392 replies to this topic

[MikeDC]

There is a mice study by Sinclair and Brenner that shows NAM improves some aspect of health and doesn’t extend lifespan. In addition NAM does not increase NAD+ over the long term due to negative feedback loop on NAMPT.
Since most of oral NMN and NR degrades into NAM, the NAD+ raising ability of NMN and NR will diminish over time. It is very important to improve the bioavailability of NR and NMN. The bio available portion of NR and NMN May not be affected by the negative feedback loop because they don’t use NAMPT.

My suggestion is to use Niacin for a couple of weeks to restore NAMPT every 1-2 months.

Edited by MikeDC, 11 November 2019 - 08:13 PM.

[LawrenceW]

Exactly. So you have no proof that NR or NMN lose all their effect on NAD-levels with time? The levels can stay higher than baseline indefinitely as long as supplementation is ongoing, right?

 

 

 

 

My point exactly.  You can either get and maintain the maximum boost or you can initially get the maximum boost for the first 2 months and then settle for a partial boost thereafter.

 

Personally, I prefer the full boost, full time. If you want to settle for less, then that is your choice and is absolutely fine with me.

[Fredrik]

My point exactly. You can either get and maintain the maximum boost or you can initially get the maximum boost for the first 2 months and then settle for a partial boost thereafter.

Personally, I prefer the full boost, full time. If you want to settle for less, then that is your choice and is absolutely fine with me.

Lawrence,

What do you mean by "full boost"? Have you measured your levels of NAD in whole blood?

If not, you have no idea what your supplementation is doing to your NAD-levels. Like the rest of us.

You never answered my question:

Where is the animal or human data showing that other supplements are needed to maintain NAD-levels when using NAD-precursors?

Edited by Fredrik, 11 November 2019 - 11:21 PM.

[LawrenceW]

Where is the animal or human data showing that other supplements are needed to maintain NAD-levels when using NAD-precursors?

 

 

You know as well as everyone else on this board that the data in the form of a published study does not exist yet.

 

And in response to your comment "So there´s no proof your patented "special sauce" is needed along with NMN." 

 

1. We have not filed a patent

2. Unlike big pharma we have no interest in filing for a patent on our "special sauce". 

 

This is not the business where I make my money and I believe that all my friends and family should be getting the most out of their NMN supplementation. 

 

I am simply not interested in endless arguing with individuals such as yourself as to whether something what I and over 100 other people know and have experienced.

 

Good luck on your quest to find the best anti-aging regimen for yourself.

[Fredrik]

You know as well as everyone else on this board that the data in the form of a published study does not exist yet.

Good of you to admit that your earlier statement that "other supplements" are needed to maintain efficacy of NAD-precursors is just based on a hunch and your gut feeling, not on any scientific evidence.

Everytime you claim that or some other nonsens I will ask you of evidence.

Edited by Fredrik, 12 November 2019 - 06:02 AM.

[LawrenceW]

Fredrik.

 

It is obvious from your statements that you are not an experimenter.  We were not patient enough to sit around and wait for the scientists to publish their studies and tell us what is what.  If we had, we would still be waiting on the sidelines getting older and deteriorating.  We started experimenting with NMN supplementation under a medical doctor's supervision with very frequent blood tests. That was late in 2014 and at that time there was no other published literature about NMN other than Dr. Sinclair's initial paper. As a result, we had to figure it out for ourselves. We focused on reducing inflammation as an important objective indicator of success.

 

Through our experimentation and blood testing, we discovered that inflammation levels dropped for the first 2 months and then slowly rose. The molecular biologist in our group researched as best he could and we experimented with adding other supplements.  We found a combination that took our inflammation markers even lower than NMN only and my current inflammation markers are still as low as they were 4 years ago.  I am 61 years old, my biological age according to www.aging.ai is 33 and at every annual  physical check my doctor marvels at my blood tests and says the same thing.  "I have no idea what that stuff you are taking is, but don't stop taking it."

 

I know that this doesn't come even close to what you consider to be scientific evidence, but I am very satisfied with my results. 

 

Now, would you please share with us about your regimen and results.

Edited by LawrenceW, 12 November 2019 - 06:29 AM.

[Fredrik]

I simply asked you for evidence supporting your claim below and you STILL haven't provided any. So please stop making claims you can't support with any references.

LawrenceW, on 10 Nov 2019 - 9:06 PM, said:
"Yes, if you supplement with only NMN or NR. You definitely need to add in other supplements to maintain the efficacy of NAD+ precursors over the long term."

This isn't the self-experimentation thread. I don't pretend to know about NAD-precursors becoming ineffective over time without a "special sauce", like you claim.

Edited by Fredrik, 12 November 2019 - 07:41 AM.

[aribadabar]

I simply asked you for evidence supporting your claim below and you STILL haven't provided any. So please stop making claims you can't support with any references.

LawrenceW, on 10 Nov 2019 - 9:06 PM, said:
"Yes, if you supplement with only NMN or NR. You definitely need to add in other supplements to maintain the efficacy of NAD+ precursors over the long term."

This isn't the self-experimentation thread. I don't pretend to know about NAD-precursors becoming ineffective over time without a "special sauce", like you claim.

 

I think you are beating a dead horse here, Fredrik.

 

You and everyone following the NMN space know there are no scientific references for this and that it's just based on extensive experimentation and bloodwork.

Asking once is fine. Trying to hound for obviously non-existent papers won't change the reality.

 

 Absent scientific studies, self-experimentation+regular bloodwork is the next best thing we can hope for, IMHO.

Edited by aribadabar, 12 November 2019 - 10:41 PM.

[Smith]

According to an April 2018 paper published in Cell Metabolism, oral supplementation of NR/NMN is nearly completely converted to NAM via first-pass metabolism in the liver.  What I'd like to know is if there is ANY benefit to oral supplementation of NMN/NR versus the inexpensive NAM??  

The study's author had this to say: 

Perhaps most importantly, we identify many distinguishing features of the in vivo context. These include high variability in NAD turnover across tissues and nearly complete first-pass metabolism of oral NR and NMN, which likely result in these compounds having systemic effects similar to or indistinguishable from oral NAM.

 

Edited by Smith, 12 November 2019 - 11:21 PM.

[Fredrik]

Aribadabar,

So absent any scientific evidence we should just make things up?

I prefer that we separate hypotheses from known facts. Otherwise it gets really messy.

[able]

According to an April 2018 paper published in Cell Metabolism, oral supplementation of NR/NMN is nearly completely converted to NAM via first-pass metabolism in the liver.  What I'd like to know is if there is ANY benefit to oral supplementation of NMN/NR versus the inexpensive NAM??  

The study's author had this to say: 

 

Rhonda Patrick asked  Dr Sinclair about this in the just released podcast.  His explanation was the small dose used in the Rabinowitz study.  They are not sure, but he thinks a larger dose is required to overwhelm the ability of liver to metabolize all the NR or NMN.

 

 

https://www.foundmyf.../david-sinclair

[LawrenceW]

According to an April 2018 paper published in Cell Metabolism, oral supplementation of NR/NMN is nearly completely converted to NAM via first-pass metabolism in the liver.  What I'd like to know is if there is ANY benefit to oral supplementation of NMN/NR versus the inexpensive NAM??  

The study's author had this to say: 

 

According to this study: https://www.nature.c...018-0009-4#Sec8

 

"Additionally, how to analyse the in vivo kinetics of NMN is also critical, and the results could be significantly affected by differences in sample collection and extraction methodologies22,23. For example, plasma samples need to be processed immediately after collection, as we did in this study, because freezing blood or plasma samples causes inaccurate measures of NMN levels." 

 

The author pointed out a major problem with the method that Lui handled her blood samples before testing for NMN. 

 

 

From: https://www.cell.com...4131(18)30196-7

 

"Blood samples (∼20 μl) were collected by tail bleeding, placed on ice in the absence of anticoagulant, and centrifuged at 16,000g for 5 min at 4oC to isolate serum. At the end of the infusion, the mouse was euthanized by cervical dislocation and tissues were quickly dissected and snap frozen in liquid nitrogen with pre-cooled Wollenberger clamp. Serum and tissue samples were kept at -80°C before metabolite extraction for mass spectrometry analysis."

 

This leads to questions as to the validity of her conclusions about NMN levels in her study.

Edited by LawrenceW, 13 November 2019 - 01:44 AM.

[Smith]

Rhonda Patrick asked  Dr Sinclair about this in the just released podcast.  His explanation was the small dose used in the Rabinowitz study.  They are not sure, but he thinks a larger dose is required to overwhelm the ability of liver to metabolize all the NR or NMN.

 

 

https://www.foundmyf.../david-sinclair

 

Thanks for this.  Dr. Sinclair thought that the dose was too small to get over the body's clearance mechanisms, the Rabinowitz study used 200mg/kg in mice, while Sinclair and others used 400mg/kg. 

 

Unfortunately, that means for a 180lb person, you would need 2g NR per day to get over the body's clearance mechanisms.  Additionally, Rhonda Patrick points out another study done with 1g of NR daily, and it showed no statistical benefit to 1g of NR supplementation.  Finally, Dr. Sinclair points out that NMN needs to be refrigerated otherwise it quickly breaks down.  Asked whether the NMN supplements available for purchase on the market are viable due to not being refrigerated, Dr. Sinclair states he doesn't know.

 

So, if I understood correctly, Dr. Sinclair basically states in this interview:

1. Likely minimum 2000mg/day of NR to cross body's clearance threshold (for a 180lb man), while less than 2g/day of NR will get metabolized by the liver to NAM and be no more effective than NAM supplementation.
2. NMN studies have shown effectiveness at lower doses in mice (200-250 mg/kg), which would be around 1000-1250mg NMN per day in a 180lb man.
3. NMN quickly breaks down and loses effectiveness if not refrigerated after manufacture.  All NMN purchased online is not refrigerated, and it is unknown whether it is as effective as what Dr. Sinclair has used in his trials.

So, it seems one would need at least around 1000-1250mg of NMN daily (that has been cooled to prevent breakdown), or 2000mg of NR daily.  Anything less would probably be metabolized by the liver and end up as NAM.  Dr Sinclair states he takes about 1g of NMN/daily.

This brings up the question, why are the NMN supplements on the market not cooled and provided in such low doses (100-200mg)?

Edited by Smith, 13 November 2019 - 07:40 PM.

[efficientcommittee]

I messaged the nadlab.uk, who I get the Alive By Nature products from, about the storage temperature. They responded

"Storage in the refrigerator is recommended if you are likely to keep the NMN for over 3 months.

 

Testing from Alive By By Nature's supplier found it begins to show appreciable depreciation after 3 months at room temperature, but no lower than 95% purity. At 12 months, it is down to 85-90%.

 

Keeping it refrigerated will slow deterioration greatly so it is not noticeable at 3 months."

 

This can be easily tested and verified. Just keep it for a few months and have it tested. Micro Labs (https://www.microqualitylabs.com/) is a good place for this.

 

Also on your point about 2 gram a day, David Sinclair takes only 1 gram, and if we are all completely honest, in the absence of human studies, the majority of us are trusting David Sinclair knows his stuff, and are merely replicating his regimen. This and also some very good antidotal reviews from users of it.

 

[Smith]

I messaged the nadlab.uk, who I get the Alive By Nature products from, about the storage temperature. They responded

"Storage in the refrigerator is recommended if you are likely to keep the NMN for over 3 months.

 

Testing from Alive By By Nature's supplier found it begins to show appreciable depreciation after 3 months at room temperature, but no lower than 95% purity. At 12 months, it is down to 85-90%.

 

 

Keeping it refrigerated will slow deterioration greatly so it is not noticeable at 3 months."

 

This can be easily tested and verified. Just keep it for a few months and have it tested. Micro Labs (https://www.microqualitylabs.com/) is a good place for this.

 

Also on your point about 2 gram a day, David Sinclair takes only 1 gram, and if we are all completely honest, in the absence of human studies, the majority of us are trusting David Sinclair knows his stuff, and are merely replicating his regimen. This and also some very good antidotal reviews from users of it.

 

Thanks for contacting Alive By Nature. 

 

In the podcast, Dr. Sinclair stated that NMN was effective at a lower dose in mice of 200-250mg/kg, which would translate around 1g to 1.25g/day in a 180lb human.  I suppose thats why Dr. Sinclair takes 1 gram per day.  

I suppose one should be around the 1.25g per day to play it safe in case their NMN has degraded to 90-95% purity.  Anything less seems to just get metabolized by the liver and turned into NAM.  We know NMN administred via IV is effective in boosting blood and tissue NAD+ levels.  I wonder if sublingual NMN would be effective as well and how much NMN could be absorbed sublingually?  The bio-availability of NMN and NR appear to be quite poor when taken orally and even the minimum 1g/day of NMN would end up costing around $150/month, unless we can find some cheaper sources.  I've been taking 400mg/day, but it would appear that might just be a waste of money due to poor bio-availability.

Edited by Smith, 13 November 2019 - 08:45 PM.

[Nate-2004]

What I do nowadays, especially after this recent human study shows NMN nearly useless even compared to NR, is take the ingredients of Nuchido's product plus all but the HGH of the recent thymus study which is much less expensive than buying Nuchido. Basically the formula for me is:

 

Nuchido stack on an empty stomach:

 

50mg Apigenin (Swanson)

2x Viva Naturals Fish Oil (as a flavonoid bioavailability enhancer)

Vitamin C 500mg (as a flavonoid bioavailability enhancer)

Piperine 10mg (as a flavonoid bioavailability enhancer)

EGCG 50% green tea extract (the above components also improve its bioavailability)

Nicotinamide 500mg

Rhodiola Rosea 500mg (I add this in for a bonus, they use rutin)

 

Thymus study stack minus HGH:

Zinc 50mg

DHEA 50mg

Metformin 500mg (only an hour or more after exercise with meal every other day)

4000 IU Vitamin D with food later on

 

I'll be adding in some R-ALA at some point again but I don't see why they bother adding that to Nuchido or what it has to do with anything. They also include zinc in their product for whatever reason so bonus points for including it in the other stack.

 

 

This is the stack you want for NAD+ according to Nuchido. It's nothing different than what I've done in the past except with bioavailability enhancement.

What I do nowadays, especially after this recent human study shows NMN nearly useless even compared to NR, is take the ingredients of Nuchido's product plus all but the HGH of the recent thymus study which is much less expensive than buying Nuchido. Basically the formula for me is:

 

On an empty stomach:

 

50mg Apigenin (Swanson)

2x Viva Naturals Fish Oil (as a flavonoid bioavailability enhancer)

Vitamin C 500mg (as a flavonoid bioavailability enhancer)

Piperine 10mg (as a flavonoid bioavailability enhancer)

EGCG 50% green tea extract (the above components also improve its bioavailability)

Nicotinamide 500mg

 

Thymus study stack minus HGH:

Zinc 50mg

DHEA 50mg

Metformin 500mg (only an hour or more after exercise with meal every other day)

4000 IU Vitamin D with food later on

 

I'll be adding in some R-ALA at some point again but I don't see why they bother adding that to Nuchido or what it has to do with anything. They also include zinc in their product for whatever reason so bonus points for including it in the other stack.

 

 

This is the stack you want for NAD+ according to Nuchido. It's nothing different than what I've done in the past except with bioavailability enhancement.

 

The price of the Nuchido stack comes out to about $103 or the price of two Nuchido bottles, but what you get is much much more than two bottles worth of the same ingredients, several months worth roughly depending on how you hack it. If you want to mix the powders and veg cap them yourself it's even cheaper but I refuse to sit around doing that.

Edited by Nate-2004, 13 November 2019 - 11:58 PM.

[LawrenceW]

 

What I do nowadays, especially after this recent human study shows NMN nearly useless even compared to NR,

 

Fredrik

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Posted Today, 04:03 AM

Fafner55, on 13 Nov 2019 - 03:53 AM, said:

A recent human trial failed to show benefit from NMN supplementation.

 

"Effect of oral administration of nicotinamide mononucleotide on clinical parameters and nicotinamide metabolite levels in healthy Japanese men" (2019) https://www.jstage.j...9-0313/_article

 

You are misrepresenting or misunderstanding the trial.

 

How can a study fail to show benefit when it was not designed to do so?

 

The study you posted was a one-time single dose safety study of oral NMN. It was ONE PILL. It didn´t look at long-term efficacy of anything. Those studies are yet to be published.

 

Quote

"A single-arm non-randomized intervention was conducted by single oral administration of 100, 250, and 500 mg NMN."

 

 

They only looked at SAFETY:

 

Quote

"The single oral administration of NMN was safe and effectively metabolized in healthy men without causing any significant deleterious effects."

 

 

Edited by Fredrik, Today, 04:11 AM.

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[Smith]

Is it reasonable to assume (based upon the Cell Metabolism paper and Dr. Sinclair's recent interview), that the minimum effective dosage of NMN for the avg  person is 1000mg/day? 

That also happens to be the amount David Sinclair takes.

 

Using those two same sources, is it also reasonable to assume the minimum effective dosage of NR is 2000mg/day?

 

The theory, proposed by Dr. Sinclair, is we probably need to overwhelm the body's clearance mechanism which is why lower dosages appear to have no effect in recent studies.  Therefore, anything less than 1000mg/day of NMN or 2000mg/day of NR wouldn't be any different than taking that same amount of NAM, since the liver first-pass metabolizes NMN and NR into NAM.

 

Finally, while we do know that NAM supplementation increases NAD+ levels, but taking NAM is not what we want because it down-regulates the SIRT1 receptor... however, this isn't even certain, because there is some research that cast that into doubt and even suggests NAM supplementation upregulates SIRT1. 

 

I personally think the supplements used in the TRIIM study might be more interesting than these NAD+ precursors, especially since we have data from nine human subjects that showed an average of 2.5 years of age reversal using the Horvath clock test (best epigenetic measurement tool we currently have).

 

TLDR Summary: Less than 1000mg of NMN or 2000mg of NR daily is a waste of money and get metabolized into NAM.  NAM supplementation may or may not have the same benefits of NR/NMN.

 

 

 

 

Edited by Smith, 14 November 2019 - 01:32 AM.

[Nate-2004]

Ok fair point, I honestly hadn't sat down to read all the details otherwise I'd probably have been just as confused as I am now by Reason's post. However, I still think going with my "Nuchido" stack will do just as good of a job and possibly a more effective job considering Conlon's arguments, of achieving the NAD+ results.

Edited by Nate-2004, 14 November 2019 - 01:28 AM.

[Harkijn]

Those considering taking amounts of NAM should not just consider SIRT1 but also think this over:

https://www.longecit...ne/#entry881484

[LawrenceW]

Nate.

 

Which bio-markers do you track to objectively determine the effectiveness of your regimen?

[Oakman]

I messaged the nadlab.uk, who I get the Alive By Nature products from, about the storage temperature. They responded

"Storage in the refrigerator is recommended if you are likely to keep the NMN for over 3 months.

 

Testing from Alive By By Nature's supplier found it begins to show appreciable depreciation after 3 months at room temperature, but no lower than 95% purity. At 12 months, it is down to 85-90%.

 

 

Keeping it refrigerated will slow deterioration greatly so it is not noticeable at 3 months."

 

This can be easily tested and verified. Just keep it for a few months and have it tested. Micro Labs (https://www.microqualitylabs.com/) is a good place for this.

 

Also on your point about 2 gram a day, David Sinclair takes only 1 gram, and if we are all completely honest, in the absence of human studies, the majority of us are trusting David Sinclair knows his stuff, and are merely replicating his regimen. This and also some very good antidotal reviews from users of it.

 I just noticed this NMN stability chart at ProHealth that looks like the storage 'problem' is not an issue with their stabilized product. Don't know how this is accomplished, but it does not require refrigeration it seems, regardless of temp. 

 

NMN Pro uses stabilized NMN that will not degrade at room temperature.

 

[Nate-2004]

Those considering taking amounts of NAM should not just consider SIRT1 but also think this over:

https://www.longecit...ne/#entry881484

 

SIRT1 inhibition was determined not to be a problem with NAM after all at some point a couple years back. See Turnbuckle's thread on Manipulating Mitochondrial Dynamics for references.

[Nate-2004]

Nate.

 

Which bio-markers do you track to objectively determine the effectiveness of your regimen?

 

Reason suggests using HRV, blood pressure and other cardiovascular tests but I don't know if this is the only thing to look at in NAD+ boosting. My HRV I found has varied a lot in morning tests, in fact I could even manipulate the test based on breathing so I dunno. What do you think would be a good way to test improved mitochondrial function.

 

There's also the DNAge test which I need to re-take soon, not sure if that's affected or not but surely if SIRT1 levels are hiked and they're responsible for DNA repair ... I dunno

[LawrenceW]

Reason suggests using HRV, blood pressure and other cardiovascular tests but I don't know if this is the only thing to look at in NAD+ boosting. My HRV I found has varied a lot in morning tests, in fact I could even manipulate the test based on breathing so I dunno. What do you think would be a good way to test improved mitochondrial function.

 

 

I track the following:

 

C-Reactive Protein Tumor Necrosis Factor (TNF-α)             Interleukin-6 (IL-6) Glucose, Serum                               Creatine, Serum                                     BUN

BUN/Creatine ratio                                   

eGFR                                          

AST (SGOT)

       

ALT (SPGT)                                

HgB A1C (Diabetes)                     

Cholesterol (Total)

Triglycerides                                

HDL Cholesterol                          

LDL Cholesterol

Testosterone                                         

PSA                                        

Biological Age

 

If most or all of these are tracking in a positive direction, then that is an indicator that the body is getting healthier which indicates that the anti-aging regimen is getting in and doing its job. 

[Stewart D]

Logically if NAM supplementation and SIRT1 is a problem so is supplementation of NMN and NR as they get turned into NAM.

[Harkijn]

Logically if NAM supplementation and SIRT1 is a problem so is supplementation of NMN and NR as they get turned into NAM.

Yes, it seems to be  because of the SIRT1 thing that several leading brands have incorporated  one or more SIRT1 enhancing polyphenols into their products.

[Linux]

 I just noticed this NMN stability chart at ProHealth that looks like the storage 'problem' is not an issue with their stabilized product. Don't know how this is accomplished, but it does not require refrigeration it seems, regardless of temp. 

 

NMN Pro uses stabilized NMN that will not degrade at room temperature.

 

 

ProHealth NMN is from Bontac Bio-engineering. It has been used in several published NMN studies.

 

http://www.bontac-bi...m/index_en.aspx

[efficientcommittee]

Official response from Alive By Nature a few days ago.

"Our NMN is over 99% pure at production (it varies a few tenths % between batches. It retails that same purity at 3 months when stored at room temperature. We have ran test leaving it in a non climate controlled garage in Las Vegas over the spring/summer months. At 3 months it degraged a bit down to 97.4%. At 6 months it was 95%."

 

[Guest]

For people who didn't bother so far reading up about "NAD-boosters" (like myself) - this new episode (no guests) of R.Patrick gives a good general overview:

 

https://www.foundmyf...odes/nad-nr-nmn

 

 

takeaway from animal studies:

 

1. at low oral dose, neither NMN nor NR are bioavailable beyond the liver

 

2. at high oral dose, there is some very limited bioavailability; but it's not generally making it out of the liver

 

More critical: at either dose, all/most of the NMN/NR that is not used up by liver cells, is metobalised into nicotimanide. The latter is part of feedback-loop that limits the endogenous production of NAD+. So you're externally upping nicotimanide and hence NAD+, but at the same time lowering endogenous production of it - maintaining a "natural" steady-state.

 

 

3. by injecting a high dose of NR (avoiding the first pass effect of the liver), kidneys and muscles are able to directly form NAD+. But it's still not able to go beyond the blood-brain-barrier.

 

 

 

I am curious: why is anyone at all taking oral NAD-boosters? Even ignoring data of detrimental effects on possibly cancer, Sirt-1 etc. If anyone is serious about NAD-boosters: why aren't you all buying needles and inject yourself a high dose every day to have any effect at all? Oral intake seems to be a complete waste of money. What am I missing?

Edited by Guest, 15 November 2019 - 11:12 PM.