20 replies to this topic

[health_nutty]

We all know that niacinamide inhibits SIRT1. Do we know anything about:
niacinamide ascorbate or nicotinamide adenine dinucleotide ?

I'm assuming the niacinamide ascobate has the same problems as niacinamide unless someone tells me different.

[krillin]

NAD doesn't, but according to Aubrey a supplement would get reduced to NADH in the bloodstream.

[lucid]

Nicotinic Acid. If you don't like the flush, try time released version (niaspan).

[inawe]

Nicotinamide riboside. May be the only vitamin precursor supporting neuronal NAD+ synthesis.
I'll like to know where to get it from.

[maxwatt]

Nicotinamide riboside. May be the only vitamin precursor supporting neuronal NAD+ synthesis.
I'll like to know where to get it from.

I think it has to be custom synthesized at this point.

I wonder how Inositol Hexanicotinate works as a no-flush niacin substitute? Does it have the same beneficial effects on cholesterol levels? I dubt that it is a sirtuin agonist.

[inawe]

Being about Niacin like supplements, this thread can be connected to the Resveratrol vs. CR saga, where NAD+ plays a very important role.
RSV is being presented (and sold) as a CR mimetic. I don't think it is. In CR, as compared to "normal" diet, less NAD+ is being used in processing glucose. The spared NAD+ is utilized in deacetylation and other life extending processes.
In contrast, by taking RSV, one doesn't spare or increase the amount of NAD+. What RSV does is to lower the Michaelis constant for deacetylation. It probably works on other pathways also.
CR mimetics should be based on NAD+ precursors or agonists. According to the latest edition of "The Complete Idiot's Guide to Deacetylation", the Sirtuins act as facilitators (enzymes). But NAD+ are needed to close the deal.
The best candidate today for a NAD+ precursor and Sirtuin promoter might be Nicotinamide riboside, a member of the Niacin family. A lot of research has been done by the Brenner group:
PMIDs: 18258590, 17914902, 17482543, 17161604, 15137942 ...
Directly from the horse's pen (or computer):
Cell. 2007 May 4;129(3):473-84.
Nicotinamide riboside promotes Sir2 silencing and extends lifespan via Nrk and Urh1/Pnp1/Meu1 pathways to NAD+.Belenky P, Racette FG, Bogan KL, McClure JM, Smith JS, Brenner C.
Departments of Genetics and Biochemistry and the Norris Cotton Cancer Center, Dartmouth Medical School, Rubin 733-HB7937, Lebanon, NH 03756, USA.

Although NAD(+) biosynthesis is required for Sir2 functions and replicative lifespan in yeast, alterations in NAD(+) precursors have been reported to accelerate aging but not to extend lifespan. In eukaryotes, nicotinamide riboside is a newly discovered NAD(+) precursor that is converted to nicotinamide mononucleotide by specific nicotinamide riboside kinases, Nrk1 and Nrk2. In this study, we discovered that exogenous nicotinamide riboside promotes Sir2-dependent repression of recombination, improves gene silencing, and extends lifespan without calorie restriction. The mechanism of action of nicotinamide riboside is totally dependent on increased net NAD(+) synthesis through two pathways, the Nrk1 pathway and the Urh1/Pnp1/Meu1 pathway, which is Nrk1 independent. Additionally, the two nicotinamide riboside salvage pathways contribute to NAD(+) metabolism in the absence of nicotinamide-riboside supplementation. Thus, like calorie restriction in the mouse, nicotinamide riboside elevates NAD(+) and increases Sir2 function.
PMID: 17482543 [PubMed - indexed for MEDLINE]

I was unable to locate an affordable source of Nicotinamide Riboside. Somebody with a better fluency of Chinese than mine, should tell them to start making it (cheap).

PS: Charles Brenner is a member of the Sirtris board. Nicotinamide Riboside could be the ace in the sleeve of Sirtris. To deacetylate us all the way to the bank.

[maxwatt]

Nicotine riboside is found in milk; it may be classified as a vitamin. I hope it doesn't get flagged as an experimental drug by the FDA, as happened to pyridoxamine . You Canadians can still get it, as well as necessary surgeries without going bankrupt if you don't mind waiting.

Does anyone have any idea what an effective dose of Nicotine riboside might be? It seems to worked by the same mechanism Benagene was purpoted to use, increasing the NAD/NADT ratio.

[inawe]

Yes, Nicotinamide Riboside is a vitamin and found in milk. But, there is a patent application for "Nicotinamide riboside and analogues thereof". #20060229265, by the Sinclair gang, who else?
I stopped looking. I'll be very upset if I discover they patented my dog.

[inawe]

Yes, Nicotinamide Riboside is a vitamin and found in milk. But, there is a patent application for "Nicotinamide riboside and analogues thereof". #20060229265, by the Sinclair gang, who else?
I stopped looking. I'll be very upset if I discover they patented my dog.

On the other hand, this could be good news. The Chinese might see this patent application as a green light to start making the stuff.

[maxwatt]

Yes, Nicotinamide Riboside is a vitamin and found in milk. But, there is a patent application for "Nicotinamide riboside and analogues thereof". #20060229265, by the Sinclair gang, who else?
I stopped looking. I'll be very upset if I discover they patented my dog.

On the other hand, this could be good news. The Chinese might see this patent application as a green light to start making the stuff.

Some of hte Chinese manufacturers are working on synthesis, and trying to gauge the size of the market before proceeding. I hope to get my hands on a sample in the next few weeks. I expect the price to start high, and come down as they recover costs and competitors pop up.

In the meantime, Benagene is supposed to have a similar effect on the NAD/NADH ratio; it might be worth a try.

[inawe]

Yes, Nicotinamide Riboside is a vitamin and found in milk. But, there is a patent application for "Nicotinamide riboside and analogues thereof". #20060229265, by the Sinclair gang, who else?
I stopped looking. I'll be very upset if I discover they patented my dog.

On the other hand, this could be good news. The Chinese might see this patent application as a green light to start making the stuff.

Some of hte Chinese manufacturers are working on synthesis, and trying to gauge the size of the market before proceeding. I hope to get my hands on a sample in the next few weeks. I expect the price to start high, and come down as they recover costs and competitors pop up.

In the meantime, Benagene is supposed to have a similar effect on the NAD/NADH ratio; it might be worth a try.

At pubmed they never heard of Benagene. Benagene website refers to a National Institute of Aging site. 19 "Compounds In Testing" are listed. I guess the one related to Benagene is Oxaloacetic acid. But there is no data at that site. Went back to pubmed and entered "oxaloacetic acid nad". Nothing useful came up. So at this point I don't know if Benagene is good for anything (except making somebody some money).

[rfarris]

...necessary surgeries without going bankrupt...

Sorry, this is off-topic, but I recently saw the bills going to the insurance company for my 'necessary surgery,' and it was $125k. $100k was a three-day stay in the hospital. $25k to the surgeon. $100k for three days in the hospital. Holy cow. No insurance; no surgery.

[inawe]

NAD doesn't, but according to Aubrey a supplement would get reduced to NADH in the bloodstream.

Not if you snort it:
Front Biosci. 2007 Jan 1;12:2728-34.
Intranasal administration with NAD+ profoundly decreases brain injury in a rat model of transient focal ischemia.Ying W, Wei G, Wang D, Wang Q, Tang X, Shi J, Zhang P, Lu H.
Department of Neurology, University of California at San Francisco and San Francisco Veterans Affairs Medical Center; 4150 Clement Street, San Francisco, CA 94121, USA. shine863@gmail.com

Excessive poly(ADP-ribose) polymerase-1 (PARP-1) activation plays a significant role in ischemic brain damage. Increasing evidence has supported the hypothesis that PARP-1 induces cell death by depleting intracellular NAD+. Based on our in vitro finding that NAD+ treatment can abolish PARP-1-mediated cell death, we hypothesized that NAD+ administration may decrease ischemic brain injury. In this study, we used a rat model of transient focal ischemia to test this hypothesis. We observed that intranasal NAD+ delivery significantly increased NAD+ contents in the brains. Intranasal delivery with 10 mg/kg NAD+ at 2 hours after ischemic onset profoundly decreased infarct formation when assessed either at 24 or 72 hours after ischemia. The NAD+ administration also significantly attenuated ischemia-induced neurological deficits. In contrast, intranasal administration with 10 mg/kg nicotinamide did not decrease ischemic brain damage. These results provide the first in vivo evidence that NAD+ metabolism is a new target for treating brain ischemia, and that NAD+ administration may be a novel strategy for decreasing brain damage in cerebral ischemia and possibly other PARP-1-associated neurological diseases.

PMID: 17127275 [PubMed - indexed for MEDLINE]

[dannov]

I actually enjoy the flush from Nicotinic Acid. Use the GNC brand, not that it really matters.

[Logic]

Nicotinamide riboside. May be the only vitamin precursor supporting neuronal NAD+ synthesis.
I'll like to know where to get it from.

Here:
http://hpnformula1.com/products/nr/

from:
https://chromadex.co...nts/NIAGEN.html
Question: How do you get a patent on something found naturally in milk, beer and Whey?

found after reading this:
http://www.marketwat...acin-2013-06-27

Thx for getting me interested.

Edited by Logic, 21 December 2013 - 01:44 PM.

[Gerrans]

If you think niacinamide (and niacin converts to niacinamide) accelerates aging, just do not supplement any. I rather doubt it does accelerate aging, because niacin advocates such as Kaufman, Hoffer, and Pauling lived to a ripe old age.

Maybe niacinamide affects aging in a regulatory way--something has to make sure we do not live for ever, after all.

Edited by Gerrans, 21 December 2013 - 05:48 PM.

[Castiel]

Any idea of what the dose response inhibition is?   Most protein, meal, multivitamins, etc have a few tens of mgs of niacinamide.   Which often equates to 100%rda.  Is this enough to substantially interfere with sirtuin activity or would you need megadosing with 100s of mgs.   Supposedly optimal activity with Riboside is achieved at several grams, I'd be very surprised if 10 or 20mg of niacinamide can counter gram doses of riboside.

Edited by Castiel, 31 May 2014 - 02:43 AM.

[blood]

Any idea of what the dose response inhibition is?   Most protein, meal, multivitamins, etc have a few tens of mgs of niacinamide...

 
Yes. Looking on iherb, I couldn't find a single B-complex which used niacin over niacinamide. (Some have a mix of the two, typically with higher amounts of niacinamide).
 

Which often equates to 100% rda.  Is this enough to substantially interfere with sirtuin activity or would you need megadosing with 100s of mgs.   Supposedly optimal activity with Riboside is achieved at several grams, I'd be very surprised if 10 or 20mg of niacinamide can counter gram doses of riboside.

 
Good questions.

[Darryl]

Most of the work on nicotinamide inhibition of sirtuins is on yeast Sir2. I've found little on systemic dose response for inhibition in mice or humans, just in vivo dosing at huge levels (200 mg/kg) to inhibit all sirtuin/PARP/CD38 activity in mice and in vitro studies. For a rough measure, 100 microM NAD+ and 100 microM nicotinamide had 35% less Sirt1 activation in neurons than just 100 microM NAD+, while in another study, 2.5 mM nicotinamide is about half-maximal inhibition, judging by NAD levels in beta cells. 

 

In humans a 2.5 mg nicotinamide/kg dose yields a plasma peak of about 25 microM, declining to a baseline of a 1-2 microM. Personally, I don't think the RDA comparable amounts in vitamins or enriched flour is enough to make much of a difference in the ratio of nicotinamide to NAD+ (and hence Sirtuin/PARP/CD38 activity).

 

 

 

As you'll note from these key papers on nicotinamide and sirtuin inhibition, the inhibition (particularly of PARP, which produces toxic poly-(ADP ribose) accumulations) can be a good thing sometimes.

 

Bitterman, K. J., Anderson, R. M., Cohen, H. Y., Latorre-Esteves, M., & Sinclair, D. A. (2002). Inhibition of silencing and accelerated aging by nicotinamide, a putative negative regulator of yeast sir2 and human SIRT1. Journal of Biological Chemistry, 277(47), 45099-45107.

Virág, L., & Szabó, C. (2002). The therapeutic potential of poly (ADP-ribose) polymerase inhibitors. Pharmacological reviews, 54(3), 375-429.

Klaidman, L., Morales, M., Kem, S., Yang, J., Chang, M. L., & Adams Jr, J. D. (2003). Nicotinamide offers multiple protective mechanisms in stroke as a precursor for NAD+, as a PARP inhibitor and by partial restoration of mitochondrial function. Pharmacology, 69(3), 150-157.

Schmidt, M. T., Smith, B. C., Jackson, M. D., & Denu, J. M. (2004). Coenzyme specificity of Sir2 protein deacetylases: implications for physiological regulation. Journal of Biological Chemistry, 279(38), 40122-40129.

Grubisha, O., Smith, B. C., & Denu, J. M. (2005). Small molecule regulation of Sir2 protein deacetylases. Febs Journal, 272(18), 4607-4616.

Avalos, J. L., Bever, K. M., & Wolberger, C. (2005). Mechanism of sirtuin inhibition by nicotinamide: altering the NAD+ cosubstrate specificity of a Sir2 enzyme. Molecular cell, 17(6), 855-868.

Liu, D., Gharavi, R., Pitta, M., Gleichmann, M., & Mattson, M. P. (2009). Nicotinamide prevents NAD+ depletion and protects neurons against excitotoxicity and cerebral ischemia: NAD+ consumption by SIRT1 may endanger energetically compromised neurons. Neuromolecular medicine, 11(1), 28-42.

Lee, S. J., Choi, S. E., Jung, I. R., Lee, K. W., & Kang, Y. (2013). Protective effect of nicotinamide on high glucose/palmitate-induced glucolipotoxicity to INS-1 beta cells is attributed to its inhibitory activity to sirtuins. Archives of biochemistry and biophysics, 535(2), 187-196.

Haar, C. V., Peterson, T. C., Martens, K. M., & Hoane, M. R. (2013). The use of nicotinamide as a treatment for experimental traumatic brain injury and stroke: a review and evaluation. Clinic Pharmacol Biopharmaceut S, 1, 2.

[Mr.No]

Unless you're on severe calorie restriction, Sirt1 is by default inhibited. So i don't know what's the point of the question? You can eat/take what ever you want.

[Castiel]

Unless you're on severe calorie restriction, Sirt1 is by default inhibited. So i don't know what's the point of the question? You can eat/take what ever you want.

 

Methionine restriction as well as glycine supplementation are said to be partial CR dietary mimetics.   There are also substances that appear to activate sirtuins such as resveratrol, pterostillbene, quercetin, fisetin, theaflavin(I think?).   Also as mentioned nicotinamide riboside in high enough doses appears to alter NAD/NADH ratio and affect sirtuin activity, making it another CR mimetic.  In yeast 75% approx lifespan extension has been achieved with riboside, iirc.

 

One can also practice moderate CR quite easily.

 

There are mutants that don't respond to CR, iirc.   So there are things that can apparently abolish its benefits.  In light of the myriad ways to partially mimic CR, and CR itself, it is important to know if some chemical could neutralize its benefits and at what dose.