65 replies to this topic

[Phoenicis]

There has been much interest in NAD+ precursors following the 2013 paper by Dr David Sinclair et al. entitled "Declining NAD+ Induces a Pseudohypoxic State Disrupting Nuclear-Mitochondrial Communication during Aging". For those that missed it the highlights in this article were that:

• Aging leads to a specific decline in mitochondrially encoded genes
• Nuclear NAD+ levels regulate mitochondirally encoded genes
• SIRT1 can regulate mitochodria via a PGC-1 alpha/beta independent pathway: HIF-1 alpha stabilization via VHL and consequent activation of TFAM via c-Myc
• AMPK acts as a switch between the PGC-1 aplha dependent and independent pathways
• Increasing NAD+ levels restores mitochondrial homeostasis through the SIRT1-HIF-1alpha-c-Myc pathway
• Old mice receiving the NAD+ precursor nicotinamide mononucleotide ('NMN') showed a reversal of impaired insulin signalling and insulin stimulated glucose uptake, muscle atrophy, and inflammation after 1 week. Muscle strength was not improved, but they hypothesized that a longer treatment could potentially reverse whole-organism aging.

The Conversion of Precursors into NAD+

 

As a result of the previous article and many others, NAD+ precursors have become a focus of attention. There are many different NAD+ precursors, these include:

• Nicotinamide ('Nam'): the most commonly found form of vitamin B3, while it is normally converted to NAD+ in vivo, the enzyme responsible for this (NAMPT) is easily saturated and its functionality declines with age. It has also been reported to act as a SIRT1 inhibitor. Nam > NMN (via NAMPT) > NAD+ (via NMNAT1-3) > Nam (via NAD+ consuming enzymes)
• Nicotinic Acid ('NA') - is also known as niacin, this NAD+ precursor is not subject to NAMPT and instead utilizes the Preiss-Handler pathway. NA > NaMN (via NaPRT1) > NaAD+ (via NMNAT1-3) > NAD+ (via glutamine dependent NaDSYN1) > Nam (via NAD+ consuming enzymes)
• Nicotinamide Riboside ('NR') - this more recently discovered NAD+ precursor is currently available to consumers as 'Niagen' and at the time of writing this is seems like a feasible, yet comparably expensive, NAD+ precursor. NR > NMN (via NRK1.2) > NAD+ (via NMNAT1-3) > Nam (via NAD+ consuming enzymes)
• Nicotinamide Mononucleotide ('NMN') - this is the precursor which was used by Dr Sinclair et al. in 2013, it is at the time of posting extremely expensive and not available to consumers. NMN > NAD+ (via NMNAT1-3) > Nam (via NAD+ consuming enzymes) [although, apparently it must be converted to Nr before entering the cell?]

See the Following Diagram:

 

[...]

 

 

 

Intracellular NAD+ metabolism in humans. Tryptophan (Trp), nicotinic acid (Na), nicotinamide (Nam), nicotinamide riboside (NR),and nicotinic acid riboside (NaR) are utilized through distinct metabolic pathways to form NAD+. 

 

Tryptophan (Trp) is converted to NAD+ in the eight-step de novo pathway through quinolinate (Quin), which is converted to nicotinic acid mononucleotide (NaMN) by quinolinate phosphoribosyltransferase (QPRT). NaMN is then adenylylated by the products of the NMNAT1-3 genes to

form nicotinic acid adenine dinucleotide (NaAD+), which is converted to NAD+ by glutamine-dependent NAD+ synthetase (NADSYN1). 

 

Nicotinic acid (Na) is utilized in the three-step Preiss-Handler pathway. Nicotinic acid phosphoribosyltransferase (NAPRT1) forms NaMN by addition of the 5-phosphoribose group from 5-phosphoribosyl-1-pyrophosphate to Na. In two steps shared with the de novo pathway, NaMN is then converted to NaAD+ and NAD+ via activity of NMNAT1-3 and NADSYN1.

 

Nicotinamide (Nam) is utilized via nicotinamide phosphoribosyltransferase (Nampt), encoded by the PBEF1 (NAMPT) gene. Nampt catalyzes the addition of a phosphoribose moiety onto Nam to form nicotinamide mononucleotide (NMN). NMN is subsequently converted to NAD+ by the products of NMNAT1-3. Nam is produced by NAD+-consuming enzymes.

 

Nicotinamide riboside (NR) is phosphorylated by the products of nicotinamide riboside kinase genes (NRK1 and NRK2) to form NMN, which is converted to NAD+ by NMNAT1-3. NR may also be utilized by the product of the NP gene, purine nucleoside phosphorylase, for subsequent Nam salvage.

 

From Bogan, K. L., & Brenner, C. (2008). Nicotinic acid, nicotinamide, and nicotinamide riboside: a molecular evaluation of NAD+ precursor vitamins in human nutrition. Annu. Rev. Nutr., 28, 115-130.

 

 

Which Precursors are Interesting?

 

NMN is not currently commercially available and does not seem to be very competitive with NR and NA in this study. Nam may be unsuitable for older people because of declining NAMPT levels with age and has also bee shown to inhibit SIRT1. That leaves NA and NR.

 

Darryl wrote this concise post, which to some extent sheds more light on this question:

 

 

Nicotinamide (Nam) and nicotinamide riboside (NR) differ only through a ribosylation on NR.

 

Its difficult to raise NAD+ levels with Nam as the enzyme Nampt is saturated at low concentration. Moreover, Nam itself functions as a feedback inhibitor of sirtuins and PARPs, but this suppression of NAD+ consumption has benefits in ischemia-reperfusion injury, like stroke.

 

Nicotinic acid utilizes the Preiss-Handler pathway, which isn't subject to the Nampt bottleneck. High doses cause flushing which many dislike, but the same mechanism has antiinflammatory benefits.

 

NMN is the subject of Sinclair's study. While an intermediate for Nam and NR, it only can enter cells as NR. 

 

NR isn't rate-limited by NAMPT, and doesn't cause flushing, but only some tissues (in animals) express NR kinases to utilize it.

 

[...]

 

From Bogan, K. L., & Brenner, C. (2008). Nicotinic acid, nicotinamide, and nicotinamide riboside: a molecular evaluation of NAD+ precursor vitamins in human nutrition. Annu. Rev. Nutr., 28, 115-130.

Is NA Converted to Nam in vivo?

 

Posts in this forum stating that NA is inferior to NR because it is "converted to Nam" in vivo are misleading. It must be said that all NAD+ precursors are converted into Nam in vivo because this is the work of NAD+ consuming enzymes. Take a look at the above diagram; the three step Preiss-Handler pathway converts NA into NAD+ and only then, once that NAD+ is used up, is Nam formed as a product. Even NMN ends up as Nam after it is converted to NAD+ and utilized by NAD+ consuming enzymes.

NR on the other hand can indeed be converted into Nam before even making it to NAD+. The exact mechanism by which this occurs and how much is converted into Nam instead of NMN needs further research.

 

NA vs NR

 

In terms of NAD+ yield, this study found that in rats (see Figure 1) NA surpasses NR in liver tissues and the two produce roughly the same amount in the muscle tissues. NA is currently much cheaper than NR: Na costs about $5.00 for 100 x 250mg capsules, whereas NR costs about $47.00 for 30 x 250mg. The most widely perceived disadvantage of NA is that it causes a vasodilatory GPR109A receptor 'flush response'.  Once again I feel obliged to refer to Darryl, who made these informative posts covering this 'side effect', which comes with benefits too:

 

Among the NAD+ precursors, nicotinic acid additionally has anti-inflammatory effects through GPR109A activation, independent of its lipid modifying effects. As the other precursors lack this activity, they may not be as effective as anti-inflammatories.

 

Plaisance, Eric P., et al. "Niacin stimulates adiponectin secretion through the GPR109A receptor." American Journal of Physiology-Endocrinology and Metabolism 296.3 (2009): E549-E558.

Digby, Janet E., et al. "Anti-inflammatory effects of nicotinic acid in adipocytes demonstrated by suppression of fractalkine, RANTES, and MCP-1 and upregulation of adiponectin." Atherosclerosis 209.1 (2010): 89-95.

Lukasova, Martina, et al. "Nicotinic acid inhibits progression of atherosclerosis in mice through its receptor GPR109A expressed by immune cells." The Journal of clinical investigation 121.3 (2011): 1163-1173.

Digby, Janet E., et al. "Anti-inflammatory effects of nicotinic acid in human monocytes are mediated by GPR109A dependent mechanisms."Arteriosclerosis, thrombosis, and vascular biology 32.3 (2012): 669-676.

Sia, Yanhong, et al. "Niacin inhibits vascular inflammation via down-regulating nuclear transcription factor-κB signaling pathway." (2014)

[...]

 

Maybe its not GPR109A activation, after all.

 

Ma, L., Lee, B. H., Mao, R., Cai, A., Jia, Y., Clifton, H., ... & Zheng, J. (2014). Nicotinic Acid Activates the Capsaicin Receptor TRPV1 Potential Mechanism for Cutaneous Flushing. Arteriosclerosis, thrombosis, and vascular biology,34(6), 1272-1280.

 

 

We observed that the nicotinic acid–induced increase in blood flow was substantially reduced in Trpv1^–/– knockout mice, indicating involvement of the channel in flushing response. Using exogenously expressed TRPV1, we confirmed that nicotinic acid at submillimolar to millimolar concentrations directly and potently activates TRPV1 from the intracellular side. Binding of nicotinic acid to TRPV1 lowers its activation threshold for heat, causing channel opening at physiological temperatures. The activation of TRPV1 by voltage or ligands (capsaicin and 2-aminoethoxydiphenyl borate) is also potentiated by nicotinic acid. We further demonstrated that nicotinic acid does not compete directly with capsaicin but may activate TRPV1 through the 2-aminoethoxydiphenyl borate activation pathway. Using live-cell fluorescence imaging, we observed that nicotinic acid can quickly enter the cell through a transportermediated pathway to activate TRPV1.

 

Safety of Nicotinic Acid

 

I must stress that I am not qualified to give medical advice, this is for personal study purposes only and does not constitute medical advice. Everyone considering to take any of these substances does so at their own risk and should get independent medical advice before administering; especially when supplementing over longer periods and at high doses.

 

It seems clear that the extended release formulations of NA have been responsible for most cases of liver toxicity. Some physician like Dr. Abram Hoffer, who pioneered Niacin treatments for schizophrenia and TB, routinely prescribed divided (immediate release) doses of 3g / day  (Anyone interested in reading more about this should see: Niacin: the Real Story by Dr. Abram Hoffer et al.). Even the immediate release formulation can affect each individual differently and it seems that with some people doses of above 1500mg can lead to health issues. These include, but are not limited to: reversible liver test abnormalities, blurry vision issues and mild glucose increases.

 

These articles address some of the the safety issues with Niacin and may be interesting to read:

• Liver Toxicity: Niacin
• Guyton, J. R., & Bays, H. E. (2007). Safety considerations with niacin therapy.The American journal of cardiology, 99(6), S22-S31.
• McKenney, J. M., Proctor, J. D., Harris, S., & Chinchili, V. M. (1994). A comparison of the efficacy and toxic effects of sustained-vs immediate-release niacin in hypercholesterolemic patients. Jama, 271(9), 672-677.

Remember, only a doctor can advise you on the side effects and safety!

 

My Own Experiences

 

Personally, I have been taking 1.5g IR NA / day for the past 2 months. I take 1g upon rising and another 500mg in the evening. I actually like the flush sensation and compare the feeling to being in the sauna. I think I have seen some improvement in energy, cognitive functions and endurance; but have not tested these.

 

I also like to take it with NAC since my research seems to indicate that this may attenuate the increase in homocysteine levels brought on by niacin. I have considered adding glutamine (NA > NAD+ involves glutamine-dependent NAD+ synthetase (NADSYN1)) and arginine, the author of this paper believes that this will increase efficacy. (note: I do not suffer for schizophrenia, I merely found the paper during research).

 

I am also interested in using this for neuro-protection from adderal induced DA decline (possibly via dopamine oxidation). I may start adderall soon if it's prescribed and will update with results in this thread and here.

 

Edited by Phoenicis, 21 July 2014 - 06:43 AM.

[Dolph]

If you are concerned about the rise of homocysteine with niacin the first thing you should do is making sure you get enough vitamin B6 (and B12 anyway).
http://www.ncbi.nlm....pubmed/9040554/

[Recortes]

If you are concerned about the rise of homocysteine with niacin the first thing you should do is making sure you get enough vitamin B6 (and B12 anyway).
http://www.ncbi.nlm....pubmed/9040554/

 

That's right. Community with CAD disease has long experince in the usage of Niacin. Niacin is a high methyl sink, that has the potential of increasing homocysteine. The way to solve this issue is

taking Naicin together methyl donors, such as B12 (in the methylcobalamin form), folic acid (in the 5MTHF fom), B6, SAMe etc.  Some doctors recommend as well taking it with grepe seed extract or pygnogenol, since

it increases arterial stickness. Anyway, it's probably one of the few substances that might have antiaging effects. 

[Primal]

What adds significantly to the anti-aging puzzle IMO is that methionine, a direct methyl donor present in high quantity in the diet and precursor of SAMe, has the particularity that restricting it mimmics calorie restriction and extends lifespan in some species

[Kevnzworld]

What adds significantly to the anti-aging puzzle IMO is that methionine, a direct methyl donor present in high quantity in the diet and precursor of SAMe, has the particularity that restricting it mimmics calorie restriction and extends lifespan in some species

I wonder if unmethylated methionine which results in elevated homocysteine is one of the causes of reduced lifespan in animals with high methionine diets..
OT, I know...but it minds us that B vitamin intake needs to be complete and balanced. I currently take 850 mg of b3, 750 NR, 100 NA . I haven't altered my other B intake since beginning NR, my last blood test my homocysteine was 7. It will be interesting to see if it has risen significantly subsequently.

[Phoenicis]

This is pretty interesting stuff about SAMe, b12, b6 and folate! Right now I'm taking B12, B6 (8mg/day), 200mg ALCAR and 600mg NAC. I think ALCAR would be good for acetyl-COA right? This recent article covers some of that, as well as the wider implications of exhausting SAMe and Acetyl-COA pools. I've linked the full text:

 

Martinez-Pastor B et al., A tale of metabolites: the cross-talk between chromatin and energy metabolism.Cancer Discov. 2013 May;3(5):497-501

 

Abstract

 

Mitochondrial metabolism influences histone and DNA modifications by retrograde signaling and activation of transcriptional programs. Considering the high number of putative sites for acetylation and methylation in chromatin, we propose in this perspective article that epigenetic modifications might impinge on cellular metabolism by affecting the pool of acetyl-CoA and S-adenosylmethionine

 

 

 

What adds significantly to the anti-aging puzzle IMO is that methionine, a direct methyl donor present in high quantity in the diet and precursor of SAMe, has the particularity that restricting it mimmics calorie restriction and extends lifespan in some species

I wonder if unmethylated methionine which results in elevated homocysteine is one of the causes of reduced lifespan in animals with high methionine diets..
OT, I know...but it minds us that B vitamin intake needs to be complete and balanced. I currently take 850 mg of b3, 750 NR, 100 NA . I haven't altered my other B intake since beginning NR, my last blood test my homocysteine was 7. It will be interesting to see if it has risen significantly subsequentl

 

Going off topic here but -

 

High methionine results in increased mTOR signalling, IGF-1 secretion and overall more reactive mitochondrial oxygen species as well [1]. Limiting even one amino acid like methionine also causes significant epigenetic changes referred to amino acid response[2], which can do wonders for autoimmune conditions because it normalizes Th17 immune cells[3]. Of course this does not mean that one must avoid the AA completely, simply eating a low methionine vegan is an example of how the response can be induced[2].

 

[1] Ines Sanchez-Roman et al, Regulation of longevity and oxidative stress by nutritional interventions: Role of methionine restriction Experimental Gerontology Volume 48, Issue 10, October 2013, Pages 1030?1042

 

[2] Michael S. Kilberg et al., The Transcription Factor Network Associated With the Amino Acid Response in Mammalian Cells, American Society for Nutrition. Adv. Nutr. 3: 295–306, 2012.

 

[3] John Y. M. Koo et al, Mild to Moderate Psoriasis, Third Edition (22 Apr 2014)

Edited by Phoenicis, 21 July 2014 - 11:36 PM.

[Primal]

 I think ALCAR would be good for acetyl-COA right? This recent article covers some of that, as well as the wider implications of exhausting SAMe and Acetyl-COA pools. I've linked the full text:

 

Martinez-Pastor B et al., A tale of metabolites: the cross-talk between chromatin and energy metabolism.Cancer Discov. 2013 May;3(5):497-501

 

Abstract

 

Mitochondrial metabolism influences histone and DNA modifications by retrograde signaling and activation of transcriptional programs. Considering the high number of putative sites for acetylation and methylation in chromatin, we propose in this perspective article that epigenetic modifications might impinge on cellular metabolism by affecting the pool of acetyl-CoA and S-adenosylmethionine

 

 

That's an interesting paper. Ties in well and answer some of the questions in the thread Can you boost deacetylation like you can boost methylation?   

 

 

 

SAM-e is the global methyl donor, what is the global acetyl donor? Acetyl phosphate (or is it as more a phospho donor)? acetyl-coenzyme A ? What about a global acetyl acceptor? 

 

 

 

Recently, acetylation of proteins was revealed to be as abundant as phosphorylation (2). This

posttranslational modification involves the covalent binding of an acetyl group obtained

 

from acetyl-CoA to a lysine.

 

Acetylation of proteins depends on the availability of acetyl-CoA in each

cellular compartment

 

These observations reveal a process

where glucose metabolism dictates histone acetylation that in a feedback mechanism

controls the rate of glycolysis.

 

Notably, deacetylation of histones also exhibits a metabolic influence. Deacetylation of

histones is achieved by class I and class II histone deacetylases (HDACs) and by a separate

class (class III), also known as sirtuins. Sirtuins use NAD+ as a cofactor for deacetylation,

and the ratio of NAD+/NADH regulates their activity.

 

In fact, low Sirt1 and

Sirt6 activity generates a global increase in protein acetylation.

 

In animal cells, both histone acetylation and deacetylation are under the control of glucose

metabolism through the availability of acetyl-CoA and NAD+, respectively.

 

For example, if histone acetylation is

drastically increased, the concentration of acetyl-CoA might suddenly drop.

 

Similarly, in cases where a sudden excess of methyl groups is retained on

chromatin, availability of SAM may be compromised, in turn altering one-carbon

metabolism. Indeed, de novo purine biosynthesis, de novo dTMP biosynthesis, and

homocysteine remethylation are thought to compete for a limiting pool of folate.

 

 

 

So it seems like acetyl-CoA is the global acetyl donor and in some way NAD+ could be seen as the global deacetylator. 

[Primal]

[1] Ines Sanchez-Roman et al, Regulation of longevity and oxidative stress by nutritional interventions: Role of methionine restriction Experimental Gerontology Volume 48, Issue 10, October 2013, Pages 1030?1042

 

 

Dietary restriction (DR), around 40%, extends the mean and maximum life span of a wide range of species and lowers mtROSp and oxidative damage to mtDNA, which supports the mitochondrial free radical theory of aging (MFRTA). Regarding the dietary factor responsible for the life extension effect of DR, neither carbohydrate nor lipid restriction seems to modify maximum longevity. However protein restriction (PR) and methionine restriction (at least 80% MetR) increase maximum lifespan in rats and mice. Interestingly, only 7weeks of 40% PR (at least in liver) or 40% MetR (in all the studied organs, heart, brain, liver or kidney) is enough to decrease mtROSp and oxidative damage to mtDNA in rats, whereas neither carbohydrate nor lipid restriction changes these parameters. In addition, old rats also conserve the capacity to respond to 7weeks of 40% MetR with these beneficial changes. Most importantly, 40% MetR, differing from what happens during both 40% DR and 80% MetR, does not decrease growth rate and body size of rats. All the available studies suggest that the decrease in methionine ingestion that occurs during DR is responsible for part of the aging-delaying effect of this intervention likely through the decrease of mtROSp and ensuing DNA damage that it exerts.

 

 

In diets rich in carbohydrates, growth

factors stimulate cellular glucose uptake and the production of energy is carried out through

glycolysis. In this context, the NAD+/NADH ratio decreases, in turn inhibiting, in theory,

sirtuins in the cytoplasm (Sirt2) and nucleus (Sirt1, Sirt6 and Sirt7). In fact, low Sirt1 and

Sirt6 activity generates a global increase in protein acetylation.

 

Maybe we should be eating more animal fat, less carbs and less proteins, like these guys http://high-fat-nutrition.blogspot.ca/ 

 

Also, trying to put everything together it seems that substances increasing methylation (methionine, B9, B12, etc) and acetylation (Apple cider vinagar, ALCAR, etc) make you feel better but live shorter, while substances that act as methyl sinks (NA, NAM, NR, NMN, etc via their metabolism) and deacetylators (NA, NAM, NR, NMN, etc via boosting NAD+) give you a long, miserable life. 

[Primal]

One thing is sure - current frontline research is starting to be much more interesting that it was just a few years ago. There is now light at the end of the tunnel that many diseases of cellular energy production/diseases of aging/diseases of civilization, including cancer, autism, CFS/ME, fibromyalgia, diabetes, hypercholesterolemia, high blood pressure, obesity, insulin resistance, metabolic syndrome, rapid deconditioning, immune system problems, increased susceptibility to molds/dusts/vaccines/chemicals/electromagnetic fields, alzheimer/parkinson/other dementias, decreased healing capacity, etc all share the same root cause which is about to get under attack

Edited by Primal, 22 July 2014 - 05:07 AM.

[Phoenicis]

Martinez-Pastor B et al state that excessive activation of growth signalling pathways has deterious effects on thing like cancer progression and aging. [1] Nutrient excess also promotes aerobic glycolisis (Warburg effect) rather than oxidative metabolism,  this is also seen in cancer cells. [1] This switch in biochemical processes and mitochondrial gene transcription can be controlled though nutrient availability. [1] Here the authors specifically mention PCG1alph as opposed to Sinclair's findings on a PGC-1 alpha/beta independent pathway: HIF-1 alpha stabilization via VHL and consequent activation of TFAM via c-Myc.

 

They state that: "...in diets rich in carbohydrates, growthfactors stimulate cellular glucose uptake and the production of energy is carried out through glycolysis. In this context, the NAD+/NADH ratio decreases, in turn inhibiting, in theory,sirtuins in the cytoplasm (Sirt2) and nucleus (Sirt1, Sirt6 and Sirt7). In fact, low Sirt1 and Sirt6 activity generates a global increase in protein acetylation." [1]

 

What they forgot to mention, or perhaps thought was obvious, is that mTOR is the central activator of the Warburg effect by inducing PKM2 and other glycolytic enzymes.

 

Mutations in mitchondrial DNA can lead to aging, disease and cancer [1], so besides the fact that high methionine and indeed leucine intake stimulates mTOR, this is another reason why the finding that high methionine intake is associated with increased mitochondrial reactive oxygen species is significant

 

To quote Ines Sanchez-Roman et al:

 

"40% MetR [methionine restriction] (in all the studied organs, heart, brain, liver or kidney) is enough to decrease mtROSp and oxidative damage to mtDNA in rats, whereas neither carbohydrate nor lipid restriction changes these parameters."

 

Martinez-Pastor B et al argue that the availability of metabolites impacts epigenetics. Citrate is required for the production of acetyl-COA in the mitochondria, when there is a lack of acetyl-COA, acetylation decreases - often around glycolytic genes leading to reduced transcription and glycolysis. The sirtuins are in fact class III deacetylases.that use NAD+ as a co-factor and reduce glycolysis. [1]

 

While it could be argued that more acetylation via acetyl-COA is therefore bad, it is also true that Histone Deacetylase inhibitors have a place in treating cancer inter alia via activation of tumor suppressor genes.

 

Mutations and the production of 2-hydroxyglutarate (2-HG) is responsible for DNA hypermethylation (gene silencing) in cancer cells and this happens as follows:

 

IDH1 & 2 mutations > decreased alphaketoglutarate  > conversion of alphaketoglutarate to 2-HG > reduced histone demethyltransferases (HMTs) > hypermethylation [1]

 

This is likely a reason why HMTs are used in the treatment of cancers and increased FAD+ and alphaketoglutarate may be useful for demethylation of tumor suppressor genes. increased HMTs (requires the coenzymes FAD+ and alphaketoglutarate) and folate (required for one carbon metabolism which converts homocysteine to methionine and is an essential methyl donor) can help with hypermethylation and thus the availability of SAM. [1]

 

In addition excessive acetylation could effect the availability of acetyl-COA for the TCA cycle/aerobic respiration. [1] Under nutrient limitation cells recycle citrate rather than metabolising it and this reduces overall acetyl-COA availability. [1] So hyperacetylation of DNA could theoretically lead to a shortfall, especially under nutrient stress conditions.      

 

It seems that mutations in chromatin modifiers like HMTs or HDACs could lead to impaired cellular methyl and acetyl pools and critically this could be compacted by nutrient stress and reduced SAM or citrate.[1] Bottom line to me: try to avoid mutations in chromatin modifiers and maintain adequate SAM/citrate.  

 

I am curious about what effects diet could have on:

• FAD+ availability, since this seems to support both HMT production and Dimethylglycine dehydrogenase (produces serine)
• Serine availability, which is essential for one carbon metabolism.

[1] Martinez-Pastor B et al., A tale of metabolites: the cross-talk between chromatin and energy metabolism.Cancer Discov. 2013 May;3(5):497-501

Edited by Phoenicis, 22 July 2014 - 11:34 AM.

[Phoenicis]

This is an interesting statement to contemplate. My autoimmune condition psoriasis shares many pathogenic similarities with cancer. For example mTOR signalling, IGF-1 and subsequent increases in angiogenesis are pathologic components required for both the proliferation of cancer cells and the various cells in psoriatic lesions.[1] The fact that animal protein has such a strong ability to enhance IGF-1 secretion [1] is one of the reasons I went vegan. Its Neu5gc content is another factor involved in the spread of both cancer and most likely also psoriasis. [1]

 

Not surprisingly:

 

"Psoriasis patients are at increased baseline risk for some malignancies, including nonmelanoma skin cancers, lymphoma, and esophageal cancer, and this risk increases with more severe disease. [35]. Thus, by reducing meat intake, psoriasis patients may decrease systemic inflammation, improve psoriasis, and possibly decrease cancer risk." [1]

 

Cancer and psoriasis also show a remarkable overlap in drug targets, examples include miR-21, PIM1 and S100A9.

 

[1] John Y. M. Koo et al, Mild to Moderate Psoriasis, Third Edition (22 Apr 2014)

 

One thing is sure - current frontline research is starting to be much more interesting that it was just a few years ago. There is now light at the end of the tunnel that many diseases of cellular energy production/diseases of aging/diseases of civilization, including cancer, autism, CFS/ME, fibromyalgia, diabetes, hypercholesterolemia, high blood pressure, obesity, insulin resistance, metabolic syndrome, rapid deconditioning, immune system problems, increased susceptibility to molds/dusts/vaccines/chemicals/electromagnetic fields, alzheimer/parkinson/other dementias, decreased healing capacity, etc all share the same root cause which is about to get under attack

 

 

Edited by Phoenicis, 22 July 2014 - 11:40 AM.

[Dolph]

Not surprisingly:
 
"Psoriasis patients are at increased baseline risk for some malignancies, including nonmelanoma skin cancers, lymphoma, and esophageal cancer, and this risk increases with more severe disease. [35]. Thus, by reducing meat intake, psoriasis patients may decrease systemic inflammation, improve psoriasis, and possibly decrease cancer risk." [1]

This is pretty controversial. The incidence of skin cancer in psoriasis patients is probably higly confounded because of PUVA- and narrow band UVB therapy. Psoriasis is also much more common in obese people and obesity is an important risk factor for cancer incidence per se.
You can also look further and will find very many strange "comorbidities" of psoriasis. Smoking and high level of alcohol consumption for example are much more common in psoriasis patients.

I wouldn't feel like estimating if there is any real connection.

[Phoenicis]

I wonder how important it is to distinguish between methyltransferase and demethyltransferase in this regard? The former is often a target for drug inhibition in cancer, not sure if that counts for the latter?

 

[...]

 

This is likely a reason why HMTs are used in the treatment of cancers and increased FAD+ and alphaketoglutarate may be useful for demethylation of tumor suppressor genes. increased HMTs (requires the coenzymes FAD+ and alphaketoglutarate) and folate (required for one carbon metabolism which converts homocysteine to methionine and is an essential methyl donor) can help with hypermethylation and thus the availability of SAM. [1]

 

 

Edited by Phoenicis, 22 July 2014 - 02:08 PM.

[Tom Andre F. (ex shinobi)]

I wonder if the homocysteine niacin induced is also true for NR since the 2 are very different in studies (regarding ROS for exemple) + NR doesnt act really as a vitamin (so maybe no competition there with B6 and B12).

Also guys should consider MSM as a methyl donor

Edited by Shinobi, 22 July 2014 - 03:24 PM.

[Primal]

I've read more and thought more and I think I have a theory that would explain all these facts - ie what goes wrong first in this (de)methylation/(de)acetylation/(de)phosphorylation/NAD+ and acetyl CoA decrease/pathogenic crosstalk/methionine restriction apparent benefits and what comes as a consequence of what, and hopefully how to reverse the whole damage chain. I'll think more about it and post the theory later.

[niner]

Here is a good paper (open access) about the role of NAD in MS.  Lots of good info.
 

Curr Pharm Des. 2009;15(1):64-99.
The importance of NAD in multiple sclerosis.
Penberthy WT, Tsunoda I.

Department of Molecular Genetics, Biochemistry, and Microbiology, University of Cincinnati, Cincinnati, Ohio 45237, USA. wtpenber@yahoo.com

The etiology of multiple sclerosis (MS) is unknown but it manifests as a chronic inflammatory demyelinating disease in the central nervous system (CNS). During chronic CNS inflammation, nicotinamide adenine dinucleotide (NAD) concentrations are altered by (T helper) Th1-derived cytokines through the coordinated induction of both indoleamine 2,3-dioxygenase (IDO) and the ADP cyclase CD38 in pathogenic microglia and lymphocytes. While IDO activation may keep auto-reactive T cells in check, hyper-activation of IDO can leave neuronal CNS cells starving for extracellular sources of NAD. Existing data indicate that glia may serve critical functions as an essential supplier of NAD to neurons during times of stress. Administration of pharmacological doses of non-tryptophan NAD precursors ameliorates pathogenesis in animal models of MS. Animal models of MS involve artificially stimulated autoimmune attack of myelin by experimental autoimmune encephalomyelitis (EAE) or by viral-mediated demyelination using Thieler's murine encephalomyelitis virus (TMEV). The Wld(S) mouse dramatically resists razor axotomy mediated axonal degeneration. This resistance is due to increased efficiency of NAD biosynthesis that delays stress-induced depletion of axonal NAD and ATP. Although the Wld(S) genotype protects against EAE pathogenesis, TMEV-mediated pathogenesis is exacerbated. In this review, we contrast the role of NAD in EAE versus TMEV demyelinating pathogenesis to increase our understanding of the pharmacotherapeutic potential of NAD signal transduction pathways. We speculate on the importance of increased SIRT1 activity in both PARP-1 inhibition and the potentially integral role of neuronal CD200 interactions through glial CD200R with induction of IDO in MS pathogenesis. A comprehensive review of immunomodulatory control of NAD biosynthesis and degradation in MS pathogenesis is presented. Distinctive pharmacological approaches designed for NAD-complementation or targeting NAD-centric proteins (SIRT1, SIRT2, PARP-1, GPR109a, and CD38) are outlined towards determining which approach may work best in the context of clinical application.

PMID: 19149604
PMCID: PMC2651433 Free PMC Article

[Raza]

Acetylation is am incredibly diverse mechanism for reversibly modifying target molecules to change their function on the fly as needed by the body/cell. A deficit in the acetyl acceptors needed for deacetylation might play a role in aging because this keeps important molecules in the wrong setting in spite of a signal to deacetylate them, and resolving this deficit might then help against aging by fixing this broad problem, but I'm pretty sure you don't want to be globally reducing acetylation or activating deacetylation by other mechanisms. The idea is that these groups are added and removed at exactly the right time and place to suit the needs of the cell, not that molecules are bad for you when they're modified with an acetyl group and good for you when they aren't.

Edited by Raza, 23 July 2014 - 01:32 PM.

[Phoenicis]

That is an excellent paper and gives some good arguments for NA being effective in the brain as well.

 

 

Here is a good paper (open access) about the role of NAD in MS.  Lots of good info.
 

Curr Pharm Des. 2009;15(1):64-99.
The importance of NAD in multiple sclerosis.
Penberthy WT, Tsunoda I.

Department of Molecular Genetics, Biochemistry, and Microbiology, University of Cincinnati, Cincinnati, Ohio 45237, USA. wtpenber@yahoo.com

The etiology of multiple sclerosis (MS) is unknown but it manifests as a chronic inflammatory demyelinating disease in the central nervous system (CNS). During chronic CNS inflammation, nicotinamide adenine dinucleotide (NAD) concentrations are altered by (T helper) Th1-derived cytokines through the coordinated induction of both indoleamine 2,3-dioxygenase (IDO) and the ADP cyclase CD38 in pathogenic microglia and lymphocytes. While IDO activation may keep auto-reactive T cells in check, hyper-activation of IDO can leave neuronal CNS cells starving for extracellular sources of NAD. Existing data indicate that glia may serve critical functions as an essential supplier of NAD to neurons during times of stress. Administration of pharmacological doses of non-tryptophan NAD precursors ameliorates pathogenesis in animal models of MS. Animal models of MS involve artificially stimulated autoimmune attack of myelin by experimental autoimmune encephalomyelitis (EAE) or by viral-mediated demyelination using Thieler's murine encephalomyelitis virus (TMEV). The Wld(S) mouse dramatically resists razor axotomy mediated axonal degeneration. This resistance is due to increased efficiency of NAD biosynthesis that delays stress-induced depletion of axonal NAD and ATP. Although the Wld(S) genotype protects against EAE pathogenesis, TMEV-mediated pathogenesis is exacerbated. In this review, we contrast the role of NAD in EAE versus TMEV demyelinating pathogenesis to increase our understanding of the pharmacotherapeutic potential of NAD signal transduction pathways. We speculate on the importance of increased SIRT1 activity in both PARP-1 inhibition and the potentially integral role of neuronal CD200 interactions through glial CD200R with induction of IDO in MS pathogenesis. A comprehensive review of immunomodulatory control of NAD biosynthesis and degradation in MS pathogenesis is presented. Distinctive pharmacological approaches designed for NAD-complementation or targeting NAD-centric proteins (SIRT1, SIRT2, PARP-1, GPR109a, and CD38) are outlined towards determining which approach may work best in the context of clinical application.

PMID: 19149604
PMCID: PMC2651433 Free PMC Article

 

 

[Phoenicis]

Despite the fact that NA sets a gold standard in terms of it's lipid lowering ability and seems like a viable way of restoring NAD reserves, I do have some negatives to discuss.

 

Nicotinic acid causes a significant increase in growth hormone (GH) as well as cortisol and glucagon. There are a few more studies that document it's effect on GH levels, but I have not been able to confirm whether this also increases IGF-1. It seems that this effect on GH comes as a response to NA's lipid lowering effects and this is somewhat confirmed by the fact that in the previous study, the adenosine derivative (which is a less effective inhibitor of lipolysis) also caused a smaller increase in GH. If it turns out that this also causes an increase in IGF-1, then this would be bad news for people following any form of dietary restriction (DR) for longevity purposes. IGF-1 can inhibit SIRT1 expression and also interferes with pro-regenerative effects of fasting on stem cells. Low IGF-1 levels also play a central role in methionine restriction's benefits.

 

 

This seems counter intuitive given the fact that NA downregulates both cAMP and PKA, since this should result in a decrease in GH/IGF-1 secretion in a similar fashion to fasting. In any case this also begs the question: could the combination of reduced PKA and cAMP from DR and NA be too significant? It has been shown that NA can have a pro-apoptotic effect on neutrophils by activating the GPR109A pathway and downregulating cAMP and PKA.

 

Even though NA increases GH secretion, at the same time it blocks GH's ability to increase FGF21 by acting as a lipolytic inhibitor. Unfortunately FGF21 plays an important part in the life extending effects of dietary restriction and is also necessary for ketogenesis. FGF21 overexpression has also been shown to extend life in mice.

 

All this begs the question of whether NA is compatible with dietary restriction. It seems likely at this point that it can be used to replete NAD+ reserves in practically all organs, but the lipid lowering effects may not be for everyone.

 

I'm going to keep using it for now because it could help with oxidative stress resulting from vyvanse use (reactive oxygen species and the auto-oxidation of dopamine), but it annoys me that it could be interfering with methionine restriction and klotho expression (?). Despite nicotinamide's ability to inhibit SIRT1 and the fact that NAMPT is restricted an NAD+ dependent negative feedback bottleneck, it was able to reduce amphetamine induced ATP depletion and NAD depletion, while also inhibiting PARP1.  NR is obviously also a good option, but the pricing makes it inaccessible for many to use in the necessary quantities.

 

 

Edited by Phoenicis, 31 July 2014 - 01:26 AM.

[Phoenicis]

would the entity who voted me ill informed care to explain why he/she/it thinks I'm wrong? I'd actually be glad if someone proved me wong on this... lol

[gt35r]

After all this, you are telling me that taking just taking Niacin will work ?

[Phoenicis]

I wonder if the homocysteine niacin induced is also true for NR since the 2 are very different in studies (regarding ROS for exemple) + NR doesnt act really as a vitamin (so maybe no competition there with B6 and B12).

Also guys should consider MSM as a methyl donor

 

The homocysteine is a result of nicotinamide methylation (Nam) by N-methyltransferase (NNMT) into 1-methylnicotinamide (MNA). Since Nam is a product of NAD+ consumption by enzymes (PARPs, Sirtuins, CD38) and both NA and NR are converted into NAD+, it would  stand to reason that both NA and NR could cause a rise in homocysteine without adequate b6, b12 SAMe. It seems the that methylation of Nam into MNA is necessary for Sirtuin mediated life extension, at least in worms. 

 

I stopped taking NAC since the cysteine can interfere with methionine restricition benefits. Luckily, that doesn't seem to be the case for taurine.

Edited by Phoenicis, 01 August 2014 - 04:36 AM.

[Phoenicis]

• Wiley et al., NAD+ controls neural stem cell fate in the aging brain, The EMBO JournalVolume 33, Issue 12, pages 1289–1291, 17 June 2014.
• Guarente et al., Sirtuin deacetylases in neurodegenerative diseases of aging, Cell Research (2013) 23:746–758. 21 May 2013
• Imai et al., NAD+ and sirtuins in aging and disease, Volume 24, Trends in Cell Biology, Issue 8, August 2014, Pages 464–471
• Herskovitis et al., SIRT1 in Neurodevelopment and Brain Senescence, Neuron Volume 81, Issue 3, 5 February 2014, Pages 471–483

 

Penberthy et al., The Importance of NAD in Multiple Sclerosis, Curr Pharm Des. PMC Mar 5, 2009 :

 

• "Neuronal explant experiments performed by Sasaki et al. reveal neurons are inefficient at de novo and salvage NAD biosynthesis.[...] Thus, surrounding glial cells may synthesize and supply NAD to neurons in vivo when NAM is administered at pharmacological doses. "
• "...the efficiency de novo and salvage NAD pathways is different in glia compared to neurons"
• "In glia, nicotinic acid provides greater levels of NAD biosynthesis per mole than nicotinamide or tryptophan by 200 and 500 fold respectively [43]."
• "Glial cells seem likely to control delivery of NAD to neurons. [...] it makes best sense to consider pharmacological administration of NAD precursors to give glia the control of NAD delivery or NAD restriction with respect to neurons in MS"
• "Nicotinic acid appears to be preferred over nicotinamide as a NAD precursor primarily when it is applied at the high concentrations [43, 197, 198]. Hara et al. [199], discovered that NAPRT is not inhibited by NAD. By contrast, NAMPT is inhibited by NAD (Fig. 1).
• "Nicotinic acid is rapidly converted to NAD in the brain within just 20 minutes [185]. High doses of oral nicotinic acid are well established in their ability to rescue pellagric dementia and to provide benefit in many cases of schizophrenia [129, 186, 187]."
• "Astrocytes (BBB) readily use NAD precursors to generate NAD and can directly transport NAD across the plasma membrane directly via the adenosine receptor P2XY7R (NA, nicotinic acid; NAM, nicotinamide; NAMR, nicotinamide riboside; W, tryptophan; NaMN, nicotinic acid mononucleotide; NMN, nicotinamide mononucleotide; NaAD, nicotinic acid adenine dinucleotide). By contrast neurons are innefficient in this energy dependent process. Similar to several other pathways, it appears as though glia are likely to serve prominent roles in supplying NAD to neurons."

 

• Picture: http://www.ncbi.nlm....1433/figure/F3/

 

 

 

Edited by Phoenicis, 01 August 2014 - 09:09 AM.

[Phoenicis]

Vinters et al., Astrocytes: biology and pathology, Acta Neuropathol. Jan 2010; 119(1): 7–35.

Abstract

 

Astrocytes are specialized glial cells that outnumber neurons by over fivefold. They contiguously tile the entire central nervous system (CNS) and exert many essential complex functions in the healthy CNS. [...]

→ source (external link)

 

Edited by Phoenicis, 01 August 2014 - 09:58 AM.

[Phoenicis]

Is the '5-methyl tetrahydrofolic acid glucosamine salt' by Jarrow the correct 5-MTHF? They call it '(6S)-5-methyl tetrahydrofolate' as well, are the two names interchangable?

Edited by Phoenicis, 01 August 2014 - 10:10 AM.

[Bryan_S]

I'm in awe of the intellectual power everyone has put into this across several topic forums. Especially Phoenicis, maxwatt, Primal, Darryl and many, many more.

 

I keep seeing references back to the 1983 study "Digestion and Absorption of NAD by the Small Intestine of the Rat" Within that study, on the first page they say; "The possibility exists that NR may be absorbed without further cleavage." Now I've spent a considerable number of hours/days researching this single point and the notion that NR is broken down into NAM before it's absorbed? I've also offered that comment taken from the 1983 study to stimulate some conversation given our immense global intellectual membership. I just cant predicate and pin my opinion on a 31-year old study which hasn't been challenged with a more recent one, especially when the researchers themselves admit; "The possibility exists that NR may be absorbed without further cleavage."

 

I also want the most bang for my buck and I will be closely following the current PK study: A Study of the Pharmacokinetics of Three Dosages of Niagen in Healthy Subjects (14NBHC)

 

Keep up the good work guys I will read every post and reference I can find the time for, thanks for your combined effort!

[gt35r]

Is the '5-methyl tetrahydrofolic acid glucosamine salt' by Jarrow the correct 5-MTHF? They call it '(6S)-5-methyl tetrahydrofolate' as well, are the two names interchangable?

 interchangeable . The 6S implies the specific steric configuration. It is always more proper to include the steric configuration of a molecule in the name. 

[Phoenicis]

Don't know how I missed this but chronic Nicotinamide Riboside (NR) administration failed to raise NAD+ levels and sirtuin activity significantly in the brain. The researchers said this may be due to lower expression of Nrk2, which is responsible for NR metabolism into NAD+. See figures 5 and 6 in Canto et al., The NAD+ Precursor Nicotinamide Riboside Enhances Oxidative Metabolism and Protects against High-Fat Diet-Induced Obesity, Cell Metabolism 2012, Volume 15, Issue 6, p838–847.

 

 

Edited by Phoenicis, 02 August 2014 - 09:41 PM.

[M-K]

Regarding NR activity in the brain, here is a contrary, more recent study:

 

http://www.ncbi.nlm....pubmed/24071780

 

My personal experience also indicates NR marked activity there.  As to sirtuins, I can't say.

Edited by M-K, 02 August 2014 - 10:50 PM.

[Phoenicis]

Very interesting, I would love to see a comparison of NR and NA efficacy for NAD+ biosynthesis in the brain. Neurons do seem a little tricky in that respect since they likely rely on glial cells for NAD+ among other things.

 

I can't access the full text version via my institution, have you read it? Does it say how effective NR was compared to other precursors?

 

 

I'm in awe of the intellectual power everyone has put into this across several topic forums. Especially Phoenicis, maxwatt, Primal, Darryl and many, many more.

 

I keep seeing references back to the 1983 study "Digestion and Absorption of NAD by the Small Intestine of the Rat" Within that study, on the first page they say; "The possibility exists that NR may be absorbed without further cleavage." Now I've spent a considerable number of hours/days researching this single point and the notion that NR is broken down into NAM before it's absorbed? I've also offered that comment taken from the 1983 study to stimulate some conversation given our immense global intellectual membership. I just cant predicate and pin my opinion on a 31-year old study which hasn't been challenged with a more recent one, especially when the researchers themselves admit; "The possibility exists that NR may be absorbed without further cleavage."

 

I also want the most bang for my buck and I will be closely following the current PK study: A Study of the Pharmacokinetics of Three Dosages of Niagen in Healthy Subjects (14NBHC)

 

Keep up the good work guys I will read every post and reference I can find the time for, thanks for your combined effort!

 

The abstract seems to confirm that some NR could be metabolized to Nam:

 

"Recent work investigating the effects of nicotinamide riboside in yeast and mammals established that it is metabolized by at least two types of metabolic pathways. The first of these is degradative and produces nicotinamide. The second pathway involves kinases called nicotinamide riboside kinases (Nrk1 and Nrk2, in humans)."

→ source (external link)

Edited by Phoenicis, 02 August 2014 - 11:24 PM.