• Log in with Facebook Log in with Twitter Log In with Google      Sign In    
  • Create Account
  LongeCity
              Advocacy & Research for Unlimited Lifespans

Photo
- - - - -

Elysium Basis Trial Published: "Repeat dose [NR + Pterostilbene] increases NAD+ levels in humans"

nad+ elysium basis nicotinamide riboside basis

  • This topic is locked This topic is locked
89 replies to this topic

#31 stefan_001

  • Guest
  • 1,070 posts
  • 222
  • Location:Munich

Posted 28 November 2017 - 11:46 PM

Curious? Any comment about your protocol, which I will quote a part of, Stephen?

"Daily: Niagen, Pterostilbine, Ginkho Biloba"
"Rotating: Honokiol, Quercitin, Luteolin, Fisitin

"I am using NR now for over 2.5 years [...]

I sometimes wrote about the recovering hair on my blog and has pictures:
http://www.timelessl...-be-the-reason/

But need to update it, because the effect stays also while only taking it orally."


This thread is about the Elysium Basis trial; Stefan, if you opt to follow up, will you please start a new thread, or do so in the "Personal Experiences" thread (or do so on your blog and link from the latter)?
No worries I will stop replying.
  • Enjoying the show x 1

#32 Nate-2004

  • Guest
  • 2,277 posts
  • 311
  • Location:Philadelphia
  • NO

Posted 30 November 2017 - 02:53 PM

This further confirms my experience of only taking it 3 or 4 days a week in my protocol. I genuinely don't think anything other than basic micronutrients should be taken chronically (every day). I get a lot more out of it I think this way. I don't know that I can put too much faith in this study though, given that it's funded by someone who benefits from positive results.


Edited by Nate-2004, 30 November 2017 - 02:54 PM.


Click HERE to rent this ad spot for the NAD+ forum to support LongeCity (this will replace the google ad above).

#33 bluemoon

  • Guest
  • 723 posts
  • 86
  • Location:south side
  • NO

Posted 30 November 2017 - 03:59 PM

  I don't know that I can put too much faith in this study though, given that it's funded by someone who benefits from positive results.

You realize that if Elysium is found to be sloppy or misleading, they get fried, right? 

 

I wish they would have run the trial another month to see where the 500 mg ended up with respect to decreasing NAD+ levels. 

 

This is the part I didn't like because for the first time in the paper the authors did not make clear if 'significantly' meant 'quite a bit' or statistically significant:

 

"With respect to mobility, the finding that NRPT 2X group demonstrated significant increase in both the 30-second chair stand and the 6-min walk test at 60 days suggests that prolonged supplementation with NRPT may support overall muscle health and/or energy in an older population."

 

It seems odd if they found no improvements at raising NAD+ 40% but did at the endpoint of 55%, just 15 percentage points higher. I think it won't be too long before NR is out-dated and replaced by a more effective drug that is based on NR and NMN and that NR wil never be widely used.  


Edited by bluemoon, 30 November 2017 - 04:01 PM.

  • unsure x 1

#34 able

  • Guest
  • 725 posts
  • 325
  • Location:austin texas
  • NO

Posted 30 November 2017 - 04:49 PM

 

  I don't know that I can put too much faith in this study though, given that it's funded by someone who benefits from positive results.

You realize that if Elysium is found to be sloppy or misleading, they get fried, right? 

 

I wish they would have run the trial another month to see where the 500 mg ended up with respect to decreasing NAD+ levels. 

 

This is the part I didn't like because for the first time in the paper the authors did not make clear if 'significantly' meant 'quite a bit' or statistically significant:

 

"With respect to mobility, the finding that NRPT 2X group demonstrated significant increase in both the 30-second chair stand and the 6-min walk test at 60 days suggests that prolonged supplementation with NRPT may support overall muscle health and/or energy in an older population."

 

It seems odd if they found no improvements at raising NAD+ 40% but did at the endpoint of 55%, just 15 percentage points higher. I think it won't be too long before NR is out-dated and replaced by a more effective drug that is based on NR and NMN and that NR wil never be widely used.  

 

 

 

Do you feel they should calculate  the %  improvement?

 

If my math and interpretation are correct, it looks like "7.8% improvement in chair stand, and 7.5% improvement in distance walked" (1.03/13.4 and 34/455).

 

If they just posted the 7.5% improvement in distance walked for the 2x dosage, they probably need to include that the placebo group showed 3.4% improvement.  And the 1x dose group shows no improvement.

 

Likewise, the2x group shows 7.7% improvement in chair stand, while placebo group shows 3.8% improvement, and 1x dosage group shows 2.1% improvement. 

 

So I can see your point that putting numbers to it shows that placebo group shows more improvement than the 1x dosage group, and around 1/2 of the improvement of the 2x dosage group.   

 

Further clarification makes the improvement less impressive, imo.

 

 

 



 

"It seems odd if they found no improvements at raising NAD+ 40% but did at the endpoint of 55%, just 15 percentage points higher"

 

It is odd that 55% improvement shows positive impact, while 40% did not, and raises some questions.   

But that is measuring blood NAD+ only - we don't know if muscles NAD+ is increased much more with 2x dose vs 1x dose.

 

 


Edited by able, 30 November 2017 - 04:57 PM.

  • Good Point x 3
  • unsure x 1

#35 Michael

  • Advisor, Moderator
  • 1,234 posts
  • 1,694
  • Location:Location Location

Posted 30 November 2017 - 07:52 PM

 

 

bluemoon wrote: We also don't know if 500 mg of NR doesn't drop even lower past 55% increase to maybe 40% or 45% after eight weeks because the study didn't look at 12 or 18 weeks.


And even the low dose NAD levels were falling after 8 weeks (although not significantly). It's probably a good bet that NAD levels will continue to fall with time (via "homeostatic mechanisms"), and that the lower they fall, and the longer this takes, the more screwed you will be if discontinuing supplementation. ...

[If] one has been taking NR for a lengthy period, with slowly declining NAD levels due to acclimation (of some sort), followed by an abrupt discontinuation. Under such circumstances, the state you'd be in on discontinuation would very likely be worse (i.e., lower NAD levels) than before supplementation started, since your body would have shut down some fraction of its unsupplemented NAD production capacity over a long period, and the time it would take to recover from that is probably related to the time it took to acclimate to the NR in the first place ...

if you were to stop cold turkey, I'm suggesting that the following day, and probably for many days after that, you'd have an NAD deficit worse than before starting supplementation, although you may not notice that, depending on what you're measuring, and how long you refrain from the NR. ...

This reminds me of testosterone supplementation that slowly shuts down one's own T production (and producing smaller testes), which can then leave you in an even more precarious state if T is discontinued. Just another feature of NR supplementation that will need to be fully characterized.

I have actually done that, stop cold turkey from 500mg for over 1 month. [...] I was surprised how well things stayed up and only after a month or so I started feeling some old aging phenomena from the past coming back. To me its not clear how such NR resistance path could develop. The NRK path seems pretty solid and independent.

Conceptually, Warner's argument seems pretty strong, and is consistent with the long-term decline observed in this trial (and its dose-dependency) and with the lower levels of NMN and the higher levels of NAM (apparently residual to what was in flux at the earlier time point), MeNAM, and other NAM metabolites before the fifth dose vs. before the 2nd dose observed in Brenner's n=1 experiment, as well as with other findings of homeostatic feedback in the system discussed here.
 
Evidently, NAD+ levels rise beyond some point, the cell compensates by downregulating biosynthetic machinery and/or (futile?) increases in consumptive pathways (CD38, PARP1, SIRT1, CD73), pushing either to divert the energy required to maintain salvage or to maintain homeostatic poise (eg, to avoid oxidative stress or disrupted NAD+:NADH tone). That the NR-NRK pathways aren't uniquely resilient against this is evident from the very fact that it happens in response to NR supplementation: it could occur by downregulation of NRKs and/or NMNATs, and/or because NAMPT is still important for salvage of the secondary NAM (and is known to be downregulated in the presence of elevated NAD+), and/or by increasing consumption. This suggests that if you abruptly discontinue supplementation, these changes will still be active for some time, potentially leading to NAD+ declining below pre-supplemetation levels until the rheostat resets.
 

 

This thread is about the Elysium Basis trial; Stefan, if you opt to follow up [about your personal protocol], will you please start a new thread, or do so in the "Personal Experiences" thread (or do so on your blog and link from the latter)?


No worries I will stop replying.

To be clear, I am absolutely not calling on you to stop posting in general (and hope you will continue, as your input is often valuable) — just that we keep the threads clean by sticking to the topic (in this case, the Elysium Basis trial).


  • Good Point x 1

#36 warner

  • Guest
  • 174 posts
  • 87
  • Location:USA
  • NO

Posted 30 November 2017 - 08:59 PM

I mentioned TRT as an example of acclimation effects.  Glaucoma drops are another good example.  The following plot shows 5 years of morning IOPs (red = right eye, blue = left eye), taken just before applying morning drops.  Each big fall in IOPs corresponds to adding or replacing a drop (w/ something more powerful), while the slower rises correspond to acclimation.  And if you stop taking drops to which you're acclimated (not shown, but I've done that experiment!), then IOPs shoot much higher than they ever were before starting drops, and requiring many months to deacclimate:

 

Attached File  drop acclimation.jpg   153.24KB   0 downloads

 

So, a person with glaucoma taking several drops each day is really stuck with those drops (barring some other approach like surgery), even if the drops lose their effect over time.  Hopefully, taking NAD precursors won't result in putting us in quite such a box.


Edited by warner, 30 November 2017 - 09:06 PM.

  • Informative x 2
  • Off-Topic x 1
  • Good Point x 1

#37 Oakman

  • Location:CO

Posted 30 November 2017 - 09:50 PM

Just a comment that I notice many are dismayed at the perceived 'lack of results' of NR supplementation in this study. I think much of this pessimism comes from the false concept that humankind will discover the 'Miracle Pill' that will alternatively save us (without further effort) from obesity, diabetes, muscle wasting, cellular dysfunction, etc., and on and on... simply on the basis of it being there in our heart, liver, blood, muscles, where ever. 

 

I don't think NR is that miracle pill. It is an important substance for optimal homeostasis. Our body will use up to a maximum of what is needed, then dispose of the rest. Need more, then use more, dispose of less. That maximum level depends on any body's overall vigor, i.e., strength and stamina before exhaustion. The study says "Participants were healthy as determined by laboratory results, medical history, and physical examination.So normal everyday people, just older. One definition of better health is better physical vigor. This study used people of healthy vigor, but NOT specifically trying to improve their physical performance.

 

Ergo, the results they got. I do think they got healthier for taking NR, but it's not going to magically turn them into super strong or anything else ... old people.  That is, unless they get more active, stronger, and so use more bodily energy to do it. Actually, that there was any strength difference between the two dosage levels is more surprising. There were no fitness classes offered during the study! Why would they get stronger? Because they took a pill? I'd venture the X2 group was just eking out the last little (single digit %) bits of strength their muscles had in them thanks to excess NAD+.

 

Hopefully these first 'baby step' studies showing proven NAD+ increases will lead to ones designed to show us where extra NAD+ can facilitate participants physical improvements. That takes time, personal workout time, AND perhaps NR. Just popping a pill and expecting miracles at 60+ yr old without effort, now would truly be a real miracle.

 

I wonder how many of us taking NR do have (N=1) positive stories of physical fitness improvements beyond the norm? Those types of results could be the precursors to encourage further research where NR supplementation could be really useful for the everyday Jane or Joe getting older.


Edited by Oakman, 30 November 2017 - 09:58 PM.

  • Good Point x 3
  • Agree x 2

#38 stefan_001

  • Guest
  • 1,070 posts
  • 222
  • Location:Munich

Posted 30 November 2017 - 10:10 PM

 

 

 

bluemoon wrote: We also don't know if 500 mg of NR doesn't drop even lower past 55% increase to maybe 40% or 45% after eight weeks because the study didn't look at 12 or 18 weeks.


And even the low dose NAD levels were falling after 8 weeks (although not significantly). It's probably a good bet that NAD levels will continue to fall with time (via "homeostatic mechanisms"), and that the lower they fall, and the longer this takes, the more screwed you will be if discontinuing supplementation. ...

I have actually done that, stop cold turkey from 500mg for over 1 month. [...] I was surprised how well things stayed up and only after a month or so I started feeling some old aging phenomena from the past coming back. To me its not clear how such NR resistance path could develop. The NRK path seems pretty solid and independent.

Conceptually, Warner's argument seems pretty strong, and is consistent with the long-term decline observed in this trial (and its dose-dependency) and with the lower levels of NMN and the higher levels of NAM (apparently residual to what was in flux at the earlier time point), MeNAM, and other NAM metabolites before the fifth dose vs. before the 2nd dose observed in Brenner's n=1 experiment, as well as with other findings of homeostatic feedback in the system discussed here. ...

 

[Exploration of mechanisms] . ... This suggests that if you abruptly discontinue supplementation, these changes will still be active for some time, potentially leading to NAD+ declining below pre-supplemetation levels until the rheostat resets.

 

Conceptually I agree that excess NAD+ may lead to cell compensation. And NRK's could be down regulated because cell do not need NAD+. But I dont believe the body will develop resistance against NR / NRK path specifically. All studies indicate that NR is very rapidly metabolized, minutes followed by almost 24 hours of "normal" NR levels till the next dose. If we would be taking NR on a continuous drip then it would be more likely.

 


Edited by Michael, 01 December 2017 - 07:40 PM.
trim quote


#39 stefan_001

  • Guest
  • 1,070 posts
  • 222
  • Location:Munich

Posted 30 November 2017 - 10:23 PM

Just a comment that I notice many are dismayed at the perceived 'lack of results' of NR supplementation in this study. I think much of this pessimism comes from the false concept that humankind will discover the 'Miracle Pill' that will alternatively save us (without further effort) from obesity, diabetes, muscle wasting, cellular dysfunction, etc., and on and on... simply on the basis of it being there in our heart, liver, blood, muscles, where ever.  [...]

 

I do think they got healthier for taking NR, but it's not going to magically turn them into super strong or anything else ... old people.  That is, unless they get more active, stronger, and so use more bodily energy to do it. Actually, that there was any strength difference between the two dosage levels is more surprising. [...] I'd venture the X2 group was just eking out the last little (single digit %) bits of strength their muscles had in them thanks to excess NAD+.

 

Hopefully these first 'baby step' studies showing proven NAD+ increases will lead to ones designed to show us where extra NAD+ can facilitate participants physical improvements. That takes time, personal workout time, AND perhaps NR. Just popping a pill and expecting miracles at 60+ yr old without effort, now would truly be a real miracle.

 

Fully agree!! In top sport when you would get a 5% performance improvement thats a miracle. Here we seem to think that NR should deliver miracles, people dropping there crutches in weeks and running around. So in that sense the EH results are surprisingly positive But again I dont take anything from EH too serious eventhough I would love to see and believe positive NR results. I dont know what people think here but my hope is that it will preserve my physical shape for a decade versus my real age.I would already call that a miracle. I am fairly sure that NR is more beneficial when combined with exercise. So you benefit less when you take it and sit in the sofa. Exercise activates various genes and the impact is likely bigger when you have sufficient NAD+. Personally I have become more athletic with same exercise routine as compared to couple years back.


Edited by Michael, 01 December 2017 - 07:58 PM.
trim quote

  • Good Point x 1

#40 able

  • Guest
  • 725 posts
  • 325
  • Location:austin texas
  • NO

Posted 30 November 2017 - 10:33 PM

Just a comment that I notice many are dismayed at the perceived 'lack of results' of NR supplementation in this study. I think much of this pessimism comes from the false concept that humankind will discover the 'Miracle Pill' that will alternatively save us (without further effort) from obesity, diabetes, muscle wasting, cellular dysfunction, etc., and on and on... simply on the basis of it being there[...]

 

 I do think they got healthier for taking NR, but it's not going to magically turn them into super strong or anything else ... old people.  That is, unless they get more active, stronger, and so use more bodily energy to do it. Actually, that there was any strength difference between the two dosage levels is more surprising. [...]I'd venture the X2 group was just eking out the last little (single digit %) bits of strength their muscles had in them thanks to excess NAD+.

 

 

I agree entirely about the mobility.  Improvement in strength, just from taking a pill, is impressive.

 

I also very much agree that getting more exercise while taking NR provides a lot more benefit.

 

We don't "get old" in a day, week, or month.  It takes years.  It is silly to think the process can be reversed in months.

 

If taking NR allows you to exercise a bit more, but you don't - results are likely to be limited.

 

If taking NR allows you to exercise a bit more, and you do, results will be better than either one alone.

 

That is what my own N=1 experiment shows.  I had a little more vigor in the gym right away.  Over the last 2 years, I have made constant progress in regaining strength and endurance I had 10-15 years ago.


Edited by Michael, 01 December 2017 - 08:00 PM.
trim quotes

  • Good Point x 1
  • like x 1

#41 Nate-2004

  • Guest
  • 2,277 posts
  • 311
  • Location:Philadelphia
  • NO

Posted 30 November 2017 - 10:56 PM

We don't "get old" in a day, week, or month.  It takes years.  It is silly to think the process can be reversed in months.
 
If taking NR allows you to exercise a bit more, but you don't - results are likely to be limited.
 
If taking NR allows you to exercise a bit more, and you do, results will be better than either one alone.
 
That is what my own N=1 experiment shows.  I had a little more vigor in the gym right away.  Over the last 2 years, I have made constant progress in regaining strength and endurance I had 10-15 years ago.

 
I do think that some things are more likely to reverse the process more quickly, AGE-breakers for glucosepane (if they ever arise) for example. ALT-711 actually showed rapid reversal in dogs as I recall, but not humans because glucosepane.
 
Michael, with regards to the debate over whether NAD+ would decline below pre-supplementation levels after quitting cold turkey due to the changes you described, do you think that would be the case for intermittent use?

Edited by Michael, 01 December 2017 - 08:01 PM.
trim quotes

  • Good Point x 1

#42 able

  • Guest
  • 725 posts
  • 325
  • Location:austin texas
  • NO

Posted 30 November 2017 - 11:48 PM

"I do think that some things are more likely to reverse the process more quickly, AGE-breakers for glucosepane (if they ever arise) for example. ALT-711 actually showed rapid reversal in dogs as I recall, but not humans because glucose pane."

 

 

 

​Yes, some approaches may theoretically be fast.  But the way I think about deterioration due to NAD+ decrease - it is years and years of NAD+ shortage that result in increasing inflammation, less DNA repair, sarcopenia, etc.  

 

We might notice increased energy immediately, but it doesn't seem likely to me that increased NAD+ can quickly repair the years of damage.

 

And even if it could lower inflammation dramatically,  a 70 year old will not perform like he did at 50, without SLOWLY increasing his exercise capacity to rebuild.

 

If it can allow the body to make  incremental progress in repairing damage over months and years, that would be fine with me.  

 

It would still be up to us to USE that improved capacity and build on it.

 

 



#43 bluemoon

  • Guest
  • 723 posts
  • 86
  • Location:south side
  • NO

Posted 01 December 2017 - 05:29 AM

 

 

Michael, with regards to the debate over whether NAD+ would decline below pre-supplementation levels after quitting cold turkey due to the changes you described, do you think that would be the case for intermittent use?

 

 

Keep in mind that Michael has insisted all along that NR is worthless since the mice in the pre-human trials had some genetic variant. I'm curious what he thinks of the study. 


  • Good Point x 1
  • dislike x 1

#44 Harkijn

  • Guest
  • 634 posts
  • 177
  • Location:Amsterdam
  • NO

Posted 01 December 2017 - 04:26 PM

"I do think that some things are more likely to reverse the process more quickly, AGE-breakers for glucosepane (if they ever arise) for example. ALT-711 actually showed rapid reversal in dogs as I recall, but not humans because glucose pane."

 

 

 

​Yes, some approaches may theoretically be fast.  But the way I think about deterioration due to NAD+ decrease - it is years and years of NAD+ shortage that result in increasing inflammation, less DNA repair, sarcopenia, etc.  

 

We might notice increased energy immediately, but it doesn't seem likely to me that increased NAD+ can quickly repair the years of damage.

 

And even if it could lower inflammation dramatically,  a 70 year old will not perform like he did at 50, without SLOWLY increasing his exercise capacity to rebuild.

 

If it can allow the body to make  incremental progress in repairing damage over months and years, that would be fine with me.  

 

It would still be up to us to USE that improved capacity and build on it.

I totally agree. No 'reversal ' was promised and achieved here. Looking back from 66 yo now to 4 years ago when I started on NR, I am convinced it gave and still gives me the energy to work out and I am in a lot better shape than I used to be. I am in this for the long haul so 60 days is just interesting.

On a another note: testpersons who repeat a  physical exercise which was unknown to them before, have a tendency to perform more selfassuredly and ambitiously.


  • Disagree x 2
  • Agree x 1

#45 Nate-2004

  • Guest
  • 2,277 posts
  • 311
  • Location:Philadelphia
  • NO

Posted 01 December 2017 - 04:26 PM

I'm open to the possibility that Michael is right. Mouse studies are mostly useless though, 80 to 95% of the time they don't translate.

 

@Able yeah I agree with that. I wonder what catching it early in precursor supplementation might do over that period of time, from age 40 to 80. Nobody knows yet. Maybe it slows aging by 10 years? I'm 43.5 now and have been supplementing NR since I was 41.8. Hopefully. Anti-aging efforts should be comprehensive and include many angles of approach. This is just one.


Edited by Nate-2004, 01 December 2017 - 04:29 PM.


#46 bluemoon

  • Guest
  • 723 posts
  • 86
  • Location:south side
  • NO

Posted 01 December 2017 - 05:26 PM

 

I totally agree. No 'reversal ' was promised and achieved here. Looking back from 66 yo now to 4 years ago when I started on NR, I am convinced it gave and still gives me the energy to work out and I am in a lot better shape than I used to be. I am in this for the long haul so 60 days is just interesting.

On a another note: testpersons who repeat a  physical exercise which was unknown to them before, have a tendency to perform more selfassuredly and ambitiously.

 

 

I don't know what to make of the anecdotes of those who say they have noticably increased energy yet the study showed only a tiny gain for the 500 mg group of about 3 percentage points over the placebo group.


  • Good Point x 1
  • Disagree x 1
  • Agree x 1

#47 Harkijn

  • Guest
  • 634 posts
  • 177
  • Location:Amsterdam
  • NO

Posted 01 December 2017 - 06:46 PM

 

 

I totally agree. No 'reversal ' was promised and achieved here. Looking back from 66 yo now to 4 years ago when I started on NR, I am convinced it gave and still gives me the energy to work out and I am in a lot better shape than I used to be. I am in this for the long haul so 60 days is just interesting.

On a another note: testpersons who repeat a  physical exercise which was unknown to them before, have a tendency to perform more selfassuredly and ambitiously.

 

 

I don't know what to make of the anecdotes of those who say they have noticably increased energy yet the study showed only a tiny gain for the 500 mg group of about 3 percentage points over the placebo group.

 

You turn things upside down. As some posters noted 60 days is a really short period to find hard facts and there are also many other things to find fault with in the study, but only if you are looking for final conclusions.  Meanwhile those who take NR should draw their own conclusions for their own personal situations..


  • Disagree x 3
  • Agree x 2

#48 able

  • Guest
  • 725 posts
  • 325
  • Location:austin texas
  • NO

Posted 01 December 2017 - 07:56 PM

 

 

I totally agree. No 'reversal ' was promised and achieved here. Looking back from 66 yo now to 4 years ago when I started on NR, I am convinced it gave and still gives me the energy to work out and I am in a lot better shape than I used to be. I am in this for the long haul so 60 days is just interesting.

On a another note: testpersons who repeat a  physical exercise which was unknown to them before, have a tendency to perform more selfassuredly and ambitiously.

 

 

I don't know what to make of the anecdotes of those who say they have noticably increased energy yet the study showed only a tiny gain for the 500 mg group of about 3 percentage points over the placebo group.

 

 

I don't see a discrepancy myself.  

 

A subject may "feel more energy", but that doesn't mean they will perform better in the gym, or in the walking test this study measured.

 

Note the subjects didn't instantly perform better.  They showed some improvement at 30 days, and more at 60.

 

To me, it makes sense if a subject "had more energy" immediately, and then was a little more active, day after day, rebuilding some strength and endurance.  

 

So by day 60, they show more strength and endurance.

 

Possible because they were more active over 60 days, not because the pills magically transformed their muscles.


Edited by able, 01 December 2017 - 08:00 PM.

  • Agree x 2
  • Good Point x 1

#49 Michael

  • Advisor, Moderator
  • 1,234 posts
  • 1,694
  • Location:Location Location

Posted 01 December 2017 - 08:30 PM

 

 

 

bluemoon wrote: We also don't know if 500 mg of NR doesn't drop even lower past 55% increase to maybe 40% or 45% after eight weeks because the study didn't look at 12 or 18 weeks.


And even the low dose NAD levels were falling after 8 weeks (although not significantly). It's probably a good bet that NAD levels will continue to fall with time (via "homeostatic mechanisms"), and that the lower they fall, and the longer this takes, the more screwed you will be if discontinuing supplementation. ...

Conceptually, Warner's argument seems pretty strong, and is consistent with the long-term decline observed in this trial (and its dose-dependency) and with the lower levels of NMN and the higher levels of NAM (apparently residual to what was in flux at the earlier time point), MeNAM, and other NAM metabolites before the fifth dose vs. before the 2nd dose observed in Brenner's n=1 experiment, as well as with other findings of homeostatic feedback in the system discussed here. ...
 
[Exploration of mechanisms] . ... This suggests that if you abruptly discontinue supplementation, these changes will still be active for some time, potentially leading to NAD+ declining below pre-supplemetation levels until the rheostat resets.

Conceptually I agree that excess NAD+ may lead to cell compensation. And NRK's could be down regulated because cell do not need NAD+. But I dont believe the body will develop resistance against NR / NRK path specifically. All studies indicate that NR is very rapidly metabolized, minutes followed by almost 24 hours of "normal" NR levels till the next dose. If we would be taking NR on a continuous drip then it would be more likely.

 
The question isn't what your levels of NR are, but what your levels of NAD+ are, since that's the (or, a known) mechanism of feedback. The evidence reviewed appears to show consistently that NAD+ levels progressively fall in response to NR supplementation, and are consistent with observations o negative feedback when NAD+ levels re raised by other means. Do you have an alternative explanation for these findings?
 

Nate-2004 wrote: Michael, with regards to the debate over whether NAD+ would decline below pre-supplementation levels after quitting cold turkey due to the changes you described, do you think that would be the case for intermittent use?

 
Well, clearly you wouldn't expect it after sufficiently intermittent use. The question is how intermittent — that is, how long at what dose do you take NR before you start to get substantial negative feedback, and how long of an "NR holiday" is required to reset or prevent it.
 

bluemoon wrote: Keep in mind that Michael has insisted all along that NR is worthless since the mice in the pre-human trials had some genetic variant.

 
I am careful not to mischaracterize others' views and expect the same in return. Anyone reading my posts with an unjaundiced eye will know that I have never asserted that NR is worthless, for that reason or any other — only that it could be (for that reason and others). I was careful not to make any definitive assertion to that effect in my main post on the NNT mutation, and when Able finally found a study in which NMN benefitted mice without the NNT mutation, I agreed that "if additional studies replicate it, I think we can stop worrying about this gene x nutrient confounder." I also agreed with Stefan's argument that the deleterious effects of high-dose NR observed in two studies conducted in rodents lacking the NNT mutation might also have been the result of the very young ages of the animals rather than genetic differences.


  • like x 1
  • Agree x 1

#50 2Sunny

  • Guest
  • 11 posts
  • 14
  • Location:Westchester, NY
  • NO

Posted 01 December 2017 - 09:15 PM

I am a 51 year old male suffering from SCA1.  I have been taking NRPTX2 + 125mg PT daily for several months.  I just started taking pictures, but I concur with the hair growth.   I have also begone experiencing moderate fatigue.  I have maintained a routine of running and weight lifting since age 14.  I started taking just NR earlier this year and saw an initial improvement in my speed, but the gain was not sustained after a month of constant 1000mg daily of NR.  I backed it off to 250mg and then switched from TruNiagen to Basis + Pteropure.  I have now seen dramatic changes in my squat strength going from a low start of 8 reps/5 sets of 40 lbs to now 6-7 reps/5 sets of 100 lbs plus my running speed has increased from 6 mph to 6.3 mph plus my pull up count has gone from 4 reps/ 5 sets to 10-12 reps/ 5 sets.  I want to emphasize that I have not altered my exercise routine and that I was seeing steady year over year decline in my strength and endurance prior to taking supplements.  I have noticed other symptoms that got better as well including: balance - now able to put pants on one leg at a time, speech - able to clearly alliterate again with no slurring, hand writing - I have samples from last year and the legibility is improved and closer to what my writing was years ago.

 

I should note however that I also am taking trehalose and 2000 IUs of vitamin D3.  I have been altering my trehalose intake.  I started at 80g/day orally switched to 40g orally and .3 g nasally, and now I use a liquid solution in a nasal spray and get an estimated .4g daily and only ingest 20g daily in coffee.

 

I am awaiting a blood analysis.  My blood pressure has gone from 120/60 range to 130/70 range.  I eat a diet low in carbs and calories and high in cruciferous vegetables.


  • Informative x 2
  • like x 1

#51 Nate-2004

  • Guest
  • 2,277 posts
  • 311
  • Location:Philadelphia
  • NO

Posted 01 December 2017 - 09:34 PM

@2Sunny I would try cycling the NR like I do, I find I get similar results of increased power and energy when I cycle 3 days of NR with 3 days of broccomax (and broccoli sprouts and/or kale).  During the NR days my bike rides to and from work seem effortless and fast but if I continue taking it for too long it drops off to some degree. I think this sort of confirms what Michael is saying. My intermittent use is more centered around the fusion/fission dynamics and the protocol that Turnbuckle talks about in another thread.



#52 stefan_001

  • Guest
  • 1,070 posts
  • 222
  • Location:Munich

Posted 01 December 2017 - 10:31 PM

 

 

 

 

bluemoon wrote: We also don't know if 500 mg of NR doesn't drop even lower past 55% increase to maybe 40% or 45% after eight weeks because the study didn't look at 12 or 18 weeks.


And even the low dose NAD levels were falling after 8 weeks (although not significantly). It's probably a good bet that NAD levels will continue to fall with time (via "homeostatic mechanisms"), and that the lower they fall, and the longer this takes, the more screwed you will be if discontinuing supplementation. ...

Conceptually, Warner's argument seems pretty strong, and is consistent with the long-term decline observed in this trial (and its dose-dependency) and with the lower levels of NMN and the higher levels of NAM (apparently residual to what was in flux at the earlier time point), MeNAM, and other NAM metabolites before the fifth dose vs. before the 2nd dose observed in Brenner's n=1 experiment, as well as with other findings of homeostatic feedback in the system discussed here. ...
 
[Exploration of mechanisms] . ... This suggests that if you abruptly discontinue supplementation, these changes will still be active for some time, potentially leading to NAD+ declining below pre-supplemetation levels until the rheostat resets.

Conceptually I agree that excess NAD+ may lead to cell compensation. And NRK's could be down regulated because cell do not need NAD+. But I dont believe the body will develop resistance against NR / NRK path specifically. All studies indicate that NR is very rapidly metabolized, minutes followed by almost 24 hours of "normal" NR levels till the next dose. If we would be taking NR on a continuous drip then it would be more likely.

 
The question isn't what your levels of NR are, but what your levels of NAD+ are, since that's the (or, a known) mechanism of feedback. The evidence reviewed appears to show consistently that NAD+ levels progressively fall in response to NR supplementation, and are consistent with observations o negative feedback when NAD+ levels re raised by other means. Do you have an alternative explanation for these findings?

I know you meant NAD+ and I agree that may happen. Having said that even with supplementation the NAD+ level at older age are still clearly lower than at younger age. So if the body would have a tendecy to build up resistance against higher NAD+ levels then we should not see those high levels of NAD+ at younger ages. Or then that resistance is always there at a certain intensity with or without supplementation. For alternative explanations a theory could be that because of the metabolic improvements after 90 days of NR supplementation the body is better and faster in processing the NR and subsequently freed NAM into NAD+ and as result we see lower levels of NAD+ after a fasting period of 12 hours.
 


Edited by stefan_001, 01 December 2017 - 10:34 PM.

  • unsure x 1
  • Good Point x 1

#53 Michael

  • Advisor, Moderator
  • 1,234 posts
  • 1,694
  • Location:Location Location

Posted 02 December 2017 - 04:36 AM

 

The question isn't what your levels of NR are, but what your levels of NAD+ are, since that's the (or, a known) mechanism of feedback. The evidence reviewed appears to show consistently that NAD+ levels progressively fall in response to NR supplementation, and are consistent with observations o negative feedback when NAD+ levels re raised by other means. Do you have an alternative explanation for these findings?


I know you meant NAD+ and I agree that may happen. Having said that even with supplementation the NAD+ level at older age are still clearly lower than at younger age. So if the body would have a tendecy to build up resistance against higher NAD+ levels then we should not see those high levels of NAD+ at younger ages.

No, because in young animals the homeostatic poise is set higher in the first place, by higher NAMPT activity and lower activity of consumers. By definition, homeostasis is the dynamic process of returning a s system back to a setpoint after perturbation: what we see with age appears to be at least in part a turning down of the NAD+ setpoint.

 

Now, that isn't the whole explanation for reduced NAD+ with age, because some of the increased activity of consumers is presumably dictated by a response to metabolic need rather than futile cycling — eg. the age-related increase in PARP1 activity reported by most investigators, presumably due to increased DNA damage, or the similar increase in SIRT1 reported by some. The suppression of NAMPT, on the other hand, seems unlikely to be explained along these lines and might instead be (mal)adaptation to reductive stress: as a higher percentage of total NAD is reduced to NADH by compromised electron transport instead of being turned over back to NAD+, the cell might attempt to reduce NAD synthesis to prevent a further absolute increase in NADH. Recall our previous discussion on this issue.

 

Additionally, aging organisms have reduced capacity to restore homeostasis and less homeostatic dynamic range, which is so central to aging that it's part of many definitions of aging.

 

Or then that resistance is always there at a certain intensity with or without supplementation.


This is true in the trivial sense that there is always homeostatic poise, and by definition, homeostasis is the dynamic process of returning to poise after something perturbs the system. But then also by definition, for there to be "resistance," there has to be has to be resistance against some perturbing force (such as supplementation).


  • Informative x 3
  • Agree x 1

#54 bluemoon

  • Guest
  • 723 posts
  • 86
  • Location:south side
  • NO

Posted 02 December 2017 - 06:18 AM

I am a 51 year old male suffering from SCA1.  I have been taking NRPTX2 + 125mg PT daily for several months.  I just started taking pictures, but I concur with the hair growth.   

 

I started taking 250 mg of NR last fall and this spring I got a short haircut and found when I ran my fingers through my hair there was resistance(!), and it felt odd. A friend who is a scientist and an overall skeptic who also started NR at 250 mg after I did, said my hair growth was obvious. "You have almost a full head of hair again."

 

@Michael: I didn't follow your more recent posts on mice. I thought your early statements were very strong but that there was a (small) possibility you were correct.    I'm still curious what you think of this human trial. 

 

@ Nate: I can't see where the study confirms your cycling NR theory. 


Edited by bluemoon, 02 December 2017 - 06:19 AM.


#55 stefan_001

  • Guest
  • 1,070 posts
  • 222
  • Location:Munich

Posted 02 December 2017 - 11:43 AM

 

 

The question isn't what your levels of NR are, but what your levels of NAD+ are, since that's the (or, a known) mechanism of feedback. The evidence reviewed appears to show consistently that NAD+ levels progressively fall in response to NR supplementation, and are consistent with observations o negative feedback when NAD+ levels re raised by other means. Do you have an alternative explanation for these findings?


I know you meant NAD+ and I agree that may happen. Having said that even with supplementation the NAD+ level at older age are still clearly lower than at younger age. So if the body would have a tendecy to build up resistance against higher NAD+ levels then we should not see those high levels of NAD+ at younger ages.

No, because in young animals the homeostatic poise is set higher in the first place, by higher NAMPT activity and lower activity of consumers. By definition, homeostasis is the dynamic process of returning a s system back to a setpoint after perturbation: what we see with age appears to be at least in part a turning down of the NAD+ setpoint.

 

Now, that isn't the whole explanation for reduced NAD+ with age, because some of the increased activity of consumers is presumably dictated by a response to metabolic need rather than futile cycling — eg. the age-related increase in PARP1 activity reported by most investigators, presumably due to increased DNA damage, or the similar increase in SIRT1 reported by some. The suppression of NAMPT, on the other hand, seems unlikely to be explained along these lines and might instead be (mal)adaptation to reductive stress: as a higher percentage of total NAD is reduced to NADH by compromised electron transport instead of being turned over back to NAD+, the cell might attempt to reduce NAD synthesis to prevent a further absolute increase in NADH. Recall our previous discussion on this issue.

 

Additionally, aging organisms have reduced capacity to restore homeostasis and less homeostatic dynamic range, which is so central to aging that it's part of many definitions of aging.

 

Or then that resistance is always there at a certain intensity with or without supplementation.


This is true in the trivial sense that there is always homeostatic poise, and by definition, homeostasis is the dynamic process of returning to poise after something perturbs the system. But then also by definition, for there to be "resistance," there has to be has to be resistance against some perturbing force (such as supplementation).

 

 

Agree its likely that there maybe increased activity of consumers. Consumption could however also be caused by the increased mobility that was reported at the higher dose.

 



#56 Michael

  • Advisor, Moderator
  • 1,234 posts
  • 1,694
  • Location:Location Location

Posted 02 December 2017 - 08:57 PM

 

in young animals the homeostatic poise is set higher in the first place, by higher NAMPT activity and lower activity of consumers. By definition, homeostasis is the dynamic process of returning a s system back to a setpoint after perturbation: what we see with age appears to be at least in part a turning down of the NAD+ setpoint.
 
Now, that isn't the whole explanation for reduced NAD+ with age, because some of the increased activity of consumers is presumably dictated by a response to metabolic need rather than futile cycling — eg. the age-related increase in PARP1 activity reported by most investigators, presumably due to increased DNA damage, or the similar increase in SIRT1 reported by some. The suppression of NAMPT, on the other hand, seems unlikely to be explained along these lines and might instead be (mal)adaptation to reductive stress: as a higher percentage of total NAD is reduced to NADH by compromised electron transport instead of being turned over back to NAD+, the cell might attempt to reduce NAD synthesis to prevent a further absolute increase in NADH. Recall our previous discussion on this issue.
 
Additionally, aging organisms have reduced capacity to restore homeostasis and less homeostatic dynamic range, which is so central to aging that it's part of many definitions of aging.

 
Agree its likely that there maybe increased activity of consumers. Consumption could however also be caused by the increased mobility that was reported at the higher dose.

 

I'm assuming that you mean here that you "Agree its likely that there maybe increased activity of consumers" as part of the homeostatic response. As to consumption being the result of increased mobility that was reported at the higher dose: no: remember, exercise increases NAD+ levels, by increasing NAMPT and likely increasing oxidation of NADH through the electron transport chain.



#57 Michael

  • Advisor, Moderator
  • 1,234 posts
  • 1,694
  • Location:Location Location

Posted 02 December 2017 - 09:03 PM

2Suny, blue: with your permission, may I move your post (Suny) and the part of your post centered on hair growth (blue) to the Personal Experiences thread?



#58 bluemoon

  • Guest
  • 723 posts
  • 86
  • Location:south side
  • NO

Posted 02 December 2017 - 10:20 PM

2Suny, blue: with your permission, may I move your post (Suny) and the part of your post centered on hair growth (blue) to the Personal Experiences thread?

Sure



#59 stefan_001

  • Guest
  • 1,070 posts
  • 222
  • Location:Munich

Posted 02 December 2017 - 10:54 PM

 

 

in young animals the homeostatic poise is set higher in the first place, by higher NAMPT activity and lower activity of consumers. By definition, homeostasis is the dynamic process of returning a s system back to a setpoint after perturbation: what we see with age appears to be at least in part a turning down of the NAD+ setpoint.
 
Now, that isn't the whole explanation for reduced NAD+ with age, because some of the increased activity of consumers is presumably dictated by a response to metabolic need rather than futile cycling — eg. the age-related increase in PARP1 activity reported by most investigators, presumably due to increased DNA damage, or the similar increase in SIRT1 reported by some. The suppression of NAMPT, on the other hand, seems unlikely to be explained along these lines and might instead be (mal)adaptation to reductive stress: as a higher percentage of total NAD is reduced to NADH by compromised electron transport instead of being turned over back to NAD+, the cell might attempt to reduce NAD synthesis to prevent a further absolute increase in NADH. Recall our previous discussion on this issue.
 
Additionally, aging organisms have reduced capacity to restore homeostasis and less homeostatic dynamic range, which is so central to aging that it's part of many definitions of aging.

 
Agree its likely that there maybe increased activity of consumers. Consumption could however also be caused by the increased mobility that was reported at the higher dose.

 

I'm assuming that you mean here that you "Agree its likely that there maybe increased activity of consumers" as part of the homeostatic response. As to consumption being the result of increased mobility that was reported at the higher dose: no: remember, exercise increases NAD+ levels, by increasing NAMPT and likely increasing oxidation of NADH through the electron transport chain.

 

 

Yes that's true that exercise should increase NAMPT. So perhaps the best way to take precursers would be by planning exercise once the NAD+ levels start to come up after supplementation. Still it would be disappointing if NR supplementation over time would not lead to reduction of PARP1, CD38 and other "age related consumers".as result of its health improving impact. Moreover SIRT1 can deacetylate and through gene expression down regulate PARP-1. In this study no change was seen in PARP activity as result of chronic NR supplemenation:

http://www.sciencedi...3112001921#fig5

 

 



Click HERE to rent this ad spot for the NAD+ forum to support LongeCity (this will replace the google ad above).

#60 Nate-2004

  • Guest
  • 2,277 posts
  • 311
  • Location:Philadelphia
  • NO

Posted 02 December 2017 - 11:43 PM

Sauna use also boosts NAMPT, someone linked that in the Manipulating Mitochondrial Dynamics thread at some point.


  • Informative x 1





Also tagged with one or more of these keywords: nad+, elysium basis, nicotinamide riboside, basis

0 user(s) are reading this topic

0 members, 0 guests, 0 anonymous users