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HUMAN placebo-controlled trial NR Does Not Elevate Muscle NAD+ But Modulates NAD+ Metabolome

human placebo-controlled randomized trial muscle nad+ anti-inflammatory aged subjects nicotinamide riboside nad+ metabolome

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#1 Fredrik

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Posted 29 June 2019 - 08:27 AM


So NAD+ doesn´t decrease with chronological aging in muscle and brain? No need to supplement with NAD+ precursors to try to boost an aging brain or skeletal muscle system then it seems. Perhaps just beneficial with certain pathological states.

 

"Nicotinamide riboside augments the human skeletal muscle NAD+ metabolome and induces transcriptomic and anti-inflammatory signatures in aged subjects: a placebo-controlled, randomized trial."

 

"We supplemented 12 aged men with NR 1g per day for 21-days in a placebo-controlled, randomized, double-blind, crossover trial.

 

Targeted metabolomics showed that NR elevated the muscle NAD+ metabolome, evident by increased nicotinic acid adenine dinucleotide and nicotinamide clearance products.

 

Muscle RNA sequencing revealed NR-mediated downregulation of energy metabolism and mitochondria pathways.

 

NR also depressed levels of circulating inflammatory cytokines. In an additional study, P magnetic resonance spectroscopy-based NAD+ measurement in muscle and brain showed no difference between young and aged individuals.

 

Our data establish that oral NR is available to aged human muscle and identify anti-inflammatory effects of NR, while suggesting that NAD+ decline is not associated with chronological aging per se in human muscle or brain."

 

 

https://www.biorxiv....680462.full.pdf

 

 


Edited by Fredrik, 29 June 2019 - 08:49 AM.

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#2 Fredrik

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Posted 29 June 2019 - 09:52 AM

Oral NR did not increase NAD+ in human muscle. Neither did NR increase blood flow, fat or carbohydrate utilisation or enhance grip-strength. 

 

The use of the expression "NAD+ metabolome" seemed curious to me.Reading the paper you can see that NR did not increase NAD+ in skeletal muscle at all, but did so in blood. NR did increase several NAM clearing products like NAAD and MeNAM, and that is what the authors are referring to as the "NAD+ metabolome".

 

Some takeaways from this small study of 12 elderly subjects:

 

MUSCLE

 

  • Oral NR results in downregulation of gene sets associated with energy metabolism in skeletal muscle.

 

  • Three weeks of oral NR does not enhance skeletal muscle mitochondrial bioenergetics or increase hand-grip strength.

 

  • Oral NR does not alter skeletal muscle blood flow or substrate utilisation.

 

  • NAD + content in skeletal muscle and brain does not decline with age.

 

  • oral NR in older humans did not increase NAD + in muscle (NR 210 pmol/mg vs. 197 pmol/mg).

 

  • NR was not elevated in muscle by supplementation (NR 1.4 pmol/mg µM vs. placebo 1.25 pmol/mg).

 

  • NR resulted in a 2-fold increase in muscle NAAD and 4-fold increase in N-methyl nicotinamide (MeNAM; NR
     
    1.45 pmol/mg vs. placebo 0.35 pmol/mg).
 
  • NR supplementation did not affect muscle nicotinamide (NAM) (NR 92.0 pmol/mg vs. placebo 86.5 pmol/mng).
 
BLOOD
 
  • Oral NR depresses circulating levels of inflammatory cytokines.

 

  • NR increased the concentrations of NAD 2-fold (NR 47.75 µM vs. placebo 20.90 µM).

 

  • After 14 hours NR was not increased in blood compared to placebo (NR 0.16 µM vs. placebo 0.15 µM).

 

  • NR increased the levels of NMN 1.4-fold (NR 1.63 µM vs. placebo 1.13 µM).

 

  • chronic NR supplementation did not elevate NAM in the blood.

 

Urinary NAD+ metabolomics may suggest that NR supplementation leads to retrograde production of NAAD, nicotinic acid mononucleotide (NAMN), and NAR, according to the authors.

 

Four subjects reported increased libido in the NR group and none in the placebo group.

 

 


Edited by Fredrik, 29 June 2019 - 10:32 AM.

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#3 Fredrik

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Posted 29 June 2019 - 11:47 AM

Attached File  Screenshot 2019-06-29 at 13.53.10.png   185.41KB   1 downloads

 

Left figure is muscle tissue showing no increase in NAD+ from 1000 mg NR supplementation and the figure to the right is blood showing an increase in NAD+ with NR.

 

Attached File  Screenshot 2019-06-29 at 14.25.25.png   207.7KB   0 downloads

Levels of inflammatory markers in serum decreased with NR supplementation.


Edited by Fredrik, 29 June 2019 - 12:13 PM.

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#4 Fredrik

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Posted 29 June 2019 - 11:57 AM

Attached File  Screenshot 2019-06-29 at 14.10.14.png   423.02KB   0 downloads

 

No decrease in muscle or brain NAD+ with aging. The study showed that 70-80-year-olds have the same amount of NAD+ in muscle and brain as 21-year olds, with or without supplementation of NR.

 


Edited by Fredrik, 29 June 2019 - 12:00 PM.

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#5 Engadin

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Posted 29 June 2019 - 12:50 PM

What's that sound? Do you hear it? Some house of cards hitting the ground. Or not?

 

Thanks Fredrik.


Edited by Engadin, 29 June 2019 - 12:52 PM.

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#6 Engadin

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Posted 29 June 2019 - 02:27 PM

Quite simultaneously and BTW: 

 

 

 

 

 


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#7 able

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Posted 29 June 2019 - 03:39 PM

attachicon.gif Screenshot 2019-06-29 at 14.10.14.png

 

No decrease in muscle or brain NAD+ with aging. The study showed that 70-80-year-olds have the same amount of NAD+ in muscle and brain as 21-year olds, with or without supplementation of NR.

 

 

It's surprising  that they found NAD+ was not lower in muscle and brain in old humans.  

 

I wonder why they don't mention if blood NAD+ levels are lower in old humans.  

 

Surely they have that data?

 

Isn't it well established that blood NAD+ drops with age, so if they found otherwise they would say?  

 

Maybe they didn't see the need to mention, but  seems like they should say  what they found for blood NAD+ in old vs young and hopefully  will add that during peer review.


Edited by able, 29 June 2019 - 04:04 PM.

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#8 Methuselahbones

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Posted 29 June 2019 - 10:12 PM

What's that sound? Do you hear it? Some house of cards hitting the ground. Or not?

Thanks Fredrik.


You have a way with words definitely. Though I wonder how these conclusions will do once this is peer reviewed?
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#9 Michael

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Posted 29 June 2019 - 10:28 PM

The title and abstract are pretty naked attempts at misdirection from the core finding, which is that NR failed to increase muscle NAD+, even after three weeks, in older people, and at a very high dose — which was surely the actual goal of the research. In fact, the clinical trial register entry (which exists precisely to weed out this kind of post hoc shenanigans) says as much:

 

Hypothesis: elevating skeletal muscle NAD+ bioavailability using NR supplementation will increase markers of mitochondrial function and that will manifest as a more favourable metabolic profile.
 
Primary Outcome Measures :

  • Mitochondrial function assessment in skeletal muscle using high resolution respirometry [ Time Frame: Following 3 weeks of NR supplementation ]
    Mitochondrial function assessment on muscle biopsies using high resolution respirometry
  • Skeletal muscle NAD+ levels in vastus lateralis biopsy using targeted metabolomics [ Time Frame: Following 3 weeks of NR supplementation ]

 

It failed on both fronts. This should be explicit in the title and abstract.
 
Note that despite the subject title of this thread, this paper has not been published: bioRxiv is a repository for scientific reports before they have undergone peer review and publication. I sincerely hope the journal editors will catch on to the weasel words and will insist on proper, transparent reporting of the primary outcome results.


Edited by Michael, 29 June 2019 - 10:30 PM.

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#10 Fredrik

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Posted 30 June 2019 - 10:45 AM

Hi Michael, 

 

Yes. They tried very hard to write this paper up in a way to disguise the negative findings. Sorry for claiming it has been published. Please change the title to something more appropriate...like "High dose NR fails to increase muscle NAD+ or mitochondrial function in older human subjects" or something to that effect. I trust you to chose an appropriate subject title.


Edited by Fredrik, 30 June 2019 - 10:47 AM.

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#11 able

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Posted 30 June 2019 - 06:23 PM

I agree they engage in deceptive wordsmithing to spin the results, as usual.

 

But I wonder if they might have a point about about muscle NAD+ metabolome being increased, even though absolute NAD+ levels are not.

 

Perhaps NAD+ levels are typically at the upper limits, and will simply not store higher levels.

 

NAAD is doubled, which may be a storage mechanism preferred by muscle.

 

MeNAM in muscle is up 5x.  Doesn't that indicate more NAD+ was utilized?    

 

They don't measure NAD+ turnover.  Is it possible the NR was reaching muscle and resulted in more NAD+ usage and turnover, but it just doesn't show up as higher NAD+ levels on average?

 


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#12 Fredrik

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Posted 30 June 2019 - 09:49 PM

One of the authors, Charles Brenner, is sparring a bit with David A Sinclair on twitter over this study.

 

https://twitter.com/davidasinclair/status/1145176718010986496

 

Sinclair: 

 

"New interesting placebo-controlled study assessing 500 mg of nicotinamide riboside [NR] taken 2X daily in 70-80 year olds. Increases in NAD+ in blood were detected, but not in muscle, despite lower inflammation and, unexpectedly, mitochondrial activity."

 

"No increases in blood flow were detected after NR dosing. Our work is cited: "Recent mouse data showed that NR increases...muscle blood flow." Must be a typo. In that study, we used NMN not NR. In ongoing work, NMN may boost mouse endurance better than NR, for reasons unclear."

 

Brenner:

 

"The study demonstrated clearly increased muscle NAD metabolism. Oral NAD boosters expand levels of NAD+ in liver. In muscle, they increase NAD metabolism (as clearly shown in this paper) without increasing the steady-state level of NAD+"

 

"People take NR orally and it’s available to multiple tissues. In some tissues like liver, NR raises the NAD+ level. In others, it increases NAD flux (some of this due to increases sirtuin activity) without actually boosting NAD. It certainly works in heart, skeletal muscle, etc"


Edited by Fredrik, 30 June 2019 - 10:00 PM.

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#13 able

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Posted 30 June 2019 - 09:54 PM

One of the authors, Charles Brenner, is sparring a bit with David A Sinclair on twitter over this study.

 

https://twitter.com/davidasinclair/status/1145176718010986496

 

Brenner:

"The study demonstrated clearly increased muscle NAD metabolism. Oral NAD boosters expand levels of NAD+ in liver. In muscle, they increase NAD metabolism (as clearly shown in this paper) without increasing the steady-state level of NAD+"

 

Ah.  It sounds like  he saying the same thing I am, but in nerd-speak?

 

Maybe they thought it was obvious from the research, but probably should be more clearly noted before publication.

 


Edited by able, 30 June 2019 - 09:58 PM.

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#14 Harkijn

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Posted 01 July 2019 - 04:09 PM

Ah.  It sounds like  he saying the same thing I am, but in nerd-speak?

 

Maybe they thought it was obvious from the research, but probably should be more clearly noted before publication.

 

I think you are right, this is a very positive outcome for NR.

 

It is not the first time btw that an unpublished, not yet peer-reviewed study posted on bioRxiv gets a title that points to the most important finding, and not so much to the original hypothesis. Actually I am glad of that...Of course, anyone will agree that their definitive publication will have to refer back to the original clinical trial register. No doubt they will do so.



#15 Harkijn

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Posted 01 July 2019 - 04:18 PM

Separate post because on a different note:  four out of twelve NR participants (median age 75) reported enhanced libido whereas the placebo group reported none. This echoes a number of posts in the NR  Personal  Experiences thread of men of various ages.


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#16 Phoebus

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Posted 01 July 2019 - 09:13 PM

 

 

NAAD is doubled, which may be a storage mechanism preferred by muscle.

 

MeNAM in muscle is up 5x.  Doesn't that indicate more NAD+ was utilized?    

 

They don't measure NAD+ turnover.  Is it possible the NR was reaching muscle and resulted in more NAD+ usage and turnover, but it just doesn't show up as higher NAD+ levels on average?

 

All good points, and also it shows anti inflammatory effects which are always welcome. All in all I don't see how this is somehow 'toppling the NR house of cards' as some in this thread suggest. Seems like they demonstrated a lot of benefits to NR here. 


 

 

Brenner:

 

"The study demonstrated clearly increased muscle NAD metabolism. Oral NAD boosters expand levels of NAD+ in liver. In muscle, they increase NAD metabolism (as clearly shown in this paper) without increasing the steady-state level of NAD+"

 

 

 I think thats a really interesting point. It can upregulate NAD usage without showing increased steady state levels. 


Edited by Phoebus, 01 July 2019 - 09:14 PM.

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#17 Methuselahbones

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Posted 02 July 2019 - 01:09 PM

Ah. It sounds like he saying the same thing I am, but in nerd-speak?

Maybe they thought it was obvious from the research, but probably should be more clearly noted before publication.


Forgive the dumb question here but is increased NAD metabolism necessarily a good thing? Maybe superficial but I thought the NAD story at least as it has been sold by the NR/NMN supplement companies is that your NAD levels fall over your lifetime and NR/NMN restore. If increased metabolism were a proxy for imcreased NAD that is otherwise not detectable, that sounds fine, but if your rate of NAD metabolism is revved up without NAD being restored, could that not be bad? Like if my car started burning gas at a higher rate, I run out faster...

Probably a stupid question so please be gentle... Use your imagination and pretend I did not get a PhD in biochemistry like seemingly everyone else here. ;)
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#18 able

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Posted 02 July 2019 - 04:18 PM

Forgive the dumb question here but is increased NAD metabolism necessarily a good thing? Maybe superficial but I thought the NAD story at least as it has been sold by the NR/NMN supplement companies is that your NAD levels fall over your lifetime and NR/NMN restore. If increased metabolism were a proxy for imcreased NAD that is otherwise not detectable, that sounds fine, but if your rate of NAD metabolism is revved up without NAD being restored, could that not be bad? Like if my car started burning gas at a higher rate, I run out faster...

Probably a stupid question so please be gentle... Use your imagination and pretend I did not get a PhD in biochemistry like seemingly everyone else here. ;)

 

 

This study found NAD+ levels do not drop in muscle and brain as we age.

 

It also found that 1 gram of NR per day does not increase levels of NAD+ or NR in the muscle.

 

Those 2 points are new, and seem contrary to how I thought about it previously, but actually make a lot of sense when taken together.

 

As Dr Brenner points out,  they did see doubled NAAD and MeNAM in muscle, which is evidence of increased NAD+ turnover.

 

If NAD+ levels do not drop as we age it really isn't surprising it doesn't increase with supplementation.  There is a  natural setpoint level for NAD+ in muscle that doesn't change with age.

 

So, NAD+ turnover is increased with supplementation, even though NR levels in blood or muscle are unchanged.  How is that?

 

NR levels in the blood and muscle are unchanged.  However:

 

NAD+ levels in the blood do drop as we age.  This study didn't mention it, but that has been confirmed numerous times.

 

NR supplementation doubled NAD+ levels in the blood.

 

The increased NAD+ in the blood results in very positive improvement in inflammation markers.

 

Muscle benefits from the increased levels of NAD+ in the blood also, with increased turnover of NAD+ even though levels of NAD+ in muscle do not lower with age or increase with supplementation.

 

It seems obvious to me that  increasing levels of NAD+ in the blood is the method of action from NR, (and likely NMN) supplementation.  

 

Whether it is direct, or broken down to NR to enter the cell, or what - it is the doubled level of NAD+ that provide benefit.

 

Some interesting observations about this here on twitter

 

Dr Sinclair:

 

" I know of a couple of labs tracing NAD precursors through mice over time. Some fraction of the precursors enter cells intact, some doesn’t, but NAD is elevated higher than other approaches - that’s the bottom line. Human trials at Metrobiotech continue to go well in that regard."

 

 

Dr Sinclair says whatever the step across a cell membrane is, doesn't matter. 

 

I agree with Dr Sinclair here.  Increasing NAD+ in the blood is what matters.  All these molecules are easily converted back and forth as needed, apparently with no bottlenecks.

 

In the body an NR molecule is likely "best" at crossing cell membrane, but taking 1 gram a day of NR has no effect on the NR levels in the body so it isn't really acting as NR, or helping to get more NAD+ into a cell.  

 

It seems the body keeps the level of NR it needs on hand, just as it keeps the level of NAD+ it needs in skeletal muscle constant.

 

In my understanding, NAD+ in the blood (fed by the liver) is the reservoir for the body that changes as we age, and can be influenced by NAD+ precursors, and many other products.

 

You cannot change the level of NR stored in blood or elsewhere by supplementation.  It is converted to NAD+ (or NMN) for storage and use throughout the body. Excess amounts end up in urine.

 

Exogenous NR increases NAD+ in the blood.  If it is most effective at that, great.  


Edited by able, 02 July 2019 - 04:30 PM.

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#19 Phoebus

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Posted 02 July 2019 - 04:20 PM

Forgive the dumb question here but is increased NAD metabolism necessarily a good thing? Maybe superficial but I thought the NAD story at least as it has been sold by the NR/NMN supplement companies is that your NAD levels fall over your lifetime and NR/NMN restore. If increased metabolism were a proxy for imcreased NAD that is otherwise not detectable, that sounds fine, but if your rate of NAD metabolism is revved up without NAD being restored, could that not be bad? Like if my car started burning gas at a higher rate, I run out faster...

Probably a stupid question so please be gentle... Use your imagination and pretend I did not get a PhD in biochemistry like seemingly everyone else here. ;)

 

 

I believe the answer to your question is in this paper, if someone wants to read thru it and report that would be awesome 

 

https://www.cell.com...(15)00266-1.pdf



#20 Mind

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Posted 02 July 2019 - 05:11 PM

This is an interesting study to add to the NAD "story".

 

As seen in this discussion, new data helps illuminate gaps in our knowledge of the complexity of human metabolism.

 

The most interesting bullet point for me is that "NAD levels in the brain and muscle do NOT drop as we age"

 

From a very high level-layman's view of cellular energy production, this does not seem logical. Nearly everything in the aged human body runs slower, mitochondria are damaged and malfunctioning, digestion becomes less efficient, etc... Why would an aged body have or use as much NAD as a young body "running at full speed"? Something is missing - doesn't add up, IMO. Not that I think NAD supplementation is some sort-of holy grail, just that this data seems to go against common sense.


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#21 able

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Posted 02 July 2019 - 05:53 PM

This is an interesting study to add to the NAD "story".

 

As seen in this discussion, new data helps illuminate gaps in our knowledge of the complexity of human metabolism.

 

The most interesting bullet point for me is that "NAD levels in the brain and muscle do NOT drop as we age"

 

From a very high level-layman's view of cellular energy production, this does not seem logical. Nearly everything in the aged human body runs slower, mitochondria are damaged and malfunctioning, digestion becomes less efficient, etc... Why would an aged body have or use as much NAD as a young body "running at full speed"? Something is missing - doesn't add up, IMO. Not that I think NAD supplementation is some sort-of holy grail, just that this data seems to go against common sense.

 

 

I thought it didn't add up either, at first.  

 

But note that this study found the absolute level of NAD+ does not change with age.

 

It says nothing about the amount of NAD+ used - the turnover.

 

My take is, muscle attempts to  maintains a certain level of NAD+ throughout life.   But it likely uses less NAD+ (lower turnover) as we age.  

 

Do some tissues like muscle respond to  the level of NAD+ in the blood?  When we are young and NAD+ levels in blood are  high, muscles tend to take in more and turnover is high.  

 

As we age and levels of NAD+ in blood drop, muscle usilizes less NAD+, to conserve it.  

 

When we supplement with NAD+ boosters such as NR and increase NAD+ in the blood, the muscles will take in more and we see the evidence of more NAD+ turnover, but the NAD+ levels in muscle don't change.

 

Just my theory.


Edited by able, 02 July 2019 - 05:54 PM.

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#22 Mind

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Posted 02 July 2019 - 07:24 PM

So here is an analogy that might help understand the issue - maybe - albeit crude.

 

The body has a NAD gas tank, which is continually topped-off.

 

Go to the grocery store, top off the tank. Go to the bank, top off the tank. No matter if the car is young or old, if you measure the amount of gas (NAD) in the tank - it will always be full or nearly so.

 

However, because the old car (body) is broken down, it cannot go very far or very fast, no matter if the tank is full.

 

The young body can do much more with the "gas in the tank", including repairing itself.


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#23 able

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Posted 02 July 2019 - 07:38 PM

So here is an analogy that might help understand the issue - maybe - albeit crude.

 

The body has a NAD gas tank, which is continually topped-off.

 

Go to the grocery store, top off the tank. Go to the bank, top off the tank. No matter if the car is young or old, if you measure the amount of gas (NAD) in the tank - it will always be full or nearly so.

 

However, because the old car (body) is broken down, it cannot go very far or very fast, no matter if the tank is full.

 

The young body can do much more with the "gas in the tank", including repairing itself.

 

 

But the tank is not always full.

 

As we age,  NAD+ levels in the blood drop to 1/2.

 

NAD+ in the blood is the tank.

 

As it gets lower when we age, the rest of the body know the tank is low, and slows down its consumption to preserve NAD+ for critical organs like heart and brain.

 

Some organs may have steady state NAD levels, but consume less as we age.

 

As we continue to age, more and more organs do not get enough NAD+, and critical repair functions are not performed.

 

It could be different tissues all perform on their own, based on NAD+ levels in the blood.  Or something like hypothalamus senses NAD+ levels in the blood and signal different organs.


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#24 able

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Posted 03 July 2019 - 05:53 PM

To me, a better analogy would be that NAD+ in the blood is like a reservoir that is used for the water supply in a small town.

 

When it is full, everyone has plenty of water to drink, wash, and water their yards, and they all use what the wish. Just as when young we have plenty of NAD+ for energy, fighting disease, dna repair, etc.

 

If there is too much demand placed on the water supply  and water levels are low the town might have rationing and some houses use are forced to use less. Synonomous with muscles using less NAD+ as we age.

 

With rationing, people in the town don't store less water in their homes. Just as muscle doesn't store less  NAD+ when we get older.   But consumption/turnover is  less.

 

Those houses still have enough water to drink, but maybe not enough to water their lawns.  Just as we have enough NAD+ to stay alive, but little by little, damage is not repaired.

 

If we replenish NAD+, it is like the town got plenty of rain and everyone resumes their normal usage.  But  the amount of water stored in their homes is unchanged.

 

The levels of water in the reservoir is what matter, not how much is stored in their homes - that never changes.

 

Just as it’s the levels of NAD+ in the blood that matter, not how much NAD+ is stored in muscle - that never changes.

 

This study agrees with Liu/Rabinowitz and shows that very little, if any NR makes it directly to cells. 

 

This study shows that NR is not stored as NR in the muscle or blood.

 

According to this study, NR itself is found at minute amounts in the body, and those minute amounts are not increased at all with supplementation.

 

It seems to me that NR is effective  as a means to increase NAD+ in the blood.  

 

This may sound contraversial, but is actually what Dr Brenner claimed is the method of action of NR in the lactating mice study, that he talks about  in the Natalie Marie podcast.

 

The research finds no NR is in the blood or mothers milk, but the increased levels of NAD+ in the blood makes it into the mothers milk and provide quite amazing benefits to the nursing pups.  From NAD+ in the blood, not NR.

 

 


Edited by able, 03 July 2019 - 06:36 PM.

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#25 joesixpack

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Posted 05 July 2019 - 03:46 AM

 

To me, a better analogy would be that NAD+ in the blood is like a reservoir that is used for the water supply in a small town.

 

When it is full, everyone has plenty of water to drink, wash, and water their yards, and they all use what the wish. Just as when young we have plenty of NAD+ for energy, fighting disease, dna repair, etc.

 

If there is too much demand placed on the water supply  and water levels are low the town might have rationing and some houses use are forced to use less. Synonomous with muscles using less NAD+ as we age.

 

With rationing, people in the town don't store less water in their homes. Just as muscle doesn't store less  NAD+ when we get older.   But consumption/turnover is  less.

 

Those houses still have enough water to drink, but maybe not enough to water their lawns.  Just as we have enough NAD+ to stay alive, but little by little, damage is not repaired.

 

If we replenish NAD+, it is like the town got plenty of rain and everyone resumes their normal usage.  But  the amount of water stored in their homes is unchanged.

 

The levels of water in the reservoir is what matter, not how much is stored in their homes - that never changes.

 

Just as it’s the levels of NAD+ in the blood that matter, not how much NAD+ is stored in muscle - that never changes.

 

This study agrees with Liu/Rabinowitz and shows that very little, if any NR makes it directly to cells. 

 

This study shows that NR is not stored as NR in the muscle or blood.

 

According to this study, NR itself is found at minute amounts in the body, and those minute amounts are not increased at all with supplementation.

 

It seems to me that NR is effective  as a means to increase NAD+ in the blood.  

 

This may sound contraversial, but is actually what Dr Brenner claimed is the method of action of NR in the lactating mice study, that he talks about  in the Natalie Marie podcast.

 

The research finds no NR is in the blood or mothers milk, but the increased levels of NAD+ in the blood makes it into the mothers milk and provide quite amazing benefits to the nursing pups.  From NAD+ in the blood, not NR.

 

 

I am not sure what your point is. If NR helps, good., If NMN helps good. I don't care who wins. If either one helps, that is a good thing. I think they might both help. So take the one you like, and tell us how it is going.. Right now I am taking NR and it is helping. I have a lot of NM in the wings. If you are taking it, tell us how it helps, I might take both.

 

Ultimately I think it is going to be both, with some other things.

 

Keep us informed, but I see no reason to weigh in on one side or another.

 

This is an experiment.

 

And we are the guinea pigs.

 



#26 Mind

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Posted 05 July 2019 - 05:49 PM

I am unsure if we have arrived at a good "gas tank" analogy yet. Are the cellular and blood "gas tanks" somewhat separate and exclusive?

 

The study found (assuming they measured correctly) that the level of NAD in muscle and brain tissue does NOT change as we age - the tank is always full.

 

The study found that levels on NAD in the blood drops as we age.



#27 able

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Posted 05 July 2019 - 08:12 PM

I am unsure if we have arrived at a good "gas tank" analogy yet. Are the cellular and blood "gas tanks" somewhat separate and exclusive?

 

The study found (assuming they measured correctly) that the level of NAD in muscle and brain tissue does NOT change as we age - the tank is always full.

 

The study found that levels on NAD in the blood drops as we age.

 

 

I like the reservoir as storage tank analogy.

 

But if you want to use a car, the gas tank is the storage that drops but can be refilled.

 

A carburetor would be synonomous with brain or muscle. 

 

The amount of gas in carburetor never changes.  It takes what it needs from the gas tank. You can find some gas there, but it is clearly a consumer of gas, not storage.

 

Blood and brain are the same. Levels of NR or NAD+ don't drop with age, nor are they replenished with supplementation.  They are consumers of NAD, not storage.

 

NAD+ in the blood is the "gas tank".  Levels of NAD+ in blood drop as we age and can be replenished by supplementation.

 

NR levels in blood or tissue don't change even with 1 gram a day supplementation, which says to me that the MOA is by raising NAD+ levels in the blood.

 

The studies such as the chromadex one that came out today measure NAD+ levels in the blood as the primary endpoint.  

 

I believe that is what really matters - not how it gets there, or how it crosses the cell membrane.


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#28 Oakman

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Posted 05 July 2019 - 11:06 PM

Here's a take a step back, philosophical response on this study. Interesting, but like many studies, shows the difficulty of generalizing and assessing the results in a meaningful way for the reader. It's easy to make a convincing case for or against something with misdirection. To me the misdirection is that the subjects are perceived as, and measured as, static subjects. Categorized as young & old, they line up, parameters are measured, they are given something, later they measure again. Results are given. Assumptions made.

 

The study's overarching aim was to verify if mice results translated to humans. We know it often does not, and so the applicable useful human parameters may be left untested. Anecdotal user reports seem to indicate that improvements can be had. Further, like the lifespan of a human compared to that of a mouse, it’s reasonable that restoration takes a lot longer and is a more complicated process than supplementing a single molecule.

 

Further, the premise is to measure changes in these isolated, static subjects. That's great for measurement in a study... eliminate all the variables possible, but isn't the goal to see if the old person can be restored to, or near to, the homeostasis of the young person?  That's not going to happen to any degree by, literally, just pouring a molecule down someone's throat IMHO.

 

Life and longevity are about reversing entropy. That takes energy input, that takes work and stress on the system involved, and that take a consciousness of purpose, a willingness to enable change. If you want to restore youthful homeostasis, purposeful activity and supplementation may be required. IOWs there is no 'magic pill' able to restore youth to the old, sans effort. Young or old, health is predicated on motion and activity to produce the vitality that is so coveted.

 

Scientists want change to happen within extremely limited timeframes. Restoring vitality and improving measured parameters likely takes not 14 days, or 56 days, but months, even years. Moreover, a holistic environment of nutrients that encourages vitality and extensive blood flow throughout the body is essential. Muscles and blood vessels and synapses need to be stressed and restored together in a nutrient and energy producing bath.

 

As people are proposing analogies, here's mine (flawed) > Take a race car (youth) and an old jalopy (old person), put race gas (Niagen) in each, and neither will perform differently from their respective baselines (this study). But the opportunities for the jalopy are myriad; change the oil, new rings and pistons to increase the compression, new spark plugs and wires, air cleaner and fuel injectors, etc. You may not beat the race car, but performance will improve, and the race gas will play a part, but it takes way more than just that.

 


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#29 Harkijn

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Posted 19 August 2019 - 03:04 PM

The study drew considerable interest and led some to make rather crass statements. Therefore I think it's worthwhile to upload the full text.

 

Attached Files


Edited by Harkijn, 19 August 2019 - 03:05 PM.


#30 joesixpack

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Posted 20 August 2019 - 01:51 AM

This is an interesting study to add to the NAD "story".

 

As seen in this discussion, new data helps illuminate gaps in our knowledge of the complexity of human metabolism.

 

The most interesting bullet point for me is that "NAD levels in the brain and muscle do NOT drop as we age"

 

From a very high level-layman's view of cellular energy production, this does not seem logical. Nearly everything in the aged human body runs slower, mitochondria are damaged and malfunctioning, digestion becomes less efficient, etc... Why would an aged body have or use as much NAD as a young body "running at full speed"? Something is missing - doesn't add up, IMO. Not that I think NAD supplementation is some sort-of holy grail, just that this data seems to go against common sense.

 

This quote is from page 16 of the study and seems speculative. It implies that NR supplementation somehow results in heathier mitochondria that is stress resistant.

 

 

  1. Our data suggest downregulation of gene sets associated with glycolysis

  2. 382  and mitochondrial function, yet our measures of mitochondrial respiration, citrate synthase

  3. 383  activity, and mitochondrial copy number were unaltered. Again, expression levels of

  4. 384  glycolysis and mitochondrial protein were unchanged with NR in this study. The

  5. 385  downregulation of energy-generating processes may be reminiscent of mechanisms

  6. 386  associated with calorie restriction (Hagopian, Ramsey and Weindruch, 2003; Ingram and

  7. 387  Roth, 2011; Lin et al., 2015) or increased mitochondrial quality control as has been observed

  8. 388  in blood stem cells (Vannini et al., 2019), or suggest that NR can tune’ the expression of

  9. 389  energy metabolism pathways to permit a more efficient and potentially stress resilient

  10. 390  mitochondrial environment.







Also tagged with one or more of these keywords: human, placebo-controlled randomized trial, muscle nad+, anti-inflammatory, aged subjects, nicotinamide riboside, nad+ metabolome

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