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NAD Boosters fail in new lifespan trial

nad nmn nad+ lifespan nia itp

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#1 Guest

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Posted 09 February 2021 - 03:13 PM


In the recent podcast of Peter Attia one of the key researchers for the NIA intervention testing program reported the result of a soon to be published major paper on NR:

 

https://youtu.be/g8bXYKeeWnc?t=6661

 

https://www.nia.nih....mpounds-testing

 

 

Mice were given NR at a dose of 1000 ppm starting at 8 month of age till death. That is the equivalent of about 1 gram of NR in an average adult human.

 

 

 

That is both good and bad:

 

good - there was the fear, that NAD-Booster might accelerate cancer; this did not happen

 

bad - there was no lifespan benefit; in fact at that dose it barely noticed in the NAD-pool

 

 

The National Institute on Aging ITP studies are seen as the gold standard in mice lifespan studies, employing huge numbers of mice. So this result is a big deal.


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#2 johnross47

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Posted 09 February 2021 - 07:06 PM

This looks like another example of the big boys asking the wrong question and then claiming that that shows the substance to be a total failure. I certainly never expected that I was going to get any significant life extension from NR. What did you hope for?

 


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#3 Guest

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Posted 09 February 2021 - 07:34 PM

People have different motivations regarding their supplements and general life style - for me life extension is an important part of it. Generally it is difficult to get a substantial increase in health span (e.g. defeating heart disease) without seeing a corresponding effect on lifespan.

 

 

Now, as the podcast discusses at length, mouse models only go so far as to figure out beneficial effects. Things that work in mice often are duds in humans (most drug trails fail in Phase 3 after being successful in rodents). There are also compounds that kill mice and rats, but are harmless for humans - e.g. 3rd generation rodenticides based on corn products. Therefore the guest on the podcast favours marmorset monkeys for future studies (a short lived primate).

 

 

Nonetheless, NAD boosters are heavily marketed as "anti-aging" and the company Chromadex proposed to do this lifespan study and sponsored the NR used. Maybe if you feel subjectively better you might continue taking it. But if you're on a budget and are interested in lifespan this is a strong data point against that notion.

 

 

Edit:

 

here is one of the journal articles from the Sinclair-Lab, where he is heavily speculating, that NAD boosters would extend lifespan in mice and by extension that would imply delaying aging in humans:

https://www.ncbi.nlm...les/PMC6342515/

 

he makes similar statements in various interviews and podcasts; though notably he is an investor in a company selling it - aka a repeat of the resveratrol hype


Edited by Guest, 09 February 2021 - 07:47 PM.

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#4 able

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Posted 10 February 2021 - 12:29 AM

I don't see anywhere in that paper that promotes NAD+ boosters for lifespan extentionsion. More like JohnRoss says, the hope is for extending health-span, which is the message from both Dr Sinclair and Dr Brenner on podcasts.

 

 

 

 

Such molecules hold the promise of increasing the body’s resilience, not just to one disease, but to many, thereby extending healthy human lifespan.

 

 

My hope is to improve healthspan with diet, exercise, and supplements until we have more effective therapies like Dr Sinclair talks about in his book, so I'm not going to stop any of those just because they don't extend lifespan.


Edited by able, 10 February 2021 - 12:35 AM.

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#5 Guest

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Posted 10 February 2021 - 01:13 AM

You must not have actually read that paper or come across any interview with Sinclair. To quote Sinclar and his lab in the paper:

 

"It is exciting to imagine an NAD+ booster being tested in humans for the ability to increase vitality, reduce all causes of mortality, and extend healthy lifespan. If that happens, more than the discoverers of NAD+ could ever have imagined, NAD+ would truly be the molecule of life."

 

 

He is very unapologetic about the life extension aspect and in promoting this sales-pitch (he is a major stakeholder for a NAD-booster business), just watch any of his videos on NAD-boosters; e.g.

 

 

Now again, there might be some effect of NAD on quality of life, that is hard to capture if you only look on disease outcomes and mortality data. If you feel that you can reap some benefit of that - there appears to be no harm in taking NAD boosters (except for your bank account). That is the good news, as there has been an extensive discussion about possible pro-cancer activities. In lab mice cancer is the major cause of death; so it would have decreased lifespan in the ITP trial.

 

 

On the other hand: it did not in fact extend lifespan. So if you're in it for that purpose and on a budget, you might be better advised ordering some high dose of spermidine etc. - or take your NAD budget an donate it to SENS

 

 

 

Edit:

 

Sinclair is also taking Resveratrol and Metformin - 2 compounds that failed in ITP-trials, too. So don't just "trust" supposedly authorities but look at if the actual evidence is supporting the claims. Especially if the authority got a very notable financial and reputational conflict of interest - e.g. as Sinclair got regarding NAD + resveratrol


Edited by Guest, 10 February 2021 - 01:23 AM.

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#6 able

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Posted 10 February 2021 - 01:44 AM

You must not have actually read that paper or come across any interview with Sinclair. To quote Sinclar and his lab in the paper:

 

"It is exciting to imagine an NAD+ booster being tested in humans for the ability to increase vitality, reduce all causes of mortality, and extend healthy lifespan. If that happens, more than the discoverers of NAD+ could ever have imagined, NAD+ would truly be the molecule of life."

 

 

He is very unapologetic about the life extension aspect and in promoting this sales-pitch (he is a major stakeholder for a NAD-booster business), just watch any of his videos on NAD-boosters; e.g.

 

 

Now again, there might be some effect of NAD on quality of life, that is hard to capture if you only look on disease outcomes and mortality data. If you feel that you can reap some benefit of that - there appears to be no harm in taking NAD boosters (except for your bank account). That is the good news, as there has been an extensive discussion about possible pro-cancer activities. In lab mice cancer is the major cause of death; so it would have decreased lifespan in the ITP trial.

 

 

On the other hand: it did not in fact extend lifespan. So if you're in it for that purpose and on a budget, you might be better advised ordering some high dose of spermidine etc. - or take your NAD budget an donate it to SENS

 

 

 

Edit:

 

Sinclair is also taking Resveratrol and Metformin - 2 compounds that failed in ITP-trials, too. So don't just "trust" supposedly authorities but look at if the actual evidence is supporting the claims. Especially if the authority got a very notable financial and reputational conflict of interest - e.g. as Sinclair got regarding NAD + resveratrol

 

 

Well, using your quote:

 

"It is exciting to imagine an NAD+ booster being tested in humans for the ability to increase vitality, reduce all causes of mortality, and extend healthy lifespan. If that happens, more than the discoverers of NAD+ could ever have imagined, NAD+ would truly be the molecule of life."

 

 

That sounds like what he always says - extending HEALTH span, not lifespan. 

 

If I can have 5-10 more healthy, active years, but still die at 90, I'll think it is worth it.

 

As for resveratrol - He has done numerous studies that proved it does what he said it does - something about benefits from activating Sirtuins.   The problem is, it is not as bioavailable as it needs to be. 


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#7 Guest

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Posted 10 February 2021 - 02:06 AM

Yes, he is also mentioning healthspan, in parallel to the life extension angle he is promoting (see the reduction in mortality directly before that or his videos). That does not invalidate, that life extension was a major part of his pitch in talking up NAD boosters to his personal financial benefit.

 

 

Back 10 years ago Sinclair was very forward about resveratrol potentially extending lifespan, going way beyond what could be scientifically claimed to sell the stuff. He even got a major pharma firm to buy another Sirtuin/resveratrol company he co-owned for 720 Million USD (he personally got 8 Million profit out of it) - an investment that GSK quietly wrote off as a 100% loss soon after that. Resveratrol did not extend lifespan or prevented disease in "normal" mice in any concentration used (the Sinclair lab used a special disease type of mice and still only got marginal benefits).

 

 

He's a sales guy leveraging the "Harvard brand" for his personal financial gain. That's completely normal in the US and this does not mean he is wrong. But it creates a conflict of interest and makes it particularly necessary to do your own research instead of relying on his statements of the "potential" of his compounds.


Edited by Guest, 10 February 2021 - 02:08 AM.

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#8 MikeDC

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Posted 10 February 2021 - 10:31 PM

In a 2016 paper, mice of 22 month of age were given 400mg/kg for 12 weeks and extended life span by 5% and rejuvenated stem cells. In another thread I have calculated maximum human dose to be less than 3mg/kg. In long term supplementation, one should use low dose probably lower than 300mg. Sinclair and Brenner have published a paper that shows long term supplementation of NAM does not extend lifespan in mice. High dose NR/NMN are similar to high dose NAM. So if you use NR and NMN long term, you need to take 300mg or less and take breaks. Ideally you should also take Taurine which can up regulate NAMPT and reduce the negative feed back loop from NAM. We know most of the NR and NMN turn into NAM.
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#9 Guest

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Posted 10 February 2021 - 10:58 PM

I don't understand what you are saying.

 

 

The first dose you are mentioning is much higher than used in the ITP trial. The second dose is much lower. (both scaled for humans/mice respectively)

 

 

Are you saying, that a dose much higher AND much lower than the one used in the ITP trial would be good? That would be a very strange dose-response relationship.

 

 

The dose was proposed by Chromadex and the NR given to the mice was directly sponsored by them.

 

 

Edit:

 

found the 2016 paper:

https://science.scie.../6292/1436.long

https://science.scie...C1/Zhang.SM.pdf

 

According to the supplement they used exlusively male mice of the inbred C57BL/6JRj strain (30 mice in the intervention group). This strain is very vulnerable to diabetes/insulin resistance, but at the same time protected against diet induced obesity. The mice did receive 400 mg/kg/day of NR for the remainder of their life in the survival analysis


Edited by Guest, 10 February 2021 - 11:33 PM.


#10 MikeDC

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Posted 11 February 2021 - 10:15 AM

In that case the good benefits of long term high dose NR could be either due to starting late at old age or the strain of mice. The ITP might used wild type mice. My point is long term and high dose use of NAM, NR, NMN are not beneficial due to high NAM levels in the body that actually inhibit NAD+ consumption. Previous dose response studies have shown that both high dose NMN and NR are worse than nothing. Low dose is beneficial. The optimum dose could just be less than 200mg.
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#11 MikeDC

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Posted 11 February 2021 - 10:25 AM

Chromadex has no clue how NR dose response works. They assume more NAD+ in the blood represent good response. They have never published long term dose response studies that also show markers such as sirt1 that means supplementation is actually beneficial. Two big issues with high dose NR and NMN. First is negative feed back loop. I remember a long term NAM study showed NAD+ is not increased after long period of time. Second is high dose may actually inhibit Sirt1 and other NAD+ consuming processes

#12 Guest

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Posted 11 February 2021 - 12:14 PM

In that case the good benefits of long term high dose NR could be either due to starting late at old age or the strain of mice. The ITP might used wild type mice. My point is long term and high dose use of NAM, NR, NMN are not beneficial due to high NAM levels in the body that actually inhibit NAD+ consumption. Previous dose response studies have shown that both high dose NMN and NR are worse than nothing. Low dose is beneficial. The optimum dose could just be less than 200mg.

 

 

Again, that would be very strange - almost all interventions function better if you start at a younger age. I don't know of any that works better for total lifespan if started at old age instead of young adulthood (caloric restriction e.g. has no effect if started late in life in mice).

 

 

Charles Brenner you mentioned earlier is the chief scientist of Chromadex. Surely he had a good reason to propose 1000ppm (about 1 gram for humans) in this study.

 

 

On the other hand: if the mice got an substantial overdose - why didn't it shorten their life?



#13 Guest

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Posted 11 February 2021 - 12:52 PM

Again, that would be very strange - almost all interventions function better if you start at a younger age. I don't know of any that works better for total lifespan if started at old age instead of young adulthood (caloric restriction e.g. has no effect if started late in life in mice).

 

 

Charles Brenner you mentioned earlier is the chief scientist of Chromadex. Surely he had a good reason to propose 1000ppm (about 1 gram for humans) in this study.

 

 

On the other hand: if the mice got an substantial overdose - why didn't it shorten their life?

 

 

Under the assumption, that the effect in the 2016 paper is reliable - and not entirely driven by the inbred mouse train - it would suggest that the ITP study under-dosed the mice.

 

The 2016 study used a dose of about 2,5 gram for humans per day if using classical scaling; per HED scaling you end up at about 3,8,gram per day.

http://clymer.alterv.../allometry.html

 

 

So there may or may not be a positive effect if you get at least 2,5g or 3,8g a day - or more. 1 gram doesn't do much in terms of lifespan based on mice.



#14 Phoebus

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Posted 11 February 2021 - 06:46 PM

I am confused by those saying Sinclair never hoped NR/NMN would increase life span

 

that was absolutely one of the selling points. 

 

I mean that is Sinclair's whole schtick is it not? 


Now they need to test actual NAD+ supplementation 

 

Of course that is difficult as it cannot be taken orally by the rats and would need multi week injections. LIkely very time consuming and expensive. 

 

And Sinclair et al don't have a profit motive to study NAD+ either so it might not happen 


Edited by Phoebus, 11 February 2021 - 06:47 PM.

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#15 Kevnzworld

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Posted 13 February 2021 - 04:27 PM

I listened to the podcast.  The one thing that stood out to me was the purported results of the mice autopsies whereas no increase in NAD was found in the tissues.  
We know that this isn’t the case in humans that take NR.  
https://www.cell.com...(19)30940-4.pdf

Could there be a reason that mice metabolize NR differently?   But certainly the lack of increase in the animals NAD contributed to its ineffective lifespan results 



#16 MikeDC

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Posted 13 February 2021 - 07:57 PM

I listened to the podcast. The one thing that stood out to me was the purported results of the mice autopsies whereas no increase in NAD was found in the tissues.
We know that this isn’t the case in humans that take NR.
https://www.cell.com...(19)30940-4.pdf
Could there be a reason that mice metabolize NR differently? But certainly the lack of increase in the animals NAD contributed to its ineffective lifespan results

This also happened to NAM on mice. Long term NAM consumption showed no increase in NAD+. This is due to negative feed back loop in NAMPT. More NAM will suppress NAMPT. So stop using high dose of NAM, NR, NMN and take breaks or take Taurine at the same time. Sinclair did a study that shows Taurine can up regulate NAMPT.

#17 MikeDC

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Posted 13 February 2021 - 08:05 PM

There are two issues with long term NR/NMN use. The first is the negative feed back loop of NAM.
This applied to NR and NMN as well since a majority of oral dose is degraded into NAM.
Another issue is high dose use is not beneficial for health as demonstrated by an NMN study and an NR study.
So using low dose is a good solution to avoid these two issues. Adding Taurine is even better.

#18 able

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Posted 13 February 2021 - 08:48 PM

There are two issues with long term NR/NMN use. The first is the negative feed back loop of NAM.
This applied to NR and NMN as well since a majority of oral dose is degraded into NAM.
Another issue is high dose use is not beneficial for health as demonstrated by an NMN study and an NR study.
So using low dose is a good solution to avoid these two issues. Adding Taurine is even better.

 

 

Yup, taking large dose of NR/NMN that is mostly degraded to NAM is possibly no better than a smaller dose, and maybe even worse.

 

Take sublingual so you bypass the gut and minimize an overload of  NAM.



#19 MikeDC

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Posted 13 February 2021 - 09:16 PM

I listened to the podcast. The one thing that stood out to me was the purported results of the mice autopsies whereas no increase in NAD was found in the tissues.
We know that this isn’t the case in humans that take NR.
https://www.cell.com...(19)30940-4.pdf
Could there be a reason that mice metabolize NR differently? But certainly the lack of increase in the animals NAD contributed to its ineffective lifespan results


We need to know how long after supplementation did they measure nad+ in the tissue?

#20 MikeDC

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Posted 14 February 2021 - 04:11 PM

This is the paper that showed NAM does not extend lifespan or increase NAD+ after long term supplementation.
Low dose is better than high dose on liver steatosis when fed standard diet. Placebo is better than high dose when mice
Is fed standard diet. So when fed a standard diet not high fat diet high dose NAM is worse than
Placebo on liver steatosis. High dose NAM/NR/NMN should be avoided at all cost.

https://www.ncbi.nlm...les/PMC5854409/

Attached Files


Edited by MikeDC, 14 February 2021 - 04:13 PM.

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