LONGECITY

 

 

SENS have weighed in on NR supplementation with their own analysis of the mouse research on NMN (Posted 23rd November 2015):

 

http://sens.org/rese...ng-mitochondria

 

From the article:

The studies showing benefits of NR supplementation in mouse models of disease have used doses of 400-500 milligrams of NR per kilogram of mouse body weight. Even after adjusting for the different metabolic rates of mice and humans, an approximate equivalent adult dose would range from 2000 to 4000 milligrams of NR per day. Commercially-available NR supplements contain between 75 and 125 mg NR per capsule, at a cost of roughly 0.6-0.8 cents per milligram of NR; to experiment with even the lower end of the human-equivalent dosage range would thus involve swallowing 18-30 NR pills a day, at a cost of $400-550 a month.

 

Oh... and is this thread a big advertisement for Chromadex? Because to me it certainly sounds like it.

 

A

 

 

Hmmm... this does sound like a good point to bring up that I hadn't considered. Why sell a supplement that is so underpowered? Are they expecting some to be able to afford the mega doses to actually take that many capsules while others just waste their money? Or are there actual benefits to taking small doses of NR? I've heard alot of testimonials to the effect that it works slowly over time... is that true? Or are we to assume we're being given to placebo effect?

 

Did a quick scan of in vivo mouse studies with full-text available on pubmed and all of them I could find administered at 400 mg/kg of body weight in feed. So Anthony's absolutely right about that. But all the studies I saw looked for quick results... most in the 1 to 4-week range with the longest at 16 weeks. So I would assume that the best to be expected at a lower dose would be a longer period before similar results. Assuming you are taking it or mixing it with your meals as was done in those mouse studies.

But that may be sub-optimal.  Based on a number of abstracts I saw dealing with digestion of NR. They all point to digestion and absorption taking place in the small intestine by enzymatic action. And stomach acids destroying much of the NR before it reaches the small intestine. That suggests that an enteric acid-resistant capsule might raise the amount of NR that reaches the small intestine, thereby increasing the amount absorbed. Something like these:  http://www.amazon.co.../dp/B014EPR180 ... which look quite a bit like those used by NR vendors, although nothing about that is mentioned on their labels or literature. Other things that might help are minimizing amounts of stomach acid by taking NR on an empty stomach, perhaps taking a fiber supplement maybe an hour earlier to clear fatty acids and bile, taking it with ice water to lower stomach temperature, or perhaps even taking it with an antacid. Another possibility is taking it with or shortly after a probiotic to enhance enzymatic action.
 

Just some thoughts.

Howard

Am I really the only person that thought this an informative and important lead!?

Nam is a negative regulator of SIRT and  recycling it by upregulating NAMPT is the only way to really keep the intracellular levels low, and SIRT levels high, IMHO, as  no matter what you take it will eventually end up as Nam in the cell:

Although NAMPT is said to be the bottleneck for converting niacinamide (NAM) to NMN/NAD, I have used NAM as a cheap replacement for niacinamide riboside (NR), and I can attest to NAM's effects. My 82-year old mother, on the other hand, doesn't respond to NAM as well - my guess is that, for her, low NAMPT is a factor. I am 52, so perhaps NAMPT level is not as important.

On a side note, many people worry about NAM's inhibition of SIRT1. However, NAM's half-life is very short (45 min - 1 hour for 1 g taken orally). Its SIRT1 suppression, therefore, won't last very long and I do not think SIRT1 inhibition is a significant factor.

"Am I really the only person that thought this an informative and important lead!?

Nam is a negative regulator of SIRT and  recycling it by upregulating NAMPT is the only way to really keep the intracellular levels low, and SIRT levels high, IMHO, as  no matter what you take it will eventually end up as Nam in the cell."

I was just waiting for you to weigh in, Logic .   When Bryan posted this link it seemed a gamechanger to me, but I am only slightly selfeducated in these matters by years long of obsessive lurking, so I hoped more knowledgeable people would confirm my impression that this could be a better way to activate NAD+ than supplementing NR.  I wish, however, the researchers had been more specific on how many animals they tested this substance orally. And:  in Vince Giuliano's blog NQO1 plays a large  role in his view of NAD. I wonder how it fits in the picture here.

If after due consideration this turns out to be safe and possibly effective, I certainy would be interested in a group buy

 

Am I really the only person that thought this an informative and important lead!?

Nam is a negative regulator of SIRT and  recycling it by upregulating NAMPT is the only way to really keep the intracellular levels low, and SIRT levels high, IMHO, as  no matter what you take it will eventually end up as Nam in the cell:

 

Although NAMPT is said to be the bottleneck for converting niacinamide (NAM) to NMN/NAD, I have used NAM as a cheap replacement for niacinamide riboside (NR), and I can attest to NAM's effects. My 82-year old mother, on the other hand, doesn't respond to NAM as well - my guess is that, for her, low NAMPT is a factor. I am 52, so perhaps NAMPT level is not as important.

 

On a side note, many people worry about NAM's inhibition of SIRT1. However, NAM's half-life is very short (45 min - 1 hour for 1 g taken orally). Its SIRT1 suppression, therefore, won't last very long and I do not think SIRT1 inhibition is a significant factor.

 

My experiences with 4 grams of NAM made me rethink this whole thing...

4 grams of NAM will knock you the hell out... you will become extremely sleepy and unproductive, and there is no way I could drive a car ... even if pricing of NR came down, I am not sure I would take it if I had a similar reaction.

Well, maybe just before bed...

A

My experiences with 4 grams of NAM made me rethink this whole thing...

 

4 grams of NAM will knock you the hell out... you will become extremely sleepy and unproductive, and there is no way I could drive a car ... even if pricing of NR came down, I am not sure I would take it if I had a similar reaction.

 

Well, maybe just before bed...

I am taking 500 mg x 4 daily, approximately 6 hours apart (total of 2 g), and I can confirm the drowsiness each time I take it. For me, it is quite manageable. I have been on it for close to 9 months now.

I think there has been reported toxicity incidents at chronic 6 g (although relatively few). At 4 grams, you are creeping up there ...

IMO, these vitamin B3 supplements (NAM, NR, NA) are pretty amazing. I see improved skin, increased body temperature, improved leanness, etc. Oh, and strangely, hair that used to grow at odd places as I got older stopped (e.g., ears). May be TMI.

"Am I really the only person that thought this an informative and important lead!?

Nam is a negative regulator of SIRT and  recycling it by upregulating NAMPT is the only way to really keep the intracellular levels low, and SIRT levels high, IMHO, as  no matter what you take it will eventually end up as Nam in the cell."

 

I was just waiting for you to weigh in, Logic .   When Bryan posted this link it seemed a gamechanger to me, but I am only slightly selfeducated in these matters by years long of obsessive lurking, so I hoped more knowledgeable people would confirm my impression that this could be a better way to activate NAD+ than supplementing NR.  I wish, however, the researchers had been more specific on how many animals they tested this substance orally. And:  in Vince Giuliano's blog NQO1 plays a large  role in his view of NAD. I wonder how it fits in the picture here.

 

If after due consideration this turns out to be safe and possibly effective, I certainy would be interested in a group buy

I've had some time to rethink my earlier assessment after reading this paper: http://www.jbc.org/c...290/3/1546.full

They increased NAMPT and reported is was not sufficient to promote oxidative metabolism. Just one study but it seems just increasing the NAM salvage cycle with NAMPT might not be the final answer.

Also for a year or so I added 2 grams per day of (NAM) Nicotinamide to my (NR) regiment  I've since stopped, but it didn't make me drowsy. Maybe a little calmer. Figured I was likely fighting the SIRT activators.

They increased NAMPT and reported is was not sufficient to promote oxidative metabolism. Just one study but it seems just increasing the NAM salvage cycle with NAMPT might not be the final answer.

In the study, by increasing NAMPT, the researchers were clearly able to increase NAD level. The point is that the increased NAD didn't lead to mitochondrial biogenesis, which they are saying should have been the case for increased oxidative capacity. I question these latter steps in the paper, because the changes in oxidative capacity should be dependent (at least for healthy mice) on energy demands. Assume that a body has the ability to adapt. However, that does not mean that the adaptation will occur without the proper context.

One interesting result: they indicated that NAD/NADH ratio was unchanged. They showed that when they increased NAD, NADH concentration also increased. This shows that NAD/NADH ratio is maintained independently of NAD concentration.

The latter part is interesting, because it suggests that supplements that change the NAD/NADH ratio may be useful for affecting cellular function (e.g., beta-lapachone), in addition to NAD boosters.

The paper is pretty neutral as to the utility of supplementing with NAM (vs NR or NA).

 

They increased NAMPT and reported is was not sufficient to promote oxidative metabolism. Just one study but it seems just increasing the NAM salvage cycle with NAMPT might not be the final answer.

 

In the study, by increasing NAMPT, the researchers were clearly able to increase NAD level. The point is that the increased NAD didn't lead to mitochondrial biogenesis, which they are saying should have been the case for increased oxidative capacity. I question these latter steps in the paper, because the changes in oxidative capacity should be dependent (at least for healthy mice) on energy demands. Assume that a body has the ability to adapt. However, that does not mean that the adaptation will occur without the proper context.

 

One interesting result: they indicated that NAD/NADH ratio was unchanged. They showed that when they increased NAD, NADH concentration also increased. This shows that NAD/NADH ratio is maintained independently of NAD concentration.

 

The latter part is interesting, because it suggests that supplements that change the NAD/NADH ratio may be useful for affecting cellular function (e.g., beta-lapachone), in addition to NAD boosters.

 

The paper is pretty neutral as to the utility of supplementing with NAM (vs NR or NA).

 

Thx for this study SearchHorizon.

NB that they used genetically modified mNAMPT mice.
One would have to know a lot more about these mice to know if the  NAD/NADH ratio effect held true for humans?

Also; although the NAD/NADH ratio remained the same, the level of Nam in the cells should be lower, leading to higher SIRT etc expression?

The interest shown in beta-lapachone by the scientists that 'To Age or not to age' speaks of, does verify the importance of changing the NAD/NADH ratio however.

All this is treating symptoms of course, rather than the cause...

 

 

They increased NAMPT and reported is was not sufficient to promote oxidative metabolism. Just one study but it seems just increasing the NAM salvage cycle with NAMPT might not be the final answer.

 

In the study, by increasing NAMPT, the researchers were clearly able to increase NAD level. The point is that the increased NAD didn't lead to mitochondrial biogenesis, which they are saying should have been the case for increased oxidative capacity. I question these latter steps in the paper, because the changes in oxidative capacity should be dependent (at least for healthy mice) on energy demands. Assume that a body has the ability to adapt. However, that does not mean that the adaptation will occur without the proper context.

 

One interesting result: they indicated that NAD/NADH ratio was unchanged. They showed that when they increased NAD, NADH concentration also increased. This shows that NAD/NADH ratio is maintained independently of NAD concentration.

 

The latter part is interesting, because it suggests that supplements that change the NAD/NADH ratio may be useful for affecting cellular function (e.g., beta-lapachone), in addition to NAD boosters.

 

The paper is pretty neutral as to the utility of supplementing with NAM (vs NR or NA).

 

 

Thx for this study SearchHorizon.

 

NB that they used genetically modified mNAMPT mice.
One would have to know a lot more about these mice to know if the  NAD/NADH ratio effect held true for humans?

Also; although the NAD/NADH ratio remained the same, the level of Nam in the cells should be lower, leading to higher SIRT etc expression?

The interest shown in beta-lapachone by the scientists that 'To Age or not to age' speaks of, does verify the importance of changing the NAD/NADH ratio however.

All this is treating symptoms of course, rather than the cause...

 

I dont quite understand this interest in the ratio. A move in either way doesn't say anything about the absolute amounts of NAD+ being utilized. 

On a side note, many people worry about NAM's inhibition of SIRT1. However, NAM's half-life is very short (45 min - 1 hour for 1 g taken orally). Its SIRT1 suppression, therefore, won't last very long and I do not think SIRT1 inhibition is a significant factor.

 

NAM's half-life where?
We are interested in intracellular levels. 

The NAD/NADH ratio says nothing about absolute values and they appear to raise and lower together. I agree there is another controlling mechanism at work governing this. Also it appears SIRT3 and SIRT1 are needed to push some of the mitochondrial benefits and as long as NAM levels remain high this could be an inhibiting factor to those benefits. Here is a question, how might we eliminate more NAM? Stay with me for a second. If we are boosting levels of NAD thru the nicotinamide riboside kinase 1 and 2 paths should we focus so much on strengthening the salvage pathway? Maybe we should think about what would happen if while on a NR regiment we somehow marked excess NAM for elimination. Just a thought. 

"SIRT1 is inhibited by Nicotinamide" - many people 

http://www.ncbi.nlm....es/PMC3596471/ 

"We also found that aggregated Aβ reduced neuronal survival and cellular NAD+ levels, and that NAM increased cellular NAD+ levels and cell viability in the presence of Aβ (Fig. 3D and E). Since SIRT1 is an NAD+-dependent deacetylase, and SIRT1 levels are closely related to cellular NAD+ availability (Liu et al., 2009; Revollo et al., 2004), we measured SIRT1 protein levels in neurons exposed to oxidative insults in the presence or absence of NAM. SIRT1 protein levels were maintained at a significantly higher level in neurons treated with NAM and then exposed to H2O2 compared to neurons exposed to H2O2 alone (Fig. 3F). " 

What's the deal? Something to do with dosing? 

I have tried Niacin and Niacinamide, and I found that both forms were good to be honest. Uplifting, a little bit like herbal supplements such as Ginkgo/Turmeric/Reishi/Valerian etc. I'd like to give Nicotinamide Riboside a go when I have the cash. I can report if I find it to be vastly different, or the same. I am quite sensitive to supplements (I can "smell" resveratrol even though it is odorless). 

Logic & Bryan - Good points. Skyguy2005 - a really good find.

One thing to note. Although, in vitro, NAM by itself may suppress SIRT1 expression, at least in mice, in vivo, the overall effect of NAM (to together with NAD into which it is converted) is to activate SIRT1, not suppress it .

From the paper cited by Skyguy2005, "Since SIRT1 is an NAD+ dependent deacetylase, and SIRT1 levels are closely related to cellular NAD availability, (Liu et al, 2009, Revollo et al. 2004), we measured SIRT1 protein levels in neurons exposed to oxidative insults in the presence or absence of NAM. SIRT1 protein levels were maintained at a significantly higher level in neurons treated with NAM and then exposed to H2O2 compared to neurons exposed to H2O2 alone ." That is, despite the fact that NAM is supposed to deactivate SIRT1, in the experiment, the presence of NAM increased SIRT1 expression.

This seems consistent with my experience with NAM.  

stefan_001 - Taking the NAD precursors changes the concentrations of both NAD and NADH, but doesn't change the ratio NAD/NADH. But Dr. Sinclair's research seems to indicate that the ratio affects longevity. So, if we could find supplements that increase NAD/NADH ratio, we could perhaps stack it with the NAD precursors and amplify their effects.

For example, beta-lapachone can shift the ratio. I have heard that methylene blue also shifts the ratio, but have not been able to confirm it. People taking MB do report physical manifestations that are likely to be associated with changing the NAD/NADH ratio (e.g., body temperature increase). 

The paper Skyguy005 found challenges the idea that NAM is an in vivo negative regulator of SIRT1. From the paper:

"It has been reported that NAM can inhibit class III NAD+-dependent histone deacetylases (HDACs) including SIRT1 (Liu et al., 2009; Green et al., 2008). However, NAM is readily converted to NAD+by salvage biosynthesis, consistent with our finding of elevated brain NAD+ levels measured 6 h after NAM administration. In addition, we previously showed that that NAM sustains cellular NAD+ levels and maintained SIRT1 protein levels in cultured neurons subjected to excitotoxins, and that NAM treatment was neuroprotective in a stroke model (Liu et al., 2009). We found that NAM treatment resulted in a small elevation of SIRT1 protein levels in the brains of 3xTgAD mice, which could be an indicator of elevated cellular NAD+ levels due to the dependency of SIRT1 activity on NAD+, and/or increased CREB activity which has been reported to induce SIRT1 expression (Noriega et al., 2011). SIRT1 might also contribute to the oxidative stress resistance in NAM-treated neurons, and better cognitive function in NAM-treated 3xTgAD mice. Other studies have suggested that Class III HDAC inhibitors can suppress the activity of multiple HDACs in addition to SIRT1, and account for their neuroprotective effects (Green et al., 2008; Langley et al., 2005; Roth et al., 2001)."

One more significant observation from the paper:

"Other approaches for elevating cellular NAD+ levels are also possible. For example, nicotinamide riboside can be phosphorylated and converted into NAM by nicotinamide riboside kinases. It was recently reported that nicotinamide riboside protects mice against diet-induced obesity by a mechanism involving elevation of NAD+ levels and activation of sirtuins 1 and 3 in skeletal muscle of mice (Canto et al., 2012). However, the latter study suggested that peripheral administration of nicotinamide riboside does not result in an elevation of NAD+ levels in the brain. Given the present findings and those ofGreen et al. (2008), together with the well-established safety of long-term dietary supplementation with NAM, clinical trials of NAM in human subjects with or at risk for AD are warranted

Of course, mice are not human beings.  

stefan_001 - Taking the NAD precursors changes the concentrations of both NAD and NADH, but doesn't change the ratio NAD/NADH. But Dr. Sinclair's research seems to indicate that the ratio affects longevity. So, if we could find supplements that increase NAD/NADH ratio, we could perhaps stack it with the NAD precursors and amplify their effects.

 

For example, beta-lapachone can shift the ratio. I have heard that methylene blue also shifts the ratio, but have not been able to confirm it. People taking MB do report physical manifestations that are likely to be associated with changing the NAD/NADH ratio (e.g., body temperature increase). 

It would in my opinion only make sense if both NAD+ and NADH are competing for binding with same substances. As far as I know they don't.

 

stefan_001 - Taking the NAD precursors changes the concentrations of both NAD and NADH, but doesn't change the ratio NAD/NADH. But Dr. Sinclair's research seems to indicate that the ratio affects longevity. So, if we could find supplements that increase NAD/NADH ratio, we could perhaps stack it with the NAD precursors and amplify their effects.

 

For example, beta-lapachone can shift the ratio. I have heard that methylene blue also shifts the ratio, but have not been able to confirm it. People taking MB do report physical manifestations that are likely to be associated with changing the NAD/NADH ratio (e.g., body temperature increase). 

 

It would in my opinion only make sense if both NAD+ and NADH are competing for binding with same substances. As far as I know they don't.

 

stefan you should read the anti aging firewall article about it: http://www.anti-agin...-interventions/

and check how important it is for such researcher http://www.ncbi.nlm....les/PMC3469505/

they got impressive result especially on mitochondria and lifespan (much more impressive that NR studies did). They really explain that the ratio NAD+/NADH is the matter and I do agree with that.

and a summarry I did : http://www.beta-lapa...f-healthy-life/

Logic & Bryan - Good points. Skyguy2005 - a really good find.

 

One thing to note. Although, in vitro, NAM by itself may suppress SIRT1 expression, at least in mice, in vivo, the overall effect of NAM (to together with NAD into which it is converted) is to activate SIRT1, not suppress it .

 

From the paper cited by Skyguy2005, "Since SIRT1 is an NAD+ dependent deacetylase, and SIRT1 levels are closely related to cellular NAD availability, (Liu et al, 2009, Revollo et al. 2004), we measured SIRT1 protein levels in neurons exposed to oxidative insults in the presence or absence of NAM. SIRT1 protein levels were maintained at a significantly higher level in neurons treated with NAM and then exposed to H2O2 compared to neurons exposed to H2O2 alone ." That is, despite the fact that NAM is supposed to deactivate SIRT1, in the experiment, the presence of NAM increased SIRT1 expression.

 

This seems consistent with my experience with NAM.  

you are heading into dangerous and confusing territory here:
I haven't researched this in quite a while so all this is IIRC!

• H2O2 and many other ROS etc type things damages DNA.
• PARP is required to repair DNA and in the apoptosis of cells where DNA repair is failing/has failed.
• Nam seems to downregulate PARP more than SIRT..?

Now; if less NAD+ is being used by PARP to repair DNA, due to Nam; more is available for SIRT...

You will feel better at the expense of DNA errors and the real possibility of cancer etc! 

ie:  Downregulating PARP for the sake of SIRT is NOT a good idea! 

https://www.google.c...off&q=H2O2 PARP

I really don't like the idea of Nam supplementation, except possibly when the immune system is overactive.

Its the end product of PARP, SIRT etc whereas NA at least has to converted into NAD+ then SIRT, PARP etc, before ending up as the end product; Nam...!

We get more than enough Nam from foods and IMHO the life extension seen from calorie restriction is in large part due to lower Nam intake..?
A point largely overlooked so far.

Interesting that the  Anti aging Firewall also mentions quercetine as an upregulator of NQO1. Since beta-laparachone is not for sale where I live, I  plan to add quercetine to my NR.

Quercetin is a less specific NQO1 regulator according to what I read. And unlike beta-lapachone, quercetin also decrease lifespan in mice in a study by 10% if i remember well. Someone can found back this study maybe. For now beta-lapachone would be the only viable option

 For now beta-lapachone would be the only viable option

 

The full text of the following might be interesting. It talks about methylene blue oxidizing NADH to NAD.

http://www.ncbi.nlm....pubmed/17614098

I googled to see beta-lapachone can be purchased cheaply, but it seems that no one is selling a convenient form of it right now.  It has the potential of being more effective health-span extender than NR. 

As for methylene blue, there are fish tank cleaning kits, but again, it is pretty inconvenient to have to prepare the solution. I have not done experimented with it, for that very reason.

I hope we will get more clarity soon about this ratio. Then again, taking a second look at the study Stefan relevated before, this study was done on healthy mice, administration was oral and there is no report of any stimulation of the NAD/NADH ratio. Still the health improvement was considerable, so there is reason to believe that exclusively  supplementing NR can have benefits.

 

 

stefan_001 - Taking the NAD precursors changes the concentrations of both NAD and NADH, but doesn't change the ratio NAD/NADH. But Dr. Sinclair's research seems to indicate that the ratio affects longevity. So, if we could find supplements that increase NAD/NADH ratio, we could perhaps stack it with the NAD precursors and amplify their effects.

 

For example, beta-lapachone can shift the ratio. I have heard that methylene blue also shifts the ratio, but have not been able to confirm it. People taking MB do report physical manifestations that are likely to be associated with changing the NAD/NADH ratio (e.g., body temperature increase). 

 

It would in my opinion only make sense if both NAD+ and NADH are competing for binding with same substances. As far as I know they don't.

 

 

stefan you should read the anti aging firewall article about it: http://www.anti-agin...-interventions/

 

and check how important it is for such researcher http://www.ncbi.nlm....les/PMC3469505/

 

they got impressive result especially on mitochondria and lifespan (much more impressive that NR studies did). They really explain that the ratio NAD+/NADH is the matter and I do agree with that.

 

and a summarry I did : http://www.beta-lapa...f-healthy-life/

 

Thanks for summarizing those.

Ok so far I manged to read the research article. Towards the end there is this statement:

- Further studies will be needed to determine the crucial factor in these experiments: the ratio of NAD+/NADH, or their turnover rate with a constant NAD+/NADH ratio, or both.

I would put my money on the turnover rate as that means more NAD+ for utilization. Again in my view the ratio is entirely irrelevant if it is not tied to an increase in NAD+ amount in the cell. That I could imagine is usefull. If the absolute amount of NAD+ in the cell goes up then statistically there is a higher chance it gets used in a reaction.

What I also understand is the beta-lapachone compensates for the reduced enzyme function of NQO1. So turnover rate goes down with age. Could be. It also claims a double function that it prevents loss of NADH. That's an interesting one. NADH leakage doesnt sound like a good plan. Need to read it again and the cited refences.

 

 

 

stefan_001 - Taking the NAD precursors changes the concentrations of both NAD and NADH, but doesn't change the ratio NAD/NADH. But Dr. Sinclair's research seems to indicate that the ratio affects longevity. So, if we could find supplements that increase NAD/NADH ratio, we could perhaps stack it with the NAD precursors and amplify their effects.

 

For example, beta-lapachone can shift the ratio. I have heard that methylene blue also shifts the ratio, but have not been able to confirm it. People taking MB do report physical manifestations that are likely to be associated with changing the NAD/NADH ratio (e.g., body temperature increase). 

 

It would in my opinion only make sense if both NAD+ and NADH are competing for binding with same substances. As far as I know they don't.

 

 

stefan you should read the anti aging firewall article about it: http://www.anti-agin...-interventions/

 

and check how important it is for such researcher http://www.ncbi.nlm....les/PMC3469505/

 

they got impressive result especially on mitochondria and lifespan (much more impressive that NR studies did). They really explain that the ratio NAD+/NADH is the matter and I do agree with that.

 

and a summarry I did : http://www.beta-lapa...f-healthy-life/

 

Thanks for summarizing those.

 

Ok so far I manged to read the research article. Towards the end there is this statement:

 

- Further studies will be needed to determine the crucial factor in these experiments: the ratio of NAD+/NADH, or their turnover rate with a constant NAD+/NADH ratio, or both.

 

I would put my money on the turnover rate as that means more NAD+ for utilization. Again in my view the ratio is entirely irrelevant if it is not tied to an increase in NAD+ amount in the cell. That I could imagine is usefull. If the absolute amount of NAD+ in the cell goes up then statistically there is a higher chance it gets used in a reaction.

 

What I also understand is the beta-lapachone compensates for the reduced enzyme function of NQO1. So turnover rate goes down with age. Could be. It also claims a double function that it prevents loss of NADH. That's an interesting one. NADH leakage doesnt sound like a good plan. Need to read it again and the cited refences.

 

I think from this : http://journals.plos...al.pone.0047122

this can answer partially at least to you:

Thus, it is plausible that βL may mimic the mechanisms of CR by increasing NAD+/NADH ratio. While CR leads to an increase of NAD⁺ since a low glucose level resulted from low food uptake facilitates the production of ATP by oxidizing NADH to NAD+ [31], βL could directly facilitate the production of NAD+ through the oxidation of NADH by NQO1 [8](Fig. 1A). The increased NAD⁺ can act as a signaling molecule and activate diverse proteins that play a beneficial role in the control of glucose and lipid metabolism, which is eventually deregulated during the aging process [32].

The increased NAD⁺ by βL may also be associated with the activity of AMPK (Fig. 1B)

in this picture, you can see mitochondria structure was better looking in the BL group than the CR group ! 

you also see BL increased some important gene within the mitochondria such as SIRT1 and SIRT3 that seems to confirm the NAD+ increase.

note this article is from 2012, and the korean team performed another one in 2013 and moved further:

http://www.ncbi.nlm....MC3944666/#sup1

Thus, intracellular regulation of NAD⁺ levels through NQO1 activation might be a promising therapeutic target for the protection of cisplatin-induced acute kidney injury.

quinone oxidoreductase 1 (NQO1) is a cytosolic antioxidant flavoprotein that catalyzes the reduction of quinones to hydroquinones by utilizing NADH as an electron donor, which consequently increases intracellular NAD⁺ levels.^{18, 19} In addition, there is evidence that NQO1 has a role in other biological activities, including anti-inflammatory processes, the scavenging of superoxide anion radicals, and the stabilization of p53 and other tumor-suppressor proteins.^{20, 21, 22, 23, 24, 25, 26}

^{the reference above 18 and 19:}

^{http://www.ncbi.nlm....pubmed/11154736}

^{http://www.ncbi.nlm....pubmed/11309386}

Several activators of the NQO1 enzyme have been identified, of which β-lapachone is the best known.^{27, 28}

We found that βL protects against cisplatin-induced renal dysfunction and that this effect is mediated by Sirt1 and Sirt3 through NQO1 activation

and indeed if you read the full study they found out BL induced again SIRT1 and SIRT3

Recently, numerous studies have reported that the enzymatic activation of NQO1 by βL mediates the beneficial effects on features of metabolic syndromes, including aging, obesity, hypertension, arterial restenosis, and salt-induced renal injury,^{30, 31, 33, 34} raising the possibility that intracellular NAD⁺ increase through NQO1 activation may be a potential therapeutic target for treating various diseases. In this report, we investigated whether NQO1 enzymatic activation by βL ameliorates cisplatin-induced renal changes.

and the most interesting part :

Interestingly, the major reason for the cellular change in the NAD⁺/NADH ratio by βL in WT mice is not the reduction in NADH but the increase in NAD⁺ levels (data not shown)

 

I think beta lapachone deserve its own thread isnt ?

Another study that confirm its potential:

http://www.nature.co...is2014255a.html

Cisplatin (cis-diaminedichloroplatinum-II) is an extensively used chemotherapeutic agent, and one of its most adverse effects is ototoxicity. A number of studies have demonstrated that these effects are related to oxidative stress and DNA damage. However, the precise mechanism underlying cisplatin-associated ototoxicity is still unclear. The cofactor nicotinamide adenine dinucleotide (NAD⁺) has emerged as a key regulator of cellular energy metabolism and homeostasis. Here, we demonstrate for the first time that, in cisplatin-mediated ototoxicity, the levels and activities of SIRT1 are suppressed by the reduction of intracellular NAD⁺ levels. We provide evidence that the decrease in SIRT1 activity and expression facilitated by increasing poly(ADP-ribose) transferase (PARP)-1 activation and microRNA-34a through p53 activation aggravates cisplatin-mediated ototoxicity. Moreover, we show that the induction of cellular NAD⁺ levels using β-lapachone (β-Lap), whose intracellular target is NQO1, prevents the toxic effects of cisplatin through the regulation of PARP-1 and SIRT1 activity. These results suggest that direct modulation of cellular NAD⁺ levels by pharmacological agents could be a promising therapeutic approach for protection from cisplatin-induced ototoxicity.

about NR, does anyone have any idea how it works with alcohol, prevents toxicity before abuse or repairs damage after abuse, studies or just theory?

btw tom andre, beta lapachol seems to be toxic to be used for anything at all! i checked around, i cannot find a single data this stuff is safe even in low doses long term.

hey check out this candy, https://www.ncbi.nlm...pubmed/20112181 too mutagenic for school!