Dr. Sinclair about the epigenome, NAD, NR, NMN

A very upbeat dr. Sinclair, talking briefly(at about 58 minutes in) about NR and NMN. The total of the presentation is very interesting btw, even if most of it is not new to many posters here.

Upbeat - a good description.  He does seem to believe we can significantly extend healthspan, and are close to major breakthroughs.

Two points he made that I found interesting:

1.  Both NR and NMN have been shown to extend lifespan in mice.  There is already a study published showing that for NR, so the news is a pending publication showing that for NMN.

2.  Says that both NR and NMN are "interesting molecules", but one difference is, he suggests refrigerating NR as it is not stable.  I was quite surprised by that, as I don't recall Chromadex ever saying anything like that about NR.

Edited by able, 12 August 2018 - 07:00 PM.

Edited by Kevnzworld, 12 August 2018 - 08:38 PM.

Fantastic discussion.  I LOVE this forum!!!

 

 

2.  Says that both NR and NMN are "interesting molecules", but one difference is, he suggests refrigerating NR as it is not stable.  I was quite surprised by that, as I don't recall Chromadex ever saying anything like that about NR.

This is a surprise to me, too. And worrisome because over the years the NR I ordered has sometimes been on transport for days or even weeks, unrefrigerated of course. I may have taken a lot less NR than I thought!

Edited by Harkijn, 13 August 2018 - 04:18 AM.

Sinclair is one of few scientists who can explain complex subjects at a level anyone can understand. Also he has a very pleasant voice to listen too. Most important - this is an excellent overview of his current thoughts on aging molecules.

Highlights I noted:

- Combinations of treatments work best, be it affecting gene transcription or molecule combos, and both he and his peers now agree.

- He says that NMN and NR have the same effects, although there seemingly are differences in speed and/or manner of absorption. So price should be the final determiner. But no one asked why he takes NMN not NR, unfortunately.

- Given that he and his father take grams of Resveratrol daily, it may not be the failed anti-aging supplement it is so often believed to be. I wished someone would have asked him about this and why he takes it at all and in so large a quantity.

- No one asked him, considering he is taking his 3-molecule combo treatment, what results he has experienced. Surprising he was not questioned on this.

Thank the stars he is here with us and willing to talk about things we all hold near and dear!

This video was posted some 5 days ago, the recording was perhaps a bit earlier. So: very recent but no mention of NR/NMN bio-availability, sublingual , buccal, etcetera. Are we overthinking things?

Edited by Harkijn, 13 August 2018 - 03:54 PM.

This video was posted some 5 days ago, the recording was perhaps a bit earlier. So: very recent but no mention of NR/NMN bio-availability, sublingual , buccal, etcetera. Are we overthinking things?

I would imagine it is difficult to get the mice to take it sublingual 

I do wonder how much difference the bioavailability  might be - putting NR/NMN in drinking water of mice, that drink in small sips.  

Wouldn't some quantity absorb in their tongue, mouth, esophagus, and all?

Is it possible the bioavailability  is very different from a human swallowing a capsule?

Good presentation. Interestingly when asked about NR, he said it boosts NAD but is somewhat unstable , that’s why it should be refrigerated
He and his dad take NMN, 500 mg, resveratrol 1000 mg and Metformin. 800mg?
He hinted at as of a yet unpublished study showing life extension in mice with NMN.

Any idea what brand of resveratrol he takes?  1,000mg seems sort of massive.  I'm reminded of curcumin, where there's seemingly a pretty large gap between taking say "curcumin" via some turmeric extract vs taking a large dose of curcumin from a formulation like Longvida, Meriva, or even BCM95 -- what's the equivalent product for resveratrol?

Edited by brosci, 14 August 2018 - 03:29 PM.

Any idea what brand of resveratrol he takes?  1,000mg seems sort of massive.  

He doesn't say.The way he says it makes you think he doesn't care about the brand just as long as the product really contains resveratrol. The bio availability of resveratrol is low, so my guess is that he tries to counter that by taking a lot. Here on Longecity is a lively subforum of resveratrol users discussing  other ways of improving bio availibility. You may want to take a look there.

As I posted above, his protocol does not seem influenced by indications that NADprecursors are mainly turned into Nicotinamide in the stomach.... That's interesting because if anyone should know about this is it would be either Sinclair or Brenner and Guarente.

He doesn't say.The way he says it makes you think he doesn't care about the brand just as long as the product really contains resveratrol. The bio availability of resveratrol is low, so my guess is that he tries to counter that by taking a lot. Here on Longecity is a lively subforum of resveratrol users discussing  other ways of improving bio availibility. You may want to take a look there.

As I posted above, his protocol does not seem influenced by indications that NADprecursors are mainly turned into Nicotinamide in the stomach.... That's interesting because if anyone should know about this is it would be either Sinclair or Brenner and Guarente.

Clarification - The Liu study showed that NAD precursors are mainly turned into Nicotinamide in the stomach AND LIVER.

It shows that none was found to "escape" the liver and reach other tissues, without first being degraded to NAM.  

Liu says some % of NR or NMN likely makes it through the stomach, is metabolized to NAD+, degraded by CD38 to NAM, then excreted as NAM to the rest of the body.  

So they have a different effect than NAM in the liver, but may have a limited difference from NAM outside the liver.

That is assuming the Liu findings always apply.  Other studies clearly show some NR/NMN do make it thru the liver intact.  Those are usually 300-400 Mg/Kg dosages - 6-8x the dose Liu used.  

So there are questions about bioavailability outside the liver. 

You're right, he doesn't seem to acknowledge that shortcoming, yet.  

He is listed on a patent application filed this past January for some NMN "derivatives".

My assumption has been, he will introduce better delivery methods or more bioavailable options when he has studies published with them, but until then he might not talk about the bioavailability problem.

Edited by able, 14 August 2018 - 04:33 PM.

Thanks Able, you're quite right in dotting the i's and crossing the t's!

Edited by Harkijn, 14 August 2018 - 04:38 PM.

True but the fact still remains that NAD+ is still raised in vivo with NAD+ precursors by 90% for a while, followed by a drop to 40% above baseline. That means it's still working, regardless if it's broken down in the liver. This is fine for now, I'll take it till better comes along. Also, apigenin inhibits CD38 to some degree or another so drink your chamomile or take it directly. Keep inflammation down. Fast regularly and maybe try some D+Q to further lower NAD+ consumers. That's all we can do in these early times. 

Homeostasis is a known problem with NAD+ precursors and pretty much any other intervention that doesn't address the upstream problem which is a loss of differentiation through damage. You can sort of get around this by cycling I think, 30 days on 30 days off. Maybe cycle NR with Sulforaphane, etc. That's what I'm considering for the moment. Saves money. 

I mean, if you can get a 90% boost in NAD+ for 6 months out of the year, that might equate to a good increase in healthspan if not lifespan.

Edited by Nate-2004, 14 August 2018 - 05:07 PM.

True but the fact still remains that NAD+ is still raised in vivo with NAD+ precursors by 90% for a while, followed by a drop to 40% above baseline. That means it's still working, regardless if it's broken down in the liver. This is fine for now, I'll take it till better comes along. Also, apigenin inhibits CD38 to some degree or another so drink your chamomile or take it directly. Keep inflammation down. Fast regularly and maybe try some D+Q to further lower NAD+ consumers. That's all we can do in these early times. 

 

Homeostasis is a known problem with NAD+ precursors and pretty much any other intervention that doesn't address the upstream problem which is a loss of differentiation through damage. You can sort of get around this by cycling I think, 30 days on 30 days off. Maybe cycle NR with Sulforaphane, etc. That's what I'm considering for the moment. Saves money. 

 

I mean, if you can get a 90% boost in NAD+ for 6 months out of the year, that might equate to a good increase in healthspan if not lifespan.

I agree with all that and practice much of those as you do Nate - fasting, exercise, cycling therapies, etc.

But I still would like to understand what is going on as much as possible, to maximize the benefits to NAD+.

NR does raise NAD+, but  as you know, so does NAM - even more than NR in the liver, mg to mg.

I'd like to know why Liu shows NO NR or NMN escapes the liver, but Mills show NMN is in the bloodstream and muscles, intact, in minutes.  

Is it  the higher dosages?  If so, I might take higher dosages intermittently - more cycling off and on.

For now, I'll stick with sublingual delivery until something better comes along.  

But it would be nice to hear some researchers discuss the elephant in the room.

Sinclair is one of few scientists who can explain complex subjects at a level anyone can understand. Also he has a very pleasant voice to listen too. Most important - this is an excellent overview of his current thoughts on aging molecules.

 

Highlights I noted:

 

- Combinations of treatments work best, be it affecting gene transcription or molecule combos, and both he and his peers now agree.

- He says that NMN and NR have the same effects, although there seemingly are differences in speed and/or manner of absorption. So price should be the final determiner. But no one asked why he takes NMN not NR, unfortunately.

- Given that he and his father take grams of Resveratrol daily, it may not be the failed anti-aging supplement it is so often believed to be. I wished someone would have asked him about this and why he takes it at all and in so large a quantity.

- No one asked him, considering he is taking his 3-molecule combo treatment, what results he has experienced. Surprising he was not questioned on this.

 

Thank the stars he is here with us and willing to talk about things we all hold near and dear!

Good Presentation.  I would have liked for someone to ask whether his Dad is on Rapamycin for longevity.  Bet he is.  I'm 72 and take N + R, Metformin, and Rapa.  Sinclair only mentioned Rapa as working better when taken with Metformin.  He is probably reluctant to get into Rapa because it is a Rx. drug with a sorted history and people could compromise there immune system if taken incorrectly.  The audience member who asked about Rapa stated that other elderly people did not take it because of compromising the immune system which has been totally disproved with intermediate dosing. (once weekly)  TORC1 inhibition enhances immune function and reduces infections in the elderly, attached.

He also did not mention supplementing NMN with hydrogen sulfide (H 2 S) to boost effectiveness as was found in his last trial. attached.  Unfortunately, many of the audience members on these talks are uneducated when it comes to treatments of ageing.

He also did not mention supplementing NMN with hydrogen sulfide (H 2 S) to boost effectiveness as was found in his last trial. attached.  

Where was this mentioned and how was it done? I couldn't find anything about it.

Where was this mentioned and how was it done? I couldn't find anything about it.

Here is the link to the study about H2S boosting

http://sci-hub.tw/10...ell.2018.02.008

Site:  https://alivebynature.com/nmn-new/

Edited by Kentavr, 18 August 2018 - 02:02 PM.

ABN's NMN is just as expensive as NR was two years ago. NR is definitely cheaper than NMN at this point. Given the differences in how people are affected by either I wonder if it's just, if NR gives you bad side effects use NMN and vice versa. Reason at Fight Aging is convinced that boosting NAD+ just pushes a damaged engine harder without addressing any of the root cause issues upstream. I tend to agree but I still cycle NR.

Edited by Nate-2004, 18 August 2018 - 02:50 PM.

Even for NAD+ only, this site has grown so vast that many here will be very selective in the threads they want to follow.

So for completeness I place a link to a thread about raising H2S for NAD+:

https://www.google.c...0ZigqKqd2rUKBP3

ABN's NMN is just as expensive as NR was two years ago. NR is definitely cheaper than NMN at this point. Given the differences in how people are affected by either I wonder if it's just, if NR gives you bad side effects use NMN and vice versa. Reason at Fight Aging is convinced that boosting NAD+ just pushes a damaged engine harder without addressing any of the root cause issues upstream. I tend to agree but I still cycle NR.

Nate, I also thought that to choose as an additive: N+R, NR or NMN.

N+R  I removed because D-ribose increases the chance of Alzheimer's disease:

https://www.ncbi.nlm...les/PMC4741441/

Why did I do this? Because side effects can develop imperceptibly, and I do not want to then suddenly discover this illness.

NR does not increase the risk of Alzheimer's.

NMN reduces the risk of Alzheimer's disease. This is a plus for NMN:

https://alivebynatur...amide-riboside/

The second positive factor is that with long use of NMN level NAD+ is higher than that of NR:

" NAD+ increase is over 500% at 60 days" - This is a very significant result. And I want to pay for the result.

NR does not increase level NAD+ so much.

I ask you to see this topic:

https://www.longecit...erience-thread/

LawrenceWB investigated the effect of NMN on the results of medical analyzes.

https://innovareacad...Suppl2/1092.pdf

 - - theoretically, this is equivalent to a dose of 333 mg / day

+ To the liver does not metabolize NMN, I chose the sublingual form NMN.

@kentavr

Would you mind posting that study where NMN boosts NAD+ in humans with 500% or any human study that uses NMN?

And why not use NR sublingually?

@kentavr

 

Не могли бы вы опубликовать это исследование, где NMN ускоряет НАД + у людей с 500% или любым человеческим исследованием, использующим NMN?

 

И почему бы не использовать сублингвально NR?

See 34 pages on the link: 

http://sci-hub.tw/ht...?code=cell-site

And why not use NR sublingually?

Edited by Kentavr, 18 August 2018 - 08:04 PM.

As far as studies, I have no idea. As far as boosting NAD +, I have no idea. All the back and forth got to be too much to follow for me. Sublingual NR did not act like sublingual NMN does, otherwise I would still be using the NR which I have. 

There is a definite cognitive, mood, and exercise boost from NMN. NMN 10 minutes before my morning fat coffee helps me to not be an ogre for the first hour of my morning. I can get out the door, and on the mountain bike trails in around an hour with my wife. She was a fast natural 100 meter sprinter in high school, and rides her bike that way on the hills. (I am mostly a spinner, but am keeping up better or beating her at times) She does not take NR or NMN, but is 12 1/2 years younger.  I am 58. I am taking the powder under the tongue 8 to 10 times a day or around 1000 mg.. I am not part of any free NMN study by ABN. The NMN does not effect my sleep like afternoon NR doses did. I can take NMN an hour or two before bed.

Nate, you train regularly, so I would guess that you are aware of your level of fitness, and would notice an improvement. I would suggest you try NMN for the benefits I mentioned if you want those things. As far as percentages of NAD + increased, if that is what you want, then I do not know if one is better.

EDIT: I TRUST OAKMAN'S QUANTIFICATION COMPLETELY. I WILL FOLLOW HOW IT GOES FOR THEM CLOSELY.I AM NOT SAYING I DISTRUST OTHERS THOUGH.

Edited by Heisok, 18 August 2018 - 08:11 PM.

As far as studies, I have no idea. As far as boosting NAD +, I have no idea. All the back and forth got to be too much to follow for me. Sublingual NR did not act like sublingual NMN does, otherwise I would still be using the NR which I have. 

 

There is a definite cognitive, mood, and exercise boost from NMN. NMN 10 minutes before my morning fat coffee helps me to not be an ogre for the first hour of my morning. I can get out the door, and on the mountain bike trails in around an hour with my wife. She was a fast natural 100 meter sprinter in high school, and rides her bike that way on the hills. (I am mostly a spinner, but am keeping up better or beating her at times) She does not take NR or NMN, but is 12 1/2 years younger.  I am 58. I am taking the powder under the tongue 8 to 10 times a day or around 1000 mg.. I am not part of any free NMN study by ABN. The NMN does not effect my sleep like afternoon NR doses did. I can take NMN an hour or two before bed.

 

Nate, you train regularly, so I would guess that you are aware of your level of fitness, and would notice an improvement. I would suggest you try NMN for the benefits I mentioned if you want those things. As far as percentages of NAD + increased, if that is what you want, then I do not know if one is better.

 

EDIT: I TRUST OAKMAN'S QUANTIFICATION COMPLETELY. I WILL FOLLOW HOW IT GOES FOR THEM CLOSELY.I AM NOT SAYING I DISTRUST OTHERS THOUGH

Sorry  

Based on recent research, I would not advise you to drink coffee:

http://www.dailymail...tudy-shows.html

I am now reviewing its use

Edited by Kentavr, 18 August 2018 - 08:18 PM.

 

See 34 pages on the link: 

 

http://sci-hub.tw/ht...?code=cell-site

 

 

For me, these 500% are not so important right now.

 

It is important that with the continuation of NMN reception, the level of NAD + increases.

With the continuation of NR reception, the level of NAD + decreases.

 

The measurement unit is normalized to protein content so you cannot simply compare that to other measurements. Love this study btw, based on it I have started taking taurine. But its in mice.

 

@Heisok, nice caps lock - you did not do that when you were on NR :-) :-). Seems you have gone up in dose quite a bit?

Edited by stefan_001, 18 August 2018 - 08:42 PM.

See 34 pages on the link:

http://sci-hub.tw/ht...?code=cell-site



For me, these 500% are not so important right now.

It is important that with the continuation of NMN reception, the level of NAD + increases.
With the continuation of NR reception, the level of NAD + decreases.

As far as studies, I have no idea. As far as boosting NAD +, I have no idea. All the back and forth got to be too much to follow for me. Sublingual NR did not act like sublingual NMN does, otherwise I would still be using the NR which I have. 

 

There is a definite cognitive, mood, and exercise boost from NMN. NMN 10 minutes before my morning fat coffee helps me to not be an ogre for the first hour of my morning. I can get out the door, and on the mountain bike trails in around an hour with my wife. She was a fast natural 100 meter sprinter in high school, and rides her bike that way on the hills. (I am mostly a spinner, but am keeping up better or beating her at times) She does not take NR or NMN, but is 12 1/2 years younger.  I am 58. I am taking the powder under the tongue 8 to 10 times a day or around 1000 mg.. I am not part of any free NMN study by ABN. The NMN does not effect my sleep like afternoon NR doses did. I can take NMN an hour or two before bed.

 

Nate, you train regularly, so I would guess that you are aware of your level of fitness, and would notice an improvement. I would suggest you try NMN for the benefits I mentioned if you want those things. As far as percentages of NAD + increased, if that is what you want, then I do not know if one is better.

 

The results are what matter to me also.  We seem to be constantly trying to interpret clues in research that show molecule x increases or decreases something in the body and what that might mean to combat disease and aging in humans long term.

But so far, the human testing hasn't shown any real benefit other than 40-50% increase in NAD+ in the liver.

NR was probably the first supplement I ever took that had a noticeable impact.  Better skin, hair, nails, sleep, and maybe better energy, but hard to say for sure on that.

The sublingual NMN has FAR more benefit for strength, energy, and endurance.   

I don't know if it does anything else.  But those, I do know without doubt.