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

nad+ elysium basis nicotinamide riboside basis

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#61 bluemoon

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Posted 04 December 2017 - 12:51 AM

 

 

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). 

 

 

 

 

 

Can you point to the section/page where you read 1.03/13.4 and 34/455? I couldn't find that with using search. Thanks.



#62 able

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Posted 04 December 2017 - 02:18 AM

 

 

 

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). 

 

 

 

 

 

Can you point to the section/page where you read 1.03/13.4 and 34/455? I couldn't find that with using search. Thanks.

 

 

The charts under supplemental information:

 

https://www.nature.c...nal-informationhttps://www.nature.c...nal-information

 

s5 and s6

 

 

 

 

(can't figure how to paste images - says png and jpg not allowed - how to post images if no url available?)

 

 

 

 

 

 

 

 

 

 


Edited by able, 04 December 2017 - 02:26 AM.


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#63 bluemoon

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Posted 04 December 2017 - 03:10 AM

Thanks. I saw they were in  S4 and S5 but couldn't find them.



#64 Kevnzworld

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Posted 07 December 2017 - 04:02 AM

I read thru the study, and something occurred to me that hasn't been mentioned. I may have missed something though I read the study twice.
In previous studies, the rise in NAD peaked a few hours after oral ingestion of NR and declined steadily thereafter.
This study tested participants after a 12 hour fast, presumably in the AM, 12-24 hours after consuming the NR. The rise 40-50% rise in NAD was sustained for at least that period of time.
What am I missing?

#65 LawrenceW

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Posted 07 December 2017 - 05:45 AM

NAD+ concentrations varies with 2 peaks and two troughs during the day, When during the day did they measure? Why is this not included in the analysis, since NAD+ concentration is the main endpoint? Measurements of NAD+ at different time periods during the day would alter a person’s concentrations of NAD+ considerably.


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#66 Michael

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Posted 07 December 2017 - 07:01 PM

NAD+ concentrations varies with 2 peaks and two troughs during the day


As discussed here, that may or may not be the case in unsupplemented individuals. OTOH, there clearly is some circadian rhythm in unsupplemented individuals, but based on Trammel & Brenner PMID 27721479's n=1 and n=12 studies (in PBMC), and even more clearly the new UWash 29211728 (in whole blood, after 9 days' supplementation to achieve likely steady-state), circulating NAD+ levels are maintained pretty steadily for 24 h after dosing with NR (and likely NMN).

 

Remember too that whatever the real circadian rhythm in circulating NAD+ in unsupplemented persons may be, that switch is based on varying the activity of NAMPT: aside from the possibility that dosing this far out from the RDA is may swamp such variations, NR and NMN bypass NAMPT (tho' this doesn't apply to NAM subsequently liberated from NR/NMN-derived NAD+ after enzymatic cleavage).
 

When during the day did they measure?


Read the paper.
 

Why is this not included in the analysis, since NAD+ concentration is the main endpoint? Measurements of NAD+ at different time periods during the day would alter a person’s concentrations of NAD+ considerably.

 

As just pointed out, reasonable as that might sound on first principles, that turns out not to be the case in practice. But even if they did, it's not clear whether measuring at different points of day would tell you anything different: you might anticipate (particularly at RDAish levels) that peaks and roughs would be elevated to a similar degree at all time points. And we don't know enough about the differential effects of different levels in blood/PBMC or indeed any other tissue to set desirable targets anyway.


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#67 Michael

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Posted 09 December 2017 - 12:24 AM

I am not very keen on Elysium, and don't think there's anything remotely approaching a good reason for humans to be taking pterostilbene, but they deserve kudos for actually funding a respectable human study with their product. Tons of dietary supplements are sold on the basis of little more than cell culture studies or "traditional use." This study looked at quite a bit, and we should be commending Elysium for conducting and publishing the results, and working to glean from it what we can, rather than blindly criticizing based on sheer suspicion or because it's not the study we would have liked to have funded if we had similar amounts of money burning holes in our own pockets.
 

Just checked who are the authors of the paper. Based on that I will not spend further time analyzing.

the mentioned ahum researchers of the study include the CFO and CEO.....so you can be sure its selective data only.

 
It's of course wise to be aware of the role of funders in research, at to be on the lookout for ways they might have affected the design or reporting, but it's unreasonable to cast aspersions on the basis (ouch ... pun not intended) of that fact alone. The presence or absence of Marcotulli's name on the paper may be a vanity project or CV-padding, and equally, if he wanted to have a corrupt influence on the reporting of the paper it would be easy to do so while remaining in the background (particularly since they used a contract research organization to conduct the trial).
 
On the specific charge: remember, this trial was registered at clinicaltrials.gov, the whole purpose of which is to make sure that (on the one hand) the results of trials are published rather than buried or left to languish in a file drawer, and (on the other hand) that they include the prespecified data and analyses rather than deciding what and how to report post facto. I haven't done a systematic line-by-line review, but I don't see anything in the registry entry that isn't reported in the paper.
 
On which subject:

 
bluemoon wrote: But it would have been nice if 500 mg of NR and 100 mg of pterostilbine further improved mobility. Of course, Elysium didn't report details on mobility for either group.


Sure they do: Tables S5 and S6.


bluemoon wrote: 250 mg doesn't realy do anything except improve ALT, and they didn't report by how much. "Significantly" doesn't mean "a lot" but instead means statistically sigificant.

 

So if 250 mg of NR doesn't do anything to improve mobility but 500 mg does then again "significantly" doesn't mean "by a lot" in that case, either. It might, but so far Elysium isn't saying.


Sure they are: Table 2.
 

bluemoon wrote: in addition, we don't know what 125 mg of NR does for mobility.


 ... or what 1250 mg, or 16 mg (the RDA for B3), or adding vitamin C does. What's your point?

 

This study raises more questions than answers.


Of course it does ... like all the others.
 

For example when was the last time participants took NR + PT before measurements. The paper says:
 

Clinic visits
Eligible volunteers returned to the clinic in the morning, after a 12-hour fast (no food or drink except water) for baseline assessments. A physical exam was conducted where weight was measured and BMI calculated. Resting blood pressure and heart rate measurements were also taken. Fasting blood samples were collected for fasting glucose, lipid panel, hs-CRP, CBC, electrolytes (Na, K, Cl), creatinine, AST, ALT, GGT, bilirubin, PBMC, and NAD+ analysis....

 
The issue with the study itself is that it doesnt explain how they tackle the transcient aspect in the measurement. All we know is that the measurement was done minimally 12 hours after the last consumption. What does it really tell if NAD+ falls off faster in the double dose after a minimal 12 hours after ingestion? Does it also peak lower?...

So does that fast include NR+PT? Everybody knows there is a rise and fall of NAD+ after NR ingestion and the peak comes after 8 hours. So what is really measured here?

 


Now that is a specific and reasonable limitation of the study to point out. On the other hand, the Elysium trial has the strength that it lasts a lot longer than the one-day Trammel & Brenner study or the 9-day UWash study (though more is coming from CDXC), so it adds a different timescale that is just as valuable — particularly granted that it has revealed the first hint of homeostatic counterregulation.
 
As to the specific point of your concern: as previously pointed out, the notion of an 8 h peak is a myth based on overinterpretation of Brenner's n=1 study. We already had evidence from Trammel & Brenner PMID 27721479 's n=12 data that levels after a first dose rise for the first 8 h and are more or less steady thereafter to the end of 24, and you'd expect that this would tend to even out more with repeated dosing; and indeed, we subsequently learned from the new UWash PMID 29211728 that this is exatly what happens after 9-day run-in.
 
As to the general question of peaks and troughs: also previously noted, even if these existed, we don't know enough about the differential effects of different levels in blood/PBMC or indeed any other tissue to set desirable targets anyway. That would come from results with actual health outcomes, including pharmacodynamics.

And the fact that this study was blinded, included a placebo group, and lasted long enough to expect metabolic effects gave us valuable information about the effects of NR on these parameters that we don't get from the other studies: if you have to have just taken the supplement an hour ago to see a metabolic change, the significance of that change for your long-term health is questionable.


Edited by Michael, 09 December 2017 - 12:32 AM.

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#68 bluemoon

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Posted 09 December 2017 - 03:14 AM

 

 
On which subject:

 
bluemoon wrote: But it would have been nice if 500 mg of NR and 100 mg of pterostilbine further improved mobility. Of course, Elysium didn't report details on mobility for either group.


Sure they do: Tables S5 and S6. 

 

Sure they are: Table 2.
 

bluemoon wrote: in addition, we don't know what 125 mg of NR does for mobility.


 ... or what 1250 mg, or 16 mg (the RDA for B3), or adding vitamin C does. What's your point? 

 

I should have seen Table 2 but couldn't find S5 and S6 as I noted above (but accidently wrote S4 and S5).

 

We know adding vitamin C does nothing. But if NR at 250 mg improves something, it would be good to know if 125 mg has effectiveness for half the price. I have a feeling this will be marketed as a 500 mg vitamin costing around $2.50 a day / $730 a year and that within a year or two NR will have strong competition.



#69 stefan_001

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Posted 09 December 2017 - 10:06 AM


On which subject:


bluemoon wrote: But it would have been nice if 500 mg of NR and 100 mg of pterostilbine further improved mobility. Of course, Elysium didn't report details on mobility for either group.

Sure they do: Tables S5 and S6.

Sure they are: Table 2.


bluemoon wrote: in addition, we don't know what 125 mg of NR does for mobility.

... or what 1250 mg, or 16 mg (the RDA for B3), or adding vitamin C does. What's your point?
I should have seen Table 2 but couldn't find S5 and S6 as I noted above (but accidently wrote S4 and S5).

We know adding vitamin C does nothing. But if NR at 250 mg improves something, it would be good to know if 125 mg has effectiveness for half the price. I have a feeling this will be marketed as a 500 mg vitamin costing around $2.50 a day / $730 a year and that within a year or two NR will have strong competition.
Maybe make a song about "that feeling", those do well in YouTube:
https://m.youtube.co...h?v=ru0K8uYEZWw

250mg / day is currently costing less than 1USD. Sounds like a bargain when you comoare to any other care taking or medications that could be potentially avoided or delayed by using NR.

Edited by stefan_001, 09 December 2017 - 10:07 AM.

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#70 bluemoon

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Posted 09 December 2017 - 01:18 PM

 


250mg / day is currently costing less than 1USD. Sounds like a bargain when you comoare to any other care taking or medications that could be potentially avoided or delayed by using NR.

 

 

Tru Nigen with their 15% discount costs $40 a month or $1.33 a day for 250 mg and $2.66 for 500 mg. Elysium's study shows almost no benefits at 250 mg for 60 - 79 year olds with no serious health problems.  Results from cognative tests from other researchers haven't been published yet and 250 mg may show a benefit there. 250 mg may also help obese adults as well.



#71 stefan_001

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Posted 09 December 2017 - 03:27 PM

250mg / day is currently costing less than 1USD. Sounds like a bargain when you comoare to any other care taking or medications that could be potentially avoided or delayed by using NR.

Tru Nigen with their 15% discount costs $40 a month or $1.33 a day for 250 mg and $2.66 for 500 mg. Elysium's study shows almost no benefits at 250 mg for 60 - 79 year olds with no serious health problems. Results from cognative tests from other researchers haven't been published yet and 250 mg may show a benefit there. 250 mg may also help obese adults as well.
People expect too much of an 8 week trial in terms of improvement. These are aging people, just halting the decline is a miracle. I am shipping Niagen to my parents who are 79. They are approaching 3 years of Niagen use. Mom on 250mg and dad on 375mg. They are very mobile compared to age pears (including brothers and sisters).

Wrt cost you can buy HPN brand for 30USD. In general this cost discussion in the scope of elderly I see entirely different. The cost for day care runs at 18kUSD / year, assisted home living 45kUSD. Delaying or reducing the amount of home nurse visits for example makes a couple dollar a month cost insignificant.

Edited by stefan_001, 09 December 2017 - 03:28 PM.

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#72 bluemoon

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Posted 09 December 2017 - 05:43 PM

 

People expect too much of an 8 week trial in terms of improvement. These are aging people, just halting the decline is a miracle. I am shipping Niagen to my parents who are 79. They are approaching 3 years of Niagen use. Mom on 250mg and dad on 375mg. They are very mobile compared to age pears (including brothers and sisters).

Wrt cost you can buy HPN brand for 30USD. In general this cost discussion in the scope of elderly I see entirely different. The cost for day care runs at 18kUSD / year, assisted home living 45kUSD. Delaying or reducing the amount of home nurse visits for example makes a couple dollar a month cost insignificant.

 

 

The only evidence for halting any decline (I'd say slowing) based on the Elysium study is walking and chair standing at the 500 mg level. We don't know HPN will be selling NR in six months based on what Chrhomadex has said. My point is that this early human evidence shows that those who are healthy under and under 50 won't see improvements with only 250 mg of NR unless the cognitive research shows improvements at that level. My guess is that any cognative improvement at 250 mg will be very small or nil for those under 50. What isn't clear is if those under 50 will be willing to pay the $730 or so a year for some 5% gain in short term memory.



#73 stefan_001

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Posted 09 December 2017 - 05:55 PM

 

 

People expect too much of an 8 week trial in terms of improvement. These are aging people, just halting the decline is a miracle. I am shipping Niagen to my parents who are 79. They are approaching 3 years of Niagen use. Mom on 250mg and dad on 375mg. They are very mobile compared to age pears (including brothers and sisters).

Wrt cost you can buy HPN brand for 30USD. In general this cost discussion in the scope of elderly I see entirely different. The cost for day care runs at 18kUSD / year, assisted home living 45kUSD. Delaying or reducing the amount of home nurse visits for example makes a couple dollar a month cost insignificant.

 

 

The only evidence for halting any decline (I'd say slowing) based on the Elysium study is walking and chair standing at the 500 mg level. We don't know HPN will be selling NR in six months based on what Chrhomadex has said. My point is that this early human evidence shows that those who are healthy under and under 50 won't see improvements with only 250 mg of NR unless the cognitive research shows improvements at that level. My guess is that any cognative improvement at 250 mg will be very small or nil for those under 50. What isn't clear is if those under 50 will be willing to pay the $730 or so a year for some 5% gain in short term memory.

 

 

I dont think this is thread about economics so propose there is a different thread for that.


Edited by stefan_001, 09 December 2017 - 05:57 PM.

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#74 bluemoon

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Posted 09 December 2017 - 07:01 PM

  

 

I dont think this is thread about economics so propose there is a different thread for that.

 

 

It was just my reaction to how this may be playing out and who may or not be interested in taking NR after this publication. It isn't a personal experience thread either, although it is good to know your parents seem to have benefited from 250mg and 375mg of NR. "The economics of the Elysium study" isn't a useful thread as new studies could change likely pricing and would have to create an "Economics of the ChromaDex study" thread, the "Economics of the Colorado study" thread , etc.  


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#75 recon

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Posted 10 December 2017 - 04:00 PM

I am not very keen on Elysium, and don't think there's anything remotely approaching a good reason for humans to be taking pterostilbene, but they deserve kudos for actually funding a respectable human study with their product.

Nothing remotely approaching a good reason for humans to be taking pterostilbene? Why is that?
I thought it was a rational idea to supplement something to activate sirtuins in order to utilise the increased NAD+ instead of being consumed by others since the main purpose is longevity. I thought it was a better substitute for that job rather than resveratrol.
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#76 Michael

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Posted 10 December 2017 - 06:49 PM

 

I am not very keen on Elysium, and don't think there's anything remotely approaching a good reason for humans to be taking pterostilbene, but they deserve kudos for actually funding a respectable human study with their product.

 

Nothing remotely approaching a good reason for humans to be taking pterostilbene? Why is that?
I thought it was a rational idea to supplement something to activate sirtuins in order to utilise the increased NAD+ instead of being consumed by others since the main purpose is longevity. I thought it was a better substitute for that job rather than resveratrol.

 

That's a nice-sounding mechanistic story ;) . Now, can you show me any evidence that PT actually elevates sirtuin activity in vivo in humans after oral supplementation? And, more importantly, even if it does: can you show me that taking PT has actual health benefits in normal, nonobese, otherwise-healthy aging mammals of any kind?

 

No ...?

 

And meanwhile it evidently raises LDL-C, in this trial and a previous one.

 

The much better-studied resveratrol ran on the sirtuin activation story, and in every experiment to date, it failed to extend the lifespan of normal, nonobese, otherwise-healthy aging mice or rats.

 

You might think it was a rational idea to supplement something to lower your LDL-C, too. If that "something" is estrogen or dexthyroxine, you'd more likely wind up dead. You might similarly think that it was a rational idea to supplement something to raise your HDL-C. If that something were a CETP inhibitor, you'd again wind up more likely dead for your speculation.

 

Niacin lowers TG and boosts HDL-C. It may or may not lower CVD events or mortality, and clearly does increase diabetes risk.

 

Nice sirtuin activator, Mr. Mallone ... but what else does it do?

 

References
Pearson KJ, Baur JA, Lewis KN, Peshkin L, Price NL, Labinskyy N, Swindell WR, Kamara D, Minor RK, Perez E, Jamieson HA, Zhang Y, Dunn SR, Sharma K, Pleshko N, Woollett LA, Csiszar A, Ikeno Y, Le Couteur D, Elliott PJ, Becker KG, Navas P, Ingram DK, Wolf NS, Ungvari Z, Sinclair DA, de Cabo R (August 2008). "Resveratrol delays age-related deterioration and mimics transcriptional aspects of dietary restriction without extending life span". Cell Metab. 8 (2): 157–68. doi:10.1016/j.cmet.2008.06.011. PMC 2538685 Freely accessible. PMID 18599363.

Miller RA, Harrison DE, Astle CM, Baur JA, Boyd AR, de Cabo R, Fernandez E, Flurkey K, Javors MA, Nelson JF, Orihuela CJ, Pletcher S, Sharp ZD, Sinclair D, Starnes JW, Wilkinson JE, Nadon NL, Strong R (February 2011). "Rapamycin, but not resveratrol or simvastatin, extends life span of genetically heterogeneous mice". J. Gerontol. A Biol. Sci. Med. Sci. 66 (2): 191–201. doi:10.1093/gerona/glq178. PMC 3021372. PMID 20974732.

Strong R, Miller RA, Astle CM, Baur JA, de Cabo R, Fernandez E, Guo W, Javors M, Kirkland JL, Nelson JF, Sinclair DA, Teter B, Williams D, Zaveri N, Nadon NL, Harrison DE (January 2013). "Evaluation of resveratrol, green tea extract, curcumin, oxaloacetic acid, and medium-chain triglyceride oil on life span of genetically heterogeneous mice". J. Gerontol. A Biol. Sci. Med. Sci. 68 (1): 6–16. doi:10.1093/gerona/gls070. PMC 3598361 Freely accessible. PMID 22451473.

da Luz PL, Tanaka L, Brum PC, Dourado PM, Favarato D, Krieger JE, Laurindo FR (September 2012). "Red wine and equivalent oral pharmacological doses of resveratrol delay vascular aging but do not extend life span in rats". Atherosclerosis. 224 (1): 136–42. doi:10.1016/j.atherosclerosis.2012.06.007. PMID 22818625


Edited by Michael, 10 December 2017 - 06:51 PM.

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#77 PAMPAGUY

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Posted 14 January 2018 - 07:10 PM

New video about Elysium clinical trial results. Bottom line, any dosage above 250 mg daily is wasted. Body adapts to higher dosage, doesn't need it and compensates by lowering NAD+ levels is there analysis.


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#78 Heisok

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Posted 14 January 2018 - 07:42 PM

Excellent results.

 

Maybe I am mistaken, but I heard it a little differently. It might not be worth the added cost, but the double dose group ended with 50% as opposed to the single dose group at 40%.

 

That is 25% higher than the single dose group.

 

"Bottom line, any dosage above 250 mg daily is wasted. Body adapts to higher dosage, doesn't need it and compensates by lowering NAD+ levels is there analysis."



#79 PAMPAGUY

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Posted 14 January 2018 - 08:10 PM

I agree. The ideal dose should be north of 250 but less than 500.

#80 Michael

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Posted 14 January 2018 - 09:23 PM

 

Bottom line, any dosage above 250 mg daily is wasted. Body adapts to higher dosage, doesn't need it and compensates by lowering NAD+ levels is there analysis.

 
Maybe I am mistaken, but I heard it a little differently. It might not be worth the added cost, but the double dose group ended with 50% as opposed to the single dose group at 40%. That is 25% higher than the single dose group.

True, but I think you're neglecting two things. First, we don't actually know that a 50% increase over baseline is any better than a 40% increase. Ideally, we'd want a large study comparing levels in unsupplemented but healthy, well-nourished twentysomethings to subjects at older ages taking various doses — and even that would only give an idea of what "youthful levels" are. It would not, itself, actually prove that there was a health benefit to achieving any given NAD+ level, which would require a larger and longer study with hard outcomes.

 

Second, and more important: remember, the cell has to actually engage in a lot of otherwise-futile metabolism to counterregulate that "excessive" spike in NAD+ and bring it back down to its homeostatic target zone. At a minimum, that's going to produce a significant excess of both NAM and N-methylnicotinamide, neither of which is likely desirable; it might also lead to excessive CD38 activity, which probably isn't a good thing either (messing with your immune system).


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#81 bluemoon

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Posted 14 January 2018 - 10:07 PM

 


True, but I think you're neglecting two things. First, we don't actually know that a 50% increase over baseline is any better than a 40% increase. 

 

 

55% higher was better for the walking and balancing test by 8% over the 250mg/50 mg group that showed no improvement, but it isn't known if the 55% level is sustained in the third or fourth months.


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#82 able

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Posted 14 January 2018 - 10:36 PM

Good Point.  

 

We are making educated guesses here.  It makes sense that restoring NAD+ to youthful levels would benefit many markers for health in humans, as it does with Mice.

 

But we really don't know what is the "right" level of NAD+, or dosage of NR/NMN.

 

It's possible that 55% increase does nothing more than a 40% increase in NAD+.

 

It's also possible that 40% doesn't cross some threshold, and has little benefit, but 50% is "enough" to drive more NAD+ into muscle, brain, and other tissues, and results in a lot more benefit.

 

I'm not proposing either scenario - just that an xx% increase in NAD+ is an imperfect measure of health benefit.

 

The  increased mobility with the 500mg dose is a better indicator of effectiveness imo.

 

 


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#83 Heisok

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Posted 14 January 2018 - 10:57 PM

Thanks Michael, I agree, especially with point number 2. What is being done within their bodies to bring it back down to that 50% level, as opposed to the flat 40%.

 

bluemoon, thanks for pointing out the walking and balancing. I agree with able, that it could be a very important outcome, as some lose skills in those as they age. Falls with injuries seem to be a common cause of serious problems with older folks. Things like broken hips.



#84 Michael

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Posted 14 January 2018 - 11:03 PM

 

 


True, but I think you're neglecting two things. First, we don't actually know that a 50% increase over baseline is any better than a 40% increase. 

 

 

55% higher was better for the walking and balancing test by 8% over the 250mg/50 mg group that showed no improvement, but it isn't known if the 55% level is sustained in the third or fourth months.

 

OTOH, they reported that the lower- but not higher-dose group enjoyed reduced diastolic BP (tho' I suspect that's statistical noise), as well as lower ALT (and possibly AST), and a lesser elevation of LDL-C (the latter possibly an artifact, if you want to call it that, of the pterostilbene).


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#85 sthira

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Posted 15 January 2018 - 02:10 AM

...we don't actually know that a 50% increase over baseline is any better than a 40% increase. Ideally, we'd want a large study comparing levels in unsupplemented but healthy, well-nourished twentysomethings to subjects at older ages taking various doses...


Rather than lengthy human trials (expensive, time consuming, possibly biased, in need of replication by disinterested labs with disinterested researchers, none of whom would profit either way) are computer models a possibility here? Recreate it with graphics? Do researchers know enough about this particular metabolic process to construct simulations? Is there any use for implementing artificial intelligence here?

— and even that would only give an idea of what "youthful levels" are. It would not, itself, actually prove that there was a health benefit to achieving any given NAD+ level, which would require a larger and longer study with hard outcomes.


This seems like such a mess. It could be that youthful NAD+ levels (even if a range is found for healthy "normal" twenty-somethings) aren't as healthy for older bodies, and that's why the body lowers NAD+ in the first place. Is this a possibility? The body seems to know what to do all on its own to keep itself alive. Then again, maybe that's a naturalistic fallacy: the body ages, we seek to stop aging.

Second, and more important: remember, the cell has to actually engage in a lot of otherwise-futile metabolism to counterregulate that "excessive" spike in NAD+ and bring it back down to its homeostatic target zone. At a minimum, that's going to produce a significant excess of both NAM and N-methylnicotinamide, neither of which is likely desirable; it might also lead to excessive CD38 activity, which probably isn't a good thing either (messing with your immune system).


And so it may turn out, years of replicated study later, that the metabolic wastes produced by artificially raising NAD+ levels in aging human bodies were more detrimental than the positive effects of raising NAD+. Is that the reasoning?

One day we shall put on a comfy pair of virtual reality glasses, we shall immerse ourselves within the sounds and lights and shapes and flows inside of just one human cell -- figure out what's going on in there -- a sort fun inner cruise ship float through cell body beautiful. Where's my jet pack?

bluemoon, thanks for pointing out the walking and balancing. I agree with able, that it could be a very important outcome, as some lose skills in those as they age. Falls with injuries seem to be a common cause of serious problems with older folks. Things like broken hips.


I agree it'd be nice to take a pill to help with walking and balancing. But wouldn't it be better to fix the problem in a way where we're not dependent upon taking a pill forever? Right now, for example, there are free ways that elderly people can learn how to walk and balance as their bodies continue to degenerate. I know 70-year olds who work out on the balance beam, I know 80-year olds who stand on one foot with eyes closed in yoga "tree pose." This helps people learn to walk and balance as they age. I agree people get injured, though, no matter what they do -- at any age -- and may lose the abilities to walk and balance. So I'm totally not discounting the use of drugs to manipulate metabolism, or repair damage, or physical therapy. Pills are seductive, certainly.
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#86 bluemoon

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Posted 15 January 2018 - 04:49 PM

 


Rather than lengthy human trials (expensive, time consuming, possibly biased, in need of replication by disinterested labs with disinterested researchers, none of whom would profit either way) are computer models a possibility here? Recreate it with graphics? Do researchers know enough about this particular metabolic process to construct simulations? Is there any use for implementing artificial intelligence here? 

bluemoon, thanks for pointing out the walking and balancing. I agree with able, that it could be a very important outcome, as some lose skills in those as they age. Falls with injuries seem to be a common cause of serious problems with older folks. Things like broken hips.


I agree it'd be nice to take a pill to help with walking and balancing. But wouldn't it be better to fix the problem in a way where we're not dependent upon taking a pill forever? Right now, for example, there are free ways that elderly people can learn how to walk and balance as their bodies continue to degenerate. I know 70-year olds who work out on the balance beam, I know 80-year olds who stand on one foot with eyes closed in yoga "tree pose." This helps people learn to walk and balance as they age. I agree people get injured, though, no matter what they do -- at any age -- and may lose the abilities to walk and balance. So I'm totally not discounting the use of drugs to manipulate metabolism, or repair damage, or physical therapy. Pills are seductive, certainly.

 

 

1. Simulations are not powerful enough yet but Sun Systems co-founder Bill Joy estimated ten years ago that it could start around 2020.

 

2. There is no reason a vitamin like NR couldn't enhance what the the elderly learn. Even if NR and NMN show effectiveness, the pharmaceticals will improve on them over time.


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#87 bluemoon

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Posted 16 January 2018 - 04:00 AM

 

 

1. Simulations are not powerful enough yet but Sun Systems co-founder Bill Joy estimated ten years ago that it could start around 2020.

 

 

 

I meant to type that Joy said computers will be powerful enough for simulations to replace trials around 2030.



#88 Michael

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Posted 23 January 2018 - 08:35 PM

Good Point.  

 

We are making educated guesses here.  It makes sense that restoring NAD+ to youthful levels would benefit many markers for health in humans, as it does with Mice.

 

But we really don't know what is the "right" level of NAD+, or dosage of NR/NMN.

 

It's possible that 55% increase does nothing more than a 40% increase in NAD+.

 

It's also possible that 40% doesn't cross some threshold, and has little benefit, but 50% is "enough" to drive more NAD+ into muscle, brain, and other tissues, and results in a lot more benefit.

 

I'm not proposing either scenario - just that an xx% increase in NAD+ is an imperfect measure of health benefit.

 

The  increased mobility with the 500mg dose is a better indicator of effectiveness imo.

 

It's also possible that 40% doesn't cross some harmful threshold, and has benefit with no downside, but 50% is "enough" to drive excess NAD+ leading to redox imbalance, or other problems (as is one possible observation for apparently deleterious effects when administered to very young mice or rats) and thus the homeostatic feedback to pull them down again — and/or, that those homeostatic responses themselves are problematic (methyl depletion resulting from increased metabolism to N-methylnicotinamide), etc).


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#89 recon

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Posted 23 January 2018 - 10:05 PM

Good Point.

We are making educated guesses here. It makes sense that restoring NAD+ to youthful levels would benefit many markers for health in humans, as it does with Mice.

But we really don't know what is the "right" level of NAD+, or dosage of NR/NMN.

It's possible that 55% increase does nothing more than a 40% increase in NAD+.

It's also possible that 40% doesn't cross some threshold, and has little benefit, but 50% is "enough" to drive more NAD+ into muscle, brain, and other tissues, and results in a lot more benefit.

I'm not proposing either scenario - just that an xx% increase in NAD+ is an imperfect measure of health benefit.

The increased mobility with the 500mg dose is a better indicator of effectiveness imo.

It's also possible that 40% doesn't cross some harmful threshold, and has benefit with no downside, but 50% is "enough" to drive excess NAD+ leading to redox imbalance, or other problems (as is one possible observation for apparently deleterious effects when administered to very young mice or rats) and thus the homeostatic feedback to pull them down again — and/or, that those homeostatic responses themselves are problematic (methyl depletion resulting from increased metabolism to N-methylnicotinamide), etc).
What are these deleterious effects to those young mice?
If there are those effects, I don’t suppose that the homeostatic response would reduce the NAD+ levels below the original baseline. Those effects should then be seen only after an abrupt end of administration. Unless, of course, your latter hypothesis that the homeostatic response brings about problems rather than a reduced NAD+.

Edited by recon, 23 January 2018 - 10:08 PM.


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#90 Michael

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Posted 23 January 2018 - 10:34 PM

 

 

we really don't know what is the "right" level of NAD+, or dosage of NR/NMN.

It's possible that 55% increase does nothing more than a 40% increase in NAD+.

It's also possible that 40% doesn't cross some threshold, and has little benefit, but 50% is "enough" to drive more NAD+ into muscle, brain, and other tissues, and results in a lot more benefit.

It's also possible that 40% doesn't cross some harmful threshold, and has benefit with no downside, but 50% is "enough" to drive excess NAD+ leading to redox imbalance, or other problems (as is one possible observation for apparently deleterious effects when administered to very young mice or rats) and thus the homeostatic feedback to pull them down again — and/or, that those homeostatic responses themselves are problematic (methyl depletion resulting from increased metabolism to N-methylnicotinamide), etc).

What are these deleterious effects to those young mice?

 
An apparent worsening of metabolic flexibility and impaired exercise performance. As discussed here, it's also possible that these effects result are the normal response to more-than-RDAish dosing of NAD+ precursors at any age in animals with an intact NNT gene (like humans, rats, and some strains of mice), whereas nearly all the mouse work on NAD+ precursors has been done in C57Bl/6J mice, which have an NNT mutation.

 

If there are those effects, I don’t suppose that the homeostatic response would reduce the NAD+ levels below the original baseline. Those effects should then be seen only after an abrupt end of administration. Unless, of course, your latter hypothesis that the homeostatic response brings about problems rather than a reduced NAD+.


Not "rather than:" the homeostatic response certainly lowers NAD+, and it is effected by several mechanisms, some of which may have deleterious effects. Eg, it certainly entails increased methylation to N-methylnicotinamide, which depletes methyl groups in cell models and has been linked to Parkinson's disease, metabolic disease, and cancer (reviewed here).


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