529 replies to this topic

[aaaaaaal]

Not yet. They will sell a form mixed with resveratrol
https://www.biotivia..._antiaging.html

I am ordering niagen

Not yet? Yes, you can. Click on the "Reserve now" button.

And it's not mixed with resveratrol. It's a 30 day regimen which includes Transmax and Biospan as seperate products.

[Ukko]

Hi all,

This is my first post here and I'm a bit of a novice, but really just want to learn more about NAD+ production and this cycle in general. The only advice I had gotten prior to reading this thread was to take NADH... which appears to be terrible advice .

Now for the brain pain. A prior member spoke of MTHF mutations, which I unfortunately am afflicted with. Both genes too. Luckily, this was caught and I am thus taking 20mg of 5-MTHF daily, (yay for compounding pharmacies.) It's helped a little with my permanent brain fog, but most of the initial overly positive effects have mellowed. Anyways, I was reading here that, in likewise affected people, taking supplements like Nicotinamide Riboside can actually make this methylation issue worse? Apologies if I'm misunderstanding.

I also take a B-Complex that has 80mg of Niacinamide as it's active form of Niacin. There's conversation here that niacinamide also causes issues, so are there other supplements to be worried about?

You are essentially restating some of my concerns re long term niacin supplementation. I would certainly stay away from niacinamide, minimize it even in multivitamins. The chain that recycles nicotinamide back to NAD+ gets easily saturated AND the excess niacinamide hanging around will serve as a signal to limit the efficiency of other NAD+ production paths. Thus, it is not surprising that nicotinamide has issues with liver toxicity and may well play a key role in the western obesity and diabetes epidemic as niacinamide has been added to flours. Niacinamide is just one breakdown product in the NAD+ chain. It is a very artificial thing to boost such intermediary, the level of which is normally fairly stable in the body. Niacin, i.e. plain old rash producing nicotinic acid is better. And niacinamide riboside is seemingly quite intriguing, as it involves a third recently found path to NAD+ production in mammals.

As so methylation, well that is my long term concern too. Niacin and NAD+ metabolism seems to be very taxing on the body's methylation capacity. Now, that can be good I guess if one is an overmethylator but an undermethylator like you might be worse off. Still looking for an answer to that myself.

GO HAWKS !!! #25

[geo12the]

Some musings from a non-expert but science person:

The Sinclair paper seems to focus on the interaction of NAD and SIRT1, but the function of NAD is more complex. NAD+ and NADH are the two forms of NAD. NAD is an oxidant (electron acceptor) and NADH is a reductant (electron donor). NAD+ and NADH function in regulating metabolic reactions by accepting (NAD+) or donating (NADH) electrons. NADH is converted to NAD+ when it gives up electrons and vice versa. The thing I wonder is if the physiological effects of NAD supplementation are not solely due to SIRT1 but also the metabolic effects of increasing NAD+.

This paper suggests that altering the ratio by increasing the amount of NAD relative to NADH is a good thing:

http://www.ncbi.nlm....one.0047122.pdf

The other related molecules are the phosphorylated forms NADP and NADPH. NAD+/NADH are believed to function more in catabolism (break down) in metabolic reactions and NADP/NADPH are believed to function more in anabolism (building up). So its very complicated, If you ingest NAD you are ingesting an oxidant which I would think is bad for you. As far as I know no one is feeding NADP or NADPH to mice.

[Dimmy]

You are essentially restating some of my concerns re long term niacin supplementation. I would certainly stay away from niacinamide, minimize it even in multivitamins. The chain that recycles nicotinamide back to NAD+ gets easily saturated AND the excess niacinamide hanging around will serve as a signal to limit the efficiency of other NAD+ production paths. Thus, it is not surprising that nicotinamide has issues with liver toxicity and may well play a key role in the western obesity and diabetes epidemic as niacinamide has been added to flours. Niacinamide is just one breakdown product in the NAD+ chain. It is a very artificial thing to boost such intermediary, the level of which is normally fairly stable in the body. Niacin, i.e. plain old rash producing nicotinic acid is better. And niacinamide riboside is seemingly quite intriguing, as it involves a third recently found path to NAD+ production in mammals.

As so methylation, well that is my long term concern too. Niacin and NAD+ metabolism seems to be very taxing on the body's methylation capacity. Now, that can be good I guess if one is an overmethylator but an undermethylator like you might be worse off. Still looking for an answer to that myself.

GO HAWKS !!! #25

Haha! Thanks! I'm excited for the game on Sunday .

Also, thank you for your response. I was worried I might not get one.

So, Since I'm afflicted with this methylation issue, (and thanks to your reply,) I realized that I might have more problems with methyl donors in my body then just the 5-MTHF could fix. Worried that this was the case, I went out and got some Trimethylglycine. I'm pleased/bewildered to report that anxiety levels plummeted in about 2-3 hours after taking it. Felt far more clear mentally then I have in years. Almost too relaxed, but I'll take it.

Why this applies to the conversation, is that even if you're an undermethylator, and consume substances that burn through what supplies you do have (Adderall in my case,) maybe you would be able to balance yourself out? I'm unsure if there is a feedback cycle to stop even this, but maybe it's a possible solution for the eventual supplementation/injection of NAD+ precursors in the affected?

Apologies if I'm missing something obvious, but I'm feeling optimistic .

[blood]

I went out and got some Trimethylglycine. I'm pleased/bewildered to report that anxiety levels plummeted in about 2-3 hours after taking it. Felt far more clear mentally then I have in years

Curious to know if you have tried small doses of SAMe?

[Dimmy]

Curious to know if you have tried small doses of SAMe?

I haven't, but I didn't do so because I read an article today (7 away from being able to link sites!) that was stating that SAMe might not be as effective in the long term? Have you heard anything like that?

[Darryl]

Two recent papers citing the CD38 inhibition approach:

Braidy, Nady, et al. "Mapping NAD+ metabolism in the brain of ageing Wistar rats: potential targets for influencing brain senescence." Biogerontology (2013): 1-22.

Among the multiple physiological pathways associated with NAD⁺ catabolism, our discovery of CD38 as the major regulator of cellular NAD⁺ levels in rat neurons indicates that CD38 is a promising therapeutic target for the treatment of age-related neurodegenerative diseases.

Dong, Jing, et al. "Quercetin reduces obesity-associated adipose tissue macrophage infiltration and inflammation in mice: a mechanism including AMPKα1/SIRT1." Journal of Lipid Research (2014): jlr-M038786.

Dietary quercetin also modified the phenotype ratio of M1/M2 macrophages, lowered the levels of pro-inflammatory cytokines, and enhanced AMPKα1 phosphorylation and SIRT1 expression in EAT. Further, using AMPK activator AICAR and inhibitor Compound C, we found that quercetin inhibited polarization and inflammation of mouse bone marrow-derived macrophage through an AMPKα1/SIRT1-mediated mechanism.
...
the effects of quercetin were similar to those of AMPK activator AICAR and could be blocked by AMPK inhibitor Compound C.

The results of co-administration of quercetin and Compound C on Nos2, IL-6, IL-1β expression (figure 6) are pretty interesting, as they suggest they indicate that about 30-70% of quercetin's effect results from AMPK induction, with other mechanisms (CD38 inhibition, alternative pathways to NF-κB inhibition (Nrf2 etc)) responsible for the remainder.

[Darryl]

I thought I had a reasonable NAD+/Sirt1 regimen with 500 mg nicotinic acid (2x daily) + 580 mg magnesium salicylate (2x daily) + plenty of berries & black rice + mild calorie restriction / exercise.

But:

Yang, Soo Jin, et al. "Nicotinamide improves glucose metabolism and affects the hepatic NAD-sirtuin pathway in a rodent model of obesity and type 2 diabetes." The Journal of nutritional biochemistry 25.1 (2014): 66-72.

Nicotinic acid (NA) and nicotinamide (NAM) are major forms of niacin and exert their physiological functions as precursors of nicotinamide adenine dinucleotide (NAD). Sirtuins, which are NAD-dependent deacetylases, regulate glucose and lipid metabolism and are implicated in the pathophysiology of aging, diabetes, and hepatic steatosis. The aim of this study was to investigate the effects of two NAD donors, NA and NAM, on glucose metabolism and the hepatic NAD-sirtuin pathway. The effects were investigated in OLETF rats, a rodent model of obesity and type 2 diabetes. OLETF rats were divided into five groups: (1) high fat (HF) diet, (2) HF diet and 10 mg NA/kg body weight (BW)/day (NA 10), (3) HF diet and 100 mg NA/kg BW/day (NA 100), (4) HF diet and 10 mg NAM/kg BW/day (NAM 10), and (5) HF diet and 100 mg NAM/kg BW/day (NAM 100). NA and NAM were delivered via drinking water for four weeks. NAM 100 treatment affected glucose control significantly, as shown by lower levels of accumulative area under the curve during oral glucose tolerance test, serum fasting glucose, serum fasting insulin, and homeostasis model assessment of insulin resistance, and higher levels of serum adiponectin. With regard to NAD-sirtuin pathway, intracellular nicotinamide phosphoribosyltransferase, NAD, the NAD/NADH ratio, Sirt1, 2, 3, and 6 mRNA expressions, and Sirt1 activity all increased in livers of NAM 100-treated rats. These alterations were accompanied by the increased levels of proliferator-activated receptor gamma, coactivator 1 alpha and mitochondrial DNA. The effect of NA treatment was less evident than that of NAM 100. These results demonstrate that NAM is more effective than NA on the regulation of glucose metabolism and the NAD-sirtuin pathway, which may relate to the altered mitochondrial biogenesis.

My concern with niacinamide is that 1) its NAD synthetic pathway is saturated at low doses in human cells, and 2) it functions as a negative-feedback inhibitor of the NAD⁺ases including the sirtuins. We definitely need some studies on pharmacological dose niacin and human erythrocyte NAD+ levels, statim.

Edited by Darryl, 07 February 2014 - 09:26 PM.

[Kevnzworld]

Thanks for the interesting articles and analysis Darryl.
I've eliminated niacinamide and substituted Niagen. I take 250 mg twice a day. I haven't " felt " anything but I didn't expect to. I am taking it to support increased levels of NAD per the Sinclair study etc.
I would be interested in hearing how and if others are taking this product.
I also found the concept of CD 38 inhibition interesting. I do take quercetin, and have begun taking a mixed berry poly phenol extract as well. My primary concern with that is possibly exceeding the level of what I consider a safe amount of exogenous polyphenol antioxidants.

[Ukko]

Haha! Thanks! I'm excited for the game on Sunday .

Also, thank you for your response. I was worried I might not get one.

So, Since I'm afflicted with this methylation issue, (and thanks to your reply,) I realized that I might have more problems with methyl donors in my body then just the 5-MTHF could fix. Worried that this was the case, I went out and got some Trimethylglycine. I'm pleased/bewildered to report that anxiety levels plummeted in about 2-3 hours after taking it. Felt far more clear mentally then I have in years. Almost too relaxed, but I'll take it.

Why this applies to the conversation, is that even if you're an undermethylator, and consume substances that burn through what supplies you do have (Adderall in my case,) maybe you would be able to balance yourself out? I'm unsure if there is a feedback cycle to stop even this, but maybe it's a possible solution for the eventual supplementation/injection of NAD+ precursors in the affected?

Apologies if I'm missing something obvious, but I'm feeling optimistic .

TMG is a substance I have used a lot. Initially due to it being a cheap SAMe booster. But I gave it up a while back when I heard that it raises cholesterol. Normally that is a proxy for an adverse impact on metabolism. Niacin lowers cholestrol, which is a good sign.

[Dallasboy]

So, Niagen Nicotinamide Riboside is the only supp out there right now? What about NOW NAD and NADH?

[APBT]

Current approaches to increasing NAD+ concentrations and sirtuin activation include
•provision of NAD+ precursors (nicotinic acid, nicotinamide riboside, injections of nicotinamide mononucleotide)
•AMPK induction to increase levels of NAD+ synthesis (exercise, fasting, aspirin, metformin, berberine, etc)
•CD38 inhibition (flavonoids especially luteolinidin, cyanidin-3-O-β-glucoside, and luteolin appear promising, see post 58)
•poly (ADP-ribose) polymerase-1 (PARP-1) inhibition.

This LEF product contains 2.2 mg of cyanidin-3-glucoside http://www.lef.org/V...ents/Item01685/

Sublingual consumption has been discussed. Would taking the Niagen product sublingually (by emptying a capsule contents under the tongue) achieve anything verses swallowing the capsule?

For those interested in picking up some Niagen (or any other supps) at a modest discount, Swanson has a coupon for $15 off any purchase of $75 or more, plus free shipping. The offer expires Tuesday 18 Feb at 11:59 PM (CST).
Enter promo code: HEART15

Edited by APBT, 18 February 2014 - 12:53 AM.

[Dimmy]

TMG is a substance I have used a lot. Initially due to it being a cheap SAMe booster. But I gave it up a while back when I heard that it raises cholesterol. Normally that is a proxy for an adverse impact on metabolism. Niacin lowers cholestrol, which is a good sign.

Hmm... interesting. The only studies I found, stated that the test subjects were on 6 grams of TMG daily, and that anything less than 6 grams didn't show any significant change?

I'm planning on trying some Niagen, and seeing whether or not an additional 1,000mg/daily of TMG, (currently taking 2,000mg/daily,) will suffice as a coupling. If I notice any ill effects, I would discontinue the Niagen immediately, but it seems like something that's worth a shot... especially since there doesn't seem to be a lot better options at the moment... At least for us undermethylators.

I noticed that NR didn't seem to be as much of a runaway bandit with methyl donors as Niacin is though... Not sure if that's entirely true, but it's the gist of what I got from a few articles that I still can't link heh... So, if that's true, maybe it would be a viable option. Any thoughts?

[Kevnzworld]

There are other methyl donors other than TMG...I used TMG once to lower my homocysteine....I prefer other methyl donors like methyl b 12, or 5 methyl folate....even MSM..
TMG didn't help me.

[timar]

This LEF product contains 2.2 mg of cyanidin-3-glucoside http://www.lef.org/V...ents/Item01685/

ROFL! That really doesn't keep me up at night. A single teaspoon (5 g) of dried, black aronia berries provides ~400 mg of cyanidin-3-glycosides*, which is roughly two hundred times(!) the ridiculously small amout contained in that LEF supplement.

As Darryl pointed out, black rice is another very potent source of cyanidin-3-glycosides, but you lose ~75% during cooking, which makes a cup of cooked black rice roughly equivalent to the said teaspoon of dried aronia berries.

If you are daring enough, you can also try my CD38-crushing Tabbouleh. Beware though, it packs quite a punch!

*consisting of cyanidin-3-galactoside, - glucoside, -arabinoside and -xylosite (source: Phenol-Explorer, calculated by fresh weight multiplied by 9 to to translate to dry weight (~1/10) and take account of losses during drying (~10%).

Edited by timar, 18 February 2014 - 12:33 PM.

[APBT]

This LEF product contains 2.2 mg of cyanidin-3-glucoside http://www.lef.org/V...ents/Item01685/

ROFL! That really doesn't keep me up at night. A single teaspoon (5 g) of dried, black aronia berries provides ~400 mg of cyanidin-3-glycosides*, which is roughly two hundred times(!) the ridiculously small amout contained in that LEF supplement.

Ah yes, right you are. That's why reading more carefully is important. I failed to process 2 mg / g dry weight. I saw the 2 mg (out of context) and ran with it.

What are your thoughts on sublingual ingestion of the NIAGEN product, improved efficacy?

[Kevnzworld]

What are your thoughts on sublingual ingestion of the NIAGEN product, improved efficacy?

I've never read that niacin isn't bio available orally, so why would ingesting Niagen sublingually improve efficacy?
I'm splitting the dosage to twice a day to limit flushing.

[Ukko]

This LEF product contains 2.2 mg of cyanidin-3-glucoside http://www.lef.org/V...ents/Item01685/

ROFL! That really doesn't keep me up at night. A single teaspoon (5 g) of dried, black aronia berries provides ~400 mg of cyanidin-3-glycosides*, which is roughly two hundred times(!) the ridiculously small amout contained in that LEF supplement.

Ah yes, right you are. That's why reading more carefully is important. I failed to process 2 mg / g dry weight. I saw the 2 mg (out of context) and ran with it.

What are your thoughts on sublingual ingestion of the NIAGEN product, improved efficacy?

I have tried Niagen sublingually. Did not really seem to work. Does not dissolve like the other things I am used to taking sublingually. I read somewhere that it is lipid soluble and problematic transdermally. Maybe it's the same issue with the sublingual route. But go ahead and try for your self. Once I even woke up after 9 hours of sleep with the pill still undissolved under my tongue

[trance]

What product are you obtaining that is a pill form of Niagen?

The only commercially available Niagen product that I've seen so far is the Chromadex powder in a gelatin capsule, currently sold by HPN to various retailers.

There wouldn't be much of a "pill" to dissolve after 9 hours if you opened the capsule & poured the contents under your tongue using one of these.


For grins, I just opened a capsule, poured the contents under my tongue, and it dissolved completely in about 45 seconds surprisingly. No grit or any substance left behind. It has a somewhat bitter & slightly less sour taste, but not nearly as bad as most nootropics. It's been 4-5 minutes now, and there's just a small lingering of the bitter taste left coating the underside of my tongue and floor of my mouth.

Edited by trance, 20 February 2014 - 06:11 AM.

[Tom Andre F. (ex shinobi)]

NMN cost is upper than 1000$ per gram.. But we have its precursor: https://chromadex.co...nts/NIAGEN.html

what do you think ? Problem seems to be the dosage... So low to be effective.

[APBT]

What are your thoughts on sublingual ingestion of the NIAGEN product, improved efficacy?

I've never read that niacin isn't bio available orally, so why would ingesting Niagen sublingually improve efficacy?
I'm splitting the dosage to twice a day to limit flushing.

Earlier in this thread (pages 3 and 4), others had raised the question of sublingual administration. My thought - possibly misguided - is that sublingual use would forego the "first-pass metabolism," thereby (mostly) missing the GI tract and the liver. Thus, potentially improving efficacy?

Several substances come to mind that are ingested orally and used sublingually.

Vitamin B12 (methylcobalamin)
DHEA
Uridine (see Mr Happy's epic mega-thread http://www.longecity...ne-uridine-dha/)
Luteloin (as LuitMAX http://lutimax.com/)

I've yet to try NIAGEN.

[APBT]

Not yet. They will sell a form mixed with resveratrol
https://www.biotivia..._antiaging.html

I am ordering niagen

Not yet? Yes, you can. Click on the "Reserve now" button.

And it's not mixed with resveratrol. It's a 30 day regimen which includes Transmax and Biospan as seperate products.

This from the biotivia site https://www.biotivia..._antiaging.html

Important Note to prospective buyers:

* This molecule is extremely complex and difficult to produce in the particular form and quality used in the Harvard, NSW, NIH trial. Many suppliers offer a molecule that they represent to be NAD+ which is actually NADH, its biological opposite coenzyme. No other supplier is offering a compound equivalent to MitoTrans. The NAD+/NADH ratio is the critical value to modulate. Adding NADH to one's diet actually worsens this ratio. Only by adding NAD+ is the ratio enhanced, as it was in the Harvard study.

+ NAD+ does not survive passage through the stomach unless protected by advanced sustained release technology. Simply consuming NAD+ absent this protection is not effective. MitoTrans is produced using the same sustained release technology we utilize to protect Transmax TR from deterioration by gastric acids and coenzymes. We have years of experience in producing supplements that survive the digestive process. This is the only way to insure that one actually absorbs the active molecule.

+ Buyer beware. With every new breakthrough comes a raft of disreputable and deceptive providers claiming to offer a product that provides its advantages. It is not only your money that is at risk if you do not select a provider of known reliability and scientific credentials. Biotivia has over 20 years as a respected expert in the field of advanced functional botanicals and their equivalents. We routinely collaborate with prestigious medical schools and research organisations worldwide on clinical trials of new and promising compounds. Do your research before making this important decision. Selecting the wrong form of NAD may produce the opposite effects of genuine MitoTrans.

*MitoTrans is the Biotivia trademark for its proprietary, purified, pharmaceutical grade NAD+ supplement manufactured using a sustained release technology which prevents destruction of the molecule by gastric fluids. The scientific name for MitoTrans is nicotinamide adenine dinucleotide. MitoTrans is not meant to prevent, diagnose, treat, or cure any disease, nor does Biotivia make any specific health claims for this supplement.

My take-away from this (if accurate) is the NIAGEN product is useless. Or, pure marketing hype. Thoughts?

[hav]

For grins, I just opened a capsule, poured the contents under my tongue, and it dissolved completely in about 45 seconds surprisingly. No grit or any substance left behind. It has a somewhat bitter & slightly less sour taste, but not nearly as bad as most nootropics. It's been 4-5 minutes now, and there's just a small lingering of the bitter taste left coating the underside of my tongue and floor of my mouth.

Thanks for doing that. Allot of folks here, including myself, have verified the same thing with resveratrol which dissolves under the tongue even through it is not soluble in plain water. But something water soluble should be even better absorbed under the tongue. I couldn't find any solubility data on Cromadex for Niagen but this site indicates NAD+ is hydrophilic:

http://www.scbt.com/...-free-acid.html

Synonym: β-Nicotinamide Adenine Dinucleotide Application: A major electron acceptor CAS Number: 53-84-9 Purity: ≥98% Molecular Weight: 663.4 Molecular Formula: C₂₁H₂₇N₇O₁₄P₂
Solubility:Soluble in water (200 mg/ml).

Howard

[eighthman]

Please correct me if I'm wrong but looking over the responses here about NADH/Niacin/NAD+, etc. , it looks like a dead end aside from a few modest benefits. Nothing such as what is seen with mice.

[Ukko]

What product are you obtaining that is a pill form of Niagen?

The only commercially available Niagen product that I've seen so far is the Chromadex powder in a gelatin capsule, currently sold by HPN to various retailers.

There wouldn't be much of a "pill" to dissolve after 9 hours if you opened the capsule & poured the contents under your tongue using one of these.


For grins, I just opened a capsule, poured the contents under my tongue, and it dissolved completely in about 45 seconds surprisingly. No grit or any substance left behind. It has a somewhat bitter & slightly less sour taste, but not nearly as bad as most nootropics. It's been 4-5 minutes now, and there's just a small lingering of the bitter taste left coating the underside of my tongue and floor of my mouth.

That is odd. My pills are the same. What I normally do with sublingual pills is that I put them intact inside my upper lip. Maybe the coating with these pills then is stronger than say all the PQQ and other pills I take like that. Thanks for pointing that out.

[Hebbeh]

What product are you obtaining that is a pill form of Niagen?

The only commercially available Niagen product that I've seen so far is the Chromadex powder in a gelatin capsule, currently sold by HPN to various retailers.

There wouldn't be much of a "pill" to dissolve after 9 hours if you opened the capsule & poured the contents under your tongue using one of these.


For grins, I just opened a capsule, poured the contents under my tongue, and it dissolved completely in about 45 seconds surprisingly. No grit or any substance left behind. It has a somewhat bitter & slightly less sour taste, but not nearly as bad as most nootropics. It's been 4-5 minutes now, and there's just a small lingering of the bitter taste left coating the underside of my tongue and floor of my mouth.

That is odd. My pills are the same. What I normally do with sublingual pills is that I put them intact inside my upper lip. Maybe the coating with these pills then is stronger than say all the PQQ and other pills I take like that. Thanks for pointing that out.

You can't put an intact capsule inside your lip or under your tongue for sublingual. You have to open a capsule and dump the powder under your tongue. That is the only way sublingual administration works.

[Ukko]

What product are you obtaining that is a pill form of Niagen?

The only commercially available Niagen product that I've seen so far is the Chromadex powder in a gelatin capsule, currently sold by HPN to various retailers.

There wouldn't be much of a "pill" to dissolve after 9 hours if you opened the capsule & poured the contents under your tongue using one of these.


For grins, I just opened a capsule, poured the contents under my tongue, and it dissolved completely in about 45 seconds surprisingly. No grit or any substance left behind. It has a somewhat bitter & slightly less sour taste, but not nearly as bad as most nootropics. It's been 4-5 minutes now, and there's just a small lingering of the bitter taste left coating the underside of my tongue and floor of my mouth.

That is odd. My pills are the same. What I normally do with sublingual pills is that I put them intact inside my upper lip. Maybe the coating with these pills then is stronger than say all the PQQ and other pills I take like that. Thanks for pointing that out.

You can't put an intact capsule inside your lip or under your tongue for sublingual. You have to open a capsule and dump the powder under your tongue. That is the only way sublingual administration works.

Not really. I have methyl folate, PQQ, DMAE, uridine etc. pills mainly from NOW Foods and LEF that work dissolve fast, even if you put them intact under the tongue or behind the upper lip. Suppose it depends on the coating.

[cudBwrong]

I don't think this was cited earlier, apologies if it is a duplication.

Resveratrol increases NAD(+) in mitochondrial metabolism through complex I activation, increasing SIRT3 activation:

http://www.ncbi.nlm....pubmed/24178296

J Biol Chem. 2013 Dec 20;288(51):36662-75. doi: 10.1074/jbc.M113.466490. Epub 2013 Oct 31.
Resveratrol induces a mitochondrial complex I-dependent increase in NADH oxidation responsible for sirtuin activation in liver cells.

Desquiret-Dumas V¹, Gueguen N, Leman G, Baron S, Nivet-Antoine V, Chupin S, Chevrollier A, Vessières E, Ayer A, Ferré M, Bonneau D, Henrion D, Reynier P, Procaccio V.
Author information

• ¹From Angers Université, Angers F-49000, France.

Abstract


Resveratrol (RSV) has been shown to be involved in the regulation of energetic metabolism, generating increasing interest in therapeutic use. SIRT1 has been described as the main target of RSV. However, recent reports have challenged the hypothesis of its direct activation by RSV, and the signaling pathways remain elusive. Here, the effects of RSV on mitochondrial metabolism are detailed both in vivo and in vitro using murine and cellular models and isolated enzymes. We demonstrate that low RSV doses (1-5 μM) directly stimulate NADH dehydrogenases and, more specifically, mitochondrial complex I activity (EC50 ∼1 μM). In HepG2 cells, this complex I activation increases the mitochondrial NAD(+)/NADH ratio. This higher NAD(+) level initiates a SIRT3-dependent increase in the mitochondrial substrate supply pathways (i.e. the tricarboxylic acid cycle and fatty acid oxidation). This effect is also seen in liver mitochondria of RSV-fed animals (50 mg/kg/day). We conclude that the increase in NADH oxidation by complex I is a crucial event for SIRT3 activation by RSV. Our results open up new perspectives in the understanding of the RSV signaling pathway and highlight the critical importance of RSV doses used for future clinical trials.

[APBT]

A single teaspoon (5 g) of dried, black aronia berries provides ~400 mg of cyanidin-3-glycosides

Thanks for the dried black aronia berry tip. This seems like the most economical source of C3G. I've placed an order for a one pound bag. Aronia berry concentrate looks good too, but pricey. http://store.sawmill...oncentrate.html

[Darryl]

A recent (just today on Scholar) thesis corroborates of CD38 inhibition by cyanidin 3-glucoside (kuromanin), and subsequently increased intracellular [NAD⁺]. This is to my knowledge only the second paper to report C3G's effects on CD38. It also corroborates that CD38 is the overwhelming consumer of intracellular NAD⁺, as PARP inhibitors and sirtuin inhibitors had no effect on [NAD⁺].

Al-Abady, Zainab N. "The role of CD38 expression on NAD levels and cell physiology in a leukaemia model." (2014).

I haven't had a chance to more than skim the figures. With the usual caveats about in vitro studies on mutant cell lines:

Figure 3.17: 8 μM C3G increased [NAD⁺] by about 70% in RAJI leukemia cells, but had a negligible effect on undifferentiated HL60 cells, which express little CD38.
Figure 3.18: The effect on [NAD⁺] was roughly linear from 3 μM (~40% increase) to 30 μM (~70%) increase. Exposure time had more impact than concentration.
Figure 5.2: 30 μM C3G decreases CD38 expression, too.

So, this suggests the trick would be to get plasma C3G to around 2-3 μM and maintain it there all day long. The oral pharmacokinetics remain a big obstacle.

Edited by Darryl, 01 March 2014 - 01:21 AM.