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Copenhagen Study: High-Dose NR Does Not Improve Insulin Sensitivity, Shows Potential for Fatty Liver

nad+ nad brenner copenhagen fatty liver niagen

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#61 Gingerbread Man

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Posted 14 July 2018 - 09:49 PM

Stefan_001,

  I apologize if my posts were considered off topic. I will refrain from posting additional thoughts on this matter. Thank you for posting this material for the NAD+ sub forum.


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#62 Hebbeh

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Posted 14 July 2018 - 10:02 PM

You posted personal information in this thread as well.

 

Glad you can read my emotions over my typed word (other then the smiley emoji's I posted).

 

My information was posted either to answer a question or to convey a correlation between my own anecdotal experiences with NR and the clinical trials results.

 

Your posting of this "NR was unable to improve on staying healthy in the first place." has nothing to do with what the trial was looking at and in my opinion, not correct.

 

Have a great day.

 

 

I suggest you re-read the study with an open mind as to what it really is saying and not read more into it than it states:

 

 

 
Results: Insulin sensitivity, endogenous glucose production, and glucose disposal and oxidation were not improved by NR supplementation. Similarly, NR supplementation had no effect on resting energy expenditure, lipolysis, oxidation of lipids, or body composition. No serious adverse events due to NR supplementation were observed and safety blood tests were normal.
Conclusion: 12 wk of NR supplementation in doses of 2000 mg/d appears safe, but does not improve insulin sensitivity and whole-body glucose metabolism in obese, insulin-resistant men. This trial was registeredatclinicaltrials.govasNCT02303483. AmJClinNutr 2018;108:1–11.

 


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#63 MikeDC

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Posted 14 July 2018 - 10:57 PM

This author sounds like anti NR to me. If their A1C is at 5.7 or below, they are not insulin resistant. If they want to test insulin resistance, they need to pick people with A1C over 6.5.
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#64 Hebbeh

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Posted 14 July 2018 - 11:07 PM

This author sounds like anti NR to me. If their A1C is at 5.7 or below, they are not insulin resistant. If they want to test insulin resistance, they need to pick people with A1C over 6.5.

 

Really?  Charles Brenner?

 

Ole L Dollerup,1,2 Britt Christensen,1,2 Mads Svart,2 Mark S Schmidt,6 Karolina Sulek,1 Steffen Ringgaard,3 Hans Stødkilde-Jørgensen,3 Niels Møller,2,4 Charles Brenner,6 Jonas T Treebak,1 and Niels Jessen5,7
1Novo Nordisk Foundation Center for Basic Metabolic Research, Section for Integrative Physiology, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark; 2Medical Research Laboratory, Department of Clinical Medicine; 3The MR Research Centre; 4Department of Endocrinology; 5Department of Clinical Pharmacology, Aarhus University Hospital, Aarhus, Denmark; 6Department of Biochemistry, Carver College of Medicine, University of Iowa, Iowa City, IA; and 7Department of Biomedicine, Aarhus University, Aarhus, Denmark
 

The authors’ contributions were as follows—JTT, NJ, and BC: conceived the study; OLD, BC, MS, NM, JTT, and NJ: designed the study; OLD: conducted the experiments; SR and HS-J: provided technical support regarding the MR techniques and aided in MR data analysis; MSS and CB: performed metabolomics on urine samples; KS: analyzed the data; OLD, JTT, CB, and NJ: interpreted the data; OLD, JTT, CB, and NJ: wrote the manuscript; and all authors: reviewed and accepted the manuscript. NJ is the guarantor of this work and, as such, had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. CB serves as chief scientific adviser of ChromaDex, Inc., holds stock in ChromaDex, Inc., and has received research grants from ChromaDex, Inc. ChromaDex, Inc. had no role in the study design, data collection, analysis, or preparation of the manuscript. The other authors have no conflicts of interest to declare in relation to this work.

 

 


Edited by Hebbeh, 14 July 2018 - 11:10 PM.

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#65 MikeDC

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Posted 14 July 2018 - 11:15 PM

Really? Charles Brenner?


I am not a fan of Charles Brenner. He has gotten over his head with the little success of NR. He refuses to achwoldge the bioavailability issue and slow down the progress of the company.
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#66 Hebbeh

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Posted 14 July 2018 - 11:23 PM

I am not a fan of Charles Brenner. He has gotten over his head with the little success of NR. He refuses to achwoldge the bioavailability issue and slow down the progress of the company.

 

Maybe he's in a professional position to distinguish between the science and the hype.



#67 MikeDC

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Posted 14 July 2018 - 11:45 PM

Maybe he's in a professional position to distinguish between the science and the hype.


Professionally you don’t say someone with 5.6 A1C is insulin resistant.

At this point we could not care less if some idiot think NR is all hype and refuse to take it. Don’t change your mind please!
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#68 Hebbeh

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Posted 14 July 2018 - 11:56 PM

Professionally you don’t say someone with 5.6 A1C is insulin resistant.

At this point we could not care less if some idiot think NR is all hype and refuse to take it. Don’t change your mind please!

 

As usual, result to ad hominem attacks when you have nothing.  I would trust the paper's authors are more up to speed on the science than you unless you can prove otherwise.  And being a loyal shareholder doesn't apply to knowledge of the science.  And as previously stated,  HbA1c of 5.6% is not a healthy marker we strive for.  HbA1c of < 5.0 would be common of healthy individuals.


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#69 bluemoon

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Posted 15 July 2018 - 08:42 AM

I am not a fan of Charles Brenner. He has gotten over his head with the little success of NR. He refuses to achwoldge the bioavailability issue and slow down the progress of the company.

 

But as long as ChromaDex is at $1,000 a share you should be happy, right?


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#70 warner

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Posted 15 July 2018 - 12:32 PM

And as previously stated,  HbA1c of 5.6% is not a healthy marker we strive for.  HbA1c of < 5.0 would be common of healthy individuals.

Probably better to say that A1C < 5 is characteristic of healthy young people, not of healthy people in general.

 

Since risk grows exponentially with A1C, it's the higher A1Cs, well above 6, that are the most dangerous.  The added risk of A1C 5.x is quite small, and most of us older folks have better things to worry about than that.  [In fact, in my case, restricting carb and calorie intake to further lower A1C produces a heart arrhythmia (an ectopic focus triggered by low heart glycogen levels).]  There are lots of charts out there showing the relationship between A1C and various risks, such as from this site.  Note both how the added relative risk at A1C 5.x is quite small (first chart), and how the risk at A1C < 5 is not zero (second chart).  (In other words, even normal blood glucose levels probably contribute to diabetic-like complications with aging, although the added relative risk of a 5.x A1C is quite small.)

 

Anyway, for me, the upshot of that, with respect to the study, was that taking a lot of NR had no significant impact on blood sugar levels.  Certainly not compared to the effect of even modest lifestyle improvements.  Probably meaning we need to next try improving delivery, and/or switch to a better B3.  Thus the interest in sublingual NMN, also corresponding to better NMN pricing and availability.


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#71 MikeDC

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Posted 15 July 2018 - 01:56 PM

Probably better to say that A1C < 5 is characteristic of healthy young people, not of healthy people in general.

Since risk grows exponentially with A1C, it's the higher A1Cs, well above 6, that are the most dangerous. The added risk of A1C 5.x is quite small, and most of us older folks have better things to worry about than that. [In fact, in my case, restricting carb and calorie intake to further lower A1C produces a heart arrhythmia (an ectopic focus triggered by low heart glycogen levels).] There are lots of charts out there showing the relationship between A1C and various risks, such as from this site. Note both how the added relative risk at A1C 5.x is quite small (first chart), and how the risk at A1C < 5 is not zero (second chart). (In other words, even normal blood glucose levels probably contribute to diabetic-like complications with aging, although the added relative risk of a 5.x A1C is quite small.)

Anyway, for me, the upshot of that, with respect to the study, was that taking a lot of NR had no significant impact on blood sugar levels. Certainly not compared to the effect of even modest lifestyle improvements. Probably meaning we need to next try improving delivery, and/or switch to a better B3. Thus the interest in sublingual NMN, also corresponding to better NMN pricing and availability.


Increasing bioavailability of NR is urgently needed. People might be shocked at the great results when NR is above 50% bioavailable. Brenner and ChromaDex are slowing down the adoption of NR by ignoring the issue. NR works great for some people and not so great for some people too. This is mainly due to differences in bioavailability between people.
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#72 Hebbeh

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Posted 15 July 2018 - 03:38 PM

Probably better to say that A1C < 5 is characteristic of healthy young people, not of healthy people in general.

 

 

Just for the record, you must of missed my post #45 where I stated:

 

 

I'm 61 and had blood work done 18 days ago (6/26/18) and tested HbA1C of 4.9%

 

And at age 61, I don't believe I'm an anomaly for the members on this site that are doing the basics with diet and exercise which is where it all should start.  And without attending to the basics, there really is nothing to build on period.  And as far as your chart, I don't believe it tells the complete story and is a little cavalier to dismiss blood glucose as long as you don't have the systems of full blown diabetes.  The members of this site spend a lot of effort to maximize health and longevity not to maintain basic optimal healthy blood glucose markers of youth just as with everything else.  After all, I believe the purpose of this site is to strive for the markers of youth which is where it starts after which magic pills may be the frosting on the cake.


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#73 Michael

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Posted 15 July 2018 - 06:06 PM

bluemoon wrote:
NR hasn't been shown to be an "overall" health supplement yet, whatever that means.

 

Indeed.


bluemoon wrote:
So far we know from trials:
 
1) 250 mg of NR doesn't improve balance or walking speed but 500 mg of NR with 100 mg of pterostilbine might improve both by 7%.

 
"Might" is certainly operative: there's reason to be skeptical here, as discussed here.

 
bluemoon wrote:
2) 1000 mg of NR lowers blood pressure (systolic) by 10 points for those with hypertension.


3) 1000 mg of NR may make arteries somewhat more flexible.

 
None of this is all clear, as discussed here.
 
bluemoon wrote:
4) 2000 mg of NR lowers fat levels in those with fatty liver by 20%.

 
That isn't clear, and it also isn't clear whether that's a meaningful reduction even if the effect is real:
 

A 2% reduction in HLC in the NR supplemented group was observed compared with a 0.2% reduction in the placebo group; however, no significant difference between groups was found (interaction: P = 0.13) (Figure 4). In a mouse model, in which obesity was rapidly induced by a diet in which 60% of the calories derived from lard, NR had a profound effect in reducing hepatic steatosis (9). We therefore considered whether our data might suggest that there are responders and nonresponders of NR to decrease hepatic steatosis. As shown in Figure 4C, there were 15 individuals in the placebo group with pretreatment HLC > 5%. Six of these individuals showed apparent decreases in HLC after placebo. In contrast, 13 individuals in the NR group (Figure 4D) had pretreatment HLC > 5% of whom 9 showed an apparent reduction in HLC after 12 wk on NR. ...

This effect size is potentially of significance given that the NR group began the trial with 2.8% lower HLC than the placebo group. Inspection of the individual data (Figure 4D) suggests that most participants in the NR group experienced a drop in HLC after 12 wk. In rodents NR displays potent capabilities in reducing hepatic steatosis in HFD-induced NAFLD (8–10). The power calculation for the study was not based on this endpoint, and the possibility of a type II error cannot be excluded. Thus, future sufficiently powered studies should address this endpoint with long-term NR supplementation. In addition, the fate of the hepatic lipid and the question of whether it is transiently mobilized to the circulation can be addressed by collection of urine, feces, and other methods. … Longer-term studies are warranted with endpoints that relate to mobilization and disposition of hepatic lipids.

 

This is all quite tentative, and they appropriately make no claim of an effect, don't mention it in the abstract, and call for more studies. Even if real, a 2% reduction on a baseline HLC of 11-12 may well have no meaningful metabolic effect; certainly no meaningful metabolic improvements were observed in this study, and NR actually increased triglycerides, despite the strong relationship of NASH with insulin resistance and lipemia. For context, in this study, hepatic lipid contents were 19.9% ± 9.0 in NASH, 14.5% ± 10.6 in simple steatosis, and 1.8% ± 1.7 in healthy controls; the normal cutoff for normal hepatic lipid content isi 5%.


bluemoon wrote:
5) NR doesn't affect insulin sensitivity in the obese.

 
Indeed: it has consistently failed to have any effect on any tested aspect of glycemia or lipids.


bluemoon wrote:
5) I think most understood "fat" to be in the liver since the focus was on those with fatty liver.


The focus certainly wasn't on those with fatty liver: they didn't specifically recruit NASH patients, hepatic lipid accumulation was not a primary outcome of the trial, and they (rightly) don't even mention liver fat in the title or abstract. If you just say "fat," people normally think you mean body fat. (This is an even worse problem with all the reporting on studies saying that "the subjects doing X burned more fat," when all they mean is a change in respiratory quotient, and people think they mean they actually burned off that much more body fat).


bluemoon wrote:
I assumed "doesn't affect insulin sensitivity" is the same as has no effect on sugar levels.



This author sounds like anti NR to me. If their A1C is at 5.7 or below, they are not insulin resistant. If they want to test insulin resistance, they need to pick people with A1C over 6.5.


Insulin sensitivity and blood sugar levels (or HbA1c) are not at all the same thing, and it certainly doesn't mean (as MikeDC apparently believes) having outright diabetic HbA1c. Insulin sensitivity is a measure of how well your tissues take up blood glucose in response to a given level of insulin, which they tested rigorously here. You can have perfectly normal blood sugar and be highly insulin resistant, so long as your beta-cells are still functional and can keep pumping out more and more insulin to push glucose into your increasingly resistant tissues. Type II diabetes is what happens when your beta-cells can no longer keep up with your insulin resistance.
 

What is interesting are the clearly higher levels of NAM and NAM metabolities in the urine. I would guess that means circulating NAM must be also higher. Could there be a break on sirtuin activity because of that?

 
There's been an increase in circulating or urinary NAM (whichever has been tested) in every NR study ever done, which increases nonlinearly with dose; why do you seem surprised?
 

Last month, Charles Brenner said he knows the results of NR on 30 heart failure patients in the U of Washington trial but that he couldn't discuss the results yet. That study ended last month where patients took 250 mg twice a day in week 1 then 500 mg twice a day in week 2 and by week 4 took 1000 mg twice a day until the final week 12.
 
Brenner mentioned his heart failure/NR mouse study which had great results in another more recent interview and wonder if he would say much about that if the human heart failure trial wasn't positive. With mice, taking NR helped prevent heart failure as well as lifted them out of it.
 
https://clinicaltria...how/NCT03423342

 
I'd say that depends on the context. What was the question? If he was asked about clinical trial results and just rattled this off, I'd say it means nothing at all; ditto if he was aksed specifically about the heart, or this specific trial. "It's not published, but I will tell you that the results were favorable" is a meaningful statement.
 

notice what they are testing on - blood glucose and fatty liver 
 
why? 
 
because both are related to obesity and weight loss. THAT right there is how you SELL and MARKET a new supplement 
 
"OMG! this pill melts the fat off! Its a weight loss program in a bottle! Get 50% off today with this coupon code!"
 
its all about marketing. But I am telling you right now they are barking up the wrong tree. Look at the personal experience threads and people are seeing great results with all kinds of things, notably skin, energy, and arthritic joints. 
 
I could not possibly care less about its insulin or fatty liver properties. Insulin problems are like super easy to take care of (barring serious genetic disorders or what have you) 
 
Intermittent fasting , healthy diet, limit sugar, excersice. Boom. Problems solved. 
 
NR/NMN will be proven to do amazing things, mark my words. But not until they stop trying to market it as yet another stupid freaking weight loss supplement. 

 
 They are focusing on these areas because there is the strongest animal data in support of these outcomes, and because we have an epidemic of diabetic obesity. Hence it's pretty disappointing that it had no effect here (or maybe a very small effect on steatosis, vs.  a profound effect in rodents — and no concomitant biochemical improvement). 
 
I am quite sure they could sell an effective supplement for skin, energy, and arthritic joints if they had one.
 
 

Looking over the data again this morning. I actually don't care for the wording they used in the results.
 
"Results: Insulin sensitivity, endogenous glucose production, and glucose disposal and oxidation were not improved by NR supplementation."
 
The "not improved" part.
 
Looking at the data in table 3, the participants in the NR treatment side were healthy and didn't need improvement in any of the areas mentioned in the quote above. An HbA1c, % of 5.6 is normal. I think if those values had been listed in the results as unchanged it would be more accurate than "not improved". As a diabetic for over 18 years who has had an HbA1c, % of over 13 and can't even think about how great a 5.6 would be I think the "not improved" sends a message as if we should be expecting a change from the group that was studied.
 
Run the study again with Type 2 diabetics.
 
My NAFLD numbers have gotten better on NR.

 
 The subjects were certainly not healthy: they were insulin-resistant obese sixtyish-year-old men with significant liver fat and high-normal HbA1c. If NR doesn't improve their insulin sensitivity or HbA1c, I see no reason why it would do so in outright diabetics.
 

From another board:
 
Fellow TruNiagen people:
I'm relaying a direct quote from Dr. Brenner (today, July 13, 2018) about the latest published study from Aarhus University Hospital. [...]
“The study was hypothesis-generating.....

 
 The study was not supposed to be hypothesis-generating. As they say in the paper and the clinicaltrials.gov entry, they enrolled obese, insulin-resistant males with the expectation of improved insulin resistance, on the basis of strong rodent data to that effect. They got nothing. Now they're grasping at the nonsignificant hint of a reduction in steatosis with no accompanying biochemical improvement.
 

[Quoting Charles Brenner]
 Differences between human and mouse obesity are major.
Person gets fat over decades,
A mouse over weeks.
Trying to reverse any parameter in 12 weeks in humans is daunting.
Essentially we found that the fat content of the liver is the most responsive parameter to high dose NR.
In hindsight that should have been the first parameter for randomization and primary endpoint
More work needed....

The reason it can’t be in the abstract of the paper is technical:
Statistical significance is defined as P < 0.05 against the placebo control.
We got to P = 0.13.
How, you might wonder, can you say this isn’t significant when the average guy loses 2% of his liver fat in 12 weeks of NR versus 0.2% on placebo? Clearly medically significant in terms of the “effect size” (i.e. 10-fold effect). But does not meet the standard for statistical significance so it can’t be responsibly touted in the abstract.
If you look carefully at the data, the guys were randomized for insulin sensitivity as the primary endpoint. By unfortunate chance, the guys getting NR started off with lower liver fat than those on placebo.
There is every indication that a study setting out to clear fatty liver with high dose NR for 26 weeks would succeed.”


The idea that any such effect would take a long time is inconsistent with the postulated mechanism of action of NR. Metabolic parameters should improve rapidly with the increased NAD+ or NAD:NADH if they're going to improve at all.
 
 

Unfortunately the researchers didn't include common liver-function-parameter tests such as AST, ALT, ALP, albumin, and bilirubin for their subjects, in spite of the fact that in the article's introduction mention is made that:
 
"NR improves glycemic control and provides resistance to weight gain, hepatic steatosis, and hypercholesterolemia in mouse models of prediabetes and diabetes (9, 35). Moreover, NR effectively reduces ectopic lipid deposition in the liver in mouse models of nonalcoholic fatty liver disease (NAFLD) (8, 10)"
 
It's clear in the researcher's cited references that NR appears to have an effect on the livers of tested mice. And, yet, they apparently didn't find a need to test for any potentially adverse affects on the livers of their test subjects that might be attributable to NR.
 
It's unknown from the information provided in the study whether there were any adverse effects on the liver, as might be indicated by abnormal liver-function test values. So, we are left wondering whether, in addition to reducing fat in the liver, the NR might also be adversely affecting it.

 
They did include such parameters: "The blood sample included creatinine, sodium, potassium, urea nitrogen, albumin, alanine aminotransferase (ALT), bilirubin, alkaline phosphatase, hemoglobin, white blood cell count, and platelets." They don't report any of them except ALT (no effect —Talbe 3), but they do say "The safety of ingestion of NR at 2000 mg/d for a 12-wk period was supported in this study by the lack of clinically relevant findings in the blood biochemistry and hematology parameters." I think we can probably trust them on that.
 
I find it very odd that everyone is engaged in speculations over what NR might have improved even though it didn't do so in this trial, while ignoring the one statistically and "soft"-diagnostically significant outcome in the trial: an increase in triglycerides from a baseline of 1.5 mmol/L (141.6 mg/dL, officially "desirable" (tho' I would say <100 mg/dL is "desirable")  to 1.8 mmol/L after NR  (159.3 mg/dL, "borderline high" (clearly high IMO)). TG were also elevated in the Elysium Basis trial, which is only other NR trial that has tested TG: the effect there was smaller, and at the time the investigators chalked up the statistical significance to the small concomitant decrease in TG in the placebo group, which was a reasonable enough interpretation based on that one study alone — but it happened in both NR+PT groups, and here it was larger at a substantially higher dose, in a patient population where you'd most expect to see an improvement.


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#74 bluemoon

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Posted 15 July 2018 - 06:57 PM

I'd say that depends on the context. What was the question? If he was asked about clinical trial results and just rattled this off, I'd say it means nothing at all; ditto if he was aksed specifically about the heart, or this specific trial. "It's not published, but I will tell you that the results were favorable" is a meaningful statement.

 

 

Brenner brought it up in March after being asked about general safety of NR:

 

Brenner: “There have been trials initiated for diabetes and heart failure, however, we can’t talk about results yet and there are trials whose results will be made public in coming months that say some things about common conditions … studies with people taking medications have not shown interactions with NR. ” 

 

34:40

http://www.llamapodc...harles-brenner/

 

 If you just say "fat," people normally think you mean body fat

 

This is trivial but the thread was on fatty liver so the use of "fat" in my list was obvious. 

 

 

 

 

 They got nothing. Now they're grasping at the nonsignificant hint of a reduction in steatosis with no accompanying biochemical improvement.

 

 

 

 

Those results were not statistically significant at the P<.1 or P<.05 levels, which is just a convention. The results were significant at the P<.15 level and that is noteworthy.


Edited by bluemoon, 15 July 2018 - 06:57 PM.

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#75 warner

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Posted 15 July 2018 - 07:47 PM

Excellent review, but you may want to back off going out on this limb... :)

The idea that any such effect would take a long time is inconsistent with the postulated mechanism of action of NR. Metabolic parameters should improve rapidly with the increased NAD+ or NAD:NADH if they're going to improve at all.

Seems reasonable to think that various tissues may take time to heal/repair themselves after years of aging with reduced NAD levels.  With respect to visual acuity, for example, Lawrence claims it took several months for improvement with NMN to occur, whereas I found no immediate (after 2 days) improvement in visual field response (although at a lower NMN dose).  On the vision front, we also have the work with NAM stopping glaucoma progression in a mouse model, but I don't recall them saying anything about the time it took to get an optimal/stable response in mice with existing glaucoma.  The timing factor is probably quite complex, dependent on the type of tissue being saved/repaired/rejuvenated.



#76 Advocatus Diaboli

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Posted 15 July 2018 - 08:00 PM

Michael, you wrote in your post #66, referring to my post #42:

 

"They did include such parameters: "The blood sample included creatinine, sodium, potassium, urea nitrogen, albumin, alanine aminotransferase (ALT), bilirubin, alkaline phosphatase, hemoglobin, white blood cell count, and platelets." They don't report any of them except ALT (no effect —Talbe 3), but they do say "The safety of ingestion of NR at 2000 mg/d for a 12-wk period was supported in this study by the lack of clinically relevant findings in the blood biochemistry and hematology parameters." I think we can probably trust them on that."

 

In my post #50 I had made the following correction to my post #42:

 

"Re: my post #42. "Similarly, no significant change in the liver marker ALT was recorded.". However, the values of other parameters I mentioned weren't reported.  It'd be interesting to see the actual values even if considered "insignificant"."

 

Your comment in post #66 (re my post #42) would have been relevant if it had preceded post #50.

 

You also wrote in post #66: "I think we can probably trust them on that." referring to the study's assertion of "the lack of clinically relevant findings in the blood biochemistry and hematology parameters.".

 

I find it odd that you’d “probably trust” the authors with respect to their assertion about the non-reported blood parameters in light of the fact that in the following quote you admit that passing over, or accepting, “subtle flaws in execution and reporting” can prove to be important with respect to the meaning of results. I’ve taken the liberty of including “omission” as a flaw of “reporting” and have taken your words as having a more catholic context than your specific use here:

 

I was surprised to see that the situation was even worse than I'd known, as subtle flaws in execution and reporting that I'd've blithely passed over or accepted prove to be important to certainty about the meaning of the results, and bring into question several good-looking studies (tho' in most cases, hyped-up reports with subtle flaws also have larger ones).

 

Quote is from from this thread post #1

 

 

 

In addition to Lord Kelvin’s: “To measure is to know” (paraphrased) I’d add: “To report the values of measured results, is to know”.

 

 

Without seeing the blood-work data it’s impossible to know if there might have been flaws in interpretation, regardless of the authors' asseverations.

 


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#77 bluemoon

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Posted 15 July 2018 - 08:29 PM

Michael, you wrote on the Colorado trial thread: "Anecdotes are not evidence"  Of course they are evidence. Maybe not very strong evidence but evidence none the less. 


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#78 Michael

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Posted 15 July 2018 - 08:46 PM

Those results [on steatosis] were not statistically significant at the P<.1 or P<.05 levels, which is just a convention. The results were significant at the P<.15 level and that is noteworthy.

 
 No, it isn't. You're right to say that the p<0.05 cutoff is just a convention, but if anything the level of improbability of nominal effect required to reject the null hypothesis should be higher, not lower. And in this case, as I noted, the likelihood that this non-significant difference represents a real biological change is undermined by the fact that biochemical factors that normally track with improved liver fat (liver enzymes, insulin sensitivity, and TG) either were unchanged or got worse (TG) in response to NR.
 

 

The idea that any such effect would take a long time is inconsistent with the postulated mechanism of action of NR. Metabolic parameters should improve rapidly with the increased NAD+ or NAD:NADH if they're going to improve at all.


Seems reasonable to think that various tissues may take time to heal/repair themselves after years of aging with reduced NAD levels.  With respect to visual acuity, for example, [...] The timing factor is probably quite complex, dependent on the type of tissue being saved/repaired/rejuvenated.

 
 With visual acuity in glaucoma, or most things driven by actual structural damage, I'd certainly agree. I stated that "Metabolic parameters should improve rapidly with the increased NAD+ or NAD:NADH if they're going to improve at all."

 

Michael, you wrote in your post #66, referring to my post #42:
 
"They did include such parameters: "The blood sample included creatinine, sodium, potassium, urea nitrogen, albumin, alanine aminotransferase (ALT), bilirubin, alkaline phosphatase, hemoglobin, white blood cell count, and platelets." They don't report any of them except ALT (no effect —Talbe 3), but they do say "The safety of ingestion of NR at 2000 mg/d for a 12-wk period was supported in this study by the lack of clinically relevant findings in the blood biochemistry and hematology parameters." I think we can probably trust them on that."

I find it odd that you’d “probably trust” the authors with respect to their assertion about the non-reported blood parameters in light of the fact that in the following quote you admit that passing over, or accepting, “subtle flaws in execution and reporting” can prove to be important with respect to the meaning of results. I’ve taken the liberty of including “omission” as a flaw of “reporting” and have taken your words as having a more catholic context than your specific use here:
 
“I was surprised to see that the situation was even worse than I'd known, as subtle flaws in execution and reporting that I'd've blithely passed over or accepted prove to be important to certainty about the meaning of the results, and bring into question several good-looking studies (tho' in most cases, hyped-up reports with subtle flaws also have larger ones). “
 
Without seeing the blood-work data it’s impossible to know if there might have been flaws in interpretation, regardless of the authors' asseverations.

 

I'd certainly agree that it's better to report all the data than not (if nothing else, in a data supplement), but unlike in rodent lifespan studies (the subject of the other post that you're quoting from), this isn't an area where there is some common experimental flaw that we would need to have details on to be confident of their statement — and especially not one that you'd uncover by simply seeing the number (versus, say, if their blood lab was just incompetent, which the numbers themselves won't tell you). Testing liver enzymes is a routine procedure, unlike doing a lifespan study, and determining if they were changed to a statistically significant degree or to a nominal magnitude that might be clinically relevant is not that complicated. I won't say it's impossible — they could get a borderline significant effect that might be suspicious in the overall context, or be nominally large and bordering on some diagnostic threshold where informed people could differ on whether they're clinically significant or not, or the investigators might be receiving bribes ;) (this last is a JOKE, OK?) — but there's no reason here to suspect anything is amiss from the nature of the test or the rest of the data.


Edited by Michael, 15 July 2018 - 08:49 PM.

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#79 bluemoon

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Posted 15 July 2018 - 09:29 PM

 
 No, it isn't. You're right to say that the p<0.05 cutoff is just a convention, but if anything the level of improbability of nominal effect required to reject the null hypothesis should be higher, not lower. And in this case, as I noted, the likelihood that this non-significant difference represents a real biological change is undermined by the fact that biochemical factors that normally track with improved liver fat (liver enzymes, insulin sensitivity, and TG) either were unchanged or got worse (TG) in response to NR.

 

"but if anything the level of improbability of nominal effect required to reject the null hypothesis should be higher, not lower."

 

This is simply not true - they are separate issues.

 

I'm also not sure why you think an almost 20% reduction in fat in the liver after 12 weeks is nominal. There are 80 million with fatty liver in the U.S. and among those 30 million have it at a more serious level. Some in that latter group, say 10% of those or 3 million, could be spared an even more life threatening with even worse levels of fat in the liver. 


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#80 warner

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Posted 15 July 2018 - 10:41 PM

 With visual acuity in glaucoma, or most things driven by actual structural damage, I'd certainly agree. I stated that "Metabolic parameters should improve rapidly with the increased NAD+ or NAD:NADH if they're going to improve at all."

Yes, I understood the distinction you were first making (metabolic vs. structural), but I don't think its very helpful, since cell metabolic changes (as in vision system) can produce structural changes that in turn produce more metabolic changes.  Also, it's not even clear that immediate cell metabolic changes (like making photoreceptors more responsive) is a good thing, versus some longer-term structural effect that makes them more stable.  In fact, some future treatment that has minimal immediate metabolic effects may turn out to be safest, while producing the greatest life extension.  So I'm skeptical about dismissing results on the basis that they don't have large, immediate metabolic effects.  (I don't recall that NAM, for example, produced such effects in the glaucoma mice.)  Anyway, just a small point, but I don't think its one that we've discussed before.


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