Canto et al, 2012): “pre-manifestation” (12 months at initiation, 16 months at termination), to test whether early NR treatment can prevent MM, and “post-manifestation” (17 months at initiation, 21 months at termination), to test whether NR can affect the progression of an already-manifested disease. The control groups received similar chow diet without NR. The dose and study protocol were exactly as published previously (Canto et al, 2012), because they showed that this dose of NR efficiently increased NAD+ in skeletal muscle."
 
Here are some insights into what may be happening to the ribose in a recently discovered pathway which seems tissue specific. Something has got to be making this pathway more potent than the typical salvage pathway for NMN. The data just doesn't outline it completely maybe there are other studies that do spell it out.
 
http://www.uniprot.org/uniprot/Q9NPI5
 
http://citeseerx.ist...10.1.1.129.1026
 
http://www.pathwayco...d2.do?id=117650
 
"The use of NR as a precursor in mammalian cell types was first demonstrated in DRG neurons, which induce the NRK2 transcript when damaged by axotomy (71). The ubiquitous expression of Nrk1 in mammalian tissues (80) sug- gests utilization of NR and/or NaR (83) in a diverse array of cell types. However, Nrk2 is present in heart, brain, and skeletal muscle, and is notably absent in kidney, liver, lung, pan- creas, and placenta (48, 71). The fact that DRG neurons cannot be protected from damage induced neuropathy by Na or Nam without concurrent gene expression of Na or Nam sal- vage genes suggests that NR is a uniquely use- ful precursor to the nervous system (71) when de novo synthesis of NAD+ from Trp is not sufficient. "http://biochem.uiowa...nts/bogan08.pdf
 
Its widely accepted that the Tryptophan de novo eight-step pathway is a 60 to 1 conversion ratio some studies peg it higher at 67:1 but this may be do to other nutritional factors. So barring huge Tryptophan ingestion which seems to hit all the tissues if you want to feed the tissues Niacin cant NR is up to the job and at higher efficiencies. "utilization of NR by neurons may provide qualitative advantages over niacins in promoting function in the central and peripheral nervous system."
 
So what I'm getting is NR is superior in specific tissues can be taken at higher doses than either of the other 2 Niacins and it does not have the inhibitory effect on sirtuins like NAM. "the specific utilization of NR by neurons may provide qualitative advantages over niacins in promoting function in the central and peripheral nervous system."
 
Call to action:
Is there a chart anywhere comparing all the NAD Precursors? If there isn't we need to put one together outlining oral absorption, tissue specific absorption/bioactivity, sirtuin interaction with an overall ranking at tolerable doses.

 
Well we do have the salvage pathway for NR Bryan, so there must NR from somewhere to be salvaged.
So either NR is a by-product of some other biological process, or some NR gets in our systems and then cells somehow.
Perhaps NR is absorbed buccaly from food or the study is wrong and a small amount of NR does make it through the intestines intact.
 
For the sake of argument lets assume the study is right and NR is actually just slow release Nam and Ribose.
If you look at the salvage pathways, the de novo pathway, and also the production of SIRT, PARP, CD38, etc. you can see that ATP s used up all over the place.
ATP requires the manufacture of Ribose from other sugars and is a slow process.  ATP is changed into ADP in the process of providing cells with energy.  If the cell demands energy faster than ADP can be changed back into ATP the 2nd phosphate is split off the ATP molecule too, leaving AMP which cannot be reconstituted back to ATP and is excreted.
When this happens it can take up to 4 days to produce the Ribose-5-Phosphate required.
Supplementing Ribose skips this slow and oxidative pentose phosphate pathway making all the required ATP and other required Ribose containing enzymes etc. quickly and easily available.
 

The problem with supplementing plain old Ribose for this purpose is that its quickly absorbed and what isn't required is as quickly excreted and eliminated.
Besides there not being a constant supply for use as required, the spike in ribose is proven to cause serious glycation damage both on entering the cell and again on leaving!
So you can see why a nice low, slow, constant supply as one would get from the slow breakdown of NR in the gut would be optimal.

I  think they would have gone with NAR to keep the SIRT limitng intracellular Nam down, but I believe its unstable and has to be stored at -20C etc.

Personally I think slow release Ribose and NA may be as god as or better than NR, but have not found any slow release Ribose anywhere.

I only have two tabs on the subject open at the moment and am fast running out of bandwidth, so you can either take my word on the above or check for yourself:

"...The metabolic basis for this effect is the low capacity of the oxidative pentose phosphate pathway in the myocardium. Ribose bypasses this pathway, elevates the available pool of 5-phosphoribosyl-l-pyrophosphate, and thus stimulates the biosynthesis of adenine nucleotides. In this study reported here the activity of glucose-6-phosphate dehydrogenase, the first and rate-limiting enzyme of the oxidative pentose phosphate shunt, was very low in the human heart and was of the same order of magnitude in the myocardium of various animal species. Furthermore, ribose had a similar stimulating effect on myocardial adenine nucleotide biosynthesis in the guinea pig, in which hemodynamic parameters are different from those in the rat. It is concluded that the metabolic basis for the effectiveness of ribose is similar in all species investigated..."
http://www.ncbi.nlm..../pubmed/6420889

http://en.wikipedia....osphate_pathway

[trance]

To benefit from increased metabolic activity associated with sirtuin activation, strategies could be employed to increase the concentration of NAD+. Most obvious would be treatment with one of the NAD+ precursors (Houtkooper, Cantó, Wanders, Auwerx, 2010).

 

Houtkooper, R. H., Cantó, C., Wanders, R. J., & Auwerx, J. (2010). The secret life of NAD+: an old metabolite controlling new metabolic signaling pathways. Endocrine reviews, 31(2), 194-223.

 

 

Comments cherry-picked from various papers:

 

Nicotinic Acid (NA): Jackson et al. (1995) also showed that nicotinic acid increases NAD+ concentrations in liver and blood, similar to nicotinamide. In addition, NAD+ biosynthesis was increased in heart (50%) and kidney (100%) as well. These results show that nicotinic acid generally has a broader effect than nicotinamide for NAD+ increases in the body. These results also indicate that the Preiss-Handler pathway is typically operating below saturation in most tissues.  Heart and kidney NAD+ were significantly higher in response to 500 and 1000 mg/kg of dietary nicotinic acid.  High doses of nicotinic acid or nicotinamide increased blood and liver NAD+, but only nicotinic acid was effective in increasing heart and kidney NAD+ levels.

 

Nicotinamide (NAM):  High doses of nicotinamide administered orally or through injection are transiently metabolized in liver to increase NAD+. The ability of nicotinamide to stimulate NAD+ synthesis in liver and blood suggests that nicotinamide is convertible to alternative forms of B3 that ultimately increase nicotinamide bioavailability and/or that nicotinamide treatment causes cellular adaptations that lead to improved NAD+ biosynthesis. Why nicotinamide is efficiently utilized in some but not all tissues for NAD+ biosynthesis is currently unexplained.  In tissues that lack the complete de novo NAD+ biosynthesis pathway, NAM is thought to be preferred over NA as the main precursor for NAD+ biosynthesis.

 

Tryptophan: In humans, 1 of 67 mg of tryptophan eventually ends up as nicotinamide if another B3 source is not available in the diet (Fukuwatari et al., 2004).  Feeding of rats with tryptophan, NA, or NAM showed that the first resulted in the highest NAD+ concentration in liver, suggesting that this is the preferred substrate at least in this organ.

 

Nicotinamide Riboside (NR): The dephosphorylated form of NMN. A highly biologically conserved nicotinamide riboside kinase is able to use NR as a substrate and can convert NR to NMN in cells (Bieganowski and Brenner, 2004). This activity allows NR to enter NAD+ metabolism via NMN and then to NAD+. Thus, NR is converted to NAD+ in only two metabolic steps.

 

 

[VERITAS INCORRUPTUS]

Good overview. Would be curious still as to efficacy of sublingual and intranasal ROA in humans of NAD+ directly, though no one seems to be doing those trials as yet.

 

Of pertinence perhaps if not prior reviewed: http://www.jbc.org/c...83/10/6367.long

 

J Biol Chem. 2008 Mar 7;283(10):6367-74. doi: 10.1074/jbc.M706204200. Epub 2008 Jan 7.

Characterization of NAD uptake in mammalian cells.

Billington RA1, Travelli C, Ercolano E, Galli U, Roman CB, Grolla AA, Canonico PL, Condorelli F, Genazzani AA.

1Dipartimento di Scienze Chimiche, Alimentari, Farmaceutiche e Farmacologiche and the Drug and Food Biotechnology Center, Università del Piemonte Orientale, Via Bovio 6, Novara, Italy.

billington@pharm.unipmn.it

 

Abstract:

Recent evidence has shown that NAD(P) plays a variety of roles in cell-signaling processes. Surprisingly, the presence of NAD(P) utilizing ectoenzymes suggests that NAD(P) is present extracellularly. Indeed, nanomolar concentrations of NAD have been found in plasma and other body fluids. Although very high concentrations of NAD have been shown to enter cells, it is not known whether lower, more physiological concentrations are able to be taken up. Here we show that two mammalian cell types are able to transport low NAD concentrations effectively. Furthermore, extracellular application of NAD was able to counteract FK866-induced cell death and restore intracellular NAD(P) levels. We propose that NAD uptake may play a role in physiological NAD homeostasis.

Edited by VERITAS INCORRUPTUS, 26 October 2014 - 05:09 PM.

[Bryan_S]

Logic,

 

How this salvage pathway evolved may have been pushed from the need to absorb extracellular NAD+ or NMN citation below. From another standpoint where long neuron axons and dendrites make intracellular distribution difficult certain advantages could be inferred by absorbing this precursor directly from the extracellular medium. NR from a nutritional source or metabolically excreted source may simply serve as a extracellular transport mechanism. Since the pathway exists it also gives rise to your slow release ribose theory. 

 

So I think this pathway gives rise to a source of ribose that enhances other intracellular reactions that would otherwise have to wait for it to be manufactured and that process is rate limited.

 

As we look at the array of NAD precursors this insight may be an overlooked advantage as we weigh one against the other. So a hat tip to your theory. Their still may be other less understood synergistic metabolic reactions to come to light but the free ribose may be one of them.

 

Phoenicis made an interesting observation to support this when we touched on it in an earlier thread discussing "Nicotinamide Mononucleotide (NMN)"

http://www.longecity...nt/#entry678289

Abstract to full text link

http://www.ncbi.nlm....les/PMC3122232/

"Thus, there are five different entry points into NAD+ biosynthesis in human cells as follows: NA, Nam, NR, NAR, and tryptophan (Fig. 1A). . . 

Together, these results established that, besides NA and Nam, only the riboside precursors NR and NAR serve as extracellular precursors of intracellular NAD+, whereas mono- (NMN and NAMN) and dinucleotides (NAD+ and NAAD) need to be processed to the corresponding nucleosides (Fig. 3G). This interpretation assumes that entry of extracellular NAD+ precursors into cells could actually be monitored using mitoPARP, a probe that resides within mitochondria. As will be shown below, all known intermediates of NAD+ metabolism, including NAD+ itself, can be converted to a precursor of mitochondrial NAD+ in the cytosol. Consequently, all extracellular NAD+ precursors indeed contribute to mitochondrial NAD+ synthesis. . . 

The presence of only NMNAT3 in the matrix strongly indicated NMN as the cytosolic precursor of mitochondrial NAD+. The absence of NADS from mitochondria ruled out the possibility of amidating NA precursors within the organelles (Fig. 4A). Moreover, localization of both NRK isoforms outside mitochondria (Fig. 4A) suggested that phosphorylation of NR does not occur within the organelles. Still, a possible side activity of thymidine kinase 2 (TK2), a mitochondrial matrix isoform, could potentially mediate phosphorylation of NR (Fig. 5D), because NRKs are homologous to pyrimidine nucleoside kinases (17). However, as shown in Fig. 5A, overexpression of TK2 had no detectable effect on mitochondrial PAR levels when NMN was the only extracellular NAD+ precursor (which is imported into cells after conversion to NR, see Fig. 3). The mitochondrial localization of the overexpressed TK2 protein was verified (supplemental Fig. S3B). Consequently, following entry into the cell, NR would have to be converted to NMN in the cytosol. Indeed, overexpression of NRK1 (which is cytoplasmic, see Fig. 4A) dramatically increased the amount of mitochondrial PAR (Fig. 5A), but only if an extracellular precursor (such as NMN) was available to provide NR (Fig. 5B). Thus, NR is a potent precursor of mitochondrial NAD+, if phosphorylated to NMN in the cytosol (Fig. 5D). Therefore, NMN has been functionally confirmed as the cytosolic precursor of mitochondrial NAD+. Overexpression of NRK1 considerably improved the use of extracellular NAD+ or NMN or NR itself for mitochondrial PAR formation (Fig. 5C). These observations strongly reinforce the notion that extracellular NMN and NAD+ are not taken up into the cells but rather have to be degraded to NR first."

 

Edited by Bryan_S, 26 October 2014 - 06:56 PM.

[VERITAS INCORRUPTUS]

Within all this, what say you of the simple theory of a sustained release niacin, ribose, and aspirin/salicylate formulation as the most logical effective/cost effective route to elevated intracellular NAD+?

 

It would not be difficult to synthesize and/or produce a simple sustained release formulation of this sort.

Edited by VERITAS INCORRUPTUS, 26 October 2014 - 10:37 PM.

[mikey]

Within all this, what say you of the simple theory of a sustained release niacin, ribose, and aspirin/salicylate formulation as the most logical effective/cost effective route to elevated intracellular NAD+?

 

It would not be difficult to synthesize and/or produce a simple sustained release formulation of this sort.

 

We should be careful of aspirin, as it increases risk of macular degeneration.

http://www.ncbi.nlm....pubmed/23337937

 

We want to see when we are 120 years old.

[VERITAS INCORRUPTUS]

^ The NAD+ enhancement will more than correct for that

As well, one needs to review the 'commentaries' 

I think it is a non-issue...

...next...

[Bryan_S]

Don't think we've arrived at a formulation stage yet.

 

The ribose is entering the cell attached to Nicotinamide (NAM) as Nicotinamide Riboside (NR) then we get a slow release of the ribose as its converted to Nicotinamide Mononucleotide (NMN). Tough to beat.

 

If we just ingested the Ribose our levels would spike and we'd excrete what we don't need. The time release Logic talks about is intracellular, not sure if a digestive time release would be as effective? If taken with a Niacin-time-release there are problems with that idea as there are many reports of problems with time released Niacin.

 

 

There are five different entry points into NAD+ biosynthesis in human cells as follows: NA, Nam, NR, NAR, and tryptophan. NAR isn't stable, tryptophan is a 67:1 conversion and not sutible. Na, NAM and NR do rise to the top.

 

Also certain tissues seem to be Na, NAM and NR specific.

NR Nrk2 is present in heart, brain, and skeletal muscle.

Na Heart and kidney.

NAM not a clear picture looks to be far reaching needs more research?

 

Sirtuin interactions for each? Wasn't NAM the weak one in this group guys? That would leave Niacin if it's a NR substitute we seek. Again what were the sirtuin interactions for each?

[VERITAS INCORRUPTUS]

I'm talking about a potential Ribose conjugate that is simpler and more cost effective to produce that can enter the cell and provide the same dynamic.  As well as a niacin conjugate.

Or within just would steady state plasma levels have similar efficacy?

 

Maybe just reaching there, as within as well it is surprising that NR is so costly to synthesize, even within what appears a best method developed by whatever chemists derived this present method as used for the material supplied by Chromadex.

 

However, I think what I have proposed may simply not have been explored or exploited in a best manner

Edited by VERITAS INCORRUPTUS, 27 October 2014 - 02:27 AM.

[M-K]

Also certain tissues seem to be Na, NAM and NR specific.
NR Nrk2 is present in heart, brain, and skeletal muscle.
Na Heart and kidney.
NAM not a clear picture looks to be far reaching needs more research?

Nrk1, however, is "ubiquitous."

[Bryan_S]

Across which tissues and precursors is it ubiquitous? I don't follow.

 

Nrk1 interacts with Nicotinamide riboside and Tiazofurin

http://www.ncbi.nlm.nih.gov/gene/54981

 

 

Also certain tissues seem to be Na, NAM and NR specific.
NR Nrk2 is present in heart, brain, and skeletal muscle.
Na Heart and kidney.
NAM not a clear picture looks to be far reaching needs more research?

Nrk1, however, is "ubiquitous."

 

 

[M-K]

I was hoping you'd recognize the reference, since I don't recall which article I saw this in.  Basically it implied that _all_ organs can use NR via Nrk1, but some specially important organs, such as heart and brain, can also use it via Nrk2.  If I run across the info again, I'll post the cite.

[Bryan_S]

I was hoping you'd recognize the reference, since I don't recall which article I saw this in.  Basically it implied that _all_ organs can use NR via Nrk1, but some specially important organs, such as heart and brain, can also use it via Nrk2.  If I run across the info again, I'll post the cite.

 

 

No you give me more credit than I deserve. What has me intrigued is how this NR pathway evolved and what that might mean. I searched and came up with a body map for where each gene is active in the system. So I gather these genes encode the enzymes so the cell can process the Nicotinamide riboside into Nicotinamide Mononucleotide (NMN). In tissues where there is more demand 2 different enzymes are produced to meet a higher demand I suppose?

 

Nicotinamide riboside kinase 1 Gene NMRK1

Expression Atlas

http://www.ebi.ac.uk...ENSG00000106733

As you indicated this one covers most tissues.

 

 

Nicotinamide riboside kinase 2 Gene NMRK2

Tissue specificityⁱ

Predominantly expressed in skeletal muscle and, at a much lower level, in the heart (at protein level). No expression in brain, kidney, liver, lung, pancreas nor placenta.

http://www.uniprot.org/uniprot/Q9NPI5

 

Expression Atlas

http://www.ebi.ac.uk...ENSG00000077009

 

If you come across it I'd like to see that article you spoke of M-K.

[M-K]

If you come across it I'd like to see that article you spoke of M-K.

 

 

This turned up in a quick search on "Nrk1" and "ubiquitous."

The dynamic regulation of NAD metabolism in mitochondria

http://www.ncbi.nlm....les/PMC3683958/

 

"Of the two mammalian isoforms, NRK1 is ubiquitously expressed, whereas NRK2 is specifically expressed in the heart, brain, and muscle."  (This is actually in the Glossary section.)

[trance]

 

There are five different entry points into NAD+ biosynthesis in human cells as follows: NA, Nam, NR, NAR, and tryptophan. NAR isn't stable, tryptophan is a 67:1 conversion and not sutible. Na, NAM and NR do rise to the top.

 

 

 

 I wouldn't entirely rule out tryptophan as a useful precursor.  

 

 There are multiple paths for NAD+ in humans and tryptophan is just one path.  If all four paths are working optimally it's probably more beneficial to the end result than concentrating on just one.

 

 There's also the possible advantage that may lay in the properties from one or more of tryptophan's intermediates formed towards the path of NAD+ synthesis that we've not yet examined.

[Bryan_S]

 

 

There are five different entry points into NAD+ biosynthesis in human cells as follows: NA, Nam, NR, NAR, and tryptophan. NAR isn't stable, tryptophan is a 67:1 conversion and not sutible. Na, NAM and NR do rise to the top.

 

 

 

 I wouldn't entirely rule out tryptophan as a useful precursor.  

 

 There are multiple paths for NAD+ in humans and tryptophan is just one path.  If all four paths are working optimally it's probably more beneficial to the end result than concentrating on just one.

 

 There's also the possible advantage that may lay in the properties from one or more of tryptophan's intermediates formed towards the path of NAD+ synthesis that we've not yet examined.

 

 

OK but our focus is still "Are Other Precursors as Effective in Increasing NAD+ as NR?" At which point in its path do you propose there is a workable intermediate?

 

 

I still think Na, NAM and NR are the winners and in terms of maximum tolerable upper limits of ingestion and toxicity I think that's pretty much the order from most to least. I've been reading about combining Niacin with (NR), haven't seen anything about (NAM) and (NR) but along this line of thinking maybe there is a way of proportionally loading multiple pathways to maximize the sirtuin benefits without hitting toxicity?

Edited by Bryan_S, 30 October 2014 - 03:20 PM.

[trance]

 The diagram above is greatly simplified of course.

 

 

 Here is a less simplified de novo diagram for tryptophan to NAD+ :

 

 

 

 Anyway, my primary point was that all pathways should possibly be optimized.

 

.

[Bryan_S]

OK so of these which are stable, available and wont breakdown upon ingestion? These are of course the same questions we've asked before. We know tryptophan is a 67:1 conversion so we want something further down the chain, right?

[Ukko]

I have taken high doses of niacin for extended periods. The science showing that it increases NAD+ is solid. In some organs better than NR. Always wondered what the role of ribose is on this context. And, as to niacin, am quite worried about its long term impact on methylation. Both niacin and niacinamide put a massive drain on methylation. And also have worries about the PGD-2 aspects for the long haul.

[Logic]

Don't think we've arrived at a formulation stage yet.
 
The ribose is entering the cell attached to Nicotinamide (NAM) as Nicotinamide Riboside (NR) then we get a slow release of the ribose as its converted to Nicotinamide Mononucleotide (NMN). Tough to beat.
 
If we just ingested the Ribose our levels would spike and we'd excrete what we don't need. The time release Logic talks about is intracellular, not sure if a digestive time release would be as effective? If taken with a Niacin-time-release there are problems with that idea as there are many reports of problems with time released Niacin.
 
 

There are five different entry points into NAD+ biosynthesis in human cells as follows: NA, Nam, NR, NAR, and tryptophan. NAR isn't stable, tryptophan is a 67:1 conversion and not sutible. Na, NAM and NR do rise to the top.

 
Also certain tissues seem to be Na, NAM and NR specific.
NR Nrk2 is present in heart, brain, and skeletal muscle.
Na Heart and kidney.
NAM not a clear picture looks to be far reaching needs more research?
 
Sirtuin interactions for each? Wasn't NAM the weak one in this group guys? That would leave Niacin if it's a NR substitute we seek. Again what were the sirtuin interactions for each?

 
No; I do not mean that the time release is intracellular.
 
The only study looking at what happened to NR in the gut said that as far a anyone knew prior to the study; NR was absorbed intact, but that the study proved that it was SLOWLY cleaved to Nam and Ribose.
 
The intracellular pathway exists to change NR into NMN, so NR must come from somewhere,  but not from popping NR.
 
Extracellular NamPT (eNamPT) exists.  It is excreted from cells and looks to be more biologically active than iNamPT.
http://www.ncbi.nlm....les/PMC2734389/

I guess that eNamPT etc. turns eNam into eNMN or something similar that is absorbed into cells or some Nam and Ribose join together again inside cells.

Whatever happens a slow release Niacin and Ribose capsule would be worth trying IMHO.
I think the lack of other B vitamins with large doses of Niacin is what cause the liver issues?

[Bryan_S]

"No; I do not mean that the time release is intracellular." Whats happing to the ribose?

 

"The only study looking at what happened to NR in the gut said that as far a anyone knew prior to the study; NR was absorbed intact, but that the study proved that it was SLOWLY cleaved to Nam and Ribose." Which study the one from 1982? If this were true we should all be taking NAM, and there are a lot of studies wasting money on NR.

 

"Whatever happens a slow release Niacin and Ribose capsule would be worth trying IMHO." I think those are all available over the counter. 

 

"I think the lack of other B vitamins with large doses of Niacin is what cause the liver issues?" B6 and some other things as memory serves.

 

I'm looking in an entirely different direction, I've been reviewing Charles Brenner's papers from 2008 and nicotinic acid riboside (NAR) caught my eye. In the paper he talks about it as a precursor. I looked and found it's no longer available for purchase, maybe there is another source? Its made from the decomposing NAD or NADH and adding a ribose molecule. (Enzymatically produced from NADH or NAD).

 

I think this extracellular pathway cells have devised to share their surplus NAD to other tissues needs further reading. The NAR and NR looks to be vehicle by which this surplus is shared and 2 pathways exist. The brain seems to have difficulties with other precursors (without concurrent gene expression of Na or Nam salvage genes suggests that NR is a uniquely useful precursor to the nervous system) but expresses an affinity to utilize these. How thats not to say using NAM or NA to raise NAD levels might not produce more NAR and NR in the extracellular environment but why not skip this step?

 

Nicotinic Acid, Nicotinamide, and Nicotinamide Riboside: A Molecular Evaluation of NAD+ Precursor Vitamins in Human Nutrition

"Because current data suggest that nicotinamide riboside may be the only vitamin precursor that supports neuronal NAD+ synthesis, we present prospects for human nicotinamide riboside supplementation and propose areas for future research."

 

"It should be realized that not every cell is capable of converting each NAD+ precursor to NAD+ at all times. Expression of the eight- step de novo pathway is required to utilize trp. Expression of the Nampt pathway is required to utilize Nam. Expression of either the Nrk pathway or nucleoside phosphorylase and the Nampt pathway is required to utilize NR. Fi- nally, expression of the Preiss-Handler pathway is required to utilize Na. Because tissue and cell- type specific enzyme expression differences ex- ist, the precursors are differentially utilized in the gut, brain, blood, and organs. Understand- ing the unique aspects of metabolism of each precursor is necessary to define the mechanisms underlying the physiological effects and side ef- fects of each."

 

I'm re-reading this paper as I write this and Dr. Charles Brenner seems to have reasoned out the topic on the precursors we're all writing about and he explores it along several different lines.

[VERITAS INCORRUPTUS]

deleted, as a 'double post of sorts'

Edited by VERITAS INCORRUPTUS, 05 November 2014 - 05:43 PM.