326 replies to this topic

[natasjlp]

My referenced link: https://www.egaceuti...application.pdf

 

""

A 61 year old Caucasian male weighing 88 kg at the beginning of the treatment was

treated with a regimine of category 1, category 2, and category 3 molecules as noted below.

 

20 Nicotinamide mononucleotide (NMN) (MW=334.22)

Betaine (trimethyl glycine) (MW =117.14)

H202 (MW=34.01)

NaSH (MW=56.06)

 

Solutions of various compounds were produced for administering to the subject by

25 mixing a set number of grams with 500 mL of water.

 

Typical final concentrations of NMN taken by subject were 3.5 grams in 500 mL

H20, betaine were 3 grams in 500 mL H20, H202 were (2 drops of 35% concentration in

500 mL H20), and NaSH were (drops of2 at 66uM per drop concentration in 500 mL H20).

 

The amounts of each composition were set so that by the subject drinking the full

30 500 mL a final dosage approximately

1.19 x 10-4 moles NMN/ kg body weight per dose,

2. 91 x 1 o-4 moles betaine I kg body weight per dose,

1.17 x 1 o-s moles of H202 I kg of body weight per dose, and

1.51 x 10-6 moles ofNaSH I kg of body weight per dose

was given to the subject through drinking the 500 mL solution.

""

[stefan_001]

 

My referenced link: https://www.egaceuti...application.pdf

 

""

A 61 year old Caucasian male weighing 88 kg at the beginning of the treatment was

treated with a regimine of category 1, category 2, and category 3 molecules as noted below.

 

20 Nicotinamide mononucleotide (NMN) (MW=334.22)

Betaine (trimethyl glycine) (MW =117.14)

H202 (MW=34.01)

NaSH (MW=56.06)

 

Solutions of various compounds were produced for administering to the subject by

25 mixing a set number of grams with 500 mL of water.

 

Typical final concentrations of NMN taken by subject were 3.5 grams in 500 mL

H20, betaine were 3 grams in 500 mL H20, H202 were (2 drops of 35% concentration in

500 mL H20), and NaSH were (drops of2 at 66uM per drop concentration in 500 mL H20).

 

The amounts of each composition were set so that by the subject drinking the full

30 500 mL a final dosage approximately

1.19 x 10-4 moles NMN/ kg body weight per dose,

2. 91 x 1 o-4 moles betaine I kg body weight per dose,

1.17 x 1 o-s moles of H202 I kg of body weight per dose, and

1.51 x 10-6 moles ofNaSH I kg of body weight per dose

was given to the subject through drinking the 500 mL solution.

""

 

 

That's an interesting user report. Company site:

https://www.egaceuti...pleted-studies/

 

but very high dosing. It reminds me of the Fafner experiments but he did it for a week or so. The patent application is a lot of text but not convinced of it as you can notice of the comments about NR. It seems the author doesnt know that NMN cannot enter the cell without being converted into NR. I wondering if this application is a "marketing trick" to lure buyers of the product. Also where does he get his NMN from?

 

 

Edited by stefan_001, 28 July 2017 - 09:11 PM.

[Harkijn]

 

 

 The patent application is a lot of text but not convinced of it as you can notice of the comments about NR. It seems the author doesnt know that NMN cannot enter the cell without being converted into NR. 

Yes, I wonder about that too... Yet, I am impressed by the scope and detail of this text. I only read the first 10 pages sofar, but will certainly return to study it in full.

Those of us who, like me, struggle to comprehend the molecular biology of NAD+ and aging will here find something to seek their teeth into. If it wasn't such a large file I would try to upload it to LC.

[MikeDC]

https://www.ncbi.nlm.../?i=2&from=nad

A new paper demonstrates NMN depending on NRK1/2 which means NMN converts to NR first. It

[able]

 

Interesting.  I see they  link to other research  that  seems to indicate NMN needs conversion to NR to enter cells.

 

But I have a question about this that I’ve pondered for a while now.

 

AFAIK, all the research agrees that NMN,NR,NA,NAM all raise NAD+ levels in liver and consequently, the blood.

 

The following research claims NAD+ crosses the cell membrane:

 

Pharmacological Effects of Exogenous NAD on Mitochondrial Bioenergetics, DNA Repair and Apoptosis 

 

“eNAD is transported intact across the plasmamembrane”

 

If this is true, perhaps its not necessary for a precursor to cross the cell membrane - they are mostly converted to NAD+ in liver and is carried in blood to cells where it crosses the membrane as needed.

 

 

Edited by able, 29 July 2017 - 05:12 PM.

[Harkijn]

 

 

 The patent application is a lot of text but not convinced of it as you can notice of the comments about NR. It seems the author doesnt know that NMN cannot enter the cell without being converted into NR. 

 

The authors prefer NMN to NR for a number of reasons. One of them is their assertion that orally taken NR is ill absorbed by the muscles. Sadly, they give no reference....

Anyone heard about this before and can point me to a study where I can check this?

[Michael]

I mixed up the titles/links in post #20 - should be:

Nicotinamide mononucleotide requires SIRT3 to improve cardiac function and bioenergetics in a Friedreich’s ataxia cardiomyopathy model
 
“Remarkably, NMN administered to FXN-KO mice restores cardiac function to near-normal levels. “
 
NAD+ replacement therapy with nicotinamide riboside does not improve cardiac function in a model of mitochondrial heart disease
  
“In conclusion, NAD+ supplementation with NR in the FRDA model of mitochondrial heart disease does not alter SIRT3 activity or improve cardiac function.”

 

These studies are discussed here.

[MikeDC]

The dose for the NR study was too low.

[able]

 

I mixed up the titles/links in post #20 - should be:

Nicotinamide mononucleotide requires SIRT3 to improve cardiac function and bioenergetics in a Friedreich’s ataxia cardiomyopathy model
 
“Remarkably, NMN administered to FXN-KO mice restores cardiac function to near-normal levels. “
 
NAD+ replacement therapy with nicotinamide riboside does not improve cardiac function in a model of mitochondrial heart disease
  
“In conclusion, NAD+ supplementation with NR in the FRDA model of mitochondrial heart disease does not alter SIRT3 activity or improve cardiac function.”

 

These studies are discussed here.

 

 

Yes, I saw the NR study was discussed there, but didn't want to clutter that thread.  Bryan made a good point that the mouse model may be flawed for the study and the culprit in why the NR did not rescue the heart function.

 

The NMN study I linked to is new than they previous conversation. I didn't see any reference to it anywhere.  And it seemed to me to be the same mouse model that NR did not work on, so wanted to see if anyone smarter than me could determine if they were indeed similar and a possible reason why NMN worked and NR did not.

 

I found it interesting they used " (500 mg/kg) 2 times per week for 6 weeks".  A massive dose, but only twice a week.  Wondering if they believe that works better than daily dosage.

 

Did the NR study use too low a dosage?   10 ml/kg per day.  I  don't see anywhere in the article where they specify the purity - how many mg in a ml?

[MikeDC]

It is probably 10mg/kg.

[able]

Thats what I was thinking, a typo and they meant 10 mg, not 10 ml. Which would be very low.  But would be nice to know for sure.

 

Edited by able, 01 August 2017 - 07:16 PM.

[MikeDC]

That study lacks credibility. Can't even communicate the dose properly.

[Nate-2004]

Everyone has their favorite brand of NR on here, mine is HPN and you can get it for $78 for 180 caps on Amazon. In the end, it all comes from Chromadex.

 

Everyone is waiting on the results of the NIH human trial that is much larger than the first ones. Nobody knows why they aren't being posted but we're suspecting something not so positive. 

 

NMN is the next hopeful but we don't see why it should be any different since it has to be NR to enter the cell.

Edited by Nate-2004, 02 August 2017 - 10:47 PM.

[MikeDC]

"Everyone is waiting on the results of the NIH human trial that is much larger than the first ones. Nobody knows why they aren't being posted but we're suspecting something not so positive. "

What trial are you talking about?

[bluemoon]

 

 

Everyone is waiting on the results of the NIH human trial that is much larger than the first ones. Nobody knows why they aren't being posted but we're suspecting something not so positive. 

 

NMN is the next hopeful but we don't see why it should be any different since it has to be NR to enter the cell.

 

Chromodex said it would release 'top line' results of its 140 person trial in June or July. Then it shifted that to July-September so almost certainly a strategy to coincide with something...ChromaDex wants to go retail but now they are competing head to head against Elysium which is conducting six new trials on Basis to get broader knowledge of results on new groups such as the obese, maybe NR without pterostilbine, etc. Charles Brenner said in his December talk at the U of Wisconsin that he thought obese people should be in the trial as well. My guess is that the results were good in both studies but maybe not convincing at the dose they thought would bring in the most revenue - something along those lines - or it is 100% a timing issue for both companies.

[MikeDC]

I don't think the ChromaDex dose trial data will make a big news anymore. It is just a dose trial. The Colorado trial is much more interesting.

[bluemoon]

I don't think the ChromaDex dose trial data will make a big news anymore. It is just a dose trial. The Colorado trial is much more interesting.

 

The Chromadex trial is with the U of Colorado and the one that they say they will report on within the next few weeks.

[able]

 

 

NMN is the next hopeful but we don't see why it should be any different since it has to be NR to enter the cell.

 

I have a question about that.

 

AFAIK, all the research agrees that NMN,NR,NA,NAM all raise NAD+ levels in liver and consequently, the blood.

The following research claims NAD+ crosses the cell membrane:

 

Pharmacological Effects of Exogenous NAD on Mitochondrial Bioenergetics, DNA Repair and Apoptosis 

 

“eNAD is transported intact across the plasmamembrane”

 

If this is true, perhaps its not necessary for a precursor to cross the cell membrane - they are mostly converted to NAD+ in liver and is carried in blood to cells where it crosses the membrane as needed.

 

Are the claims by Dr Brenner and his research team about NMN being inferior because it cannot cross cell membrane just a lot of smoke?

[Anthony_Loera]

According to David Sinclair

 

"NAD is too large to cross the cell membrane, but NMN can slip across it easily. Once inside the cell, NMN binds to another NMN molecule to form NAD."

 

http://news.harvard....cellular-aging/

 

A

[MikeDC]

According to David Sinclair

"NAD is too large to cross the cell membrane, but NMN can slip across it easily. Once inside the cell, NMN binds to another NMN molecule to form NAD."

http://news.harvard....cellular-aging/

A

Sinclair is no longer a true scientist. He ignores NR and keep marketing NMN. He has no basis to say NMN can enter cells. Show some experiment details. Dr. Brenner has designed experiments to show that external NMN depends on NRK1,2 to convert to NAD+.

Scientists become non scientists when money is involved. His PhD supervisor who is one of the founders of Elysium becomes a criminal trying defraud ChromaDex in order to make money. Elysium now sells counterfeit NIagen from China. How Sad.

Edited by MikeDC, 03 August 2017 - 11:33 PM.

[able]

According to David Sinclair

 

"NAD is too large to cross the cell membrane, but NMN can slip across it easily. Once inside the cell, NMN binds to another NMN molecule to form NAD."

 

http://news.harvard....cellular-aging/

 

A

 

That article you quote doesn't make clear if Dr Sinclair said that, or the author.

 

The rest of that  quote is:

 

"the NAD precursor NMN, which makes up half of an NAD molecule. NAD is too large to cross the cell membrane, but NMN can slip across it easily"

 

I've never seen anything that describes NMN as "half of an NAD molecule", which makes me question the accuracy of the article/author.

 

Also, they are claiming "NMN can slip across it easily", which Dr Brenner and his team disagree with.

 

The source article in science magazine  makes no such claim about NAD+ or NMN ability to cross the cell membrane:

 

http://science.scien...6331/1312.full 

 

The study I am referencing seems to prove NAD+ does cross the cell membrane, so I am wondering if their is actual proof that study is wrong, or just some random statements.

 

Pharmacological Effects of Exogenous NAD on Mitochondrial Bioenergetics, DNA Repair and Apoptosis 

 

“eNAD is transported intact across the plasmamembrane”

Edited by able, 04 August 2017 - 12:07 AM.

[MikeDC]

I think the statement is from Sinclair. He is willing to give wrong information to promote NMN which he plan to commercialize. He ignores NR because it has been commercialized Already.

Scientists are no more scientists when money is involved.
Just like in politics, science has been corrupted also.

No hope for this country.

[able]

It does seem they have obvious bias due to business interest.

 

I just noticed Sinclair IS listed as an author of that science magazine article.  

 

And the disclaimer at bottom points to some of his business plans:

 

"D.A.S. is an unpaid consultant, board member, inventor on patent applications, and holds equity in companies developing NAD precursor–based medicines (EdenRoc, Liberty Biosecurity, Metrobiotech, and Jumpstart Fertility)"

[MikeDC]

NAD+ precursor is the holly grail of anti aging. The smart scientists are all jumping on it to profit. The benefits will be validated eventually. The smart consumers are taking Niagen. The not so smart ones are ignoring it.

[Anthony_Loera]

Holy Grail? 

 

Maybe its Glycine that we should be after...

 

In the article by Hashizume and his colleagues, the researcher may have come up with a reason for how mitochondria DNA is affecting aging (Scientific Reports, 5:10434). 

https://www.nature.c...icles/srep10434

 

read about that first... then tell me if you still think NAD is the holy grail.

 

While I believe NAD is important...

IMHO....

 

It isn't the "Holy Grail" by a long shot.

 

A

 

 

[MikeDC]

Just one odd in vitro study, you want to turn the table on NAD+ which has over 50,000 paper and many clinical trials? Glycine has been experimented extensively and its effectiveness is unknown.
I don't think people reported Aging reversal from it.

[Michael]

In the article by Hashizume and his colleagues, the researcher may have come up with a reason for how mitochondria DNA is affecting aging (Scientific Reports, 5:10434). [/size]
https://www.nature.c...icles/srep10434

 

This study really doesn't reveal much of relevance to aging: please see Question of the Month #11: Are Mitochondrial Mutations Really All That Important?

[Nate-2004]

 

In the article by Hashizume and his colleagues, the researcher may have come up with a reason for how mitochondria DNA is affecting aging (Scientific Reports, 5:10434). [/size]
https://www.nature.c...icles/srep10434

 

This study really doesn't reveal much of relevance to aging: please see Question of the Month #11: Are Mitochondrial Mutations Really All That Important?

 

 

Hugely important article to have read thanks Michael. What effect does NAD+ or NR/NMN have on these mitochondrial mutations then?

 

The article also mentions that insulin resistance is a huge contributor to mutations. Why then are we not seeing people with much longer youthspans when taking metformin or on a low carb diet?

[Michael]

 

This study really doesn't reveal much of relevance to aging: please see Question of the Month #11: Are Mitochondrial Mutations Really All That Important?

 
Hugely important article to have read thanks Michael. What effect does NAD+ or NR/NMN have on these mitochondrial mutations then?

 

I don't see any reason to think that they would have any effect.
 

The article also mentions that insulin resistance is a huge contributor to mutations. Why then are we not seeing people with much longer youthspans when taking metformin or on a low carb diet?

To be clear, insulin resistance is not a huge or even a moderate contributor to mtDNA mutations. I think you're thinkning of the discussion of regulated, non-mutational (mal)adaptations of mitochondrial function that result from insulin resistance:

 

 

mitochondria are dynamic organelles, which adapt their activity to respond to differences in fuel quantity and quality, redox status, energy demands, and dynamics, as well as being at the center of cellular processes such as apoptosis (cellular suicide). Thus, as the cellular and systemic environment changes, so necessarily must mitochondrial function. It is therefore unsurprising that many forms of the cellular and molecular damage of aging drive deviations in mitochondrial function from the healthy norm of youth.

 

For example, [...] rising insulin resistance with age, independent of body fat, appears to be driven by the secretions of senescent preadipocytes (the stem-like precursors of fat cells) in key fat depots.^[42] Because insulin resistance leads to aberrant mitochondrial function (see below), ablation of these senescent cells can be expected to restore insulin sensitivity — a prediction for which some preliminary proof-of-concept has recently been generated.^[43] [...]

 

And again, rising oxidative stress from accumulating numbers of cells bearing deletion mutations in their mitochondria can trigger aberrant mitochondrial function in cells whose own mitochondrial DNA remains intact.^[32],[38]

 

Confounding matters further, some of these same functional deviations can also occur for reasons that are partially or completely independent of age, but that are often overlaid upon the primary aging process. Such age-independent phenomena can often be reversed by lifestyle changes or medication: such is the case for changes in mitochondrial function due to overweight and obesity (reversible with exercise and/or weight loss via diet^[53],[54] or bariatric surgery^[55]), insulin-resistant states (often substantially reversible with some medications^[56] and often with weight loss and/or exercise^[57],[58]), or sedentary lifestyle (reversible by spending less time on the couch^[59],[60]).

 

[MikeDC]

The value of NR is it can reverse epigenetic changes and chromasome damages. So it reverses aging in short term and slow down aging in long term.