471 replies to this topic

[albedo]

A bit encouraged by Bryan's post here, I was researching more a on possible synergy between oxaloacetate and NR and post it in this thread but got quite understandably "punished" by an "off topic" (e.g. here). Sorry for that, I will move oxaloacetate somewhere else (wonder what would be the best place, likely http://www.longecity...te-supplements/ as Bryan suggests) and focus here on NR only. My apologizes.

Edited by albedo, 21 September 2015 - 04:17 PM.

[Tom Andre F. (ex shinobi)]

 

The next studies are to shine a finer light on long term supplementation and what happens to your NAD+ levels over the course of many weeks taking NR. 

 

Here is what they released in the last study:

"The oral presentation and poster presented data which indicate that single doses of NIAGEN® NR can elevate the co-enzyme NAD+ in the blood by as much as 2.7-fold. In the first-in-humans clinical trial which involved dosing twelve healthy adult subjects, the group showed that blood cell NAD+ increased with single 100 mg, 300 mg and 1 gram doses of NIAGEN® NR. Average maximal increases in blood NAD+ were approximately 30% at the 100 mg dose and approximately 50% at the higher doses. Increases in blood NAD+ tended to be sustained for longer times at higher doses."

 

That's the best I can interpret from the data so far. Overall I think we need more complete data and I await the long term studies but it appears beyond a certain dosage we are wasting our money and under a certain dosage the benefits might be slim and fade fast.

 

JMHO Hope that helps.

 

Thanks bryan,

 

Actually this makes me back to the original question:

 

does increasing NAD+ will really slow down aging ? I mean an old person who increase its NAD+ get back to his normal level very fast from what they say.. 

 

Also, if we keep increasing the NAD+ level at lets say 30 yo, does this is enough to slow down the aging and have the "original NAD+" level 10 years later near by the same from the 30yo ?

 

We really need to know because what we dont want here is short term result but rather really keep down aging under control / reverse some aging part within the cells

 

Edited by Tom Andre F. (ex shinobi), 21 September 2015 - 11:29 PM.

[Tom Andre F. (ex shinobi)]

More (podcast) on Cash and Oxaloacetate:

https://thequantifie...(Episode Title)

 

 "We can essentially “bio-hack” our systems by tricking the cells into thinking that the NAD to NADH ratio is high so that fat production is reduced (12:50)."

"Oxaloacetate is used in the Kreb’s cycle to oxidize NADH to NAD (17:09)."

"Alan Cash spent years proving to the FDA that there do not seem to be any negative effects found with taking large doses of oxaloacetate (38:35)."

"Recently, clinical trials have begun to study oxaloacetate as a treatment for different conditions such as mitochondrial dysfunction, Parkinson’s disease, and Alzheimer’s disease (30:13)."

"When trying your own experiment, take a daily fasting glucose level for a couple weeks to see the normal variability and then follow with oxaloacetate supplementation along with daily reading of your glucose levels (48:06)."

"Long term potentiation, the restoration of the ability to learn, may improve for patients after a stroke or closed head injury if oxaloacetate is used in combination with acetyl-l-carnitine (36:18)."

 

See also here for the mechanisms:

 

Oxaloacetate supplementation increases lifespan in Caenorhabditis elegans through an AMPK/FOXO-dependent pathway

http://www.ncbi.nlm....les/PMC2988682/

Does Oxaloacetic acid has the same effect as Oxaloacetate ?
 

[Bryan_S]

 

 

The next studies are to shine a finer light on long term supplementation and what happens to your NAD+ levels over the course of many weeks taking NR. 

 

Here is what they released in the last study:

"The oral presentation and poster presented data which indicate that single doses of NIAGEN® NR can elevate the co-enzyme NAD+ in the blood by as much as 2.7-fold. In the first-in-humans clinical trial which involved dosing twelve healthy adult subjects, the group showed that blood cell NAD+ increased with single 100 mg, 300 mg and 1 gram doses of NIAGEN® NR. Average maximal increases in blood NAD+ were approximately 30% at the 100 mg dose and approximately 50% at the higher doses. Increases in blood NAD+ tended to be sustained for longer times at higher doses."

 

That's the best I can interpret from the data so far. Overall I think we need more complete data and I await the long term studies but it appears beyond a certain dosage we are wasting our money and under a certain dosage the benefits might be slim and fade fast.

 

JMHO Hope that helps.

 

Thanks bryan,

 

Actually this makes me back to the original question:

 

does increasing NAD+ will really slow down aging ? I mean an old person who increase its NAD+ get back to his normal level very fast from what they say.. 

 

Also, if we keep increasing the NAD+ level at lets say 30 yo, does this is enough to slow down the aging and have the "original NAD+" level 10 years later near by the same from the 30yo ?

 

We really need to know because what we dont want here is short term result but rather really keep down aging under control / reverse some aging part within the cells

 

 

Tom,

 

Its the question on everyones mind. I think NAD+ supplementation will reverse "some" aspects of aging but as we've been reading this year the whole theory of aging is being challenged. We've seen a host of NAD consuming enzymes uncovered and these are responsible for our day to day cellular maintenance among many other things. Lets harken back to an earlier study this year "Oncogene-induced NAD+ depletion in tumorigenesis" One NAD consuming enzyme PARP is responsible for correcting DNA damage. So yes I think we are better off taking our NAD precursors like Nicotinamide Riboside than not but I don't expect to get younger, just feel better, more focused and keep up with my wife.

 

Earlier this year Professor Hayashi threw a monkey wrench into the theory of Mitochondrial aging. So I think the whole field of aging is in total flux and the way we approach it in future may have changed this year. What the Doctor found is no DNA or Mitochondrial damage was found in 97-year old cells . . . and he restored them to a youthful state. Now we can't take the in vitro approach he used for a whole organism but he still made the point that you can make old cells young and the DNA and Mitochondria can be reset epigenetically. 

 

This whole new epigenetic picture seems central to the new ideas being developed. Our group has already been exposed to the epigenetic sirtuin ideas being driven by David Sinclair and Leonard Guarantee. If this path of investigation holds up we might possibly be able to reprogram the on and off switches of our epigenome and restore a younger profile.

 

Do you remember the article "Repression of the Heat Shock Response Is a Programmed Event at the Onset of Reproduction" If this research holds true into higher animals like us we might find one simple area of our epigenome being turned off effects the decline of our cellular maintenance and begins the long coast to the end of life. From what I'm reading aging isn't a programed event its a lack or ramp down of maintenance programing. It seems like we are programed for reproduction and after we sexually mature the cellular maintenance programing is switched off. It consumes a lot of energy to fight off entropy and disorder begins to set in. It remains to be seen but this one study may prove to be the most significant one published this year.

 

So until a treatment is devised to reset my epigenome to a youthful state I'll take the NAD+ supplementation path and increase my cellular respiration, fuel my cellular maintenance and delay the inevitable as long as possible. If I die tomorrow at least I will have felt better today.

[Bryan_S]

The multifaceted functions of sirtuins in cancer

Angeliki Chalkiadaki & Leonard Guarente

 

We were just talking about Leonard Guarente in the last post and he just published this paper the other day. This is more support for the idea of NAD consuming enzymes that keep us healthy. Here they explore both sides, activating or inhibiting sirtuins in preventing or treating cancer. If someone has access to the full paper please share some excerpts.

 

Nature Reviews Cancer (2015) doi:10.1038/nrc3985

Published online 18 September 2015

http://www.nature.co...ll/nrc3985.html

 

"The sirtuins (SIRTs; of which there are seven in mammals) are NAD⁺-dependent enzymes that regulate a large number of cellular pathways and forestall the progression of ageing and age-associated diseases. In recent years, the role of sirtuins in cancer biology has become increasingly apparent, and growing evidence demonstrates that sirtuins regulate many processes that go awry in cancer cells, such as cellular metabolism, the regulation of chromatin structure and the maintenance of genomic stability. In this article, we review recent advances in our understanding of how sirtuins affect cancer metabolism, DNA repair and the tumor microenvironment and how activating or inhibiting sirtuins may be important in preventing or treating cancer."

 

Figure 1: Overview of the role of sirtuins in the regulation of cancer metabolism.

The inhibitory effects of sirtuin 3 (SIRT3), SIRT4 and SIRT6 on metabolic pathways that drive cancer cells are depicted. In normal cells, SIRT6 functions as a co-repressor for the transcription factors hypoxia-inducible factor 1α (HIF1α…

 

Figure 2: Sirtuins regulate multiple steps of the DNA damage response pathways.

Poly-ADP-ribose polymerase (PARP) family members recognize simple alterations of DNA bases and activate the base excision repair (BER) pathway. SIRT6 regulates the BER pathway by activating PARP1 and acting upstream of DNA polymerase-β…

 

Edited by Bryan_S, 22 September 2015 - 08:32 PM.

[TaiChiKid]

The released study info suggested a NAD+ ceiling was reached @ 300mg and higher. To me this would suggest taking two 125mg capsules or 250mg (our typical dosage) would be as high as we could reasonably raise our NAD levels approximately 50%. You could take more but at some point you'll be excreting and wasting some portion of it but it will keep NAD+ levels elevated longer at higher dosages.

 

Then we have to consider the time component, the (terminal half-life) of NR, the rate at which it will be metabolized and or excreted. "The biological half-life or terminal half-life of a substance is the time it takes for a substance (for example a metabolite, drug, signaling molecule, radioactive nuclide, or other substance) to lose half of its pharmacologic, physiologic, or radiologic activity, as per the MeSH definition." This was to be answered in the aforementioned study "Primary Outcome Measures: t1/2 (terminal half-life) [ Time Frame: 24 hours ] [ Designated as safety issue: No ] 24 hour dosing period; 3 dosing periods each separated by 7 day washout" I'm a little disappointed they have not released this latest data but earlier ChromaDex said;

 

"Thank you for your email. The half-life of Nicotinamide Riboside Chloride is 4 hours.

Kind regards,

Collene Villalobos

Sales Manager - Ingredients"

Credit APBT

 

We can also make some other assumptions, we know intracellular NAD+ levels drop fairly fast, with the short half-life of NAD+, which is estimated around 1 to 2 h. So its consumed pretty fast but NR lingers long enough in the blood stream to replenish the demand because we know our blood plasma concentrations drop 50% every 4 hours. (when we get better data we will update this)

 

So after an initial dose the question becomes "what is the maintenance regiment to maintain consistently elevated NAD+ levels thru the day?" That question also invokes yet another which is "elevated to what percent?" And that question is best answered by your wallet and how much of your monetary resources your willing to commit. Its sad but true.

 

Knowing the approximate t1/2 (terminal half-life) maybe one of our Math Majors can work up some graphs on different dosing schemes.

 

I'm sure we'll debate the ideal dosing for maximum sustainable NAD levels until Charles Brenner, PhD publishes his accurate terminal half-life data but right now if I was taking 250mg per day I'd split the dose 12 hrs apart, pretty simple decision with 125mg capsules. If I was taking 500mg/per/day I'd likely break it down into 4 dosages or two dosages 12 hrs apart. At 1000mg/per/day you can even out the dose thru the day and smooth out the NAD+ peaks and valleys. I'm on this 1000mg regiment and take 250mg followed by 125mg every 2 hours.

 

The next studies are to shine a finer light on long term supplementation and what happens to your NAD+ levels over the course of many weeks taking NR. 

 

Here is what they released in the last study:

"The oral presentation and poster presented data which indicate that single doses of NIAGEN® NR can elevate the co-enzyme NAD+ in the blood by as much as 2.7-fold. In the first-in-humans clinical trial which involved dosing twelve healthy adult subjects, the group showed that blood cell NAD+ increased with single 100 mg, 300 mg and 1 gram doses of NIAGEN® NR. Average maximal increases in blood NAD+ were approximately 30% at the 100 mg dose and approximately 50% at the higher doses. Increases in blood NAD+ tended to be sustained for longer times at higher doses."

 

That's the best I can interpret from the data so far. Overall I think we need more complete data and I await the long term studies but it appears beyond a certain dosage we are wasting our money and under a certain dosage the benefits might be slim and fade fast.

 

JMHO Hope that helps.

 

 

 

 

You can guestimate blood serum levels using a simple chain calculation on a calculator.  

Each person has differing metabolic rates so their half-lives will differ from 4 hours. 

 

But assuming you took a dose of 250mg a day, beginning at 8pm with a full day's dose, your levels would be:

250mg at 8pm   so at 8am the level would fall by 1/8 (falls in half each 4 hours)   to 33.125

at 8am you take another 125 mg so you get 125 + 33.125 = 158.125.  At 8pm this would fall to 1/8, or 19.76.

at 8pm you take another 125 mg so you get 125 + 19.765 = 144.766.  At 8am this would fall to 1/8 or 18.096

at 8am you take another 125 mg so you get 125 + 18.096 = 143.096.  At 8pm this would fall to 1/8 or 17.887

 

And this stays at a fairly steady minimum level  0f 17.8 after more calculations, so that is your 'steady state.'

 

Edited by TaiChiKid, 23 September 2015 - 07:08 PM.

[TaiChiKid]

The 'Reviews' section of Nature Reviews Cancer for Sept 2015 shows only the following three entries:

 

Reviews

The dynamic control of signal transduction networks in cancer cells

Walter Kolch, Melinda Halasz, Marina Granovskaya & Boris N. Kholodenko

p515 | doi:10.1038/nrc3983

Cancer cells exhibit huge phenotypic plasticity, which can lead to adaptations to the tumour microenvironment and therapy. Much of this plasticity seems to be encoded in signal transduction networks, such that alterations in signalling dynamics can affect many cancer-associated phenotypes and therapeutic response.

    Abstract
    Full Text
    PDF (583 KB)

 

Deoxyribonucleotide metabolism, mutagenesis and cancer

Christopher K. Mathews

p528 | doi:10.1038/nrc3981

This Review discusses nucleotide metabolism and how fluctuations in deoxyribonucleoside triphosphate (dNTP) pools affect genomic instability. Drugs that target this system have been in use for many years and some of these are discussed, as well as newer approaches to manipulating deoxyribonucleotide metabolism for cancer treatment.

    Abstract
    Full Text
    PDF (414 KB)

 

Glycosylation in cancer: mechanisms and clinical implications

Salomé S. Pinho & Celso A. Reis

p540 | doi:10.1038/nrc3982

This Review discusses the importance of glycobiology in cancer research, given its role in cancer development and progression, and provides an overview of possible targets for diagnostic application and therapeutic strategies.

    Abstract
    Full Text
    PDF (921 KB)

 

 

 

[romtm]

I am new here and I neep a little help.
After taking 9 bottles of NR from Live Cell Research,they stopped shipping outside US,(I am in EU),and I found another supplier from US and they sold to me NAD+.I paid 40 USD for 4 grams powder.I bought 20 grams.
They send me also a chinese COA. They advise to disolve in water and take it nasal spray,.for much higher absorbtion.
I know that NR is a precursor of NAD+,so taking direct NAD+,in nasal spray ,or under tongue,is a solution? How I can check if is working?And what concentration?

Thanks in advance.

Andrei

[Bryan_S]

Eliciting the mitochondrial unfolded protein response via NAD+ repletion reverses fatty liver disease

 

http://onlinelibrary....28245/abstract

 

http://onlinelibrary...2ffaaf9974e3bbf

 

 

Abstract

With no approved pharmacological treatment, non-alcoholic fatty liver disease (NAFLD)

is now the most common cause of chronic liver disease in western countries and its

worldwide prevalence continues to increase along with the growing obesity epidemic.

Here we show that a high-fat high-sucrose (HFHS) diet, eliciting chronic hepatosteatosis

resembling human fatty liver, lowers hepatic NAD+ levels driving reductions in hepatic

mitochondrial content, function and ATP levels, in conjunction with robust increases in

hepatic weight, lipid content and peroxidation in C57BL/6J mice. In an effort to assess

the effect of NAD+ repletion on the development of steatosis in mice, nicotinamide

riboside (NR), a precursor for NAD+ biosynthesis, was given to mice concomitant, as

preventive strategy (NR-Prev), and as a therapeutic intervention (NR-Ther), to a HFHS

diet. We demonstrate that NR prevents and reverts NAFLD by inducing a SIRT1- and

SIRT3-dependent mitochondrial unfolded protein response (UPRmt), triggering an

adaptive mitohormetic pathway to increase hepatic β-oxidation and mitochondrial

complex content and activity. The cell-autonomous beneficial component of NR

treatment was revealed in liver-specific Sirt1 KO mice (Sirt1hep-/-), while Apolipoprotein Edeficient

(Apoe-/-) mice challenged with a high-fat high-cholesterol diet (HFC), affirmed

the use of NR in other independent models of NAFLD. Conclusion: Our data warrant the

future evaluation of NAD+ boosting strategies to manage the development or

progression of NAFLD. 

 

 

What is the mitochondrial unfolded protein response?

http://jcs.biologist...2/3849.full.pdf

Edited by Bryan_S, 25 September 2015 - 04:12 PM.

[tunt01]

My apologizes if this is off topic here but always wondered about the double role of sirtuins in cancer (I particularly look at prostate cancer because of my increased risk). What is you view and should we strive to keep a good balance between an over activation and under activation of sirtuins?

 

“…. Sirt1 has been shown to be overexpressed in several cancers, including prostate [53], acute myeloid leukaemia [54], colon cancer [55], and some nonmelanoma skin cancers [56]. 

 

Sirtuins, Bioageing, and Cancer

http://www.ncbi.nlm....les/PMC3134127/

 

Also here: Sirtuin inhibitors as anticancer agents

http://www.ncbi.nlm....les/PMC4384657/

 

This issue is something I was thinking recently.  Does anyone know what Leonard Guarente thinks about sirtuins and cancer?

[Bryan_S]

 

My apologizes if this is off topic here but always wondered about the double role of sirtuins in cancer (I particularly look at prostate cancer because of my increased risk). What is you view and should we strive to keep a good balance between an over activation and under activation of sirtuins?

 

“…. Sirt1 has been shown to be overexpressed in several cancers, including prostate [53], acute myeloid leukaemia [54], colon cancer [55], and some nonmelanoma skin cancers [56]. 

 

Sirtuins, Bioageing, and Cancer

http://www.ncbi.nlm....les/PMC3134127/

 

Also here: Sirtuin inhibitors as anticancer agents

http://www.ncbi.nlm....les/PMC4384657/

 

This issue is something I was thinking recently.  Does anyone know what Leonard Guarente thinks about sirtuins and cancer?

 

 

He just published those thoughts on the subject.

 

The multifaceted functions of sirtuins in cancer

 

Angeliki Chalkiadaki & Leonard Guarente

 

http://www.ncbi.nlm....pubmed/26383140

 

http://www.readcube....10.1038/nrc3985

[Tom Andre F. (ex shinobi)]

I read that we should take a thermally stabilized form of Oxaloacetate. But the brands also package it with 150mg of vitamin C because: Vitamin C acts as an electron acceptor, stabilizing the oxaloacetate and preventing it from turning into pyruvate.

 

Is this really necessary ?  and is pyruvate really a concern ?

[Tom Andre F. (ex shinobi)]

 

The released study info suggested a NAD+ ceiling was reached @ 300mg and higher. To me this would suggest taking two 125mg capsules or 250mg (our typical dosage) would be as high as we could reasonably raise our NAD levels approximately 50%. You could take more but at some point you'll be excreting and wasting some portion of it but it will keep NAD+ levels elevated longer at higher dosages.

 

Then we have to consider the time component, the (terminal half-life) of NR, the rate at which it will be metabolized and or excreted. "The biological half-life or terminal half-life of a substance is the time it takes for a substance (for example a metabolite, drug, signaling molecule, radioactive nuclide, or other substance) to lose half of its pharmacologic, physiologic, or radiologic activity, as per the MeSH definition." This was to be answered in the aforementioned study "Primary Outcome Measures: t1/2 (terminal half-life) [ Time Frame: 24 hours ] [ Designated as safety issue: No ] 24 hour dosing period; 3 dosing periods each separated by 7 day washout" I'm a little disappointed they have not released this latest data but earlier ChromaDex said;

 

"Thank you for your email. The half-life of Nicotinamide Riboside Chloride is 4 hours.

Kind regards,

Collene Villalobos

Sales Manager - Ingredients"

Credit APBT

 

We can also make some other assumptions, we know intracellular NAD+ levels drop fairly fast, with the short half-life of NAD+, which is estimated around 1 to 2 h. So its consumed pretty fast but NR lingers long enough in the blood stream to replenish the demand because we know our blood plasma concentrations drop 50% every 4 hours. (when we get better data we will update this)

 

So after an initial dose the question becomes "what is the maintenance regiment to maintain consistently elevated NAD+ levels thru the day?" That question also invokes yet another which is "elevated to what percent?" And that question is best answered by your wallet and how much of your monetary resources your willing to commit. Its sad but true.

 

Knowing the approximate t1/2 (terminal half-life) maybe one of our Math Majors can work up some graphs on different dosing schemes.

 

I'm sure we'll debate the ideal dosing for maximum sustainable NAD levels until Charles Brenner, PhD publishes his accurate terminal half-life data but right now if I was taking 250mg per day I'd split the dose 12 hrs apart, pretty simple decision with 125mg capsules. If I was taking 500mg/per/day I'd likely break it down into 4 dosages or two dosages 12 hrs apart. At 1000mg/per/day you can even out the dose thru the day and smooth out the NAD+ peaks and valleys. I'm on this 1000mg regiment and take 250mg followed by 125mg every 2 hours.

 

The next studies are to shine a finer light on long term supplementation and what happens to your NAD+ levels over the course of many weeks taking NR. 

 

Here is what they released in the last study:

"The oral presentation and poster presented data which indicate that single doses of NIAGEN® NR can elevate the co-enzyme NAD+ in the blood by as much as 2.7-fold. In the first-in-humans clinical trial which involved dosing twelve healthy adult subjects, the group showed that blood cell NAD+ increased with single 100 mg, 300 mg and 1 gram doses of NIAGEN® NR. Average maximal increases in blood NAD+ were approximately 30% at the 100 mg dose and approximately 50% at the higher doses. Increases in blood NAD+ tended to be sustained for longer times at higher doses."

 

That's the best I can interpret from the data so far. Overall I think we need more complete data and I await the long term studies but it appears beyond a certain dosage we are wasting our money and under a certain dosage the benefits might be slim and fade fast.

 

JMHO Hope that helps.

 

 

 

 

You can guestimate blood serum levels using a simple chain calculation on a calculator.  

Each person has differing metabolic rates so their half-lives will differ from 4 hours. 

 

But assuming you took a dose of 250mg a day, beginning at 8pm with a full day's dose, your levels would be:

250mg at 8pm   so at 8am the level would fall by 1/8 (falls in half each 4 hours)   to 33.125

at 8am you take another 125 mg so you get 125 + 33.125 = 158.125.  At 8pm this would fall to 1/8, or 19.76.

at 8pm you take another 125 mg so you get 125 + 19.765 = 144.766.  At 8am this would fall to 1/8 or 18.096

at 8am you take another 125 mg so you get 125 + 18.096 = 143.096.  At 8pm this would fall to 1/8 or 17.887

 

And this stays at a fairly steady minimum level  0f 17.8 after more calculations, so that is your 'steady state.'

 

 

Im really not sure its safe to consume even 250mg a day on a medium / long term basis NR due to the niacinamide part. Too high metabolite level can then being found in the blood and I think its not that healthy.

 

[stefan_001]

As part of the discussion around sirt stimulation in combination with NR I was wondering has anybody looked at Citicoline. It seems to have interesting qualities in combination with high bioavailability:

 

Pharmacokinetic studies suggested that it is well absorbed and highly bioavailable with oral dosing. A number of studies have clearly shown the possible role of citicoline in cognitive impairment of diverse etiology. It can also modulate the activity/expression of some protein kinases involved in neuronal death and increases SIRT1 expression in the central nervous system.

https://www.dovepres...wed-article-CIA

 

and it appears to have a good safety record:

Citicoline has a very low toxicity profile in animals and humans. Clinically, doses of 2000 mg per day have been observed and approved.

https://en.wikipedia...ne#Side_effects

 

Anybody tried this? Views?

Edited by stefan_001, 27 September 2015 - 05:08 PM.

[Bryan_S]

Oral nicotinamide for skin cancer prevention

 

There was already plenty of interest surrounding the May 31, 2015 study release. This poster is dated Sep 23, 2011 from a presentation at the 41st European Society for Dermatological Research Annual Meeting 2011.

 

http://f1000research.com/posters/2229

 

http://cdn.f1000.com/posters/docs/2229

 

 

Additional studies:

http://www.ncbi.nlm....pubmed/23349012

 

https://am.asco.org/...ancer-formation

 

[stefan_001]

PARP-1 inhibition increases mitochondrial metabolism through SIRT1 activation.  PARP-1 has been implicated in multiple DNA repair pathways 

 

http://molpharm.aspe...80/6/1136.full  http://www.sciencedi...568786414002353

http://www.anti-agin...he-nad-world-2/

http://genesdev.cshl...19/17/1951.long

 

Someone will have to connect the dots for me. On one hand Higher NAD levels are necessary for repair but on the other hand doesn't Nicotinamide Riboside inhibit PARP-1?

 

 

This discussion was never really finished. I am taking Pterostilbene as it is supposed to be a more effective SIRT1 activator.

 

But it would appear the Resveratrol mechanism is different as could be read in this link that was posted earlier:

http://www.eurekaler...i-sun121914.php

 

"Tracking the resveratrol-bound TyrRS in the nucleus, the researchers determined that it grabs and activates the protein, PARP-1, a major stress response and DNA-repair factor thought to have a significance influence on lifespan. The scientists confirmed the interaction in mice injected with resveratrol. TyrRS's activation of PARP-1 led, in turn, to the activation of a host of protective genes including the tumor-suppressor gene p53 and the longevity genes FOXO3A and SIRT6"

 

Or could it be that actually Pterostilbene is not a SIRT1 activator but does the same as described above as it was supposed to work via same pathways as Resveratrol? And if that is the case then it would make sense to clarify the question Brian wrote down above.

 

Edited by stefan_001, 04 October 2015 - 07:41 PM.

[ceridwen]

or could it be that it doesn't. Do we know how it works. It seems more effective than Resveratrol anyway. Resveratrol Guy pointed out that Resveratrol might even STOP hippocampal growth and found a paper that says that. Perhaps Pterostilbene is completely different

[Bryan_S]

 

PARP-1 inhibition increases mitochondrial metabolism through SIRT1 activation.  PARP-1 has been implicated in multiple DNA repair pathways 

 

http://molpharm.aspe...80/6/1136.full  http://www.sciencedi...568786414002353

http://www.anti-agin...he-nad-world-2/

http://genesdev.cshl...19/17/1951.long

 

Someone will have to connect the dots for me. On one hand Higher NAD levels are necessary for repair but on the other hand doesn't Nicotinamide Riboside inhibit PARP-1?

 

 

This discussion was never really finished. I am taking Pterostilbene as it is supposed to be a more effective SIRT1 activator.

 

But it would appear the Resveratrol mechanism is different as could be read in this link that was posted earlier:

http://www.eurekaler...i-sun121914.php

 

"Tracking the resveratrol-bound TyrRS in the nucleus, the researchers determined that it grabs and activates the protein, PARP-1, a major stress response and DNA-repair factor thought to have a significance influence on lifespan. The scientists confirmed the interaction in mice injected with resveratrol. TyrRS's activation of PARP-1 led, in turn, to the activation of a host of protective genes including the tumor-suppressor gene p53 and the longevity genes FOXO3A and SIRT6"

 

Or could it be that actually Pterostilbene is not a SIRT1 activator but does the same as described above as it was supposed to work via same pathways as Resveratrol? And if that is the case then it would make sense to clarify the question Brian wrote down above.

 

 

I wrote that question and I've looked over the context of the surrounding posts from last year as a refresher. This was a time when I and others were still grappling with the NAD/PARP relationship and have since pinned it down. What I understand today is the PARP's are NAD consuming enzymes responsible for DNA maintenance among many other things. What we've read from studies on artificial PARP inhibition is they resulted in raising NAD levels which should be expected because these enzymes are major NAD consumers. The following excerpt is from a study that puts my earlier question to the test.

 

"To further solidify our data, we also wondered whether the enhanced NAD+ levels upon NR treatment could derive from alterations in the NAD+ salvage pathway or PARP activity. However, we could not see any change in Nampt mRNA or protein content in response to NR treatment (Fig.1G). Similarly, PARP activity and PARP-1 content were not affected by NR (Fig.1H). Altogether, these results suggest that NR increases NAD+ by direct NAD+ biosynthesis rather than by indirectly affecting the major NAD+ salvage (Nampt) or consumption (PARPs) pathways. Importantly, this increase in NAD+ was not linked to changes in cellular glycolytic rates or ATP levels (data not shown), which would be expected if NAD+/NADH ratios had been altered to the point of compromising basic cellular functions." http://www.ncbi.nlm....les/PMC3616313/

 

So increasing NAD levels with NR supplementation did not alter PARP activity. (no inhibition) So the backbone of those studies was to eventually see what would happen if every NAD consuming enzyme had its adequate amount to function. As might be expected "NR treatment enhances SIRT1 and SIRT3 activity" because all the NAD is not being depleted by PARP activity alone with the added NR supplementation.

 

Those PARP inhibition experiments showed us how much NAD was being consumed and what would happen if we limited PARP/NAD consumption. The result was increased oxidative metabolism and increased sirtuin activity. "Robbing Peter to Pay Paul," so to speak, but in an ideal world we would like all these enzymatic processes to have enough NAD to do their jobs uninhibited, hence NAD boosting via NR.

 

Now lets back away from the above and consider the results of just simply boosting our NAD. In doing so we get both SIRT1 and SIRT3 activation.

 

Returning to your last question and taking it one step further; if we are already boosting NAD, do we need Pterostilbene or Resveratrol? These are both similar molecules however Pterostilbene is claimed to be many times more bioactive. If we are stimulating the production of SIRT1 we have to consider that sirtuins are themselves NAD consumers. But these sirtuins will also help raise NAD background levels once stimulated, so eventually we should see some effect by taking them alone without NAD boosting. However they have not fully deciphered the pathways these molecules stimulate SIRT1. But evidence is suggesting Pterostilbene is more soluble than Resveratrol in reaching the blood plasma. To me its still a wait and see.

 

Hope that in part answers your question? We have discussed the NR, NAD, PARP relationship on subsequent posts since my question last year, obviously Pterostilbene or Resveratrol supplementation would factor into this but Pterostilbene or Resveratrol alone would not likely raise NAD levels as much as approaching it directly thru the NAD salvage cycle as we do with NR. I see both as adjuncts to NAD boosting "if they even work" and I do currently take Pterostilbene on the chance it does. Be aware there is controversy surrounding these molecules and a clear path of Sirtuin activation is still being studied. Both are reported to stimulate additional pathways besides SIRT1 activation either directly or as secondary effects so the research on both will be ongoing as these paths may be as or more important.

 

Their AMPK connection may be how they work. http://diabetes.diab...t/59/3/554.full

 

Here is a broad overview of Sirtuin-activating compounds (STACs), I personally do not support one side or the other and I'm waiting for more data to support the STAC notion.

http://biopharmconso...rtris-founders/

Edited by Bryan_S, 05 October 2015 - 07:45 PM.

[stefan_001]

Hello Brian,

Thanks for your explanation, makes fully sense. It made me wonder about dosing. The key with the dosing would be to raise the levels of NAD+ to fuel the "anti aging" activities beyond basic. But as we age I understand the NAD + levels go down. Could it be that after a certain age the basic level of NAD+ is so low that even if you take NR it would not come up to the level needed for the basic repair. So in that sense NR as supplement can help extend life but can never keep you going forever....once it dips below a certain threshold some processes can simply not be fueled.

It would be interesting to have the ability to measure the level of NAD+. Is there any way to have a "home kit"?

Stefan

Edited by stefan_001, 06 October 2015 - 06:34 PM.

[Bryan_S]

Stefan,

 

Some of us are working on an ideal dosing regiment, I see the questions and I have them too. The last PK study hinted at a maximum effective oral dose. With accurate Half-Life data we should have the foundation to calculate a rough dosage regiment.

 

As in the study I referenced in my previous post we can see Nampt mRNA or its protein content did not change in response to NR treatment. Similarly, PARP activity and PARP-1 content were not affected by NR supplementation either. Those results suggest that NR increases NAD+ by direct NAD+ biosynthesis rather than by indirectly affecting the major NAD+ salvage (Nampt) or consumption (PARPs) pathways. This is very important for us to know that we aren't going to upset the NAD+/NADH ratios or alter them to the point of compromising our basic cellular functions.

 

As far as aging and dropping NAD levels, I think anything less than youthful NAD+ levels puts us at risk of not meeting our basic repair and maintenance quota anyway. With accumulated damage due to aging and the slow inevitable down regulation of some genes, our cellular machinery likely won't work as efficiently as when we were young. So realistically the thought of arresting or reversing our aging may be a pie in the sky goal anyway with simple NAD boosting. So I agree its going to help stabilize our demise but its only going to help prolong your health because we have this uncontrolled ramp down in gene expression from our epigenetic side.  http://www.nature.co...icles/srep13589 " We start from the organism in a “normal” initial state, in which all genes have youthful/healthy expression profiles. With the passage of time, t, most of the genes retain “normal” expression profiles, while a few genes, eg(t) genes in total, subsequently become either damaged or (epigenetically) dysregulated and represent a few “defects” or “errors” in the genetic program." So in the end we still have to contend with a cellular machine that has many of its youthful capabilities downregulated.

 

I don't know about any home NAD testing but I did contact these people who said they could put together the proper testing. https://www.gdx.net/

 

So as I mentioned, some of us are working on an ideal dosing regiment and I'm awaiting confirmation from some outside NR sources.

 

Just to be totally forthcoming what we end up calculating will be very basic at best. I've already written up some basic dosing regiments using a 4-hour-half-life calculation and have sent this off to ChromaDex as an example of how we'd like to outline this and they in turn are collaborating with the study PhDs to best correct any assumptions. So our group has their ear. The kicker is, its possible that we might be a bit early in the NR studies to consider this task because all of the PK data is still being processed, so there may be a wide area of error at this early stage. We also have to consider studies on Long-term dosing is totally lacking at the moment, however we know a study is planned. We do have 2 completed PK studies that could suggest a maximum oral dose with followup maintenance dosing thru the day to maintain useful NR blood serum levels. So that is the long and short of it and when I get something useful I'll post it with as many disclaimers as it needs. That's the best I can do from the bleeding edge.

 

BTW I just posted the next LongeCity Group Buy from HPN.

Edited by Bryan_S, 06 October 2015 - 11:03 PM.

[maxwatt]

I am new here and I neep a little help.
After taking 9 bottles of NR from Live Cell Research,they stopped shipping outside US,(I am in EU),and I found another supplier from US and they sold to me NAD+.I paid 40 USD for 4 grams powder.I bought 20 grams.
They send me also a chinese COA. They advise to disolve in water and take it nasal spray,.for much higher absorbtion.
I know that NR is a precursor of NAD+,so taking direct NAD+,in nasal spray ,or under tongue,is a solution? How I can check if is working?And what concentration?

Thanks in advance.

Andrei

Sorry no one has responded sooner, I just saw your question.

 

NAD+ is a large molecule which does not get into your cells, so is useless for the purposes of boosting intercellular NAD+.   NR gets into the cells, where it is a precursor to NAD+ and so boosts levels.  This is somewhat over-simplified, but essentially is what is going on.

[Tom Andre F. (ex shinobi)]

Bryan, I updated this page http://www.beta-lapa...f-healthy-life/ and quoted Dr Ross Grant who wrote " Age Related Changes in NAD+ Metabolism Oxidative Stress and Sirt1 Activity in Wistar Rats" (a study you quoted I think few page ago)

 

and a new study confirm the potential of beta-lapachone to increase NAD+ and health factors in another murine model

Edited by Tom Andre F. (ex shinobi), 07 October 2015 - 10:25 AM.

[bluemoon]

 

 

NAD+ is a large molecule which does not get into your cells, so is useless for the purposes of boosting intercellular NAD+.   NR gets into the cells, where it is a precursor to NAD+ and so boosts levels.  This is somewhat over-simplified, but essentially is what is going on.

 

 

I know a scientist (not bio/chem) who has been taking NADH+  at 20mg for almost 2 years and says he at age 60 has better stamina walking up hills, has seen his age spots significantly fade and no longer had eye floaters.

 

It seems to be getting into his cells. How is NADH+ different from NR? 

[Bryan_S]

I know a scientist (not bio/chem) who has been taking NADH+  at 20mg for almost 2 years and says he at age 60 has better stamina walking up hills, has seen his age spots significantly fade and no longer had eye floaters.

 

It seems to be getting into his cells. How is NADH+ different from NR? 

 

 

We seem to revisit this question with some regularity and I guess this is to be expected so here we go. http://www.longecity...-23#entry746369

 

Guys this is what happens when we have a slack in news. I'm looking for the next news item as we speak but the last week or so has been light.

 

Let's momentarily put the differences in the molecules aside, which we'll return to. . .

 

First off have you attached a per/gram price to NADH or NAD? Second these molecules are very sensitive to the digestive system.

 

Now that isn't to say you wont benefit from from the residuals that finally get digested but if this is the case, wouldn't a cheaper NAD precursor give you more bang for the buck? Also before I leave this point, in all of the research I've read on NADH or NAD it appears they were most effective when injected, which would make perfect sense. I for one don't like needles when there are better alternatives.

 

Continuing . . . if you get NADH intact past this first hurdle in the gut we now have to contend with the cell membrane. "Our results demonstrate that, besides nicotinamide and nicotinic acid, only the corresponding nucleosides readily enter the cells. Nucleotides (e.g. NAD and NMN) undergo extracellular degradation resulting in the formation of permeable precursors." 

 

Here is another recent Longecity post on the topic.

 

So in all we are left with 4 NAD precursors that readily pass the cell membrane unchanged nicotinic acid riboside (NaR), niacin (Na), nicotinamide (Nam) and nicotinamide riboside (NR). What gives NR or NaR (NaR if we could get it) a leg up on the other precursors is the (NMRK1 & NMRK2) nicotinamide riboside kinase 1 or 2 enzymes. These are expressed in varying degrees in different cell types but the point is they convert these 2 precursors directly to NMN which is one step away from NAD. So in effect these 2 precursors cut to the front of the line at the cell membrane and again inside the cell in the NAD salvage cycle. The salvage cycle is the circular part of the diagram below.

 

 

So the question is what's to be gained by supplementing with expensive molecules like NAD and NADH, which in all likelihood will be broken down before they get to their destination and if they do make it they'll have to undergo degradation resulting in the formation of permeable precursors to be absorbed at the cell membrane. Also you have to consider the cost of NAD and NADH which on a per/gram basis is currently more than NR (some of us are buying NR at $4.27 per/gram bulk price, the last time I looked at NADH it was @ around $30 per/gram retail.) So again, "what's to be gained vs what's the cost?" Hope that helps.

 

Also guys since I'm posting I'll plug the next LongeCity NR Group Buy from HPN because we need to keep this on going.

Edited by Bryan_S, 07 October 2015 - 10:09 PM.

[Bryan_S]

High-Dose Nicotinamide Suppresses ROS Generation and Augments Population Expansion during CD8+ T Cell Activation

 

Here is some news.

 

During T cell activation, mitochondrial content increases to meet the high energy demand of rapid cell proliferation. With this increase, the level of reactive oxygen species (ROS) also increases and causes the rapid apoptotic death of activated cells, thereby facilitating T cell homeostasis. Nicotinamide (NAM) has previously been shown to enhance mitochondria quality and extend the replicative life span of human fibroblasts. In this study, we examined the effect of NAM on CD8+ T cell activation. NAM treatment attenuated the increase of mitochondrial content and ROS in T cells activated by CD3/CD28 antibodies. This was accompanied by an accelerated and higher-level clonal expansion resulting from attenuated apoptotic death but not increased division of the activated cells. Attenuation of ROS-triggered pro-apoptotic events and upregulation of Bcl-2 expression appeared to be involved. Although cells activated in the presence of NAM exhibited compromised cytokine gene expression, our results suggest a means to augment the size of T cell expansion during activation without consuming their limited replicative potential.

Keywords: mitochondria, nicotinamide, ROS, T cell activation

 

T Cell Activation - Molecules and Cells

Edited by Bryan_S, 07 October 2015 - 10:30 PM.

[bluemoon]

  So again, "what's to be gained vs what',s the cost?" Hope that helps.

 

 

 

 

Thanks a lot for your explanation. I haven't talked to this scientist for a while but will surely run into him soon! I just remembered that he cut from 20mg of NADH+ to 5mg a day. He told me that he saw all brands have the same distributor so gets the cheapest. I forgot to ask the cost since at the time was waiting for more information before I'd try.

 

He also said that he has been taking 250mg of resveratrol for a few years but noticed his positive effects after taking NADH+. (I told him of my positive experience with resverstrol at 500 mg including rapid but healthy weight loss after a week -- weight came back in a month after dropping to 250mg. I also had his clear "don't get out of breath" experience when walking up steep hills.

 

I told him in February about Elysium's NR supplement, but he didn't seem interested, and I wondered why. (I'll just get the cheapest NR out there.) I'll email your post to him.

[Bryan_S]

Postdoc position available

 

The Novo Nordisk Foundation Center for Basic Metabolic Research

Faculty of Health and Medical Sciences, University of Copenhagen

 

Postdoctoral Fellow, Molecular Metabolism

 

Project Description

 

"Evidence is emerging that a family of nicotinamide adenine dinucleotide (NAD)-requiring enzymes called sirtuins activate specific transcription factors involved in mitochondrial biogenesis. Furthermore, sirtuins directly regulate the enzymatic activity of mitochondrial enzymes involved in mitochondrial function and substrate utilization. Mammalian cells have several NAD salvage systems of which the most important involves Nicotinamide phosphoribosyltransferase (Nampt). However, supplementation of vitamin B3 family members such as nicotinamide riboside and derivatives has also been shown to increase NAD levels. The overall goal in this project is to provide mechanistic evidence for a role of mammalian NAD salvage pathways in maintaining mitochondrial function and insulin sensitivity. The successful candidate will carry out extensive experiments involving in vivo and in vitro approaches in cultured cells and unique animal models. We hope to translate our findings to clinically relevant settings, ultimately in type 2 diabetes."

 

https://www.linkedin...able-jonas-thue

 

By the way I found this available Postdoc position by searching for the PK study results. I believe this is the same group responsible for "Pharmacokinetic Analysis of Nicotinamide Riboside" See Primary Outcome Measures below. A study publication by the way that has eluded our search so far. I'm awaiting news from this source to help in calculating viable dosing regiments. So if anyone can catch a glimpse of info originating from this lab please post it here! 

 

 

• serum concentrations of metabolites of nicotinamide riboside [ Time Frame: 8 hour, blood samples every 15 min ] [ Designated as safety issue: No ]
• area under the curve for serum nicotinamide riboside [ Time Frame: 8 hours, blood samples every 15 min ] [ Designated as safety issue: No ]
• calculation of halftime of serum nicotinamide riboside [ Time Frame: 8 hours, blood samples every 15 min ] [ Designated as safety issue: No ]
• calculation of C-max of serum nicotinamide riboside [ Time Frame: 8 hours, blood samples every 15 min ] [ Designated as safety issue: No ]
• calculation of t-max of serum nicotinamide riboside [ Time Frame: 8 hours, blood samples every 15 min ] [ Designated as safety issue: No ]

 

Edited by Bryan_S, 08 October 2015 - 07:16 PM.

[stefan_001]

Stefan,

 

Some of us are working on an ideal dosing regiment, I see the questions and I have them too. The last PK study hinted at a maximum effective oral dose. With accurate Half-Life data we should have the foundation to calculate a rough dosage regiment.

 

As in the study I referenced in my previous post we can see Nampt mRNA or its protein content did not change in response to NR treatment. Similarly, PARP activity and PARP-1 content were not affected by NR supplementation either. Those results suggest that NR increases NAD+ by direct NAD+ biosynthesis rather than by indirectly affecting the major NAD+ salvage (Nampt) or consumption (PARPs) pathways. This is very important for us to know that we aren't going to upset the NAD+/NADH ratios or alter them to the point of compromising our basic cellular functions.

 

As far as aging and dropping NAD levels, I think anything less than youthful NAD+ levels puts us at risk of not meeting our basic repair and maintenance quota anyway. With accumulated damage due to aging and the slow inevitable down regulation of some genes, our cellular machinery likely won't work as efficiently as when we were young. So realistically the thought of arresting or reversing our aging may be a pie in the sky goal anyway with simple NAD boosting. So I agree its going to help stabilize our demise but its only going to help prolong your health because we have this uncontrolled ramp down in gene expression from our epigenetic side.  http://www.nature.co...icles/srep13589 " We start from the organism in a “normal” initial state, in which all genes have youthful/healthy expression profiles. With the passage of time, t, most of the genes retain “normal” expression profiles, while a few genes, eg(t) genes in total, subsequently become either damaged or (epigenetically) dysregulated and represent a few “defects” or “errors” in the genetic program." So in the end we still have to contend with a cellular machine that has many of its youthful capabilities downregulated.

 

I don't know about any home NAD testing but I did contact these people who said they could put together the proper testing. https://www.gdx.net/

 

So as I mentioned, some of us are working on an ideal dosing regiment and I'm awaiting confirmation from some outside NR sources.

 

Just to be totally forthcoming what we end up calculating will be very basic at best. I've already written up some basic dosing regiments using a 4-hour-half-life calculation and have sent this off to ChromaDex as an example of how we'd like to outline this and they in turn are collaborating with the study PhDs to best correct any assumptions. So our group has their ear. The kicker is, its possible that we might be a bit early in the NR studies to consider this task because all of the PK data is still being processed, so there may be a wide area of error at this early stage. We also have to consider studies on Long-term dosing is totally lacking at the moment, however we know a study is planned. We do have 2 completed PK studies that could suggest a maximum oral dose with followup maintenance dosing thru the day to maintain useful NR blood serum levels. So that is the long and short of it and when I get something useful I'll post it with as many disclaimers as it needs. That's the best I can do from the bleeding edge.

 

BTW I just posted the next LongeCity Group Buy from HPN.

Hello Brian,

Appreciate your thoughtfull reply. Learned something again. So the great part is that NAD+ levels can be increased (even if there is a ceiling), so now the challenge is then to ensure the right genes are switched on to benefit when we have a NAD+ boost ongoing. It may be coincidental but I always have the impression that after medium exercise in the evening I look more fresh in the morning than in those days when I only use NAD+/Honikiol/Pterostilbene. Incidently there was also this study published:

http://sydney.edu.au...-a-reality.html

http://www.cell.com/...4131(15)00458-1

"Research finds around 1000 molecular reactions to exercise"

So next to SIRT boosting simple exercise may be a good way to prime the body to benefit in optimal way from NAD+ boosting.

Stefan

 

 

Edited by stefan_001, 08 October 2015 - 08:41 PM.

[Bryan_S]

Lethal Cardiomyopathy in Mice Lacking Transferrin Receptor in the Heart

http://www.cell.com/...1247(15)01034-7

http://dx.doi.org/10...iom.2015.09.041

 

Access is limited until 2016-02-13T00:00:00Z

 

It appears NAD boosting has other far reaching benefits. Anything that helps keep hearts heathy is a positive indicator for me!  

 

In Brief

Coexisting iron deficiency worsens the prognosis for patients with heart failure. Xu et al. show that the transferrin receptor is essential in the mouse heart, iron is needed continuously to support oxidative phosphorylation, mitophagy is ineffective when iron is insufficient, and nicotinamide riboside benefits mice with cardiac iron deficiency.

 

Summary

"Both iron overload and iron deficiency have been associated with cardiomyopathy and heart failure, but cardiac iron utilization is incompletely understood. We hypothesized that the transferrin receptor (Tfr1) might play a role in cardiac iron uptake and used gene targeting to examine the role of Tfr1 in vivo. Surprisingly, we found that decreased iron, due to inactivation of Tfr1, was associated with severe cardiac consequences. Mice lacking Tfr1 in the heart died in the second week of life and had cardiomegaly, poor cardiac function, failure of mitochondrial respiration, and ineffective mitophagy. The phenotype could only be rescued by aggressive iron therapy, but it was ameliorated by administration of nicotinamide riboside, an NAD precursor. Our findings underscore the importance of both Tfr1 and iron in the heart, and may inform therapy for patients with heart failure." http://www.cell.com/...(15)01034-7.pdf

 

Please cite this article in press as: Xu et al., Lethal Cardiomyopathy in Mice Lacking Transferrin Receptor in the Heart, Cell Reports (2015), http:// dx.doi.org/10.1016/j.celrep.2015.09.023

Edited by Bryan_S, 10 October 2015 - 06:19 PM.

[ironfistx]

how is nicotinamide riboside different from