115 replies to this topic

[Bryan_S]

I'm confused about some of the pathways involved here.

 

Over on AntiAging Firewalls, they claim that Niacin (Na) should be avoided, as it is all converted to Nicotinamide (Nam) in vivo (referencing the Wikipedia page on Nicotinamide), and Nam is a SIRT1 inhibitor, etc etc.

 

But the Wikipedia page on Niacin says there is no direct pathway for conversion of Na to Nam--and that matches with what I have read in various flowcharts pasted at this site.

 

What I see from the flowcharts are three possible pathways to NAD+. The Niacin pathway seems to be entirely independent:

 

Niacin (Na)--->NaMN--->NaAD--->NAD+

 

Both Nicotinamide and NR use a pathway that runs via NMN:

 

Nam--->NMN--->NAD+

NR--->NMN--->NAD+

 

NAD+ can of course be degraded to Nam (and recycled if there is enough NamPT around).

 

But it looks to me as if, on a molar basis, Niacin and NR both probably produce the same amount of free Nam.

 

Am I missing something? Does dosing with Niacin really produce more Nam per molecule than dosing with NR?

 

For that matter, do we know that NR is more effective than Niacin in raising NAD+?

 

I'm about to sit down to lunch so I'll be short. (Na) Niacin is dependent on the liver for conversion. So in large amounts it can become toxic, so there is reason for pause with this path. It also produces an intense flush and those of us with inflammatory skin conditions are not as tolerant as others to this, others are and some are seeking the raise their HDL ("good") cholesterol and Niacin will do that. The other 2 forms of B3 do not produce a flush and can be taken in much larger dosages as suggested before. Of these 2, nicotinamide riboside (NR) raises NAD levels the highest and some reports suggest nicotinamide (NAM)  "the supplementation of (Nam) does not seem so effective in elevating cellular NAD contents beyond the basal level" study Revollo, J. R., Grimm, A. A., and Imai, S. (2004) J. Biol. Chem. 279, 50754–50763 There is much more to this and maybe this evening if you haven't found all the differences we can focus on them more deeply and get a discussion going.

Edited by Bryan_S, 13 June 2015 - 07:16 PM.

[BigLabRat]

Hi, Bryan. I'm aware that high-dose niacin can be sketchy for the liver; what I've seen suggests high-dose Nam is even worse. (I exclude time-release niacin, which I think is risky at almost any dosage; most of the reported problem with niacin seem to trace back to time-release formulations.)

 

I also understand that the flush is intolerable for many people, and could have consequences for skin conditions. (It always seems to improve my skin afterwards, probably because of better circulation, but I can see how it could have very contrary effects.)

 

I agree that Nam seems to do little to basal NAD levels. Niacin and NR seem to be roughly comparable in the few studies I've seen (but there doesn't appear to be all that much in the literature).

 

The real root of my questions here, though, is about the contention from the Anti-Aging Firewalls site that 1) dietary niacin is converted into Nam, and 2) Nam downregulates SIRT1, and therefore 3) both niacin and Nam should be avoided for that reason.

 

I gather than some niacin is converted to Nam in the liver--but I can't figure out how much. Obviously not all of it, or non-liver cells wouldn't have a pathway from niacin to NAD. And if niacin is converted to Nam in the liver, does it go into general circulation--or is it methylated and disposed of, or what? I'm trying to make sense of their statement. Any light you can throw on this is appreciated! 

 

 

[Bryan_S]

BigLabRat,

 

I don't have all the answers but have asked many of the same questions. Nicotinamide aka Niacinamide is converted into NMN by nicotinamide phosphoribosyltransferase (Nampt).  Many cells all over the body produce this enzyme. Niacin is more rate limited by its dependence on the liver but I have not seen a direct comparison putting an exact NAD conversion rate to each but their half life figures have been calculated and Niacin seems to be quickly eliminated. http://www.ncbi.nlm....pubmed/17725178 If this study is true it appears just from a pure tissue saturation standpoint (Nam) would likely reach and penetrate more tissues before concentration levels fall, if you are comparing the 2.  

 

The Anti-Aging Firewalls statement you focused on bothered me for awhile as well. Its funny that David Sinclair's study was one to say Nam downregulates SIRT1 he also came around 180 degrees and defended Niacinamide, have you read that? This sounds odd but he makes a good point. http://www.alzforum....anism-involving "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." I don't worry about it now and have added Pterostilbene for SIRT1 insurance anyway.

 

I consume both (Nam) and (NR) but I also do it at opposite ends of the day. Both are water soluble. If (Nam) downregulates SIRT1 I figure by the time I take my (NR) levels of plasma (Nam) are already at a minimum. If you are concerned about the inhibition of SIRT1 (PMID: 17725178) lists a plasma half life of 4.3 hours for niacinamide and the half life figures for (NR) are still pending from last years PK study but its assumed to be similar.  A Study of the Pharmacokinetics of Three Dosages of Niagen in Healthy Subjects (14NBHC) Hopefully they publish their data soon but in separating both forms I'm hoping to keep each NAD precursor pathway as active as possible without negating the efficiency of the other or silencing SIRT1 as you mention.

 

If you look at only Sirtuin's nicotinamide riboside is the clear choice giving you both SIRT1 and SIRT3 activation but who can afford more than a gram per day, certainly not me. Keep in mind after NAD is produced the resulting Niacinamide is recycled. So does this mean the resulting Nam it produces will down-regulate your SIRT1? Plenty to think about but there is likely a continuous ping pong between states and we should not worry. Also at some point you just have to consider researchers used incredibly high dosages on mice systemically and in cell culture, and we wouldn't take these levels ourselves and we should question if the modest amounts we might ingest would produce the same results? I think and this is opinion the Anti-Aging Firewalls statement is interpreting the data to literal and they are looking at the experimental extremes.

 

Edited by Bryan_S, 14 June 2015 - 07:26 AM.

[Bryan_S]

David Sinclair uses the words in vivo not in vitro as he defends Nicotinamide aka Niacinamide. Look each up and you will see the difference. When cells are within a whole organism, within a normal biological context we get the truest results.

[BigLabRat]

Thanks for the info. I'm already familiar with in vitro vs. in vivo--but in many cases what is drawn from the research doesn't make the distinction (which is crucial).

 

As to the pharmokinetics studies of NR, I'm excited to see them, too. But I don't think they are going to answer the most pressing questions. Sinclair and Co showed that NR pumped up NAD and had beneficial effects on mice for a week. Does it stay that way, or rapidly downregulate? It doesn't look to me as if the human studies will get to the bottom of the longer-term effects. The basic pathways, and the statement from Sinclair that you quote, make me worry that there is a fairly tightly regulated feedback loop that will eventually dial down the effects of NAD precursors--faster in the case of Nam, but soon in the case of niacin or NR.

 

------------------------

 

Of course, the production of NAD doesn't automatically result in the production of nicotinamide, since NAD is built out of nicotinamide. That only occurs when the NAD is degraded by specific uses. Most of the time it just cycles through different redox states. So there's no clear relationship between NAD produced and Nam output; It all depends on the things that cleave NAD, as opposed to the things that simply use NAD.

 

I am, as you noted, concerned about Nam inhibition of SIRT1. But some folks seem to think that there is always enough Nam around to inhibit SIRT1 all the time, so it's a non-issue, and the real issue is about the level of SIRT1 activators. That is, Nam inhibition of SIRT1 may be the 'ground state.'

 

I'm really not sure what to make of the niacin blood plasma levels--especially since it was conducted with extended release niacin. The fact that niacin has a short half-life in the blood doesn't tell me anything about what it does to NAD. It might disappear rapidly because it is turned into NAD.* Or because it is a combination of conversion to NAD, plus conversion to nicotinamide, plus conversion to nicotinamide followed by methylation and excretion. And it certainly doesn't all go to the liver first--or why have the niacin ---> NAD pathway? So I still end up scratching my head.

 

============================

 

* A good example of this is found in different forms of vitamin K2. MK7 has a much longer half-life in the blood than MK4, so many have asserted that this means MK7 is more 'effective' than MK4. But others argue that this is because MK7 must be converted to MK4 to be active, and therefore the high levels of circulating MK7 actually mean that it is less effective.

 

This applies to non-NAD uses of niacin as well: some researchers actually think the extended-release form is less beneficial (and much more dangerous) because the main benefits come from the process of clearance. Prolonged half-life in the blood, in this model, is a bad thing, not a benefit.

 

=============================

 

The more I look at this, the less sure I am of anything. I'm taking NR, experimentally, but it seems to me that that the claims of Elysium, and Guarente et al, seem to be way ahead of the data. I have to admit I'm a little surprised that such a distinguished crowd signed on to this. Rapid downregulation seems to me to be not only a possibility, but a probability...

 

Sigh. These are exciting times, but I could do with a little less excitement and a little more clarity.

[Bryan_S]

This whole exercise of NAD boosting is a cheat anyway, I agree there needs to be more long term data to show levels can be maintained. For some of us with skin issues and inflammatory joint problems there is a more immediate feedback loop when you look into the mirror or move without pain. I've discontinued my regiment before and have seen and felt the results of that. So in terms of confirmation, what ever they finally unveil about boosting NAD levels, futile or not, there are benefits/offshoots of this that will hold some of us here that other conventional treatments can not maintain. I've come to accept something positive is happening to me. I am at 507-days now and my questions aren't so agonizing anymore. 

[Kevnzworld]

Re : NR being reduced to NAM ( hypothetically ) and the possible Sirt 1 inhibition effect.
One would expect that if NR orally ingested increases the body's stores of NAD, even temporarily that would partially offset that effect given that Sirt1 requires NAD.
One can also take other Sirt1 activators like resveratrol or pterostilbene to further offset this possible hypothetical side effect.
We've been waiting almost eight months for the NR pharmakinetics study results. One would have expected Chromadex to have facilitated and expedited it's review and publication if the results were positive.....

[Bryan_S]

I don't think Chromadex has a say in the matter. The minute the scientific community catches wind of corporate interference that would lay waste to the whole (NR) venture. If they know whats good from them they will let the data unfold without outside interference.

 

Since David Sinclair provided some clarity on his nicotinamide (Nam) study about downregulating SIRT1 I don't think this is as big a deal because the inhibitor findings have been taken out of context. http://www.alzforum....anism-involving "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."

 

David Sinclair uses the words in vivo not in vitro as he defends Nicotinamide aka Niacinamide. This makes a significant difference as isolated cells in an artificial culture medium are outside their normal biological support context. So as he points out in vivo there is abundant eNampt (extra-cellular nicotinamide phosphoribosyltransferase) and iNampt intracellular Nicotinamide phosphoribosyltransferase helping to initiate the the process. In this context he points out nicotinamide is activating SIRT1 in vivo, not inhibiting it.

 

Like I said I don't worry about it now and have added Pterostilbene as my SIRT1 insurance anyway. On that topic has anyone looked into Honokiol as a SIRT3 activator? It also seems to have some other interesting benefits i.e. Honokiol blocks and reverses cardiac hypertrophy in mice by activating mitochondrial Sirt3

Edited by Bryan_S, 14 June 2015 - 09:46 PM.

[BigLabRat]

Hi, Bryan and Kenz...

 

Thanks for the intelligent responses.

 

I find myself a bit at sea here. I tend to agree, if Chromadex had massive support from their experiments, I think it would have come out in force. I have very little confidence in the scientific peer-review system in the US at present. Many drug trials have been published as massively successful when the difference from placebo is minor and the side-effects are significant.

 

Most of what I have read suggests to me that NamPT (in its various flavors) is rate-limiting, and poses a problem--though there seem to be plenty of things that raise NamPT (exercise and fasting and possibly stressors like cold).

 

Whether these stressors also affect NaPRT (the niacin to NAD limitation) isn't clear. I'd bet that they operate in something very much like parallel.

 

It seems clear to me that there must be a feedback loop somewhere in the NAD world, or we could supplement until our cells exploded with NAD.

 

But I am unconvinced that:

 

1) Nicotinamide is a problem rather than a benefit

2) NR is "better" than Niacin (if you can stand the flush)

3) We can, in the long term, use precursors to achieve lasting higher NAD levels.

 

The Honokiol reseach looks interesting... 

[Bryan_S]

Correct on many assumptions and I think there has been somewhat of a smear campaign on Nicotinamide. This battle goes back many years before my time when Doctors were first discovering the benefits. Once a compound is uncontrollable and in the patent free zone there isn't a lot of business support behind it to push these ideas forward to provide the clinical trials to back-up the observations from what amounts to a few scattered medical professionals. If I were with a pharmaceutical interest and had a compound that did something similar I might magnify key pieces of data over others and not clarify its source in hopes of keeping people from adopting this "public" compound that did a comparable or better job than mine. I'm not saying this happened but this sirtuin inhibitor story is a red flashing light for many who might adopt (Nam).

 

I read an interesting article on A practical guide to countering science denial. Its not a straight crossover to this situation but the part about "debunking science myths" resonated with me concerning Nicotinamide aka Niacinamide in terms of arguments derived from in vitro experiments with those writers not acknowledging the in vivo results. In vivo testing is often employed over in vitro because it is better suited for observing the overall effects of an experiment on a living subject. Even with the complementary comments from David Sinclair clarifying and debunking the (Nam) issue on Sirtuin's/NAD-precursors this myth has continued to gain strength.

 

As far as your 2) and 3) I'll have to think on those awhile. But the first thing that comes to mind on using precursors to achieve lasting higher NAD levels are the study results supporting mitochondrial biogenesis. Simply google NAD mitochondrial biogenesis and you will generate a host of results. I wont go in depth here but here is a definitive marker showing increased cellular capacity is achievable. Now as far as limiting factors . . . absorption is one, the number of molecular sites where NAD can be produced (within the mitochondria) and the available enzymes supporting the conversion of the precursor to NAD. I don't think we will produce any more than our body needs. There are built in controls that mediate the production of NAD related to the NAD/HADH ratios when they exceed certain levels. http://web.mit.edu/b...ferences/15.pdf

 

So I'm in agreement that you can only raise levels just so high and no higher. There also must be a limit to the number of Mitochondria a cell can support to create these reactions. 

Edited by Bryan_S, 16 June 2015 - 02:21 AM.

[mikeinnaples]

I do find it interesting that Nicotinic Acid raises NAD+ better than NR in some cases, but is anyone really surprised that one of them happens to be in the liver?

 

 

 

 

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Edited by mikeinnaples, 22 June 2015 - 04:00 PM.

[mikeinnaples]

BLR ....does this help at all?

 

 

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•  350px-NAD_metabolism.svg.png   7.6KB   1 downloads

[Tom Andre F. (ex shinobi)]

Correct on many assumptions and I think there has been somewhat of a smear campaign on Nicotinamide. This battle goes back many years before my time when Doctors were first discovering the benefits. Once a compound is uncontrollable and in the patent free zone there isn't a lot of business support behind it to push these ideas forward to provide the clinical trials to back-up the observations from what amounts to a few scattered medical professionals. If I were with a pharmaceutical interest and had a compound that did something similar I might magnify key pieces of data over others and not clarify its source in hopes of keeping people from adopting this "public" compound that did a comparable or better job than mine. I'm not saying this happened but this sirtuin inhibitor story is a red flashing light for many who might adopt (Nam).

 

I read an interesting article on A practical guide to countering science denial. Its not a straight crossover to this situation but the part about "debunking science myths" resonated with me concerning Nicotinamide aka Niacinamide in terms of arguments derived from in vitro experiments with those writers not acknowledging the in vivo results. In vivo testing is often employed over in vitro because it is better suited for observing the overall effects of an experiment on a living subject. Even with the complementary comments from David Sinclair clarifying and debunking the (Nam) issue on Sirtuin's/NAD-precursors this myth has continued to gain strength.

 

As far as your 2) and 3) I'll have to think on those awhile. But the first thing that comes to mind on using precursors to achieve lasting higher NAD levels are the study results supporting mitochondrial biogenesis. Simply google NAD mitochondrial biogenesis and you will generate a host of results. I wont go in depth here but here is a definitive marker showing increased cellular capacity is achievable. Now as far as limiting factors . . . absorption is one, the number of molecular sites where NAD can be produced (within the mitochondria) and the available enzymes supporting the conversion of the precursor to NAD. I don't think we will produce any more than our body needs. There are built in controls that mediate the production of NAD related to the NAD/HADH ratios when they exceed certain levels. http://web.mit.edu/b...ferences/15.pdf

 

So I'm in agreement that you can only raise levels just so high and no higher. There also must be a limit to the number of Mitochondria a cell can support to create these reactions. 

Very interesting Bryan but do you think PQQ and others mitochondria booster can actually destroy a cell due to a massive increasement in the production ?

 

Another point that you mention is the NAD+ level that a cell "need". It makes me wonder if an old cell will be actually requiering less NAD+ than a younger one ? this is important because it would mean "no place" for further  NAD+ . Well you know what I mean.

 

And a last point I have is this one: on that topic: http://www.anti-agin...-interventions/ they speak about beta lapachone. It oxidize nadh to nad+ and is maybe the key to maintain the perfect ratio and allow the cells to have high nad+ level. Only problem is... I found that 6 doses of 9mg beta lapachone can be lethal in human.. So 54mg for a day can be death. What about that then ?!

 

[BigLabRat]

Yeah, I spent a little time looking into beta lapachone. It is widely used in its herbal form as lapacho tea or pau d'arco tea, and it seems to have many beneficial effects. But even as a tea, it can have serious side effects at high doses.

 

From an anti-aging perspective, death isn't a tolerable side effect.

[Tom Andre F. (ex shinobi)]

what about low dose ?

[Bryan_S]

Very interesting Bryan but do you think PQQ and others mitochondria booster can actually destroy a cell due to a massive increasement in the production ?

 

Another point that you mention is the NAD+ level that a cell "need". It makes me wonder if an old cell will be actually requiering less NAD+ than a younger one ? this is important because it would mean "no place" for further  NAD+ . Well you know what I mean.

 

And a last point I have is this one: on that topic: http://www.anti-agin...-interventions/ they speak about beta lapachone. It oxidize nadh to nad+ and is maybe the key to maintain the perfect ratio and allow the cells to have high nad+ level. Only problem is... I found that 6 doses of 9mg beta lapachone can be lethal in human.. So 54mg for a day can be death. What about that then ?!

 

 

I don't think you will kill the cell but again this depends on your approach, as you pointed out with lapachone. The jury is still out on PQQ Pyrroloquinoline quinone and I've read "No mammalian PQQ-containing enzymes (quinoprotein) has been described" (Felton & Anthony, Nature Vol. 433, 2005) I've also been told this has been contested and at least four human quinoproteins do exist. I will not weigh into this controversy and do not understand all the underlying points of contention. 

 

I also feel that beyond a certain point NAD production is self terminating and our cells wont naturally self destruct using our own natural precursors. Depending on the precursor there are different enzymes needed to utilize them and natural mechanisms to shut down production. But I have not seen a LD50 study on all of the NAD precursors but they all seem relatively safe. FDA Nicotinamide: "The LD50 for various laboratory animals given the substances parenterally has generally been found to be more than 1g per kg per day. Limited data on oral ingestion by mice and rats suggest that the LD50 may be more than 4g per kg per day." Unless you really consume large cost prohibitive bulk quantities I think your pretty safe with these and will invoke inhibitors of NMN-synthesising enzyme before NAD becomes your problem. 

 

Here is what I "think." I believe overall we can increase mitochondrial capacity thru stimulating mitochondrial biogenesis. We can also increase mitochondrial size and the Mitochondrial Cristae density thru NAD-precursor supplementation.  Obviously their are other methods to this end besides NAD boosting, but not all these have been investigated here on this thread. i.e. . . aerobic exercise, strict caloric restriction, and certain medications such as thiazolidinediones and the diabetes drug metformin. Some other methods like lapachone are not without risk. Here are some comparative results of feeding mice NR for 12-weeks. Results taken from The NAD+ precursor nicotinamide riboside enhances oxidative metabolism and protects against high-fat diet induced obesity http://www.ncbi.nlm....6313/figure/F4/

 

These are the types of results which suggest capacity can be safely increased and this aforementioned study lasted 4 months. 

 

I don't think these results are necessarily confined to just the precursor (NR) but maybe these results are the best so far documented. Many of you have read my posts in this thread pointing to the benefits from other NAD precursors. The capacity of our bodies/cells to adapt to their environment is a hallmark of our human evolution. Many factors separately or together can influence our cellular metabolic capacity. When I look to our forefathers on the African Savanna as an example running their prey into heat exhaustion over many miles I know we are only seeing the tip of the iceberg in terms of our adaptability. We can head to the Arctic where Eskimos have adapted to their cold environment and we see a difference in the amount of brown fat their bodies contain which is required for thermogenesis. Our oxygen metabolism is very flexible and our mitochondria have the mechanisms to respond to new environmental demands over time.

 

I think we are only now beginning to realize that such things as cellular maintenance and repair can also be influenced by our NAD capacity. And to this point I see the study Nicotinamide Reduces Nonmelanoma Skin Cancer Formation as a perfect recent example. https://am.asco.org/...ancer-formation

 

And I'll also point to how Oral nicotinamide protects against ultraviolet UV immunosuppression. http://www.ncbi.nlm....pubmed/19028705

 

We could also get into cardiac and neural cell protection by one or more precursors and we've posted ischemia studies on both.

 

I can continue along these lines to make this point but on the other hand I also see a possible downside to increasing capacity "if" that capacity is unused. Many of us have read about reactive oxygen species (ROS) and how the mitochondria can produce these. I see idle mitochondria as a downside. My fear is that if we induce a larger NAD capacity beyond our immediate cellular needs this unused capacity could produce its own cellular stress. See "Mitochondrial Biogenesis and Reactive Oxygen Species" this could be an area of concern but not much research to support a lot of concern "yet."

[BigLabRat]

what about low dose ?

 

Well, it has long been used at low doses in traditional herbal preparations, so it probably is safe if not overdone.

 

On the other hand, when herbal medicines are administered to treat a condition, they are not necessarily used for long periods of time (though some are...). I guess we need to ask a South American herbalist.
 

[Bryan_S]

It makes me wonder if an old cell will be actually requiring less NAD+ than a younger one ? this is important because it would mean "no place" for further  NAD+ . Well you know what I mean.

 

 

Tom,

 

This part of your question has still been on my mind and helped me find this. http://www.longecity...e-8#entry734049

See graphic at the bottom of the page. As it turns out the answer was in the bottom right hand corner of the graphic and I needed to do some reading to piece it together.

 

This is at the very heart of your question because PARP is a NAD dependent enzyme that consumes massive amounts of NAD+ and this need only increases as we age. It has been an area of intense research as a path of intervention for preventing cancers and age related metabolic dysfunctions.

 

 

See What makes and what eats-up NAD+?  Causes of NAD+ deficiency with aging. Link

http://www.anti-agin...-interventions/

 

All the studies I've reviewed on aging and DNA repair suggest that "PARPs, CD38 and possibly a decline in the expression of NAMPT" may be the culprits for depleting our NAD+ levels.  Most studies suggest that it is a combination of all four factors and that “genotoxic stress” is a major driving force for nuclear NAD+ deficiency.

 

We can also include sirtuins as NAD+ consumers. David Sinclair and Leonard Guarente found this to be true as well. They discovered even after increasing levels of certain sirtuins they simply didn't work unless there was ample NAD within the cell. "The dependence of sirtuins on NAD+ links their enzymatic activity directly to the energy status of the cell via the cellular NAD:NADH ratio, the absolute levels of NAD, NADH or nicotinamide or a combination of these variables." So once NAD levels fall below a certain threshold our sirtuins that maintain our epigenome cease working properly. That can't be good.

 

So Tom if we are to interpret these studies in the light of your question, our cellular NAD+ consumption increases with age and eventually we surpass our ability to keep up with the demand. Studies have also tackled the question of what if we inhibit PARP and CD38 and yes, this does raise NAD+ levels confirming wide-ranging health benefits on the metabolic, immune, and nervous systems. But . . . and I emphasize "but" what are the consequences of inhibiting DNA repair? PARPs are responsible for initiating DNA repair.

 

NAD+ levels are maintained by balancing biosynthesis/salvage and breakdown and we inhibit NAD+ consuming activities (our cellular machinery) at our own peril.

 

Additional reading.

http://www.sciencedi...550413115002661

 

http://www.hindawi.c...na/2010/157591/

 

http://jcb.rupress.o.../199/2/205.full

 

http://eurheartj.oxf...urheartj.ehv290

 

 

Edited by Bryan_S, 28 June 2015 - 06:03 AM.

[Tom Andre F. (ex shinobi)]

Very interesting Bryan but do you think PQQ and others mitochondria booster can actually destroy a cell due to a massive increasement in the production ?

Another point that you mention is the NAD+ level that a cell "need". It makes me wonder if an old cell will be actually requiering less NAD+ than a younger one ? this is important because it would mean "no place" for further NAD+ . Well you know what I mean.

And a last point I have is this one: on that topic: http://www.anti-agin...-interventions/ they speak about beta lapachone. It oxidize nadh to nad+ and is maybe the key to maintain the perfect ratio and allow the cells to have high nad+ level. Only problem is... I found that 6 doses of 9mg beta lapachone can be lethal in human.. So 54mg for a day can be death. What about that then ?!

I don't think you will kill the cell but again this depends on your approach, as you pointed out with lapachone. The jury is still out on PQQ Pyrroloquinoline quinone and I've read "No mammalian PQQ-containing enzymes (quinoprotein) has been described" (Felton & Anthony, Nature Vol. 433, 2005) I've also been told this has been contested and at least four human quinoproteins do exist. I will not weigh into this controversy and do not understand all the underlying points of contention.

I also feel that beyond a certain point NAD production is self terminating and our cells wont naturally self destruct using our own natural precursors. Depending on the precursor there are different enzymes needed to utilize them and natural mechanisms to shut down production. But I have not seen a LD50 study on all of the NAD precursors but they all seem relatively safe. FDA Nicotinamide: "The LD50 for various laboratory animals given the substances parenterally has generally been found to be more than 1g per kg per day. Limited data on oral ingestion by mice and rats suggest that the LD50 may be more than 4g per kg per day." Unless you really consume large cost prohibitive bulk quantities I think your pretty safe with these and will invoke inhibitors of NMN-synthesising enzyme before NAD becomes your problem.

Here is what I "think." I believe overall we can increase mitochondrial capacity thru stimulating mitochondrial biogenesis. We can also increase mitochondrial size and the Mitochondrial Cristae density thru NAD-precursor supplementation. Obviously their are other methods to this end besides NAD boosting, but not all these have been investigated here on this thread. i.e. . . aerobic exercise, strict caloric restriction, and certain medications such as thiazolidinediones and the diabetes drug metformin. Some other methods like lapachone are not without risk. Here are some comparative results of feeding mice NR for 12-weeks. Results taken from The NAD+ precursor nicotinamide riboside enhances oxidative metabolism and protects against high-fat diet induced obesity http://www.ncbi.nlm....6313/figure/F4/

These are the types of results which suggest capacity can be safely increased and this aforementioned study lasted 4 months.

I don't think these results are necessarily confined to just the precursor (NR) but maybe these results are the best so far documented. Many of you have read my posts in this thread pointing to the benefits from other NAD precursors. The capacity of our bodies/cells to adapt to their environment is a hallmark of our human evolution. Many factors separately or together can influence our cellular metabolic capacity. When I look to our forefathers on the African Savanna as an example running their prey into heat exhaustion over many miles I know we are only seeing the tip of the iceberg in terms of our adaptability. We can head to the Arctic where Eskimos have adapted to their cold environment and we see a difference in the amount of brown fat their bodies contain which is required for thermogenesis. Our oxygen metabolism is very flexible and our mitochondria have the mechanisms to respond to new environmental demands over time.

I think we are only now beginning to realize that such things as cellular maintenance and repair can also be influenced by our NAD capacity. And to this point I see the study Nicotinamide Reduces Nonmelanoma Skin Cancer Formation as a perfect recent example. https://am.asco.org/...ancer-formation

And I'll also point to how Oral nicotinamide protects against ultraviolet UV immunosuppression. http://www.ncbi.nlm....pubmed/19028705

We could also get into cardiac and neural cell protection by one or more precursors and we've posted ischemia studies on both.

I can continue along these lines to make this point but on the other hand I also see a possible downside to increasing capacity "if" that capacity is unused. Many of us have read about reactive oxygen species (ROS) and how the mitochondria can produce these. I see idle mitochondria as a downside. My fear is that if we induce a larger NAD capacity beyond our immediate cellular needs this unused capacity could produce its own cellular stress. See "Mitochondrial Biogenesis and Reactive Oxygen Species" this could be an area of concern but not much research to support a lot of concern "yet."

Bryan,

Thanks a lot for your well documented answer. However i still feel my hunger
Can you say why you feel beta lapachone will not make the job properly ?
If i understand well the combination of NR and resveratrol (or even better pterostilbene) would be an ideal way right ?

[Tom Andre F. (ex shinobi)]

Btw I can have beta lapachone pharmaceutical grade for the cheapest price on the market if anyone can be interested in..

Maybe if we supplement daily with 500mcg its can be fine ?

[follies]

What is the source and price for the beta Lapachone?

[Tom Andre F. (ex shinobi)]

the source is synthetic since its not possible to extract from the tree (no real source for it.. to supply enough). Purity would be over 98% and the price range would be 18 dollar for 30 mg = 500mcg per day for a 60 day supply (600 dollar per gram as the final retail price to start with = 18 dollar for 2 months). In the same time, i can produce all kind of peptide including epitalon for better price than the current marke but lets speak all of that in others topic because this one is pretty interesting. 

 

 

[Tom Andre F. (ex shinobi)]

 

It makes me wonder if an old cell will be actually requiring less NAD+ than a younger one ? this is important because it would mean "no place" for further  NAD+ . Well you know what I mean.

 

 

Tom,

 

This part of your question has still been on my mind and helped me find this. http://www.longecity...e-8#entry734049

See graphic at the bottom of the page. As it turns out the answer was in the bottom right hand corner of the graphic and I needed to do some reading to piece it together.

 

This is at the very heart of your question because PARP is a NAD dependent enzyme that consumes massive amounts of NAD+ and this need only increases as we age. It has been an area of intense research as a path of intervention for preventing cancers and age related metabolic dysfunctions.

 

 

See What makes and what eats-up NAD+?  Causes of NAD+ deficiency with aging. Link

http://www.anti-agin...-interventions/

 

All the studies I've reviewed on aging and DNA repair suggest that "PARPs, CD38 and possibly a decline in the expression of NAMPT" may be the culprits for depleting our NAD+ levels.  Most studies suggest that it is a combination of all four factors and that “genotoxic stress” is a major driving force for nuclear NAD+ deficiency.

 

We can also include sirtuins as NAD+ consumers. David Sinclair and Leonard Guarente found this to be true as well. They discovered even after increasing levels of certain sirtuins they simply didn't work unless there was ample NAD within the cell. "The dependence of sirtuins on NAD+ links their enzymatic activity directly to the energy status of the cell via the cellular NAD:NADH ratio, the absolute levels of NAD, NADH or nicotinamide or a combination of these variables." So once NAD levels fall below a certain threshold our sirtuins that maintain our epigenome cease working properly. That can't be good.

 

So Tom if we are to interpret these studies in the light of your question, our cellular NAD+ consumption increases with age and eventually we surpass our ability to keep up with the demand. Studies have also tackled the question of what if we inhibit PARP and CD38 and yes, this does raise NAD+ levels confirming wide-ranging health benefits on the metabolic, immune, and nervous systems. But . . . and I emphasize "but" what are the consequences of inhibiting DNA repair? PARPs are responsible for initiating DNA repair.

 

NAD+ levels are maintained by balancing biosynthesis/salvage and breakdown and we inhibit NAD+ consuming activities (our cellular machinery) at our own peril.

 

Additional reading.

http://www.sciencedi...550413115002661

 

http://www.hindawi.c...na/2010/157591/

 

http://jcb.rupress.o.../199/2/205.full

 

http://eurheartj.oxf...urheartj.ehv290

 

 

 

 

so what if.. increasing NAD+ ratio increase in the same time PARP ? this would be totally the opposite result wanted. Thats why I ask what if we add too much NAD+ in healthy cells. On the other hand, Its hard to understand why they put sirtuins and parp at the same level, their role are opposite, sirtuins increase NAD+ in an indirect way while PARP does not
 

Edited by Tom Andre F. (ex shinobi), 09 July 2015 - 02:01 PM.

[Bryan_S]

 

so what if.. increasing NAD+ ratio increase in the same time PARP ? this would be totally the opposite result wanted. Thats why I ask what if we add too much NAD+ in healthy cells. On the other hand, Its hard to understand why they put sirtuins and parp at the same level, their role are opposite, sirtuins increase NAD+ in an indirect way while PARP does not
 

 

 

Both are NAD consumers and if its at all possible we simply don't want to limit their access to this energy substrate.

 

As we've come to understand many cellular functions compete for the same NAD pool. Diminish this supply and some metabolic function gets delayed or is limited to complete its task but pushed to these extremes eventually the cell will initiate its anaerobic glucose pathway which is a less desired energy backup mode producing reactive oxygen species (ROS) and lactic acid. This mode however produces 100 times the ATP of oxidative phosphorylation but it is more costly from a long term perspective and produces its own cellular stress. In of itself this is not a bad thing and we're built to operate this way. Endurance athletes routinely enter this mode in fact we all do for brief periods when ATP levels drop low enough. Its only when we look at NAD levels from an aging perspective does it become evident that its slow decline impacts our cellular maintenance.

 

PARP consumes NAD mainly for DNA repair and sirtuins for histone deacetylation inside the nucleus and Mitochondrial sirtuins as regulators of protein acylation and energy metabolism. The balance of histone acetylation and deacetylation is how our cell operates at an epigenetic level so think of sirtuins as signaling molecules turning on or off sections of DNA. Limit their access to NAD and the message is lost no matter how much of a certain sirtuin is produced. Again NAD is needed for the desired task/message to be accomplished. NAD metabolism trickles down into all of our cellular processes in one form or the other. In a young body the supply isn't a problem as there is plenty of NAD to go around to get the job done. One recognized factor is as we age the nicotinamide phosphoribosyltransferase NAMPT salvage pathway declines.

 

http://www.anti-agin...he-nad-world-2/

 

http://journals.plos...al.pone.0044933

 

This is the path niacinamide takes to become NMN and NAD once again. Fix this problem as the theory goes and and the whole problem of cellular decline may be stemmed. Personally I think this is only one problem of many. But the fact remains eventually cellular maintenance declines because all NAD dependent activities compete for the same diminishing resource. 

 

In the end we are not increasing PARP our only desire is seeing that it can function properly without limiting its role. 

https://en.wikipedia...bose_polymerase

 

Its very unlikely we could ever attain the NAD levels of our youth. 

 

Sirtuins have been implicated in influencing a wide range of cellular processes. Certain Sirtuins help "signal" and support NAD production but they also need it to accomplish this roll.

 

They put these activities at the same level because they are both NAD dependent enzymes.

[Tom Andre F. (ex shinobi)]

Maybe there is also a balance isnt between parp and sirtuins ? This could explain why we need both increasing sirtuins activity and control the NAD+/NADH ratio.

[Bryan_S]

Maybe there is also a balance isnt between parp and sirtuins ? This could explain why we need both increasing sirtuins activity and control the NAD+/NADH ratio.

 

I don't know about increasing sirtuin activity with age, I just think we have decreased NAD levels and sirtuin activity falls as a result of this deficit. This in itself has far reaching health implications and may be at the root of some age related health issues. A healthy young cell is constantly cycling histone acetylation and deacetylation requiring NAD, old cells just become increasingly impaired over time from a gradual NAD deficit. There are several articles out on circadian clock sirtuin activity. We aren't aware of it but our epigenome is constantly being re-written as the demands on our cells and bodies change thru the day.

 

Along these lines it was sad to see my father-in-law in his 80's not knowing when to sleep or wake. This is what partially sparked my interest in finding something to help him. He passed away but my interest remained.

 

Also don't know about a balance between sirtuin and PARP's as these enzymes work in different rolls. Each will take what NAD it needs to complete its task until it can't find enough.

 

I haven't read anything yet that exactly describes why the nicotinamide phosphoribosyltransferase NAMPT salvage pathway declines with age and what can be done to restore it but obviously there is a feedback regulator at work that begins to falter with age. The NAD+/NADH ratio is thought to be one such mechanism but it isn't the whole story. Exercise has been proven to increase NAMPT and is currently recommended, in the wings are some drugs that are exercise mimic's increasing NAMPT but I wouldn't recommend taking the mimic path just yet.

 

Until this feedback regulator can be fully understood and fixed my interest is drawn to the nicotinamide riboside kinase 1 and 2 salvage paths which are separate from the nicotinamide phosphoribosyltransferase NAMPT salvage pathway which niacinamide takes. This discovery provides a secondary path to NAD synthesis and is thought to be a conserved NAD path from our ancient ancestry and is common among many species. Maybe not a fix but certainly a work around until a better solution materializes.

Edited by caliban, 14 October 2015 - 07:03 PM.
CLOSED - topic continued here http://www.longecity.org/forum/topic/82770-nicotinamide-riboside-curated/