2255 replies to this topic

[Nate-2004]

 

 

The problem is that Nicotinamide by itself inhibits Sirtuins which defeats the whole point of increasing NAD+

 

You don't wanna take that pathway. There are multiple pathways and that's the worst one.

 

 

Really ?  Thanks for mentioning that.

Do you have a handy reference (or two, or three) about that ?

I'd like to give it (or them) a good perusal.

 

Thanks Nate
 

 

 

Yes that was the reason for experimenting with NMN which lead to the discovery that precursors several steps ahead in the process could avoid the inhibition caused by Nicotinamide. Since NMN is both expensive and apparently required injection because of how it was broken down orally, the only precursor prior to that was NR, which could be taken orally. 

 

Some on this thread would argue that Na is sufficient but there are problems with it raising homocysteine levels. Whether NR results in the same remains to be seen and from reports, it is sounding like it doesn't have that problem. I'd go back through this whole thread because the details and references are linked all throughout, you can also do a search for it on the search function in the upper right. Also this Google search reveals a lot.

 

Edited by Nate-2004, 25 July 2016 - 07:47 PM.

[playground]

Thanks Nate

 

I found this blog post very interesting on the whole niacin & nicotinamide supplementation issue.

 

http://www.anti-agin...od-or-bad-idea/

 

Okay.. if we cant mega dose nicotinamide nor niacin... how about Tryptophan ?

 

Where are the Tryptophan mega dose horror stories ?

Edited by playground, 25 July 2016 - 10:52 PM.

[mikeinnaples]

 

 

 

The problem is that Nicotinamide by itself inhibits Sirtuins which defeats the whole point of increasing NAD+

 

You don't wanna take that pathway. There are multiple pathways and that's the worst one.

 

 

Really ?  Thanks for mentioning that.

Do you have a handy reference (or two, or three) about that ?

I'd like to give it (or them) a good perusal.

 

Thanks Nate
 

 

 

Yes that was the reason for experimenting with NMN which lead to the discovery that precursors several steps ahead in the process could avoid the inhibition caused by Nicotinamide. Since NMN is both expensive and apparently required injection because of how it was broken down orally, the only precursor prior to that was NR, which could be taken orally. 

 

Some on this thread would argue that Na is sufficient but there are problems with it raising homocysteine levels. Whether NR results in the same remains to be seen and from reports, it is sounding like it doesn't have that problem. I'd go back through this whole thread because the details and references are linked all throughout, you can also do a search for it on the search function in the upper right. Also this Google search reveals a lot.

 

 

 

The homocysteine issue is with Na more than manageable and the flush can be mitigated easily as well. There are some pretty good reads in the forums on that.

 

Edit: Also the liver issue is really more of a non-issue with immediate release Niacin, assuming healthy liver of course. The vast majority of liver related issues were with the time release formulas
 

Edited by mikeinnaples, 26 July 2016 - 02:30 PM.

[Nate-2004]

Thanks Nate

 

I found this blog post very interesting on the whole niacin & nicotinamide supplementation issue.

 

http://www.anti-agin...od-or-bad-idea/

 

Okay.. if we cant mega dose nicotinamide nor niacin... how about Tryptophan ?

 

Where are the Tryptophan mega dose horror stories ?

 

Wait, so according to this, niacinamide *is* nicotinamide? Well that's no good, this is the type they use in the B complex I take, though it's a very small amount, less than 50mg, possibly 25mg. Not only that it's in my face wash and CeraVe face moisturizer. 

Edited by Nate-2004, 26 July 2016 - 02:56 PM.

[Tom Andre F. (ex shinobi)]

yes niacinamide is nicotinamide. And NR is converted also directly into niacinamide via enzymes. so there is a part of NR that will be converted into NMN via NRK1, 2 and another part that is converted to niacinamide.

 

Nicotinic acid in the other hand does not convert into niacinamide, at least not directly. Mix the 2 are a good option to reach all tissue. Or someone should put his hand on nicotinic acic riboside that use the same kinase as NR and has some fraction converted into Niacin instead of niacinamide. But problem comes with patent, chromadex owns NR patent and invested millions in NR research while I do not remember who owns patent for Nicotinic acid riboside ?

[playground]

yes niacinamide is nicotinamide. And NR is converted also directly into niacinamide via enzymes. so there is a part of NR that will be converted into NMN via NRK1, 2 and another part that is converted to niacinamide.

 

Nicotinic acid in the other hand does not convert into niacinamide, at least not directly. Mix the 2 are a good option to reach all tissue. Or someone should put his hand on nicotinic acic riboside that use the same kinase as NR and has some fraction converted into Niacin instead of niacinamide. But problem comes with patent, chromadex owns NR patent and invested millions in NR research while I do not remember who owns patent for Nicotinic acid riboside ?

 

hmmm...    are you _sure_  niacin (nicotinic acid) doesn't convert into nicotinamide (niacinamide) once ingested ?

 

It was only yesterday that i got through reading a lengthy blog which asserts that niacin turns into

nicotinamide in the body... and hence, any evils of nicotinamide are transmitted to niacin.

 

Or maybe the proportion of, say, a 100 mg volume of niacin that converts into nicotinamide is minor ?

Does anyone have any conversion rate numbers ?

 

Here's the blog in question: 

 

http://www.anti-agin...od-or-bad-idea/

Edited by playground, 26 July 2016 - 03:20 PM.

[Nate-2004]

 

yes niacinamide is nicotinamide. And NR is converted also directly into niacinamide via enzymes. so there is a part of NR that will be converted into NMN via NRK1, 2 and another part that is converted to niacinamide.

 

Nicotinic acid in the other hand does not convert into niacinamide, at least not directly. Mix the 2 are a good option to reach all tissue. Or someone should put his hand on nicotinic acic riboside that use the same kinase as NR and has some fraction converted into Niacin instead of niacinamide. But problem comes with patent, chromadex owns NR patent and invested millions in NR research while I do not remember who owns patent for Nicotinic acid riboside ?

 

hmmm...    are you _sure_  niacin (nicotinic acid) doesn't convert into nicotinamide (niacinamide) ?

 

It was only yesterday that i got through reading a lengthy blog which asserts that niacin turns into

nicotinamide in the body... and hence, any evils of nicotinamide are transmitted to niacin.

 

Here's the blog in question: 

 

http://www.anti-agin...od-or-bad-idea/

 

 

This leads me to wonder why nicotinamide is said to help with skin and is put in face creams and washes. It also makes me wonder whether NR can be absorbed into skin and whether that would have the same or better effect seen in dermatology studies.

[playground]

 

This leads me to wonder why nicotinamide is said to help with skin and is put in face creams and washes. It also makes me wonder whether NR can be absorbed into skin and whether that would have the same or better effect seen in dermatology studies.

 

 

What an excellent question. 

I have recently read some articles talking about niacin in skin creams.

So your question is a good one.

 

My follow up question is, what base would you put the niacin into.

Would it be a cream or a gel ?

In other words, what cream or gel  is 'face cream/gel' or 'skin cream/gel' ?

It would be fun to make my own.

 

 

Taking this further....

I wonder if NMN can be absorbed dermally.

Wouldn't that side step the oral administration problem ?

Again, we'd need to know what gel or cream would help

transmit the NMN through the skin.

 

 

 

 

[samstersam]

 

 

This leads me to wonder why nicotinamide is said to help with skin and is put in face creams and washes. It also makes me wonder whether NR can be absorbed into skin and whether that would have the same or better effect seen in dermatology studies.

 

 

What an excellent question. 

I have recently read some articles talking about niacin in skin creams.

So your question is a good one.

 

My follow up question is, what base would you put the niacin into.

Would it be a cream or a gel ?

In other words, what cream or gel  is 'face cream/gel' or 'skin cream/gel' ?

It would be fun to make my own.

 

 

Taking this further....

I wonder if NMN can be absorbed dermally.

Wouldn't that side step the oral administration problem ?

Again, we'd need to know what gel or cream would help

transmit the NMN through the skin.

 

 

 

Playground, I had some extra niacinamide/nicotinamide that I no longer wanted to orally supplement and asked the exact same thing regarding topical application and got a wonderful answer from one of our members:

 

http://www.longecity...orbing-vehicle/

 

Also regarding the possibility of going systemic after topical absorption, I think it would be far less than oral ingestion and not a big concern unless you were megadosing or using a very powerful vehicle like DMSO. But at the amounts used to generate a 5% topical solution, the possible amounts going systemic would be trivial I think.

 

Edited by samstersam, 26 July 2016 - 03:38 PM.

[Nate-2004]

 

 

This leads me to wonder why nicotinamide is said to help with skin and is put in face creams and washes. It also makes me wonder whether NR can be absorbed into skin and whether that would have the same or better effect seen in dermatology studies.

 

 

What an excellent question. 

I have recently read some articles talking about niacin in skin creams.

So your question is a good one.

 

My follow up question is, what base would you put the niacin into.

Would it be a cream or a gel ?

In other words, what cream or gel  is 'face cream/gel' or 'skin cream/gel' ?

It would be fun to make my own.

 

 

Taking this further....

I wonder if NMN can be absorbed dermally.

Wouldn't that side step the oral administration problem ?

Again, we'd need to know what gel or cream would help

transmit the NMN through the skin.

 

 

 

Well I would probably put Nicotinamide Riboside (not niacin) in hyaluronic acid gel (EDITED). I wonder the same about NMN. This is all speculation though, I dunno if it would work the same as niacinamide and I don't know why NAM works that way on skin.

 

CereVe puts it in their face cream along with a variety of ceramides.

 

EDIT: I just learned from the thread linked above that Niacin and probably Nicotinamide Riboside is hydrophilic. So I'd need to put it in hyaluronic acid instead.

Edited by Nate-2004, 26 July 2016 - 04:37 PM.

[Harkijn]

One of the issues of some concern to me is the fact that NAD+ (and SIRT1, for that matter) are modulated in a circadian manner. That is: we want to  boost it but not all the time.

Since Bryan perhaps enjoys a well deserved holiday, I take the liberty to point to:

 

http://www.timelessl...-somatic-cells/

 

This article does not provide simple answers but gives me some more insight in NADboosting and the possible role of NR in it.

[Bryan_S]

I'm here monitoring, not on vacation.

 

The water solubility aspect of NR is being explored for skin products and gels. The P&G Chromadex relationship has outlined this. "Stable forms of Niagen nicotinamide riboside" Here is another investor announcement. The NR we buy in capsules is stabilized as a salt. This is a common practice to stabilize synthesized molecules. Once water is added the clock begins ticking and the stability is around 6-hours after which it begins to break down. This was a hard lesson learned when Basis from Elysium Health first introduced their product. So to put NR into a skin cream, ship it, put it on a shelf for a consumer would defeat the whole purpose of including it in a "wet" formulation in the first place.

 

Now if you want to gather up the studies trying to reconcile advancements in this area I believe studies like "Nicotinamide Riboside Is a Major NAD+ Precursor Vitamin in Cow Milk." represents the beginnings of how and why NR remains stable in Milk.

 

 

[Bryan_S]

Two for the Price of One: A Neuroprotective Chaperone Kit within NAD Synthase Protein NMNAT2

http://journals.plos...bio.1002522.PDF

 

Abstract

One of the most fascinating properties of the brain is the ability to function smoothly across decades of a lifespan. Neurons are nondividing mature cells specialized in fast electrical and chemical communication at synapses. Often, neurons and synapses operate at high levels of activity through sophisticated arborizations of long axons and dendrites that never- theless stay healthy throughout years. On the other hand, aging and activity-dependent stress strike onto the protein machineries turning proteins unfolded and prone to form path- ological aggregates associated with neurodegeneration. How do neurons protect from those insults and remain healthy for their whole life? Ali and colleagues now present a molecular mechanism by which the enzyme nicotinamide mononucleotide adenylyltransfer- ase 2 (NMNAT2) acts not only as a NAD synthase involved in axonal maintenance but as a molecular chaperone helping neurons to overcome protein unfolding and protein aggregation. 

 

[playground]

Safety Assessment of NR published using 100, 300, 1000 & 3000 mg dosages.

But notice, these dosages are per KG of body weight, per day.  Not a simply X mg dose.

(This safety assessment involved lab rats)

 

http://www.timelessl...side-published/

 

 

The lowest dosage at which an adverse event was noticed as 1000mg / per KG / per day.

 

NR is approximately as safe, or as toxic,  as nicotinamide :

 

It should be also noted that the research mentions the safety profile to be similar to nicotinamide (also called niacinamide). Nicotinamide is typically rated as LIKELY SAFE with the note that at dosing above 3 grams / day serious side effect can occur: liver problems, gout, ulcers of the digestive tract, loss of vision, high blood sugar, irregular heartbeat, and other serious problems.

 

 

 

So....  wont be long before everyone's popping gram quantities.  :-)

[playground]

 

Playground, I had some extra niacinamide/nicotinamide that I no longer wanted to orally supplement and asked the exact same thing regarding topical application and got a wonderful answer from one of our members:

 

http://www.longecity...orbing-vehicle/

 

Also regarding the possibility of going systemic after topical absorption, I think it would be far less than oral ingestion and not a big concern unless you were megadosing or using a very powerful vehicle like DMSO. But at the amounts used to generate a 5% topical solution, the possible amounts going systemic would be trivial I think.

 

 

Thanks samstersam,  very useful

[Nate-2004]

I'm here monitoring, not on vacation.

 

The water solubility aspect of NR is being explored for skin products and gels. The P&G Chromadex relationship has outlined this. "Stable forms of Niagen nicotinamide riboside" Here is another investor announcement. The NR we buy in capsules is stabilized as a salt. This is a common practice to stabilize synthesized molecules. Once water is added the clock begins ticking and the stability is around 6-hours after which it begins to break down. This was a hard lesson learned when Basis from Elysium Health first introduced their product. So to put NR into a skin cream, ship it, put it on a shelf for a consumer would defeat the whole purpose of including it in a "wet" formulation in the first place.

 

Now if you want to gather up the studies trying to reconcile advancements in this area I believe studies like "Nicotinamide Riboside Is a Major NAD+ Precursor Vitamin in Cow Milk." represents the beginnings of how and why NR remains stable in Milk.

 

What does it begin to break down into? I wonder what is in the milk that's stabilizing it? It mentions that non-organic contains more NR than Organic, maybe it's something to do with hormones or antibiotics? 

[Tom Andre F. (ex shinobi)]

 

yes niacinamide is nicotinamide. And NR is converted also directly into niacinamide via enzymes. so there is a part of NR that will be converted into NMN via NRK1, 2 and another part that is converted to niacinamide.

 

Nicotinic acid in the other hand does not convert into niacinamide, at least not directly. Mix the 2 are a good option to reach all tissue. Or someone should put his hand on nicotinic acic riboside that use the same kinase as NR and has some fraction converted into Niacin instead of niacinamide. But problem comes with patent, chromadex owns NR patent and invested millions in NR research while I do not remember who owns patent for Nicotinic acid riboside ?

 

hmmm...    are you _sure_  niacin (nicotinic acid) doesn't convert into nicotinamide (niacinamide) once ingested ?

 

It was only yesterday that i got through reading a lengthy blog which asserts that niacin turns into

nicotinamide in the body... and hence, any evils of nicotinamide are transmitted to niacin.

 

Or maybe the proportion of, say, a 100 mg volume of niacin that converts into nicotinamide is minor ?

Does anyone have any conversion rate numbers ?

 

Here's the blog in question: 

 

http://www.anti-agin...od-or-bad-idea/

 

 

Not possible. Nicotinic acid cant be converted into niacinamide, at least not directly (because then NAD+ release niacinamide).

 

Its actually the opposite that may occur : niacinamide being converted into nicotinic acid by bacterial nicotinamidase

 

However I noticed most studies confuse the 2: they call also nicotinamide : niacin. So better now to say nicotinic acid to make sure of what we speak about

 

Edited by Tom Andre F. (ex shinobi), 26 July 2016 - 07:07 PM.

[playground]

I just want to check my understanding of the legal issues around

buying a patented chemical....

 

My understanding is...  that to patent chemical X gives company Y

the sole rights to supply chemical X.

So this is a law granting a monopoly to company Y.

 

If company Z comes along and tries to supply ... me...  with

chemical X... then company Y can complain to the courts about company Z.

 

Importantly,... a retail customer,... is under no legal threats.

There's no laws against my possession of Chemical X and there

are no laws forbidding me from buying from company Z.

 

That's right, isn't it ?

 

So for example, if I happen to find an Asian supplier of NR then

i have no legal worries about being sued.

 

However, if i order 10 Kilos and try to sell my surplus.. then i'm

in potential legal jeopardy.

 

Is my thinking on this correct ?

 

Edited by playground, 26 July 2016 - 07:14 PM.

[playground]

 

 

hmmm...    are you _sure_  niacin (nicotinic acid) doesn't convert into nicotinamide (niacinamide) once ingested ?

 

It was only yesterday that i got through reading a lengthy blog which asserts that niacin turns into

nicotinamide in the body... and hence, any evils of nicotinamide are transmitted to niacin.

 

Or maybe the proportion of, say, a 100 mg volume of niacin that converts into nicotinamide is minor ?

Does anyone have any conversion rate numbers ?

 

Here's the blog in question: 

 

http://www.anti-agin...od-or-bad-idea/

 

 

Not possible. Nicotinic acid cant be converted into niacinamide, at least not directly (because then NAD+ release niacinamide).

 

Its actually the opposite that may occur : niacinamide being converted into nicotinic acid by bacterial nicotinamidase

 

However I noticed most studies confuse the 2: they call also nicotinamide : niacin. So better now to say nicotinic acid to make sure of what we speak about
 

 

I might take up this point with the author of the cited blog  "anti-agingfirewalls.com".

 

I would be most grateful, Tom, if you could offer me a reference or two to read

which supports your assertion that niacin (nicotinic acid) doesn't convert into nicotinamide in vivo.

 

It's an important point because.. the implications is that.... 

we can supplement some quantity of niacin for NAD+ enhancement.

 

(yes.. i know there's an ancillary issue relating to niacin & homocysteine)

 

Thanks Tom

 

[Tom Andre F. (ex shinobi)]

I posted the full paper a few page ago.. where I spoke about kinase that can convert NR are not expressed in all tissue. Sorry i dont have saved them as PDF on my pc.. Its something I should do actually because every time new debate comes up we have to show reference. If I have time tommorow will check for you. For homocysteine also I posted data. Its due to methylation process, so even NR wich have a niacinamide part should have an impact on homocysteine, but this shouldnt be a concern as far as one consume B6, folate and B12, there is a thread about this topic also in this supplement forum section. Some even showed from a person to another many mutations can happen. But Im really not an expert into that.

[Kirito]

"Energy uptake and expenditure also impact on the circadian clock mechanism.

Binding of the BMAL1/CLOCK or BMAL1/NPAS2 heterodimer to their cognate

E-box sequence in clock gene or clock-controlled gene (CCG) promoters (Fig. 2) is

sensitive to the NAD(P)/NAD(P)H ratio (Rutter et al. 2001) that is determined by

metabolic status. Because nicotinamide phosphoribosyltransferase (NAMPT, the rate-limiting enzyme in the NAD

salvage pathway) is transcriptionally regulated by the circadian clock, NAD

levels oscillate in the cytosol and probably also in the nucleus in a daily fashion (Nakahata et al. 2009; Ramsey et al. 2009). Disruption of the NAD oscillation by mutating the NAD hydrolase CD38 altered behavioral

and metabolic circadian rhythms (Sahar et al. 2011). CD38 deficient mice showed

a shortened circadian period and alterations in plasma amino acid levels. This

may contribute to abnormal brain function, because many amino acids including

tryptophan, tyrosine, and glutamate are precursors of neurotransmitters or are

neurotransmitters, respectively."

 

https://www.unifr.ch...lbrecht2013.pdf

[midas]

Safety Assessment of NR published using 100, 300, 1000 & 3000 mg dosages.

But notice, these dosages are per KG of body weight, per day.  Not a simply X mg dose.

(This safety assessment involved lab rats)

 

http://www.timelessl...side-published/

 

 

The lowest dosage at which an adverse event was noticed as 1000mg / per KG / per day.

 

NR is approximately as safe, or as toxic,  as nicotinamide :

 

It should be also noted that the research mentions the safety profile to be similar to nicotinamide (also called niacinamide). Nicotinamide is typically rated as LIKELY SAFE with the note that at dosing above 3 grams / day serious side effect can occur: liver problems, gout, ulcers of the digestive tract, loss of vision, high blood sugar, irregular heartbeat, and other serious problems.

 

 

 

So....  wont be long before everyone's popping gram quantities.  :-)

 

I'm not sure if you have read this thread from the begining as you seem to be posting stuff that has been posted before, so in case you missed this...... http://globenewswire...nd-is-Safe.html

[playground]

 

I'm not sure if you have read this thread from the begining as you seem to be posting stuff that has been posted before, so in case you missed this...... http://globenewswire...nd-is-Safe.html

 

 

You're right.. I skimmed only the last few pages of this thread. 

Thanks Midas.   I hadn't see that paper before.

 

[Bryan_S]

Resveratrol appears to restore blood-brain barrier integrity in Alzheimer's disease

http://medicalxpress...er-disease.html

 

I wonder if the same can be said of pterostilbene? Maybe I'll keep my pterostilbene regiment going for a little longer.

 

Edit:

Interesting how someone might think a SIRT1 activator article to be off topic. Also Resveratrol and pterostilbene have been consistent topics on this thread.

 

"Previous studies with animals found that age-related diseases—including Alzheimer's—can be prevented or delayed by long-term caloric restriction (consuming two-thirds the normal caloric intake). The researchers studied resveratrol because it mimics the effects of caloric restriction by also activating proteins called sirtuins.

In this new study, Moussa and Turner found that treated patients had a 50 percent reduction in matrix metalloproteinase-9 (MMP-9) levels in the cerebrospinal fluid. MMP-9 is decreased when sirtuin1 (SIRT1) is activated. High levels of MMP-9 cause a breakdown in the blood-brain barrier, allowing proteins and molecules from the body to enter the brain. Normally low MMP-9 levels maintain the barrier, say the researchers.

"These new findings are exciting because they increase our understanding of how resveratrol may be clinically beneficial to individuals with Alzheimer's disease. In particular, they point to the important role of inflammation in the disease, and the potent anti-inflammatory effects of resveratrol," says Turner, director of GUMC's Memory Disorders Program and co-director of the Translational Neurotherapeutics Program.

They also found that resveratrol increased the level of molecules linked to a long-term beneficial or "adaptive" immune reaction, suggesting involvement of inflammatory cells that are resident in the brain, says Moussa. "This is the kind of immune response you want—it is there to remove and degrade neurotoxic proteins."

"A puzzling finding from the resveratrol study (as well as immunotherapy strategies for Alzheimer's under investigation) is the greater shrinkage of the brain found with treatment. These new findings support the notion that resveratrol decreases swelling that results from inflammation in Alzheimer's brain," says Turner. "This seemingly paradoxical effect is also found with many of the drugs that are beneficial for patients with multiple sclerosis—another brain disease characterized by excessive inflammation.""

 

Study Link http://www.neurology...85/16/1383.full

Edited by Bryan_S, 11 October 2016 - 09:26 PM.

[stefan_001]

Resveratrol appears to restore blood-brain barrier integrity in Alzheimer's disease

http://medicalxpress...er-disease.html

 

I wonder if the same can be said of pterostilbene? Maybe I'll keep my pterostilbene regiment going for a little longer.

 

Thats an interesting study, you may be right as SIRT1 seems to be involved:

In this new study, Moussa and Turner found that treated patients had a 50 percent reduction in matrix metalloproteinase-9 (MMP-9) levels in the cerebrospinal fluid. MMP-9 is decreased when sirtuin1 (SIRT1) is activated.

[Bryan_S]

Emerging therapeutic roles for NAD+ metabolism in mitochondrial and age-related disorders

http://clintransmed....0169-016-0104-7 This article is open access.

• Sarika Srivastava

Clinical and Translational Medicine20165:25

DOI: 10.1186/s40169-016-0104-7

©  The Author(s) 2016

Received: 12 February 2016

Accepted: 26 June 2016

Published: 27 July 2016

 

 

Abstract

Nicotinamide adenine dinucleotide (NAD+) is a central metabolic cofactor in eukaryotic cells that plays a critical role in regulating cellular metabolism and energy homeostasis. NAD+ in its reduced form (i.e. NADH) serves as the primary electron donor in mitochondrial respiratory chain, which involves adenosine triphosphate production by oxidative phosphorylation. The NAD+/NADH ratio also regulates the activity of various metabolic pathway enzymes such as those involved in glycolysis, Kreb’s cycle, and fatty acid oxidation. Intracellular NAD+ is synthesized de novo from l-tryptophan, although its main source of synthesis is through salvage pathways from dietary niacin as precursors. NAD+ is utilized by various proteins including sirtuins, poly ADP-ribose polymerases (PARPs) and cyclic ADP-ribose synthases. The NAD+ pool is thus set by a critical balance between NAD+ biosynthetic and NAD+consuming pathways. Raising cellular NAD+ content by inducing its biosynthesis or inhibiting the activity of PARP and cADP-ribose synthases via genetic or pharmacological means lead to sirtuins activation. Sirtuins modulate distinct metabolic, energetic and stress response pathways, and through their activation, NAD+ directly links the cellular redox state with signaling and transcriptional events. NAD+ levels decline with mitochondrial dysfunction and reduced NAD+/NADH ratio is implicated in mitochondrial disorders, various age-related pathologies as well as during aging. Here, I will provide an overview of the current knowledge on NAD+ metabolism including its biosynthesis, utilization, compartmentalization and role in the regulation of metabolic homoeostasis. I will further discuss how augmenting intracellular NAD+ content increases oxidative metabolism to prevent bioenergetic and functional decline in multiple models of mitochondrial diseases and age-related disorders, and how this knowledge could be translated to the clinic for human relevance.

 

Edited by Bryan_S, 28 July 2016 - 01:51 AM.

[Bryan_S]

Restoration of Mitochondrial NAD+ Levels Delays Stem Cell Senescence and Facilitates Reprogramming of Aged Somatic Cells.

Son MJ1,2, Kwon Y1,2, Son T3, Cho YS1,2.

 

Stem Cells. 2016 Jul 18. doi: 10.1002/stem.2460. [Epub ahead of print]

 

Abstract

The fundamental tenet that aging is irreversible has been challenged by the development of reprogramming technology that can restore molecular and cellular age by reversing the progression of aging. The use of cells from aged individuals as sources for reprogramming or transplantation creates a major barrier in stem cell therapy with respect to cell quality and quantity. Here, we investigated the molecular features underlying senescence and rejuvenation during aged cell reprogramming and identified novel factors that can overcome age-associated barriers. Enzymes, such as nicotinamide nucleotide transhydrogenase (NNT) and nicotinamide mononucleotide adenylyltransferase 3 (NMNAT3), that control mitochondrial NAD+ levels appear to be susceptible to aging. In aged cells, mitochondrial NAD+ levels decrease, accompanied by reduced SIRT3 activity; these changes severely impede cell fate transition. However, in cells collected from aged p16 knockout mice, which exhibit delayed cellular senescence, no changes in NNT or NMNAT3 expression were found. Importantly, restoring mitochondrial NAD+ levels by overexpressing NNT and NMNAT3 enhanced reprogramming efficiency of aged somatic cells and extended the lifespan of human mesenchymal stem cells by delaying replicative senescence. These results demonstrate that maintenance of mitochondrial NAD+ levels is critical for reversing the mechanisms of aging and ensuring that cells collected from aged individuals are of high quality. Stem Cells 2016.

 

Conclusion

Our data indicate that enzymes, such as NNT and NMNAT3, that control mitochondrial NAD+ levels ap‐ pear to be susceptible to aging. Importantly, the recov‐ ery of mitochondrial NAD+ levels by NNT or NMNAT3 overexpression facilitates reprogramming efficiency of aged somatic cells and extends the lifespan of MSCs by delaying replicative senescence. Ultimately, maintaining a controlled metabolic environment may help over‐ come age‐associated barriers in patient‐specific stem cell reprogramming and restore cellular age. 

 

[Bryan_S]

Skeletal muscle mitochondria as a target to prevent or treat type 2 diabetes mellitus

http://www.nature.co...o.2016.104.html

Matthijs K. C. Hesselink, Vera Schrauwen-Hinderling & Patrick Schrauwen

AffiliationsContributionsCorresponding author

Nature Reviews Endocrinology (2016) doi:10.1038/nrendo.2016.104

 

Published online 22 July 2016

 

Abstract

 

Low levels of physical activity and the presence of obesity are associated with mitochondrial dysfunction. In addition, mitochondrial dysfunction has been associated with the development of insulin resistance and type 2 diabetes mellitus (T2DM). Although the evidence for a causal relationship between mitochondrial function and insulin resistance is still weak, emerging evidence indicates that boosting mitochondrial function might be beneficial to patient health. Exercise training is probably the most recognized promoter of mitochondrial function and insulin sensitivity and hence is still regarded as the best strategy to prevent and treat T2DM. Animal data, however, have revealed several new insights into the regulation of mitochondrial metabolism, and novel targets for interventions to boost mitochondrial function have emerged. Importantly, many of these targets seem to be regulated by factors such as nutrition, ambient temperature and circadian rhythms, which provides a basis for nonpharmacological strategies to prevent or treat T2DM in humans. Here, we will review the current evidence that mitochondrial function can be targeted therapeutically to improve insulin sensitivity and to prevent T2DM, focusing mainly on human intervention studies.

 

In a more direct way to affect mitochondrial meta- bolism, NAD+ levels could be increased by supplementation of the natural NAD+ precursor nicotinamide riboside. In mice, this approach resulted in improved oxidative capacity and alleviation of high-fat-diet-induced metabolic aberrations116, and both prevented and reverted development of nonalcoholic fatty liver disease in mice via induction of an imbalance in mitochondrial-encoded proteins compared with nuclear-encoded mitochondrial proteins in a SIRT1 and SIRT3-dependent manner117. The likelihood that nicotinamide riboside supplementation is also beneficial for humans was underscored by a 2015 paper that reported ex vivo nicotinamide riboside treatment of peripheral blood mononuclear cells from healthy volunteers, which revealed increased mitochondrial respiratory capacity, increased antioxidant capacity and reduced mitochondrial ROS production upon nicotinamide riboside treatment118. Furthermore, using an indirect approach, our group showed that boosting NAD+ levels via the NAD+ precursor acipimox robustly induced an imbalance in mitochondrial-encoded and nuclear-encoded mitochondrial proteins and improved muscle mitochondrial respiration in patients with T2DM119. Clearly, more human intervention studies are needed to reveal the true potential of targeting the AMPK–NAD+– SIRT1 pathway (FIG. 3) to improve insulin sensitivity, but the data available so far are certainly promising. 

 

Conclusion and future perspectives

 

The association between mitochondrial function and insulin sensitivity has been well established and ample evidence exists that boosting mitochondrial function improves whole-body and skeletal muscle insulin sen- sitivity and glucose homeostasis, at least in mice and rats. Albeit more limited in number than animal model studies, most human studies also provide compelling evidence that therapeutically targeting mitochondria to improve insulin sensitivity is a promising route. Importantly, mitochondria are central in the regulation of human cellular metabolism and cells relevant to meta- bolic control are equipped with robust regulatory path- ways enabling them to adapt mitochondrial metabolism to cellular conditions and demands. These findings identify mitochondria as targets for pharmacological or exercise interventions to treat T2DM, and also suggest that these organelles can be manipulated by lifestyle factors such as nutrition, environmental temperature and circadian rhythms. Despite the abundance of animal data, mechanistic human clinical intervention studies to target the diverse aspects of mitochondrial function in the treatment or prevention of T2DM are still limited, but urgently awaited.

[Tom Andre F. (ex shinobi)]

Im not sure this was already discussed: but NAM seems to have some benefits instead of just NAD+ salvage pathway:

 

from the study : Nicotinamide Overcomes Pluripotency Deficits and Reprogramming Barriers

 

Supplemental NAM, but not other NAD+ precursors, greatly enhances the efficiency and kinetics of hiPSC generation

 

Importantly, among the NAD (because they also used NAD+ directly to show it was not dependent) and NAD+ precursors evaluated, NAM alone remarkably increased the number of AP+ colonies compared to untreated controls

 

Nicotinic acid was better than NAM to increase NAD+

 

We further confirmed that NAM not only increased the reprogramming efficiency but also accelerated the reprogramming time course compared to untreated controls. With NAM supplementation, Nanog+ and Tra-1-60+ clusters were detected after a relatively short period of reprogramming (8-10 days after transduction), whereas their appearance was delayed by 4-5 days in untreated controls (Fig. 4Aa). Increased numbers of Nanog+ and Tra-1- 60+ clusters, up to 3-fold and 8-fold, espectively, were observed at 10 days after
transduction in NAM-treated cells compared to untreated controls

 

Consistently, higher mRNA expression levels of the pluripotency markers Nanog and TERT were detected in NAM-treated cells compared to untreated controls

 

NAM increases the proliferation rate and lowers the apoptosis rate during the reprogramming process

 

NAM alleviates pro-senescence phenotypes triggered by OSKM reprogramming factor

 

NAM potentially down-regulates p53, p16INK4a, and p21CIP1, the active barriers to reprogramming

 

blocking NAMPT activity with the pharmacological inhibitor FK866 induces premature senescence by suppressing SIRT1-mediated p53 degradation (probably due to increased free NAM ?)

 

Any thought ?

 

[Nate-2004]

Nice but NAM still has the problem of inhibiting SIRT1 right?