529 replies to this topic

[M-K]

Chromadex has announced a scientific advisory board headed by a Nobel prize winner:

 

http://www.marketwat...oard-2014-07-08

[Razor444]

A new press release: ChromaDex Initiates First Human Clinical Study to Confirm ChromaDex's NIAGEN™ Nicotinamide Riboside Will Increase NAD+

 

 

Published research has shown that NR is perhaps the most effective precursor to boost the co-enzyme NAD+ in the cell.  NAD+ is arguably the most important cellular co-factor for improvement of mitochondrial performance and energy. In recent years, NAD+ has also been shown to participate as an extracellular signaling molecule in cell-to-cell communication.  NAD+ is essential in supporting healthy cellular metabolism including the efficient conversion of blood glucose into energy. 

 

As organisms age, NAD+ levels drop, which leads to a decrease in mitochondrial health; this in turn leads to age-related health issues. Low NAD+ levels limit activity of a group of enzymes called sirtuins, which are believed to play a key role in longevity. NAD+ levels can be depleted by lifestyle choices such as overeating and lack of exercise. By boosting NAD+, NR can increase mitochondrial health and induce creation of new mitochondria.

 

Frank Jaksch, Jr., founder and CEO of ChromaDex, commented, "The primary goal of this human study is to confirm previous published research in animals showing that NR is an effective precursor to NAD+. Confirming that NR leads to a meaningful increase in NAD+ metabolites in humans is perhaps the single most important clinical endpoint in proving that NR will have significant impact on human health."

 

 

[Phoenicis]

Its looking like NAD+ precursors may be a double edged sword, SIRT1 increases angiogenesis:

 

Genes Cancer. 2013 Mar;4(3-4):82-90. doi: 10.1177/1947601912473826.

 

Emerging Roles of SIRT1 in Cancer Drug Resistance.

Wang Z¹, Chen W.

Author information

Abstract

Innate resistance to various therapeutic interventions is a hallmark of cancer. In recent years, acquired resistance has emerged as a daunting challenge to targeted cancer therapy, which abolishes the efficacy of otherwise successful targeting drugs. Cancer cells gain the resistance property through a variety of mechanisms in primary and metastatic cancers, involving cellular intrinsic and extrinsic factors. Increasing evidence suggests that the mammalian stress response gene sirtuin 1 (SIRT1) plays a critical role in multiple aspects of cancer drug resistance. SIRT1 decreases drug penetration, confers proliferation and antiapoptotic survival advantages to cancer cells, facilitates acquired resistance through genetic mutations, promotes the survival of cancer stem cells, and changes the tumor microenvironment for resistance in cell-autonomous and -nonautonomous manners. This article provides an overview of research advances in the roles of SIRT1 in cancer drug resistance and highlights the prospect of targeting SIRT1 as a new strategy to overcome cancer drug resistance and improve therapeutic outcomes.

→ source (external link)

 

[Darryl]

About 23,600 Google Scholar results for "double-edged sword" 

 

We should be surprised when any intervention has unequivocally universal benefits.

 

Apologies for the OT, but coming across so many "double-edged sword" titles in the literature on a near daily basis has gone beyond bemusement to mild exasperation.

[timar]

If you think about it, there's really no downside to a double-edged sword. If I was a knight I would prefer it so a single-edged one any day

[Phoenicis]

Well there's plenty of references to SIRT1 controlling endothelial angiogenic growth. The fact that cancer fighting agents like resveratrol and curcumin also activate SIRT1 would seem to rebutt the presumption that this causes cancer, on the other hand angiogenesis does mediate cancer growth. It's a little strange and makes me curious about why NAMPT has a negative feedback mechanism in the first place. Aside from the fact that NAMPT declines with age, it is also easily saturated as NAD+ accumulates because of that feedback mechanism. It also makes wonder why nicotinamide would inhibit SIRT1, these things must have evolved for a reason.

 

We know that the NAD+ levels oscillate with the circadian rhythm and that NAMPT modulates circadian gene expression. So as asked elsewhere, I wonder what the best time is to replete NAD+ reserves? It could be different for intermediaries like NR and vitamin b3 forms.

 

I guess the question that needs to be answered is: are NAD+ precursors restoring homeostasis and if the answer is yes, is possible to disrupt this balance by going in the other direction and taking too much?

 

Edit: Yeah I know double edged swords are abundant, but so is cancer. Also I wasn't the one who down-voted Timar, but I'd appreciate some input.

Edited by Phoenicis, 30 July 2014 - 07:58 PM.

[sthira]

Unless your horse stumbled.

[1thoughtMaze1]

mitoTrans is now being manufactured

"We have reached a very exciting milestone, and wanted to tell you first.  After years of research to perfect our process for creating a pure, stable form of NAD+, we’ve succeeded.  Our first production run has passed a full slate of rigorous tests and is now being prepared for distribution. Within a few short weeks, we expect to have MitoTrans™ into the hands of our loyal customers."

Does anyone have it preordered?

[midas]

mitoTrans is now being manufactured

"We have reached a very exciting milestone, and wanted to tell you first.  After years of research to perfect our process for creating a pure, stable form of NAD+, we’ve succeeded.  Our first production run has passed a full slate of rigorous tests and is now being prepared for distribution. Within a few short weeks, we expect to have MitoTrans™ into the hands of our loyal customers."

Does anyone have it preordered?

 

Has anyone seen any evidence other than that claimed by the manufacturer that it actually does something?

 

I looked into this a few months ago and could find no evidence of any benefits.

They just tell you to do a search for NAD+ on google scholar on there website!

 

I would need to see some evidence that it actually does produce NAD+........And the cost of this stuff (MitoTrans) is very expensive.

[StevesPetRat]

mitoTrans is now being manufactured

....

Could not find dose or price anywhere. However, as I understand it, NAD+ cannot enter the cell directly without being broken down into precursors first. So unless it's a liposomal formulation or something, I am unsure that it offers any advantage over NR, NA, or Nam.

Edited by StevesPetRat, 12 August 2014 - 12:33 AM.

[krillin]

I'm not sure I'd want extracellular NAD+. Aubrey deGrey said it'd be reduced to NADH in the blood, and that could lead to a lot of superoxide production.

 

Biochem J. 1996 Sep 15;318 ( Pt 3):805-12.
High rates of extracellular superoxide generation by cultured human fibroblasts: involvement of a lipid-metabolizing enzyme.
O'Donnell VB, Azzi A.
Institute of Biochemistry and Molecular Biology, Bern, Switzerland.

Expression of NADPH oxidase and low superoxide generation (approx. 0.06 nmol/min per 10(6) cells) by cytokine- or ionophore-stimulated human fibroblasts is known. However, we here show that these cells also contain an ectoplasmic enzyme, distinct from NADPH oxidase, which can generate superoxide (2.19 +/- 0.14 nmol/min per 10(6) cells) at levels similar to phorbol ester-stimulated monocytes on exogenous NADH addition. Superoxide generation was temperature-dependent, insensitive to chelation (desferal), and had a K(m) (app)(NADH) of 11.5 microM. Inhibitor studies showed that there was no involvement of NADPH oxidase (diphenylene iodonium, diphenyl iodonium), prostaglandin H synthase (indomethacin), xanthine oxidase (allopurinol), cytochrome P-450 (metyrapone) or mitochondrial respiration (rotenone, antimycin A). NAD+ was a competitive inhibitor, whereas NADPH supported 40% of the rate seen with NADH. No luminescence was observed after the addition of lactate, malate, pyruvate, GSH or L-cysteine. NADH-stimulated superoxide generation was enhanced by the addition of (3-30 microM) arachidonic acid, linoleic acid or (5S)-hydroxyeicosatetraenoic acid [(5S)-HETE] but not palmitic acid, (15S)-hydroperoxyeicosatetraenoic acid [(15S)-HPETE], (15S)-HETE or (12S)-HETE. Several features suggest involvement of an enzyme related to 15-lipoxygenase, and, in support of this, we show superoxide generation and NADH oxidation by recombinant rabbit reticulocyte 15-lipoxygenase. The large amounts of superoxide measured suggest that the fibroblast extracellular enzyme could be a major source of reactive oxygen species after tissue damage.

PMID: 8836123

[krillin]

I forgot I had this in my notes. Extracellular NAD+ causes hyperglycemia due to liver glycogenolysis stimulation. (PMID: 20085812 search for glycogenolysis and PMID: 14744616)

[Kevnzworld]

I forgot I had this in my notes. Extracellular NAD+ causes hyperglycemia due to liver glycogenolysis stimulation. (PMID: 20085812 search for glycogenolysis and PMID: 14744616)

I take 750 mg of NR, 100 mg NA, plus 200 mg of resveratrol, daily
My last blood test , fasting glucose 90.... ( previous, 88 ).
hbA1C. 5.1. Previous , 5.1

Edited by Kevnzworld, 12 August 2014 - 08:28 AM.

[Phoenicis]

Apparently NAD+ can work via intranasal administration -

 

 

Prevention of Traumatic Brain Injury-Induced Neuron Death by Intranasal Delivery of Nicotinamide Adenine Dinucleotide

Abstract-

"Traumatic brain injury (TBI) is one of the most devastating injuries experienced by military personnel, as well as the general population, and can result in acute and chronic complications such as cognitive impairments. Since there are currently no effective tools for the treatment of TBI, it is of great importance to determine the mechanisms of neuronal death that characterize this insult. Several studies have indicated that TBI-induced neuronal death arises in part due to excessive activation of poly(ADP-ribose) polymerase-1 (PARP-1), which results in nicotinamide adenine dinucleotide (NAD+) depletion and subsequent energy failure. In this study, we investigated whether intranasal administration of NAD+ could reduce neuronal death after TBI. Rats were subjected to a weight-drop TBI model that induces cortical and hippocampal neuronal death. The intranasal administration of NAD+ (20 mg/kg) immediately after TBI protected neurons in CA1, CA3, and dentate gyrus of the hippocampus, but not in the cortex. In addition, delayed microglial activation normally seen after TBI was reduced by NAD+ treatment at 7 days after insult. Neuronal superoxide production and PARP-1 accumulation after TBI were not inhibited by NAD+ treatment, indicating that reactive oxygen species (ROS) production and PARP-1 activation are events that occur upstream of NAD+ depletion. This study suggests that intranasal delivery of NAD+ represents a novel, inexpensive, and non-toxic intervention for preventing TBI-induced neuronal death."

→ source (external link)

Edited by Phoenicis, 12 August 2014 - 10:38 AM.

[1thoughtMaze1]

mitoTrans is now being manufactured

"We have reached a very exciting milestone, and wanted to tell you first. After years of research to perfect our process for creating a pure, stable form of NAD+, we’ve succeeded. Our first production run has passed a full slate of rigorous tests and is now being prepared for distribution. Within a few short weeks, we expect to have MitoTrans™ into the hands of our loyal customers."

Does anyone have it preordered?

Has anyone seen any evidence other than that claimed by the manufacturer that it actually does something?

I looked into this a few months ago and could find no evidence of any benefits.
They just tell you to do a search for NAD+ on google scholar on there website!

I would need to see some evidence that it actually does produce NAD+........And the cost of this stuff (MitoTrans) is very expensive.

The claim to have a novel delivery system, just read their site.

[Primal]

All those alcool/drug addiction clinics that offer IV NAD Therapy I wonder where they get their NAD+ from and how stable it is. The highly raised extracellular concentration does not appear to cause much problems, and many people apparently have had good responses to the treatment.

[niner]

I went to one "IV NAD" therapy site.  It's very expensive ($10,000), but they didn't say what was in the iv.  There was a reference to "nutrients", suggesting more than one component.  I'm very dubious of this new oral NAD product.  The vendor isn't known for scientific expertise.

[Phoenicis]

Can anyone make a guess about whether nicotinamide riboside might also work if administered intranasally? 
I can't get my hands on the full text of this, so I'm not sure about the mechanism, or why Nam didn't work. I don't see how NAD+ could work better than Nr though, since NAD+ has to be degraded to NR before entering a cell. 

Edited by Phoenicis, 12 August 2014 - 07:09 PM.

[Primal]

Can anyone make a guess about whether nicotinamide riboside might also work if administered intranasally? 

 

if you can buy pure NR I would say infuse it instead of intranasal, unless money is too tight and you want to focus the delivery to your brain then snorting should work

[krillin]

More extracellular NAD+ fun: NAD-induced T cell death PMID: 14563321 PMID: 18404420. Extracellular NAD+ and ATP are interpretted as a sign that tissue damage has occurred and that 1) unprimed T cell bystanders should be killed off so that an autoimmune response doesn't occur and 2) T-regulatory cells need to be killed off to increase the immune response to pathogens.

[Logic]

I have just finished reading this whole thread.
Thx to all for a very interesting and informative read.

I found he below info interesting in that it points to the riboside as also being very useful once its been split off?
Also I wonder if Uridine and Phosphatidylcholine/Phosphate  would not be synergistic with increasing NAD+?
Perhaps some of Mr Happy's stack success is to do with increased NAD+?

Nicotinamide Riboside and Nicotinic Acid Riboside Salvage in Fungi and Mammals
QUANTITATIVE BASIS FOR Urh1 AND PURINE NUCLEOSIDE PHOSPHORYLASE FUNCTION IN NAD+METABOLISM
"...We demonstrate that so-called uridine hydrolase is 100-fold more active as a nicotinamide riboside hydrolase than as a uridine hydrolase and that uridine hydrolase and mammalian purine nucleoside phosphorylase cleave nicotinic acid riboside...

...Sirtuins utilize the ADP-ribose moiety of NAD+ to accept the acetyl modification of lysine, thereby producing a deacetylated protein plus Nam and a mixture of 2′- and 3′-acetylated ADP-ribose (2–4). Such reactions are important for chromatin silencing (5) and regulation of transcription factors and enzymes, thereby controlling a variety of genomic transactions (6), metabolic switches (7, 8), and lifespan...

...Finally, cyclic ADP-ribose synthases produce and hydrolyze the calcium-mobilizing compound, cADP-ribose (14, 15). Thus, via pleiotropic ways and means, NAD+ is a central mediator of cellular and organismal metabolism and signaling...

we demonstrate that NR cleavage in mammalian systems is entirely phosphate-dependent and is sensitive to a specific inhibitor of Pnp..." (purine nucleoside phosphorylase)

http://www.jbc.org/c.../284/1/158.full

Edited by Logic, 31 August 2014 - 03:48 PM.

[Logic]

(Thx to curious_sle)

Extension of human cell lifespan by nicotinamide
phosphoribosyltransferase.

http://www.longecity...y-nicotinamide/
"... nicotinamide phosphoribosyltransferase (Nampt/
PBEF/ Visfatin), the rate-limiting enzyme for NAD+ salvage from
nicotinamide..."

[Logic]

"...The primary driver of this “metabolic reprogramming” is the transcription factor, Hypoxia Inducing Factor 1 alpha (HIF-1α), which normally only activates Warburg-type metabolism when oxygen levels are low. Unfortunately, when nuclear NAD+ levels are low, HIF-1α is stabilized and is not degraded by VHL as would normally be the case. As a result, cells are “metabolically reprogrammed” to use aerobic glycolysis in the presence of normal oxygen. HIF-1α inhibits a chain of events that ultimately results in a reduced expression of the mitochondrial transcription factor, TFAM, which normally migrates from the cell nucleus to the mitochondria to stimulate mitochondrial DNA replication. As a result, mitochondrial encoded genes are expressed. When HIF-1α inhibits TFAM, this does not occur. The nuclear encoded mitochondrial proteins are still created via the transcription factor Nrf1, but because TFAM is suppressed by HIF-1α no mitochondrial-encoded protein components of the electron transport chain are expressed. This results in mitochondria that cannot make ATP but still have defective electron transport chains that “run in reverse”. This “reverse electron transport” results in the production of uncontrolled amounts of free radicals from the mitochondria, which then create the “Universal Signature of Aging” which is mitochondrial dysfunction with high free radical production. All of these events can be traced back to inadequate NAD+ in the nucleus. Without adequate NAD+ in the nucleus, SIRT1 cannot function, since NAD+ is a mandatory co-factor for all of the Sirtuins. What David Sinclair and colleagues from both Harvard and Australia showed in a landmark publication late in 2013 was that supplementation with an NAD+ precursor could reverse this mitochondrial dysfunction and “Warburg-like” metabolic state in mice in one week. Sinclair and associates used an NAD+ precursor called NMN, but previous work showed that another NAD+ precursor could also work, Nicotinamide Riboside (NR). NMN is only one step away from NAD+, but is difficult to make and is very expensive. NR is two steps away from NAD+, but is much easier to make, is much less expensive, and is already available for sale under the proprietary name, Niagen. To date, no studies in humans have replicated the findings from Sinclair’s mice studies. Until these are done, we must “hold our breath”. However, in Sinclair’s studies, all of the mitochondrial dysfunction seen in aging mouse skeletal muscle was reversed (with the exception of muscle strength).

In summary, deficiency of NAD+ in the nucleus of muscle cells produces a state of “pseudohypoxia”, where there is adequate oxygen but high levels of HIF-1α. This results in the inhibition of the mitochondrial transcription factor, TFAM, which inhibits the expression of mtDNA. As a result, mitochondria do not produce the proteins encoded in mitochondrial DNA that are required for “forward electron transport” and ATP production. “Reverse electron transport” occurs and high levels of free radicals are produced, giving the exact picture of aging. In this picture cells are dependent on aerobic glycolysis in the cytoplasm and cannot burn fat. They develop the exact metabolic picture of cancer, called the Warburg effect. The mitochondrial dysfunction and this Warburg-type metabolism are fully reversible with the supplementation of NAD+ precursors."
http://www.anti-agin...-aging-in-2013/

I have not seen mention of these defective electron transport chains that “run in reverse”. causinguncontrolled amounts of free radicals?

[mikeinnaples]

Going to necro this because the discussion doesn't need to be buried.

[follies]

What does "going to necro" mean?

[APBT]

What does "going to necro" mean?

 

http://www.urbandict...erm=necrothread

Negatively: an old, decaying thread that refuses to die. 

Positively: a threaded conversation that had retained its usefulness so long that new comments are still being added years later. 

Example relates to both definitions.

Example of a necrothread: "Where's the bestplace to meet people in (insert city here)?"

 

 

http://www.internets...-definition.asp

What is NECRO?

 

NECRO is "Revive a very old forum thread"

[CatChelator]

Not sure if any of this is new, but was posted by ABC news last night. Sorry if this is the wrong thread for it. Came here to see if anything had been posted recently to see if anything in particular prompted this interview.

If you search for it you'll find the original radio interview.


Post:

Scientists from Harvard and the University of New South Wales say they have discovered how to reverse the ageing process.

The research has focused on mice, but early clinical trials have also been conducted on humans.

The scientists said they switched youthful genes on and older genes off, using naturally occurring proteins and molecules.

Professor of genetics at Harvard and UNSW, David Sinclair, led the research team.

Audio: Listen to Sue Lannin's report (THE WORLD TODAY)
"We've discovered genes that control how the body fights against ageing and these genes, if you turn them on just the right way, they can have very powerful effects, even reversing ageing - at least in mice so far," he said.

"We fed them a molecule that's called NMN and this reversed ageing completely within just a week of treatment in the muscle, and now we're looking to reverse all aspects of ageing if possible."

Professor Sinclair said the breakthroughs could be used to develop drugs to restore youthfulness in human cells.

"We've gone from mice into early human studies actually. There have been some clinical trials around the world, and we're hoping in the next few years to know if this will actually work in people as well," he said.

The clinical trials were small studies but showed promising results in humans, he said.

"They show that the molecules that extend lifespan in mice are safe in people; they seem to be anti-inflammatory, so they might be useful against disease's inflammation, like skin redness or even inflammatory bowel disease," he said.


"Eventually we want these molecules to be taken by many people to prevent diseases of ageing and make them live longer, healthier lives."

Professor Sinclair was named by Time Magazine as one of most influential people in the world.

He has been taking the red wine molecule, resveratrol, for a decade.

"I've been taking resveratrol for the last 10 years because it seemed to be very safe," he said.

"I think the risks are, for myself, worth it, though I don't ever promote it.

"But the more research that I see done, and there are now thousands of papers on it, I think that there's a good chance that it'll have some benefit."

Professor Sinclair said the latest discovery could, one day, be seen in the same light as antibiotics.

"Some people say it's like playing God, but if you ask somebody 100 years ago, what about antibiotics? They probably would have said the same thing," he said.

"Some people worry about big advances in technology and medicine, but once it's adapted and it's natural for people to live until they're 90 in a healthy way ... we'll look back at today like we do at the times before antibiotics when people died from an infected splinter."

[midas]

Not sure if any of this is new, but was posted by ABC news last night. Sorry if this is the wrong thread for it. Came here to see if anything had been posted recently to see if anything in particular prompted this interview.

If you search for it you'll find the original radio interview.


Post:

Scientists from Harvard and the University of New South Wales say they have discovered how to reverse the ageing process.

The research has focused on mice, but early clinical trials have also been conducted on humans.

The scientists said they switched youthful genes on and older genes off, using naturally occurring proteins and molecules.

Professor of genetics at Harvard and UNSW, David Sinclair, led the research team.

Audio: Listen to Sue Lannin's report (THE WORLD TODAY)
"We've discovered genes that control how the body fights against ageing and these genes, if you turn them on just the right way, they can have very powerful effects, even reversing ageing - at least in mice so far," he said.

"We fed them a molecule that's called NMN and this reversed ageing completely within just a week of treatment in the muscle, and now we're looking to reverse all aspects of ageing if possible."

Professor Sinclair said the breakthroughs could be used to develop drugs to restore youthfulness in human cells.

"We've gone from mice into early human studies actually. There have been some clinical trials around the world, and we're hoping in the next few years to know if this will actually work in people as well," he said.

The clinical trials were small studies but showed promising results in humans, he said.

"They show that the molecules that extend lifespan in mice are safe in people; they seem to be anti-inflammatory, so they might be useful against disease's inflammation, like skin redness or even inflammatory bowel disease," he said.


"Eventually we want these molecules to be taken by many people to prevent diseases of ageing and make them live longer, healthier lives."

Professor Sinclair was named by Time Magazine as one of most influential people in the world.

He has been taking the red wine molecule, resveratrol, for a decade.

"I've been taking resveratrol for the last 10 years because it seemed to be very safe," he said.

"I think the risks are, for myself, worth it, though I don't ever promote it.

"But the more research that I see done, and there are now thousands of papers on it, I think that there's a good chance that it'll have some benefit."

Professor Sinclair said the latest discovery could, one day, be seen in the same light as antibiotics.

"Some people say it's like playing God, but if you ask somebody 100 years ago, what about antibiotics? They probably would have said the same thing," he said.

"Some people worry about big advances in technology and medicine, but once it's adapted and it's natural for people to live until they're 90 in a healthy way ... we'll look back at today like we do at the times before antibiotics when people died from an infected splinter."

 

It seems to be a rehash of the information that was released about this time last year with the exeption of the parts I have highlited in your post.

 

Here is a link to the short interview.....

 

http://mobile.abc.ne...in-mice/5865630

[Jharper1966]

β-Lapachone ameliorates murine cisplatin nephrotoxicity: NAD+, NQO1, and SIRT1 at the crossroads of metabolism, injury, and inflammation

In this issue of Kidney International, Oh et al.1 show that β-lapachone exerts its salutary effects on cisplatin nephrotoxicity by being reduced by NAD(P)H:quinone oxidoreductase 1 (NQO1). This results in an increased ratio of NAD+ to NADH (nicotinamide adenine dinucleotide). The increased NAD+ mimics that seen during caloric restriction and may mediate the beneficial effects of caloric restriction, without malnutrition, on inappropriate inflammation and apoptosis.2 In other words, and as discussed in greater detail below, the increased NAD+, induced by β-lapachone, activates the deacetylase SIRT1 and may thus ‘fool’ the cell into detecting caloric restriction when there is none; this, in turn, may affect the cell’s ‘decisions’ about its own life and death, and its production of proinflammatory molecules. Consistent with this idea is the known beneficial effect of caloric restriction on cisplatin nephrotoxicity, which is indeed mediated by NAD+-activated SIRT1 expression. Thus, the major components of the beneficial effects of β-lapachone are NQO1, NAD+, and SIRT1.

Kidney International (2014) 85, 547–560; doi:10.1038/ki.2013.330; published online 11 September 2013

Pharmacological activation of NQO1 increases NAD+ levels and attenuates cisplatin-mediated acute kidney injury in mice

Just wanted to see what others thought about the possibility of lapachone being useful to increase NAD+.

[Kevnzworld]

An interesting article:
" NAD+ an emerging framework for life extension — Part 1: The NAD World "

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