142 replies to this topic

[VERITAS INCORRUPTUS]

...

 

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."

 

....

 

Great paper in many review aspects, and ironic how his main assertion(hypothesis) is so wrong.  Think about it... (also a little thing called conflict of interest bias)

Edited by VERITAS INCORRUPTUS, 05 November 2014 - 05:27 PM.

[Logic]

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.

I have no read all the studies Bryan, but those that I have read all seem to neatly sidestep the question by going right to intracellular NR or in vitro studies where cells absorb NR added to the test tube.
If there are any other studies looking at what happens to NR from ingestion please do post them.

I really don't know what happens to Nicotinamide and Ribose once it is split apart in the gut. I do know that slow release Ribose skips the slow production process and is used all over the place in the production of NAD+, SIRT, PARP etc. and recycling of Nam.

I also know that there is extracellular NamPT in our bodies and so the possibility that it reacts with extracellular Nam to form extracellular NMN, as used in Sinclair's 1st paper, exists.
From a paper you linked here I know that NMN cannot be absorbed into cells, but undergoes further changes before its able to be absorbed. These changes may require extracellular Ribose, but all this speculation is unnecessary as we know that NMN works from Sinclair's study.
 

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

Slow release Niacin exists but I have not found slow release ribose anywhere. Have you?
If so; it would be easy to anecdotally test my hypothesis!

[Logic]

I really don't know what happens to Nicotinamide and Ribose once it is split apart in the gut. I do know that slow release Ribose skips the slow production process and is used all over the place in the production of NAD+, SIRT, PARP etc. and recycling of Nam.

I also know that there is extracellular NamPT in our bodies and so the possibility that it reacts with extracellular Nam to form extracellular NMN, as used in Sinclair's 1st paper, exists.
From a paper you linked here I know that NMN cannot be absorbed into cells, but undergoes further changes before its able to be absorbed. These changes may require extracellular Ribose, but all this speculation is unnecessary as we know that NMN works from Sinclair's study.

"... The likely mechanism of NMN uptake is extracellular conversion to nicotinamide riboside (NR).33, 34, 35 Although direct uptake of phosphorylated nucleotides may occur,31 the ectoenzymes nucleotide pyrophosphatase and 5′ nucleotidase are proposed to catalyse two- or one-step conversion of NAD and NMN to NR33 (Supplementary Figure S4A). Intracellular NR kinases (NRKs) use NR to resynthesize NMN,36 which in turn is used to synthesize NAD..."
http://www.nature.co...dd2014164a.html

So it looks like NR is split to Nam and Ribose in the gut.
The Nam is converted to NMN and then probably turned back into NR (Ribose used))outside the cell, absorbed, and then turned back into NMN inside the cell.

The point remains that the only reason to take NR looks to be to get the slow cleavage/release and thus constant supply of Nam and Ribose and all that is required to test this theory is slow release ribose.

[VERITAS INCORRUPTUS]

^ RE: http://www.nature.co...dd2014164a.html

Earlier today I just reviewed that same study and sent it to you via PM with quite a few other studies and reviews. A 'formidable' study with a great deal of information to process within this area as a whole.

 

So, noting those so interested should give it a good read.

Edited by VERITAS INCORRUPTUS, 05 November 2014 - 10:10 PM.

[Logic]

^ RE: http://www.nature.co...dd2014164a.html

Earlier today I just reviewed that same study and sent it to you via PM with quite a few other studies and reviews. A 'formidable' study with a great deal of information to process within this area as a whole.

 

So, noting those so interested should give it a good read.

 

Sorry I missed that VI;  I received other PMs and thought I had read them all.
I am oing through the links you sent me now, but its going to take a while!
 

[Bryan_S]

 

...

 

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."

 

....

 

Great paper in many review aspects, and ironic how his main assertion(hypothesis) is so wrong.  Think about it... (also a little thing called conflict of interest bias)

 

 

Look at the year it was written, this was before commercial enterprise picked up on the stuff. So if you doubt the initial research and feel some bias sorry I cant help you there but I think that's a moot point.

[VERITAS INCORRUPTUS]

^ Read the paper within the disclosure it states the inherent situation that is inherently a conflict of interest bias (as most would see it), if I recall correct.

Not saying he has not done largely real good work, though there is bias, inescapable.

And think about it....it's just wrong, simply...simple enough that I will not state it. We all fall prey to one degree or another to bias though of course.

 

[Bryan_S]

 

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.

I have no read all the studies Bryan, but those that I have read all seem to neatly sidestep the question by going right to intracellular NR or in vitro studies where cells absorb NR added to the test tube.
If there are any other studies looking at what happens to NR from ingestion please do post them.

I really don't know what happens to Nicotinamide and Ribose once it is split apart in the gut. I do know that slow release Ribose skips the slow production process and is used all over the place in the production of NAD+, SIRT, PARP etc. and recycling of Nam.

I also know that there is extracellular NamPT in our bodies and so the possibility that it reacts with extracellular Nam to form extracellular NMN, as used in Sinclair's 1st paper, exists.
From a paper you linked here I know that NMN cannot be absorbed into cells, but undergoes further changes before its able to be absorbed. These changes may require extracellular Ribose, but all this speculation is unnecessary as we know that NMN works from Sinclair's study.
 

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

Slow release Niacin exists but I have not found slow release ribose anywhere. Have you?
If so; it would be easy to anecdotally test my hypothesis!

 

 

Logic partly why I take NR under my tongue. As you are all well aware the 1982 study has never been replicated again and the author of his own volition states "The possibility exists that NR may be absorbed without further cleavage." So I'm a little hesitant to hang my hat on the Gross and Henderson study until someone sets up the experiment with todays materials and practices. Remember their conclusions were based on the movement of Carbon-14 as a molecular marker. They did not use a verified NR source already tagged with Carbon-14, they synthesized their own NR from the original NAD tagged with Carbon-14 which is questionable. Every researcher since has used NR as an ingestible NAD precursor when not working with NMN but as you suggest research also suggests NMN must also be modified before it can be absorbed by the cell.

 

Lets get back to the ribose and the NAR I've been reading about which was the precursor I was looking at that has a dedicated metabolic path. As far as the Ribose is concerned it's a simple sugar and I don't think you need a slow release version as there should be plenty available to work with.

 

I also need to ask whats the relevance to the NAMPT inhibitor study? Obviously once you sever the connection between the nucleus and the mitochondria the salvage pathway will break down without the feedback.

[Bryan_S]

 

...

 

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."

 

....

 

Great paper in many review aspects, and ironic how his main assertion(hypothesis) is so wrong.  Think about it... (also a little thing called conflict of interest bias)

 

 

OK lets trash his whole paper as rubbish.

 

 

 

DISCLOSURE STATEMENT

C.B. is an inventor of intellectual property related to nutritional and therapeutic uses of nicotinamide riboside.

 

VERITAS INCORRUPTUS you want to pick Charles Brenner's paper apart please do but I could point out your bias as well. Useful NAD research has spanned some 40-years and some of it dates back almost 70 but as far as I'm concerned only the last 15-years have really provided anything we can use as a path to longevity. If you take away these recent pioneers and ditch their research as bias I guarantee we wouldn't be having this conversation and guys like Sinclair and Leonard Guarente wouldn't have a leg to stand on.

 

So if his hypothesis is so wrong and we are all barking up the wrong tree post your conjecture and we will see where you stand against the experts! 

 

Most of us here are trying to find equivalent paths to the same results as Sinclair and the other researchers but I'm not sure you've even followed the subject as long as the rest of us. Its one thing to stir the pot and another to contribute and with you I'm not sure.

Edited by Bryan_S, 06 November 2014 - 01:25 AM.

[VERITAS INCORRUPTUS]

I said it largely seems a great paper, just that he insinuates things pushing a superiority of NR supplementation that is not necessarily so.  Please don't change what I said that I trashed him or his paper.

However, has he even stepped forth to clearly demonstrate NR is absorbed intact and orally bioavailable as to first pass?  

And I will note when one has reviewed thousands of papers, there are prompts that make one aware to look for potential bias.

 

As has been made clear by myself and Logic it may be no more than an expensive 'time-release' of NAM and R.

As well, NAD+ itself may be orally absorbed within stability in acidic media, and there is a paper showing eNAD has plasmamembrane permeability among other (potential) fun facts , which I sent to Logic, among other papers to review on the subject matter. 

Hello: http://molpharm.aspe...073916.full.pdf

 

Also be aware, as I have stated elsewhere, there is a tendency within such things to promote them beyond what they have capacity to achieve.  Especially within not accounting for other pathways that play a role within all of it.  

 

With that said, I like the potentials within all of this, and perhaps I am playing a bit of Devil's Advocate.  I think that is perhaps a good thing and I believe am also contributing ideas along the lines of tweaking out just what is optimal. That's the idea, right?

 

 

Edited by VERITAS INCORRUPTUS, 06 November 2014 - 03:06 AM.

[Bryan_S]

D-Ribose + nicotinamide who will kick this off? The Ribose is already used by bodybuilders and athletes and nicotinamide is also readily available.

[Bryan_S]

 

I really don't know what happens to Nicotinamide and Ribose once it is split apart in the gut. I do know that slow release Ribose skips the slow production process and is used all over the place in the production of NAD+, SIRT, PARP etc. and recycling of Nam.

I also know that there is extracellular NamPT in our bodies and so the possibility that it reacts with extracellular Nam to form extracellular NMN, as used in Sinclair's 1st paper, exists.
From a paper you linked here I know that NMN cannot be absorbed into cells, but undergoes further changes before its able to be absorbed. These changes may require extracellular Ribose, but all this speculation is unnecessary as we know that NMN works from Sinclair's study.

"... The likely mechanism of NMN uptake is extracellular conversion to nicotinamide riboside (NR).33, 34, 35 Although direct uptake of phosphorylated nucleotides may occur,31 the ectoenzymes nucleotide pyrophosphatase and 5′ nucleotidase are proposed to catalyse two- or one-step conversion of NAD and NMN to NR33 (Supplementary Figure S4A). Intracellular NR kinases (NRKs) use NR to resynthesize NMN,36 which in turn is used to synthesize NAD..."
http://www.nature.co...dd2014164a.html

So it looks like NR is split to Nam and Ribose in the gut.
The Nam is converted to NMN and then probably turned back into NR (Ribose used))outside the cell, absorbed, and then turned back into NMN inside the cell.

The point remains that the only reason to take NR looks to be to get the slow cleavage/release and thus constant supply of Nam and Ribose and all that is required to test this theory is slow release ribose.

 

 

Wasn't very expensive I'll give it a test drive and report the results. There isn't a slow release version of ribose but you can buy NAM that way. 

Edited by Bryan_S, 10 November 2014 - 03:58 AM.

[Logic]

I wonder if one couldn't dissolve Ribose and Nicotinamide and/or Niacin in ones daily water and sip it throughout the day as a means of getting a more constant supply.

The reason for saying 'Nicotinamide and/or Niacin':
Extracellular NamPT may be used up by extracellular Nam??
This would decrease the survival of old macrophages that should have died rather than misfolding proteins and causing inflammation and atherosclerosis?
http://www.ncbi.nlm....les/PMC3122232/
(Note that NA is known to have the opposite effect)
But you don't want too much Nam as it limits SIRT.

Dosage???

Edited by Logic, 11 November 2014 - 06:09 AM.

[Bryan_S]

Don't have all the answers. Logic my feeling is as we load the Krebs Cycle with NR eventually we end up with a surplus of NAM to be excreted anyway. Maybe more available ribose can help us hold on to more before its lost. The excess has to go somewhere, keeping it would be ideal rather than flushing it down the drain.

 

Why are we not limiting the SIRT as if we were consuming massive amounts of niacinamide in the first place?

 

Dosage??? Open for discussion. Both niacinamide and D-Ribose are water soluble. Why stretch out the dosing I thought the NA and NAM studies showed time released versions weren't as heathy.

Edited by Bryan_S, 11 November 2014 - 08:30 AM.

[Logic]

"...Deacetylases such as sirtuins (SIRTs) convert NAD to nicotinamide (NAM). Nicotinamide phosphoribosyl transferase (Nampt) is the rate-limiting enzyme in the NAD salvage pathway responsible for converting NAM to NAD to maintain cellular redox state. Activation of AMP-activated protein kinase (AMPK) increases SIRT activity by elevating NAD levels. As NAM directly inhibits SIRTs, increased Nampt activation or expression could be a metabolic stress response..."
http://www.ncbi.nlm....pubmed/23918774

"...This highlights how NAM can influence SIRT1 activity through different means: first, as a noncompetitive SIRT1 inhibitor, and, second, as an NAD+ precursor. Low levels of NAM might therefore be beneficial for SIRT1 activity, because NAM can act as an NAD+ precursor, but, more importantly, accumulation of NAM could be deleterious through the inhibition of SIRT1 (Yang and Sauve, 2006)..."
http://pharmrev.aspe...t/64/1/166.full

"...To further confirm this observation, matched-control and SIRT1-depleted HeLa cells were treated with the SIRT1 inhibitor nicotinamide (NAM)..."
http://www.plosone.o...al.pone.0009199
 
So higher Nam levels = lower SIRT levels Bryan.
In fact its possible that a large part of calorie restriction has to do with decreased NAM levels from food. ?
The difference between NA and NAM is that NA first has to go through the NAMN - NMNAT1,2,3 - NADS - NAD+ cycle and be used up in the production of SIRT, PARP etc. before what is left is turned into NAM, rather than adding to the end product...
http://www.ncbi.nlm....2232/figure/F7/

"...Surprisingly, the use of NA as an extracellular precursor of mitochondrial NAD+ is efficient, even though four enzymatic activities (NAPRT, NMNAT, NADS, and NAD+ cleavage, Fig. 6E) are required, compared with a single one (e.g. NRK) when using amidated precursors (Fig. 5D). However, only overexpression of NAPRT, but not NMNAT1 or NADS, substantially increased mitochondrial PAR when NA was added as NAD+ precursor (Fig. 6, C and D) indicating that only NAPRT activity is rate-limiting..."
http://www.ncbi.nlm....les/PMC3122232/
 
So overexpression of NAMPT is desired to increase the recycling of NAM, keeping its levels to a minimum to increase SIRT. (see AMPK in the 1st link)
If one goes with NA; ways to increase NAPRT would be nice.

eNamPT looks to be the product of fat cells and dying cells and cause the survival of old, misbehaving macrophages that cause inflammation and atherosclerosis.
As such it looks to be very undesirable and avoiding/supressing it is probably the 'game changer' that Sinclair is currently working on.
Note that NA is known to slow and sometimes reverse atherosclerosis, so it may be a way to either lower eNamPT or neutralise it. ?
 
Its also important to clear up confusion about Nicotinamide, Niacinamide, niacin etc.
If I understand this correctly; if the word ends in Amide its the Amided version of B3 and the same thing. ie: Nicotinamide, Niacinamide are the same thing. ?
The acid; NA or Niacin is the other.

Time Release:
Mikey says that the studies showing the negative effects of Time Release Niacin are a hatchet job by Big Pharma to kill competition to statins. ???
My memory is a 'bit' sketchy but if I recall correctly the problem arises from getting the balance of all the B vitamins out of whack and has to do with under methylation, but this has to be re examined.
I think adding all the B's in the correct ratios to a time release formula might fix the problem if it really exists.

I think that NR is effective due to its slow breakdown in the gut. This results in a nice constant, steady supply of NAM and Ribose rather than spikes that give glycation issues in the case of Ribose. ie: its pointless having extra NAD+ for the short duration of the NA/NAM and Ribose spike only, with 'normal', sub optimal levels for the other 23 hours of the day.
Adding Ribose and Niacin (plus the other B's?) to your daily water supply is the cheapest way I could think of to get a semi constant supply.
 
It would be nice if the more educated people would chip in with their thought on all this as I am just an amateur with an ever decreasing memory.  Especially now that I am off all supps.

[VERITAS INCORRUPTUS]

I like the way you think Brother Logic, and your moniker is well deserved, so whether quite wholly accurate or not it is all a very good effort

I largely concur on a quick review.  A couple of points to perhaps clarify:

 

Logic:  In fact its possible that a large part of calorie restriction has to do with decreased NAM levels from food. ?

Not so much I gather within that other mechanisms other than actual restriction effect these pathways, so it can likely only be marginal within the scope I would think.  Along with some other reasons perhaps, within my quick eval.

 

Logic:  Nicotinamide, Niacinamide are the same thing.??

 

 

Yes, as well as aka nicotinic amide, the 'amidated form' of niacin (niacin aka nicotinic acid, et al., the 'acid form')

Their in vivo effects are not identical, but both function within the context of B3 pathways of course > NAD+ (Coenzyme 1)

 

An 'optimized' supplemental form of NAD+ may as well be of great worth, as so prior speculated and as so presented to you in my 'review draft'.

Uncouplers and other CR-M (mimetics) as well as SIRT modulators seem to potentially factor in of course as well.

 

Within all this, one potentially important factor I feel is worthwhile to reiterate, is within that homeostatic mechanisms may be tight within these pathways.  As such, that is a factor within supplementation of any sort, may demand a comprehensive 'stack' for any truly profound potentials, and again likely will be far superior 'therapy' for those deficient.

Edited by VERITAS INCORRUPTUS, 11 November 2014 - 08:34 PM.

[Dolph]

Time Release:
Mikey says that the studies showing the negative effects of Time Release Niacin are a hatchet job by Big Pharma to kill competition to statins. ???

 

Mmmmm, no... But feel free to try. One liver more or less, who cares?

I guess what Mikey wanted to say is that some studies using Time Release Niacin were meant to make niacin look bad BECAUSE OF THE KNOWN TOXIC EFFECTS OF TIME RELEASE NIACIN!!! It's the immedate release stuff that is the safe option!

 

My memory is a 'bit' sketchy but if I recall correctly the problem arises from getting the balance of all the B vitamins out of whack and has to do with under methylation, but this has to be re examined.
I think adding all the B's in the correct ratios to a time release formula might fix the problem if it really exists.

 

No, certainly not. "The B's" don't have much to do with each other anyways with a few exceptions. They are just called that way for historical reasons. They are all water soluble, that's all. No, they won't prevent toxicity of time release niacin!

I think that NR is effective due to its slow breakdown in the gut. This results in a nice constant, steady supply of NAM and Ribose rather than spikes that give glycation issues in the case of Ribose. ie: its pointless having extra NAD+ for the short duration of the NA/NAM and Ribose spike only, with 'normal', sub optimal levels for the other 23 hours of the day.
Adding Ribose and Niacin (plus the other B's?) to your daily water supply is the cheapest way I could think of to get a semi constant supply.

 

Complete Bullshit. 
 
It would be nice if the more educated people would chip in with their thought on all this as I am just an amateur with an ever decreasing memory.  Especially now that I am off all supps.

 

If you want to suffer serious liver damage, feel free to use >2g of time release niacin. Good luck, you'll need it!

 

Edited by Dolph, 11 November 2014 - 08:18 PM.

[VERITAS INCORRUPTUS]

^

Yeah, additional B vitamins will not do anything, but what is the mechanism of toxicity is the question?  

Why the differential within instant release, and as to time released NAM?

Can it be countered in a benign fashion?

 

Notably, NR may again be just acting as time released (TR) Niacinamide-Ribose (conjugate).  Therein NAM-TR is another option, within as well being respectful perhaps to studies showing such to as well have some potential (albeit lower than Niacin-TR) toward hepatotoxicity. As such, this would need to be respected for both NAM-TR (or a constant supply as within low dose administered throughout the day) and with NR itself it would seem.

 

[VERITAS INCORRUPTUS]

This sheds some pertinent insfight on the role of NAMPT and other dynamics of these pathways, especially as regards mitochondrial NAD+:

http://www.alzforum....tochondrial-nad

 

One thing perhaps to be taken away at this point may be to discern if the speculation that NR may be not much superior to NAM/R-TR than certainly a more economical means to achieve the dynamic involved is within a NAM/R-TR formulation or similar administration that would result in a similar dynamic.  Obviously one can as well add Niacin to some degree and manner that would seem to balance an optimum supplementation without pushing into territory engendering potential hepatotoxicity.

 

NAD+ administration, particularly sub-L, i.n., or other optimized method to achieve a sound bioavailable format may as well be of some merit within the scope of an optimized 'stack' protocol.

 

As well, 'MitoNAD+' anyone

 

Is this making sense?

Edited by VERITAS INCORRUPTUS, 11 November 2014 - 09:14 PM.

[mikey]

 

Time Release:
Mikey says that the studies showing the negative effects of Time Release Niacin are a hatchet job by Big Pharma to kill competition to statins. ???

 

Mmmmm, no... But feel free to try. One liver more or less, who cares?

I guess what Mikey wanted to say is that some studies using Time Release Niacin were meant to make niacin look bad BECAUSE OF THE KNOWN TOXIC EFFECTS OF TIME RELEASE NIACIN!!! It's the immedate release stuff that is the safe option!

 

My memory is a 'bit' sketchy but if I recall correctly the problem arises from getting the balance of all the B vitamins out of whack and has to do with under methylation, but this has to be re examined.
I think adding all the B's in the correct ratios to a time release formula might fix the problem if it really exists.

 

No, certainly not. "The B's" don't have much to do with each other anyways with a few exceptions. They are just called that way for historical reasons. They are all water soluble, that's all. No, they won't prevent toxicity of time release niacin!

I think that NR is effective due to its slow breakdown in the gut. This results in a nice constant, steady supply of NAM and Ribose rather than spikes that give glycation issues in the case of Ribose. ie: its pointless having extra NAD+ for the short duration of the NA/NAM and Ribose spike only, with 'normal', sub optimal levels for the other 23 hours of the day.
Adding Ribose and Niacin (plus the other B's?) to your daily water supply is the cheapest way I could think of to get a semi constant supply.

 

Complete Bullshit. 
 
It would be nice if the more educated people would chip in with their thought on all this as I am just an amateur with an ever decreasing memory.  Especially now that I am off all supps.

 

If you want to suffer serious liver damage, feel free to use >2g of time release niacin. Good luck, you'll need it!

 

 

What I said was that a world authority on niacin, William Parsons, MD, who did the original research at Mayo Clinic that confirmed niacin's beneficial lipid effects told me that the McKenney study that said that time-released niacin "was a hatchet job paid for by Merck Labs" to kill the competition that niacin created - when they released their first statin.

 

I was just quoting a world authority on niacin's beneficial lipid effects. See his book - http://www.amazon.com/Cholesterol-Control-Without-William-Parsons/dp/0966256875

 

I've had communication with both he and the original niacin authority, Abram Hoffer, MD, PhD, who gave his niacin research to Dr. Parsons after Hoffer saw the beneficial lipid effects in his psychiatric patients that Hoffer treated with high dose niacin for schizophrenia. 

 

I've been taking high dose niacin - 1,000 - 3,000 mg a day for 47 of my 61 years, after getting out of the mental hospital and reading about Hoffer's work and starting on 3,000 mg/day at 14 years of age. It changed my life completely. I went from being a depressed, confused kid to having my brain working and being basically happy. I mean, it really changed my life and continues to have a positive effect.

 

So, I turned my biochemist father on to it and he found that niacin significally improved his memory.

 

My Dad was a math wiz and very analytical. So he created a formula with 425 mg a day that he sold and 8 years later Loriaux, et al. published a placebo-controlled study using my Dad's dose (141.7 mg t.i.d.= 425.1 mg/day) and showed that it improved short term memory test scores as much as 40%. 

 

This validated my Dad's product, but both I and my Dad continued to use 1,000 to 3,000 mg/day of some form of niacin since then. 

 

I’ve used both sustained-release and immediate-release niacin in high doses, and my liver function tests, including GGT and the liver isoenzyme of LDH, as well as transaminases have never shown liver problems – this is over a 47 year period of time.

 

Parsons and Hoffer both told me the liver problem thing with niacin was not exactly true.

 

Hoffer said that if he had a patient with liver problems that he would monitor them carefully, but he didn’t see the acute liver problems that have continued to plague slow-niacin’s reputation. Check his books on the link above out. He goes through the liver issue in his books. 

 

I've scanned some of the publications that appeared some years ago, but not really dug deeply into them, so I can't give a good analysis of the hepatotoxicity issue. But I haven't seen any problems in my own blood tests, so it is just another one of the many things to take some time studying... so many things and so little time...

 

Just my dos centavos!

[VERITAS INCORRUPTUS]

Muchas gracias por los dos centavos!

 

Within that, this is one reason why I ask as to what mechanism is this hepatotoxicity occurring, as methinks if such is valid this would be easily well understood and documented...further food for thought...

[Logic]

Time Release:
Mikey says that the studies showing the negative effects of Time Release Niacin are a hatchet job by Big Pharma to kill competition to statins. ???
 
Mmmmm, no... But feel free to try. One liver more or less, who cares?
I guess what Mikey wanted to say is that some studies using Time Release Niacin were meant to make niacin look bad BECAUSE OF THE KNOWN TOXIC EFFECTS OF TIME RELEASE NIACIN!!! It's the immedate release stuff that is the safe option!

Mikey has answered this for me and I was correct. (Thx Mikey)
 

My memory is a 'bit' sketchy but if I recall correctly the problem arises from getting the balance of all the B vitamins out of whack and has to do with under methylation, but this has to be re examined.
I think adding all the B's in the correct ratios to a time release formula might fix the problem if it really exists.
 
No, certainly not. "The B's" don't have much to do with each other anyways with a few exceptions. They are just called that way for historical reasons. They are all water soluble, that's all. No, they won't prevent toxicity of time release niacin!

I am here to learn. Thx for the heads up on the B's. Do you have any links to pertinent info?

As I said 'this has to be re examined' and I was wrong about the methylation angle.
It seems NA is probably metabolised by either conjugation (flush) or amidation (changed into Nicotinamide) in the liver, but then where does the extracellular NA come from???

"...The differences in hepatotoxicity among formulations are likely explained by two metabolic pathways.22 Conjugation of niacin with glycine to form nicotinuric acid is a low-affinity, high-capacity system, which leads to flushing. The second nonconjugative pathway involves multiple reactions that convert niacin to nicotinamide, and is a high-affinity, low-capacity system with greater potential for hepatotoxicity. IR products will quickly saturate the nonconjugative pathway, with most of the drug being metabolized by conjugation, resulting in increased flushing and a low incidence of hepatotoxicity. Slowly absorbed preparations (e.g., SR niacin) are metabolized primarily by the high-affinity nonconjugative pathway, resulting in less flushing but increased hepatotoxicity..."
http://www.uspharmac...ontent/c/36627/

 

 

I think that NR is effective due to its slow breakdown in the gut. This results in a nice constant, steady supply of NAM and Ribose rather than spikes that give glycation issues in the case of Ribose. ie: its pointless having extra NAD+ for the short duration of the NA/NAM and Ribose spike only, with 'normal', sub optimal levels for the other 23 hours of the day.
Adding Ribose and Niacin (plus the other B's?) to your daily water supply is the cheapest way I could think of to get a semi constant supply.
 
Complete Bullshit. 

Have you read the rest of the thread? The paper that says NR is slowly broken down to Nam and Ribose in the gut?
I have gone to great lengths to explain my theory in this thread and elsewhere. Take the time to properly explain your POV if you don't want people to think your reply more completely 'Bullshit' than my theory.
 

If you want to suffer serious liver damage, feel free to use >2g of time release niacin. Good luck, you'll need it!

I never had any intention of taking >2g of SR Niacin.
In fact the question at this point of the discussion was 'How much Ribose, Niacin and Nicotinamide to add to ones drinking water to get a similar effect to the slow release one would get from NR while minimising intracellular Nam?'

This assumption is further proof that you have not read the thread and thus cannot have an opinion that is less 'Bullshit' than my  theory.

[mikey]

You're quite welcome, Dolph!

 

Thanks Logic, for the great chemistry lesson!

 

It's interesting that I have never seen the comprehensive blood tests I do about twice a year show any liver abnormalities, but I take so many supplements that are hepatoprotectants, including C60oo since August, 2012, that I'm not typical.

 

Someone else who doesn't do what I do might experience SR niacin differently.

[Logic]

You're quite welcome, Dolph!
 
Thanks Logic, for the great chemistry lesson!
 
It's interesting that I have never seen the comprehensive blood tests I do about twice a year show any liver abnormalities, but I take so many supplements that are hepatoprotectants, including C60oo since August, 2012, that I'm not typical.
 
Someone else who doesn't do what I do might experience SR niacin differently.

 

I don't know if its as much a lesson as a misdirection Mikey.
If all the NA one takes is amided to Nicotinamide or conjugated to nicotinuric acid; where the hell does the extracellular NA that all the researchers are talking about come from???

Note that the author says the explanation is likely, not proven.

Other authors are saying the production of NAD is associated with hepatoxicity. WTF!?!?
Apparently NAD causes oxidative stress on the liver by inhibiting
β-oxidation.
http://www.pharmacol...-hepatotoxicity

Cursory searches don't even have NAD and β-oxidation in the same paper!?

Edited by Logic, 13 November 2014 - 11:53 AM.

[Bryan_S]

Logic, I think this is what we were looking for and it looks like the reaction goes both ways.  Is this right, looks like nicotinamide riboside (NR) can be split and recombined. Any of you biochemists have any insights?

 

REACTION: R10046 URL

 

nicotinate D-ribonucleoside ribohydrolase

 

Nicotinate D-ribonucleoside + H2O <=> Nicotinate + D-Ribose

 

"The chemical reaction in the form of an equation. The reaction is assumed to be reversible and reactants (substrates and products) are separated by '<=>'. Each compound in the left or the right side is separated by ' + '. There may be a coefficient before the compound name."

 

 

[Logic]

I think the biochemists may be ignoring this thread as they have already read this one:
http://www.longecity...ols-true-target

The info there, especially by geddarkstorm, covers almost all the questions we are asking here and makes me feel kinda stupid for re-hashing old news. I wish I had been directed to it earlier.

[Bryan_S]

2009 really, not sure we're re-hashing their topic but I will agree they touched on some similar material and it is a thought provoking thread. I think we have taken a slightly different path for a different if not similar purpose. (Are Other Precursors as Effective in Increasing NAD+ as NR?) I'm reviewing the thread now but we're not trying to improve the effects of Resveratrol. The Nampt feedback loop controls aspects of what we are seeking but I feel there is less attention given to Resveratrol today than when this thread was active.

[Vastmandana]

Duarte, in one of his vids, feels the rate limiting impact of Resveratrol might be NAD+ levels, so I am doing a couple grams of micronized/day...yes, a bit off topic but...

 

I am curious, as I've ordered both Ribose and niacinamide... will Ribose theoretically work equally well with Niacin? I like the burn and would rather avoid any Sirt-1 suppression issues... (did I say that rights?  I feel so ignorant...old brain already overflowing!)

As an aside, I'll try growing Gynostemma pentaphyllum this winter as an AMPK activator...seems easy to grow.  

Edited by Vastmandana, 17 November 2014 - 01:12 AM.

[VERITAS INCORRUPTUS]

For NAD+ enhancement, niacinamide and ribose (less important to supplement, as may not be rate limiting as to normal endogenous supply) are the way to go, within best taking low dose through the day.

In the end it all goes through niacinamide, within this pathway, so niacin in the end will only be effectively yielding niacinamide indirectly for your purposes anyway.  With some liver stress as to the amidation so required (though as long as it is not SR it will not overburden the liver in any significant way; this is why as so explained prior only SR will yield a constant taxation of this high affinity/low capacity pathway, if such is at all accurate - RE: http://www.pharmacol...-hepatotoxicity )

 

Within that, they key is as well not to overload the conversion pathway to NAD+ as that will engender greater levels of niacinamide available for SIRT1 inhibition - obviously undesirable.

(to clarify if any confusion here, anything that gets one to excessive niacinamide, which has to happen to get to NAD+, will engender the SIRT1 inhibition)

 

The way to 'top it off' effectively, above this, within saturation of the pathway, and the need to avoid the aforementioned excessive levels of NAM, is to supplement with pure NAD+ (I think I heard someone say this before )

This is best done in a manner that bypasses the gut, as NAD+ may survive the gut to some degree (it does have some reasonably stability in acidic media), but certainly bypassing the gut, and first pass as well, would be most optimal.  That leaves injections (best, but less viable for most), intranasal, and subligual/buccal (as prior stated).  

 

NR in essence as to supplemental use is simply overpriced SR-niacinamide/(ribose) (as likely the ribose is in adequate supply, though perhaps it assists).  It is as seemed noted prior what Logic pointed out fully hydrolyzed in a SR fashion, so all seems pretty simple as to that. A lot to pay for sustained release of very inexpensive substrates.

 

Notably, I am aware of an entity that can make an orally bioavailable SR niacinamide/ribose/NAD+ product, if enough people have some heavy interest.  This entity already has a proprietary established technology to achieve this.  Likely be quite a bit more of course that just going by the aforementioned recommendation, albeit somewhat more effective and easy for compliance.

 

Anyway, again it appears NR itself can be effectively (and far more economically) mimicked by SR-niacinamide, or simply taking niacinamide throughout the day, perhaps best with some ribose, which certainly could not hurt, is cheap and available enough - a 'better safe than sorry' means to ensure an adequate supply.

 

Stated all this more or less before, but reiterating, in case anyone wishes to make a clear argument against it.

Edited by VERITAS INCORRUPTUS, 17 November 2014 - 03:08 AM.

[Bryan_S]

Leonard Guarente speaks directly to the NAD absorption issue @ 5:05 but the entire piece is worth watching.

 

Only 2 precursors are mentioned that give that preform the proper sirtuin activation and rise NAD levels.

 

 

If you watch the entire Robert Kane Pappas series you get a sense of why we've arrived at NR and why finding another substitute may be futile. 

 

 

 

 

 

Edited by Bryan_S, 17 November 2014 - 02:56 AM.