2255 replies to this topic

[Nate-2004]

I don't think half-life matters as much as the length of time that NAD+ is boosted. From other studies and reviews linked a couple weeks ago in this thread it shows that it starts tapering back off around 24 hrs. That and peak NAMPT times was my basis for reducing my dosage to 375 once at lunch.

Edited by Nate-2004, 10 October 2016 - 07:49 PM.

[Female Scientist]

Thanks for the link, Bryan -- Can I just say how amazing it is that many of us around the world are able to watch this simultaneously -- I can't help but sound like an old fogey, but this new technology still blows me away! Fascinating to hear it directly from Brenner.....

 

 

 

You read the study we posted by Samuel Trammell correct? That was Samuel Trammell's Postdoc PhD thesis. Download thesis. This new one was the full study release from the University of Iowa under Charles Brenner just published in the prestigious Publication Nature. So it represents the conclusions of the entire team. It included the pre-trial of a 52-year old man (Charles Brenner was the subject) and the first Clinical trial of 12 healthy men and women under the 100, 300 and 1,000 mg dosages. Here is the raw study data so you can confirm this for yourself https://www.ebi.ac.u...lights/MTBLS368

So does this give us anything new on half-life?

 

 I didn't see anything specific to half-life. Watching Brenner live now. Watch Lots of great insight!!!!!!

 

 

[midas]

 

 

You read the study we posted by Samuel Trammell correct? That was Samuel Trammell's Postdoc PhD thesis. Download thesis. This new one was the full study release from the University of Iowa under Charles Brenner just published in the prestigious Publication Nature. So it represents the conclusions of the entire team. It included the pre-trial of a 52-year old man (Charles Brenner was the subject) and the first Clinical trial of 12 healthy men and women under the 100, 300 and 1,000 mg dosages. Here is the raw study data so you can confirm this for yourself https://www.ebi.ac.u...lights/MTBLS368

So does this give us anything new on half-life?

 

 I didn't see anything specific to half-life. Watching Brenner live now. Watch Lots of great insight!!!!!!

 

 

Just watched it, very interesting for me, not sure why but it made more sense to me to listen to him than it does reading research papers....Extremely glad I watched it.

Though I was shocked to see that the peak watching figure on YouTube was five of us which had dropped to four by the end..

[Oakman]

 

 

 

You read the study we posted by Samuel Trammell correct? That was Samuel Trammell's Postdoc PhD thesis. Download thesis. This new one was the full study release from the University of Iowa under Charles Brenner just published in the prestigious Publication Nature. So it represents the conclusions of the entire team. It included the pre-trial of a 52-year old man (Charles Brenner was the subject) and the first Clinical trial of 12 healthy men and women under the 100, 300 and 1,000 mg dosages. Here is the raw study data so you can confirm this for yourself https://www.ebi.ac.u...lights/MTBLS368

So does this give us anything new on half-life?

 

 I didn't see anything specific to half-life. Watching Brenner live now. Watch Lots of great insight!!!!!!

 

 

Just watched it, very interesting for me, not sure why but it made more sense to me to listen to him than it does reading research papers....Extremely glad I watched it.

Though I was shocked to see that the peak watching figure on YouTube was five of us which had dropped to four by the end..

 

======

 

I do so enjoy listening to someone who says so much, and quickly, that I need to concentrate 100% to comprehend all the information imparted.  The power of focus !  And I agree that a good talk like this covers much, and concentrates reams of dedicated work nicely into a hour or so of learning. 

 

So glad I found the link here yesterday...

[malbecman]

 From reading the Nature paper, it looks like it might be nice to take 300 or even 1000mgs to get a real boost in levels.  Most supplements being sold are ~125mg.  I realize we don't really know what the optimal levels are, of course...just operating

on the more is better principle (which might not be best).

[Bryan_S]

If I could have gotten a hold of the announcement sooner I bet we could have drawn in a larger audience. Hurricane Matthew had me off-line for a few days doing coverage. My eyes are open again.

Edited by Bryan_S, 10 October 2016 - 10:13 PM.

[bluemoon]

 From reading the Nature paper, it looks like it might be nice to take 300 or even 1000mgs to get a real boost in levels.  Most supplements being sold are ~125mg.  I realize we don't really know what the optimal levels are, of course...just operating

on the more is better principle (which might not be best).

 

Elysium Basis' dose is 250 mg per day even though two 125 capsules. I remember reading that David Sinclair thought you'd need at least 1000 mg, which starts to get expensive. It is possible he said 500 mg, but I think 1,000 mg. 

[SearchHorizon]

I realize that this post is somewhat "out of order" but just wanted to interject my observation on co-administering melatonin with NAD precursors.

 

Melatonin appears to increase SIRT1 and NAMPT expressions. NAMPT is relevant here, because after NR is converted to NAD, it will go through different salvage pathways, one of which involves NAMPT. Basically, melatonin appears to amplify the effect of NAD precursors, such as NR.

[Oakman]

Now that I have had time to reflect on Dr. Brenner's video, (tried) to read and understand the paper, a couple items got me pondering. 

 

1. He said that NR helped (in mouse and rat) the more DIS-regulated the diet and metabolism was, or the older it was. He describes that (@50 min 45 sec), but for healthy individuals, it did little, or nothing noticeable. Basically, "If it ain't broke, you can't fix it". We're left to decide how much to take, and piece together why.

 

As healthy metabolism begins to break down esp. as we age, it appears NR holds most promise for those that need it most, old people, sick or metabolically deficient people. I can include myself in the old part, but I'm pretty healthy otherwise. And it follows that the healthier we try to keep ourselves, the less NR may assist us. Frustrating.

 

It also might explain why many say it's hard to tell what NR is doing for them, if anything, esp. age < 60 or so.  Also, perhaps (over) supplementation is causing the inflammation people (including myself) have experienced, because we don't need as much as we are currently taking.  IOW “the dose makes the poison.”  I found this interesting concerning extra-cellular NAMPT (eNAMPT) causing inflamation > http://www.anti-agin...n-inflammation/

 

2. He talked about a divided dose of 125mg, 250mg total in the study, although for himself, he used 1g/day. What I got was the blood serum levels of NAAD are a good indicator, but what about actual invivo positive/negative effects over time? Maybe less is more or maybe less is, well, not good at all  > http://www.nature.co...g-curve-1.11644

 

Exciting times.

Edited by Oakman, 11 October 2016 - 02:26 AM.

[Bryan_S]

Now that I have had time to reflect on Dr. Brenner's video, (tried) to read and understand the paper, a couple items got me pondering. 

 

1. He said that NR helped (in mouse and rat) the more DIS-regulated the diet and metabolism was, or the older it was. He describes that (@50 min 45 sec), but for healthy individuals, it did little, or nothing noticeable. Basically, "If it ain't broke, you can't fix it". We're left to decide how much to take, and piece together why.

 

As healthy metabolism begins to break down esp. as we age, it appears NR holds most promise for those that need it most, old people, sick or metabolically deficient people. I can include myself in the old part, but I'm pretty healthy otherwise. And it follows that the healthier we try to keep ourselves, the less NR may assist us. Frustrating.

 

It also might explain why many say it's hard to tell what NR is doing for them, if anything, esp. age < 60 or so.  Also, perhaps (over) supplementation is causing the inflammation people (including myself) have experienced, because we don't need as much as we are currently taking.  IOW “the dose makes the poison.”  I found this interesting concerning extra-cellular NAMPT (eNAMPT) causing inflamation > http://www.anti-agin...n-inflammation/

 

2. He talked about a divided dose of 125mg, 250mg total in the study, although for himself, he used 1g/day. What I got was the blood serum levels of NAAD are a good indicator, but what about actual invivo positive/negative effects over time? Maybe less is more or maybe less is, well, not good at all  > http://www.nature.co...g-curve-1.11644

 

Exciting times.

 

We've established here on LongeCity the effects are more noticeable the older you are. That's not to say it won't help the young. Take the hearing loss experiments or muscle or nerve damage experiments, these are situations where NAD supplementation helps save off tissue damage in younger individuals. I think these are peak demand situations. We can also look at DNA damage as something we wouldn't notice happening that would also be helped by supplementation. The "A Phase 3 Randomized Trial of Nicotinamide for Skin-Cancer Chemoprevention" also demonstrated how administration of NAM helped save off cancers. So UV, ionizing radiation or just free radicals are all things that take their toll on our DNA and the repair processes largely go unnoticed but require a lot of NAD.

 

 

I liked his Pellagra examples in the beginning of his talk. It totally brought home the point of depleted NAD levels where the skin was exposed to UV radiation and cellular repair was hindered.

 

As far as the NAAD those are intracellular levels, blood serum would be extracellular. What I found really interesting is NAD being converted to NAAD at 45 times normal levels and used as NAD levels began to fall to boost and maintain levels. 

 

The paper and video will be worth reading and watching again to gain other insights.

Edited by Bryan_S, 11 October 2016 - 04:08 AM.

[TaiChiKid]

And human trial says NR is 'safe:'  https://www.scienced...61010135418.htm

[Harkijn]

Dr. Brenner invites questions by email (a link I clicked on was broke). Perhaps we can send one collective email with questions we have.

 

One thing I would really like to know: did the human participants take NR with their breakfast or well before it? In other words: are there any foodstuffs that help or hinder NR absorption?

 

 

[bluemoon]

With respect to dose, didn't a study last year show that 300 mg raised NAD+ as much as 1000 mg? 

[midas]

 

 From reading the Nature paper, it looks like it might be nice to take 300 or even 1000mgs to get a real boost in levels.  Most supplements being sold are ~125mg.  I realize we don't really know what the optimal levels are, of course...just operating

on the more is better principle (which might not be best).

 

 I remember reading that David Sinclair thought you'd need at least 1000 mg, which starts to get expensive. It is possible he said 500 mg, but I think 1,000 mg. 

 

 

 

 

I seem to remember that Sinclair was actually talking about NMN and not NR when he said this......The NMN thing has been conveniently used by some companies whilst promoting NR which has caused a fair bit of confusion over the last couple of years. And if I am not mistaken NR actually works out to be the more efficientprecursor of NAD out of the two...

 

 

 

 

With respect to dose, didn't a study last year show that 300 mg raised NAD+ as much as 1000 mg? 

 

 

This is how I remember the results, or at least I remember thinking it was not worth me taking 1 gram rather than the 250-300mg dose...

 

Also I am convinced that the thing with NAD depletion is 100% age related in most of us other than those that are unlucky enough to have a  genetic issue in younger years that may restrict the NAD supply in some way...

Some of use IMO are predisposed to earlier ageing and illness because of our genetic make-up rather than our lifestyle. People with genes that are maybe not so good are far more susceptible to earlier onset health issues than others, and this is possibly due to earlier NAD depletion which again IMO is due to genetics and so leaves them more open to earlier onset age related illness..These people in my mind are far more likely to benefit from NR supplementation, I am one of these people.

 

I have a couple of health issues and researching one of those in particular is what brought me to NR research around three years ago, I didn't start taking it until I was sure that it was not going to do any harm, once I was convinced of this I started using NR which was around 12 months ago, almost instantly I felt better in several ways, more energy, much clearer mind, far better ability to do some exercise and a huge jump over all feeling of better health. So much so I am convinced that NR is a VERY special discovery......Some things to note here are I am 56 years old, have a heart condition and have also another underlying illness that has been related to CFS (Chronic Fatigue Syndrome)  although I think CFS is just a label for some sort of viral issue that has not really been figured out yet....

Oh yeah, I only take 125mg of NR which is more due to my financial situation and the fact that it is not readily available here in the UK more than anything else, but the big surprise for me is that the relatively small dose of NR makes a massive difference....One last thing, this IS NOT a placebo affect, I stopped taking the NR for about four weeks and my health started to slip again, went back to it and felt the benefit again within a couple of days.   

 

 Maybe younger people that still have a good natural supply of NAD will not feel the benefits of NR in the same way as people without Pellagra would not have felt the benefit of a diet that included high levels of B3/Niacin back in the day. Chances are the body will only use whats there if its actually needed  healthy older and younger people in general may not feel any difference.... This is why early on in a couple NR related threads I asked if people could say how old they were and whether they were in good health or not. I really think that is a big issue when it comes to NR supplementation...

 

Sorry if this wandered off topic slightly and please keep in mind that I am no scientist, some of the research I find difficult to understand but I understand enough to get what's going on......One thing I do know for sure is how I feel physically, this stuff works, well for me at least, and of that I have no doubt.

The only down side that I can think of is some joint pain, mostly in my wrists and fingers every now and then, but absolutely nothing that would make me think twice about taking NR...

 

Edited by midas, 11 October 2016 - 02:18 PM.

[bluemoon]

 

 

I seem to remember that Sinclair was actually talking about NMN and not NR when he said this......The NMN thing has been conveniently used by some companies whilst promoting NR which has caused a fair bit of confusion over the last couple of years. And if I am not mistaken NR actually works out to be the more efficientprecursor of NAD out of the two...

 

 

 

 

Sinclair was talking about NR and that made my ears perk up since I have been wanting to try it for a while until he said that. I'll try to find the quote since it was likely on an NR thread here. What I can't remember is that he said a person would likely need at least 500mg, or he said at least 1000mg. Both were out of my price range at the time. I thought he might be wrong but of course not sure.

 

Some have reported good results at 125 mg while others have said they have needed at least 500 mg to feel an effect. Unfortunately, people rarely state their age or weight. 

[Harkijn]

In today's issue of Cell Metabolism, Leonard Guarente summarizes a study(also published today) about giving NR to mice with the disease Ataxia telangiectasia. The results on mice are sensational:

 

 http://dx.doi.org/10...met.2016.09.019

 

 

 

[Bryan_S]

Dr. Brenner invites questions by email (a link I clicked on was broke). Perhaps we can send one collective email with questions we have.

 

One thing I would really like to know: did the human participants take NR with their breakfast or well before it? In other words: are there any foodstuffs that help or hinder NR absorption?

 

I've written him before and can submit a list of questions.

 

With respect to dose, didn't a study last year show that 300 mg raised NAD+ as much as 1000 mg? 

 

It was part of the ChromaDex release after the 4th Federation of American Societies for Experimental Biology (FASEB) Science Research Conference on NAD+ Metabolism and Signaling Aug. 12, 2015

 

"The oral presentation and poster presented data which indicate that single doses of NIAGEN® NR can elevate the co-enzyme NAD+ in the blood by as much as 2.7-fold. In the first-in-humans clinical trial which involved dosing twelve healthy adult subjects, the group showed that blood cell NAD+ increased with single 100 mg, 300 mg and 1 gram doses of NIAGEN® NR. Average maximal increases in blood NAD+ were approximately 30% at the 100 mg dose and approximately 50% at the higher doses. Increases in blood NAD+ tended to be sustained for longer times at higher doses."

 

We are all looking for suggestive data supporting dosage. However I think that "total Daily dosage" will be a sliding scale depending on the age, health and special circumstances of the individual. If I'm a young football player and I want to guard against TBI (Traumatic Brain Injury (unproven in humans but in clinical trial)) my needs are going to be different than a 65-year old man trying to feel more energetic. So I think injury/prevention and disease are the 2 factors favoring higher dosages. For aging I think dosages spanning 100-1000 mg all depend on where you fall on the depletion scale.

 

 

Since NR is water soluble I just don't want to take more at anyone time than my body can process. Thats why I advocate breaking the dose up over the day, splitting it up in the morning and evening, even more if you're taking higher amounts. So we're asking questions about the half-life of NR not about the persistence of NAD within the cell as Brenner so thoughtfully answered. So if NAAD is a storehoused NAD reserve the idea of flushing unprocessed NR down the drain might be moot, I just want a concrete answer as do others

 

It would be wonderful if it worked this way but not the way I've understood water soluble vitamins to work.

[Nate-2004]

In today's issue of Cell Metabolism, Leonard Guarente summarizes a study(also published today) about giving NR to mice with the disease Ataxia telangiectasia. The results on mice are sensational:

 

 http://dx.doi.org/10...met.2016.09.019

 

This is good news, though I wish it were the case that it affected neurodegenerative disorders like essential tremor. Then again I take any mouse studies with a grain of salt, and I also don't get why they don't just test these things on humans with Ataxia telangiectasia, given that NR is proven safe in humans. I guess it's always coming down to money, but it seems like the money would be better saved for humans than wasted on mice.

[APBT]

In today's issue of Cell Metabolism, Leonard Guarente summarizes a study(also published today) about giving NR to mice with the disease Ataxia telangiectasia. The results on mice are sensational:

 

 http://dx.doi.org/10...met.2016.09.019

 

FULL TEXT:

Attached Files

•  Overcoming ATM Deficiency by Activating the NAD+ SIRT1 Axis.pdf   531.27KB   19 downloads

[midas]

 

Sinclair was talking about NR

 

 

I  would be very interested to see where you read that. All I have seen over the last three years are company's marketing NR use the Sinclair study on NMN which he found raised NAD falsely to market NR.....And ironically we have recently seen that NR seems to be a better precursor of NAD than NMN anyway...

[Thell]

I've written him before and can submit a list of questions.

 

A short list would be great. I'd like to ask about his plans with nromics regarding the NR levels testing kit. As in, does he envision an inexpensive home test kit or clinic run test procedure done during Dr. visits and blood panels? And has any progress been made in this direction or are we still some years and some breakthroughs away from reality?

 

Also, what can he tell us about the synergistic effect of pterostilbene and resveratrol to NR.

Edited by Thell, 11 October 2016 - 09:17 PM.

[bluemoon]

 

 

Sinclair was talking about NR

 

 

I  would be very interested to see where you read that. All I have seen over the last three years are company's marketing NR use the Sinclair study on NMN which he found raised NAD falsely to market NR.....And ironically we have recently seen that NR seems to be a better precursor of NAD than NMN anyway...

 

 

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

 

Sinclair was definiately talking about NR. Keep in mind that almost no one was taking NMN then or even now. What I can't remember is if he said at least 500 mg or at least 1000 mg. I think it was the latter but that was two years ago and am relying on more recent studies.

 

 

 

 

 

 

 

 

 

 

 

 

 

[midas]

 

 

 

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

 

Sinclair was definiately talking about NR. Keep in mind that almost no one was taking NMN then or even now. What I can't remember is if he said at least 500 mg or at least 1000 mg. I think it was the latter but that was two years ago and am relying on more recent studies.

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Maybe this you remember..?

 

http://www.rexresear...ir/sinclair.htm

 

"The only hiccup is the cure is unaffordable for most people because it costs $1,000 per gram.

 

The research used the equivalent of 500mg of NMN for every kilogram of body weight per day."

[stefan_001]

 

So if NAAD is a storehoused NAD reserve the idea of flushing unprocessed NR down the drain might be moot, I just want a concrete answer as do others

 

It would be wonderful if it worked this way but not the way I've understood water soluble vitamins to work.

 

 

Hi Bryan,

I dont think this is the case. NAAD reacts strongly so it a great indicator to estimate NAD levels. But the total storage volume is not very big. If recall the Trammell file correctly the actual pmol concentations of NAD+ were some factor larger that the NAAD concentrations. So it kind of like a level gauge in my oipinion.
 

[bluemoon]

 

Maybe this you remember..?

 

http://www.rexresear...ir/sinclair.htm

 

"The only hiccup is the cure is unaffordable for most people because it costs $1,000 per gram.

 

The research used the equivalent of 500mg of NMN for every kilogram of body weight per day."

 

 

 

 

I just checked and my hunch was correct - I thought "to age or not to age" who interviewed Guarante and Sinclair a couple of years ago mentioned it on this forum since I know I didn't see Sinclair say this on a youtube clip

 

And I found it: "to age or not to age" wrote in July 2014:

 

"Okay, I'm back from Boston.  I had dinner with the speakers at Harvard Glenn Lab Symposium, including David SInclair and

Lenny Guarente.  Off the record, I was told that a minimum of 1/2gram to 1 gram of NR is necessary to achieve effects.

But, it is clear to me that the scientists believe this precursor works."

 

He implies that either Sinclair or Guarente told him this suspected minimum dosage. If not, he should have clarified with something like "Other researchers told me that..."

 

Guarente said last April he was taking 250 mg of resveratrol and his Elysium BASIS, which contains 250mg of NR/day. I've wondered if he takes another 250mg of NR on top of that.  

 

Edited by bluemoon, 12 October 2016 - 03:58 PM.

[Nate-2004]

From what I have understood so far, just from what's been posted in the past on this thread, there seems to be a diminishing returns in terms of dosage. The data shows that 300-1000mg results in a 50% increase in NAD for roughly 24 hrs. So anything beyond 300 (assuming body mass as a factor), for most people is probably a waste.  I take 375 per day now and haven't noticed any change. 

 

I also think it may matter *when* you take it. I take mine at noon because somewhere earlier in this thread (page 38) it was pointed out that NAMPT peaks in the early afternoon.  This coincides incidentally with a second peak in cortisol, which is why you shouldn't drink coffee between 1 and 2pm. 

 

Given that NAMPT and NAD+ levels display robust circadian oscillation in peripheral tissues,45 it is conceivable that eNAMPT secretion would also show circadian oscillation. Indeed, it has been reported that serum eNAMPT levels follow a diurnal rhythm, making a peak during early afternoon, in humans,55 which appears to be opposite to plasma eNAMPT oscillation in mice (a preliminary observation in the Imai lab). This eNAMPT oscillation would likely produce another oscillation of its enzymatic reaction product, NMN, in blood circulation. NMN is rapidly incorporated to major metabolic tissues and converted to NAD+.56Therefore, in mammals, adipose tissue has an important role in generating the circadian oscillation of eNAMPT and possibly NMN in blood circulation, potentially synchronizing metabolic and neurobehavioral functions through other peripheral tissues and the hypothalamus in a circadian rhythm-dependent manner. In each tissue, NAD+ and sirtuins are critical mediators to orchestrate such inter-tissue communications. The loss of this orchestration is likely an important driver of aging in a wide variety of organisms.

[rarefried]

Relevant to current discussion is Fafner55's recent post to Turnbuckle's thread, "A Protocol to Upgrade Mitochondria'.  Post #59, entitled 'Estimated Dose of NR Needed to Induce Mitophagy:"

 

http://www.longecity...e-2#entry791918

 

 

 

From what I have understood so far, just from what's been posted in the past on this thread, there seems to be a diminishing returns in terms of dosage. The data shows that 300-1000mg results in a 50% increase in NAD for roughly 24 hrs. So anything beyond 300 (assuming body mass as a factor), for most people is probably a waste.  I take 375 per day now and haven't noticed any change. 

 

I also think it may matter *when* you take it. I take mine at noon because somewhere earlier in this thread (page 38) it was pointed out that NAMPT peaks in the early afternoon.  This coincides incidentally with a second peak in cortisol, which is why you shouldn't drink coffee between 1 and 2pm. 

 

 

[midas]

 

 I take 375 per day now and haven't noticed any change. 

 

 

 

 

If you dont mind me asking, how old are you and what is your general state of health please?

[Nate-2004]

I'm 42 and quite healthy, in very good shape.

[midas]

I'm 42 and quite healthy, in very good shape.

 

Thanks...

 

To be honest assuming your personal NAD levels are optimal I wouldn't expect to feel much if any gain with NR at your age and state of health.... The more I learn about NR the more convinced I am that it will only really show benefits in people with depleted NAD..

I'm not insinuating you shouldn't take it but maybe a smaller dose (125mg) per day would benefit you more?