Niacinamide/nicotinamide
geddarkstorm 14 Dec 2008
I was of course only talking about its ability to activate sirt1. The studies you pointed to, show fysiological benefits. And I know there are numerous studies that show benefits in other areas as well. But should we somehow automatically attribute it to to sirt1 activity? Is there any study besides the dutch one that show intracellular activation of sirt1 in mammals? If so please let me know.
Yes indeed there is. Here. Even makes it plain right in the title. If you get rid of Sirt1, resveratrol does nothing. If you block Sirt1's ability to deacetylate the PGC-1alpha gene (which is actually what turns on the gene, whereas usually deacetylation turns off genes), then resveratrol does nothing. Apparently, from this data, all of resveratrol's metabolic and gene enhancing effects are mediated through Sirt1 and PGC-1alpha by extension, as far as the study could detect in vivo in mice.
Edited by geddarkstorm, 14 December 2008 - 09:34 PM.
100YearsToGo 14 Dec 2008
Well, not trying to put a bummer on everything but:
" Resveratrol was able to stimulate the activity of SIRT1 in HT29 cells by 1.65-fold. This relatively low stimulation of intracellular SIRT1 activity as compared to the effects of resveratrol on the recombinant protein, points to an effectivemetabolism or low uptake of resveratrol in HT29 cells"
1.65 fold. Is this sufficient to work agains niacinamide? Remember these are colon cells that in vivo would be in direct contact with resv. In other cells the activation could be much lower, as less resv would reach them.
Increasing NAMPT/PBEF enzyme may be a better approach as it appears to be the rate limiting factor for NAM NAD conversion.
http://www.jbc.org/c...ct/279/49/50754
"Increased dosage of Nampt, but not Nmnat, increased the total cellular NAD level and enhanced the transcriptional regulatory activity of the catalytic domain of Sir2 recruited onto a reporter gene in mouse fibroblasts."
That approach would more closely mimmic calorie restriction. It is probaly sacrilege to say it around here but I'm not really convinced on resveratrol in vivo.
Don't let that one study fool you. Both the cell line it chose, and its in vitro conditions are suspect. Not to mention both quercetin and resveratrol have a different effect on cancer cells (kills them) verses healthy cells (protects them from necrosis and apoptosis; only once the death signal in a cell is activated does the game change, such as is the case with cancer). The effects of resveratrol in vivo are well established by numerous studies. Here's a post of mine that does a break down of several of those studies in a short synopsis.
So no, you have every right to be convinced about resveratrol's effects in vivo as they are very well documented and supported over numerous studies (not to mention proven to be the chemical in red wine that gives such a benefit to drinkers, so it works great in vivo in humans too, especially paired with quercetin and potentially other unknowns). This also proves that resveratrol beats out niacinamide to activate sirtuins, freeing them from niacinamide inhibition under physiological, in vivo, conditions.
However, if we could also get a PBEF stimulator going, then it paired with resveratrol would be much more effective and could gives us some amazingly great benefits.
I was of course only talking about its ability to activate sirt1. The studies you pointed to, show fysiological benefits. And I know there are numerous studies that show benefits in other areas as well. But should we somehow automatically attribute it to to sirt1 activity? Is there any study besides the dutch one that show intracellular activation of sirt1 in mammals? If so please let me know.
Great study. It makes a very good case of resveratrol activating sirt1 in a way that effects fysiological benefits similar to cr. I'm impressed.
Brainbox 04 Jan 2009
This was still on my to-do list. What do you all think? My first conclusion is that the "TOA being immune suppressive" issue might be a bit exaggerated indeed. But I had no time to find original studies.I would consider the TOA free cat's claw extract as a potentially useful adjunct to antibiotics but I would not depend on them alone -- they are also light on proven evidence of their efficacy in Lyme Disease compared to traditional antibiotics.
Cat's claw TOA - POA Controversy.
FunkOdyssey 07 Jan 2009
Nicotinamide Riboside definitely seems like the most promising variety of niacin, the problem is finding a source. I don't know why supplement manufacturers have yet to jump on this train. If any are reading, get on it.
Where is Nicotinamide Riboside? Why haven't we been inundated with Chinese chemical company spam offering it? Should I assume that supplement manufacturers don't like money anymore? I've never seen an opportunity left on the table this long.
rwac 07 Jan 2009
Nicotinamide Riboside definitely seems like the most promising variety of niacin, the problem is finding a source. I don't know why supplement manufacturers have yet to jump on this train. If any are reading, get on it.
Where is Nicotinamide Riboside? Why haven't we been inundated with Chinese chemical company spam offering it? Should I assume that supplement manufacturers don't like money anymore? I've never seen an opportunity left on the table this long.
Is Nicotinamide Riboside similar to Nicotinic Acid Riboside ?
It seems that Sigma Aldrich used to manufacture Nicotinic Acid Riboside.
They don't seem to anymore though.
http://www.sigmaaldr...c..._KEY&F=SPEC
Edited by rwac, 07 January 2009 - 11:08 PM.
100YearsToGo 08 Jan 2009
Maybe the whole sirt1 thing has been overrated in mammals?
The obsession with Sirt1 started with the discovery that CR activated Sirt2 (yeast). The mammal homolog Sirt1 was then proposed as a target for life extension. However some studies show that CR does not upregulate Sirt1 in all tissues and that in fact metabolic changes that influence NAD and NADH may occur upstream of sirt1:
"These findings suggest that SIRT1 activity in the liver may decrease in CR, opposite to what occurs in the muscle and the WAT. Very similar changes in NAD and NADH were observed in the same tissues derived from whole-body SIRT1 KO mice (Fig. 1B), indicating that diet-induced metabolic changes that influence NAD and NADH occur upstream of SIRT1, similar to what was observed in the case of yeast"
http://www.pubmedcen...i?artid=2492662
Nicotinamide on the other hand is needed throughout the body. Some people think that depleting nicotinamide in the body would be good for Sirt1 and longevity. You could actually do this with nicotine supplementation. Nicotine competes with nicotinamide for the binding sites in the enzymes needed for the absorption of nicotinamide, thereby lowering the amounts of nicotinamide available to cells. This however results in dimished mitochondria function. Not good for life extension or life quality.
I'm still taking 500mg Nicotinamide a day. That is guaranteed to increase the NAD/NADH ratio.
Michael 18 Jan 2009
[Nicotinamide] is not necessarily the enemy of resveratrol:
Comment by: David Sinclair
Submitted 11 November 2008
One must be careful when calling nicotinamide an "inhibitor" in this experiment. While it is true that our lab showed that nicotinamide is a direct inhibitor of SIRT1 enzyme, it is also a precursor of NAD+, and NAD+ is a co-substrate (i.e., activator) of SIRT1.
In vivo, there is an abundant enzyme called Nampt in cells and serum that initiates the conversion of nicotinamide to NAD+. Therefore we should entertain the possibility that nicotinamide is activating SIRT1 in vivo, not inhibiting it. This would fit with other papers showing that SIRT1 is neuroprotective.
Well, the investigators did take a pretty good stab at testing this: they crossed the triple-transgenic AD mice with SIRT1+/- mice, yielding animals with the same production of aggregate-prone human tau and Abeta but only half the SIRT1 production (ie, genetic "SIRT1 inhibition"), and found the same highly selective depletion of the Thr231-phospho-tau that was observed with high-dose nicotinamide. That seems to be, if anything, stroinger evidence that this effect was mediated by SIRT1 inhibition. There were other effects also associated with nicotinamide supplementation on tubule-associated proteins that were not mediated by SIRT1, but depletion of a toxic tau species seems likely to have played a considerable role in the observed neuroprotection.
It's worth noting that this is not the first time that inhibiting SIRT1 has been found to have neuroprotective effects, although the previous study wasn't exactly a smoking gun (it protected cultured neurons from oxidative stress, which is a dime-a-dozen finding).(1)
Except for the teensy tinsy matter that it doesn't actually provide any lifespan benefits in normal, nonobese, well-cared-for animals (1) ...Great study. It makes a very good case of resveratrol activating sirt1 in a way that effects fysiological benefits similar to cr.
-Michael
1. SirT1 inhibition reduces IGF-I/IRS-2/Ras/ERK1/2 signaling and protects neurons.
Li Y, Xu W, McBurney MW, Longo VD.
Cell Metab. 2008 Jul;8(1):38-48.
PMID: 18590691 [PubMed - indexed for MEDLINE]
2. Pearson KJ, Baur JA, Lewis KN, Peshkin L, Price NL, Labinskyy N, Swindell WR, Kamara D, Minor RK, Perez E, Jamieson HA, Zhang Y, Dunn SR, Sharma K, Pleshko N, Woollett LA, Csiszar A, Ikeno Y, Le Couteur D, Elliott PJ, Becker KG, Navas P, Ingram DK, Wolf NS, Ungvari Z, Sinclair DA, de Cabo R.
Resveratrol Delays Age-Related Deterioration and Mimics Transcriptional Aspects of Dietary Restriction without Extending Life Span.
Cell Metab. 2008 Aug;8(2):157-68.
PMID: 18599363 [PubMed - as supplied by publisher]
geddarkstorm 19 Jan 2009
Tau pathology is quite complex. Why does it occur only very late in life, after reproductive age has come and gone, as a consequence of neurodegeneration? CR has been shown to activate Sirt1, though you are right that this activity can be modulated differently in different tissue types, but the fact is, activation of Sirt1 is a neuroprotectant that fights Alzheimer's as shown in other studies, including this one. So I'm skeptical of that study, Michael, especially since Sirt1 was not knocked out, and since numerous other studies have shown directly the opposite. In fact, here's a study, Michael, that shows that Sirt1 is greatly reduced in Alzheimer's patience, but not normal disease free humans of the same age group, and that Sirt1 loss correlates strongly to tau pathology and death, not the other way around. An even stronger counter to that triple transgenic study in mice which was using human proteins in the mouse brain - and which challenges that system as being an accurate model for Alzheimer's studies.
Also, we know, since normal in vivo concentrations of niacinamide are always high enough to mostly inhibit Sirt1, that Sirt1 is turned on by naicinamide processing into NAD by Nampt. So even additions of lots of niacinamide wouldn't inhibit Sirt1 anymore than it always is, but if Nampt is activated, would actually serve to turn on Sirt1 instead. As stated by 100YearsAgo, this is an upstream event that relieves inhibition of Sirt1 by processing niacinamide. This is due to activation of Nampt switching the cellular energy state to an increased ratio of NAD/NADH, and NAD/niacinamide. Here's a nice overview connecting all these ideas. Obviously, activating Nampt would be expected to be highly beneficial, and apparently AMPK is one such activator. Anything that activates AMPK would be expected to turn on Nampt, and in turn activate Sirt1 - and Sirt1 will respond in a tissue specific manner, which is why it's activity is not globally the same (which is a good thing).
On a final note, it's also important to remember there are more sirtuins than Sirt1 in mammals and humans, all the way through Sirt4 at least, and all have similar functions. Though Sirt1 is the one primarily looked at, these others are surely playing rolls that might confound the results from CR and other experiments. For instance, here's a paper showing Nampt activity upregulating Sir(t)2 in mice fibroblasts.
To answer FunkOdyssey and rwac: nicotinamide riboside, or nicotinic acid riboside will be rapidly converted to niacinamide/niacine in the gut prior to uptake, and in fact, this conversion is the rate limiting step in niacinamide/niacine absorption. So, taking the riboside form would be only different from taking straight niacinamide in that it'll be absorbed slower, as niacinamide, into your blood stream.
Edit: Oh, and Michael, that second paper you quoted does show resveratrol significantly increasing the life span of every other day feeding mice, which is a curious result, and it did increase standard feeding mouse life span though just beneith the threshold of significance. At any rate, it proves the issue is more complex than any single molecule alone can address, as is expected, and resveratrol is just one tool in the tool shed.
Edited by geddarkstorm, 19 January 2009 - 07:38 PM.
FunkOdyssey 10 Feb 2009
To answer FunkOdyssey and rwac: nicotinamide riboside, or nicotinic acid riboside will be rapidly converted to niacinamide/niacine in the gut prior to uptake, and in fact, this conversion is the rate limiting step in niacinamide/niacine absorption. So, taking the riboside form would be only different from taking straight niacinamide in that it'll be absorbed slower, as niacinamide, into your blood stream.
But -- what if NAD is absorbed sublingually? The Now NAD product is a lozenge that you can dissolve under your tongue. If you absorb the NAD directly through the lining of the mouth, wouldn't this change the picture?
http://www.iherb.com...c...id=711&at=0
neogenic 10 Feb 2009
I asked that very question a few months ago. I love that NOW product and it blows away NADH for me. I take 2 sublinguals of NAD+ and 2 5mg methylcobalamin sublinguals (and I've dosed the two separately and love them both) together and it is awesome for a natural energy lift. Very noticeable. I quite enjoy that "stack".To answer FunkOdyssey and rwac: nicotinamide riboside, or nicotinic acid riboside will be rapidly converted to niacinamide/niacine in the gut prior to uptake, and in fact, this conversion is the rate limiting step in niacinamide/niacine absorption. So, taking the riboside form would be only different from taking straight niacinamide in that it'll be absorbed slower, as niacinamide, into your blood stream.
But -- what if NAD is absorbed sublingually? The Now NAD product is a lozenge that you can dissolve under your tongue. If you absorb the NAD directly through the lining of the mouth, wouldn't this change the picture?
http://www.iherb.com...c...id=711&at=0
100YearsToGo 11 Feb 2009
The cell membrane can take up extracellular NAD. So sublingually you probably have a good chance untill the liver breaks it up.
http://www.jbc.org/c...act/283/10/6367
Once in the cell it could be used by cell organelles. Mainly the mitochondria does not produce NAD and NAD must be transported into it. So the boost of energy feeling could be explained that way.
Edited by 100YearsToGo, 11 February 2009 - 12:58 AM.
geddarkstorm 11 Feb 2009
It's nice to see navigators revive threads. Good job.
The cell membrane can take up extracellular NAD. So sublingually you probably have a good chance untill the liver breaks it up.
http://www.jbc.org/c...act/283/10/6367
Once in the cell it could be used by cell organelles. Mainly the mitochondria does not produce NAD and NAD must be transported into it. So the boost of energy feeling could be explained that way.
Hm, yes, using a lozenge greatly increases the chance of taking in actual NAD without it being stripped down to niacinamide first, it seems. Great catch, FunkOdyssey. Makes this product and system actually sound interesting and useful, and not a gimmick. Hopefully NAD taken into the system this way will be able to disseminate throughout the body before breakdown. If so, then we would expect it to effectively stimulate Sirt1 activity - as long as the NAD dose from the lozenge was high enough to push the NAD/niacinamide ratio over the tipping point. You wouldn't want to take this at the same time as a niacinamide containing pill.
zawy 17 Feb 2009
100YearsToGo 17 Feb 2009
It's nice to see navigators revive threads. Good job.
The cell membrane can take up extracellular NAD. So sublingually you probably have a good chance untill the liver breaks it up.
http://www.jbc.org/c...act/283/10/6367
Once in the cell it could be used by cell organelles. Mainly the mitochondria does not produce NAD and NAD must be transported into it. So the boost of energy feeling could be explained that way.
Hm, yes, using a lozenge greatly increases the chance of taking in actual NAD without it being stripped down to niacinamide first, it seems. Great catch, FunkOdyssey. Makes this product and system actually sound interesting and useful, and not a gimmick. Hopefully NAD taken into the system this way will be able to disseminate throughout the body before breakdown. If so, then we would expect it to effectively stimulate Sirt1 activity - as long as the NAD dose from the lozenge was high enough to push the NAD/niacinamide ratio over the tipping point. You wouldn't want to take this at the same time as a niacinamide containing pill.
For the sporters. Not me.
Apparently you can combine this with moderate excercise to get a double whammy. Moderate exercise elevates NAD levels in the blood.
http://cat.inist.fr/...&cpsidt=1109643
Take your lozenge and get out for a short 5 minutes run.
Edited by 100YearsToGo, 17 February 2009 - 08:43 PM.
100YearsToGo 22 Feb 2009
To answer FunkOdyssey and rwac: nicotinamide riboside, or nicotinic acid riboside will be rapidly converted to niacinamide/niacine in the gut prior to uptake, and in fact, this conversion is the rate limiting step in niacinamide/niacine absorption. So, taking the riboside form would be only different from taking straight niacinamide in that it'll be absorbed slower, as niacinamide, into your blood stream.
But -- what if NAD is absorbed sublingually? The Now NAD product is a lozenge that you can dissolve under your tongue. If you absorb the NAD directly through the lining of the mouth, wouldn't this change the picture?
http://www.iherb.com...c...id=711&at=0
Be carefull. Extracellular NAD+ seems to affect the immune response. Cells seems to transport NAD outside the cell when under stress to enlist the immune system. I'm not sure yet if the immune system response to extracellular NAD is beneficial. It could be pro inflamation among others. Take a look at these two:
http://www.biochemj....849/3820849.pdf
and
http://www.pubmedcen...i?artid=2096762
Edited by 100YearsToGo, 22 February 2009 - 07:06 PM.
FunkOdyssey 22 Feb 2009
hackeboy 04 Nov 2009
FunkOdyssey 04 Nov 2009
How long time does it take to feel the effect of niacinamide for anxious? Is it the same day?
Yes, you should feel the effects of a given dose acutely, its not something that has to build up over time.
hackeboy 04 Nov 2009
FunkyOdyssey, can you please give it to me in seconds, cause every second of my life is worth more than your mom, and everything beyond your mom is great.
Iam Empathy 15 Jan 2010
Sorry for making a stupid question. And your answer didnt help me at all so your answer is more stupid than my question. How many hours does it last or is it a very short effect?
FunkyOdyssey, can you please give it to me in seconds, cause every second of my life is worth more than your mom, and everything beyond your mom is great.
What does this mean?
tintinet 15 Jan 2010
Sorry for making a stupid question. And your answer didnt help me at all so your answer is more stupid than my question. How many hours does it last or is it a very short effect?
FunkyOdyssey, can you please give it to me in seconds, cause every second of my life is worth more than your mom, and everything beyond your mom is great.
What does this mean?
42
imipolex 23 Jan 2010
You can save some money on the Igenex Lyme testing by starting with just the IgM and IgG Western Blots (the most sensitive test available), which are $200 together. After coming up positive on that, there was no need to spend money on additional tests.
I read/skimmed Klinghardt's paper, and it has some interesting ideas but it is very light on references. The reference for his statement that niacin is antibacterial is a web link that points to a defunct website: http://www.vorsoft.c...iacin/index.htm. I think its entirely possible that he noticed psychological improvements with neuroborelliosis that he describes, but I continue to be skeptical that it has anything to do with killing of the bacteria.
I would consider the TOA free cat's claw extract as a potentially useful adjunct to antibiotics but I would not depend on them alone -- they are also light on proven evidence of their efficacy in Lyme Disease compared to traditional antibiotics.
Any PoV on teasel and/or andrographis? The first has some research (at least anecdotal) against Lyme, and the second is death to (garden-variety, at least) spirochetes.
imipolex 23 Jan 2010
You can save some money on the Igenex Lyme testing by starting with just the IgM and IgG Western Blots (the most sensitive test available), which are $200 together. After coming up positive on that, there was no need to spend money on additional tests.
I read/skimmed Klinghardt's paper, and it has some interesting ideas but it is very light on references. The reference for his statement that niacin is antibacterial is a web link that points to a defunct website: http://www.vorsoft.c...iacin/index.htm. I think its entirely possible that he noticed psychological improvements with neuroborelliosis that he describes, but I continue to be skeptical that it has anything to do with killing of the bacteria.
I would consider the TOA free cat's claw extract as a potentially useful adjunct to antibiotics but I would not depend on them alone -- they are also light on proven evidence of their efficacy in Lyme Disease compared to traditional antibiotics.
Any PoV on teasel and/or andrographis? The first has some research (at least anecdotal) against Lyme, and the second is death to (garden-variety, at least) spirochetes.
This was in reference to the Lyme discussion upthread. Apparently the login process dropped me down to the end of thread with my question.
Cappa 24 Jan 2010
I've wanted to know this for some time. Is there evidence that the other forms don't inhibit SIRT, specifically Inositol Hexanicotinate?I bet the same results could be obtained with plain old Niacin, only people don't like to take it because of the flush..... or Inositol Hexanicotinate, only its expensive.
Personally if I were to mega dose niacin I would stick to the forms that wouldn't inhibit SIRT, that's just me. I haven't read anything that shows that niacinamide does anything positive that can't be accomplished by other forms.
Anthony_Loera 16 Feb 2010
Complain to Anthony about the availability of nicotinamide riboside. I brought it to his attention and said he's looking into it but I don't think he fully grasps its potential as a supplement yet or how many people are interested.
I am heading to Expo West in March... and will be specifically looking for this Funk..
Sorry it took so long... (uhm.. Very very long...)
While I'm there, anything else I should be looking for?
Thanks
A
Edited by Anthony_Loera, 16 February 2010 - 10:18 PM.
Anthony_Loera 25 May 2010
Complain to Anthony about the availability of nicotinamide riboside. I brought it to his attention and said he's looking into it but I don't think he fully grasps its potential as a supplement yet or how many people are interested.
I just found this from a strange source... sorry it took a while FunkOdyssey.
I am arranging a sample for testing.
A