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Nicotinamide, NAD(P)(H), and Methyl-Group Homeostasis

Sidereal

Senior Member
Messages
4,856
Int J Tryptophan Res. 2013; 6: 73–88.
Published online Oct 15, 2013. doi: 10.4137/IJTR.S12838
PMCID: PMC3825668
Big Brains, Meat, Tuberculosis, and the Nicotinamide Switches: Co-Evolutionary Relationships with Modern Repercussions?
Adrian C. Williams1 and Robin I.M. Dunbar2

Nicotinamide (vitamin B3) is essential to the production of NAD, the electron carrier that feeds mitochondria and is oxidized to produce proton-motive forces to form adenosine triphosphate (ATP), which in turn drives household cellular activities, defends against microbes, and facilitates a wealth of metabolic transformations. NAD is often limiting and is the key regulator within NAD/NADH redox ratios. NAD forms NADH which, in turn, acts as the cosubstrate for various redox reactions and dehydrogenases (such as of alcohol and lactate), thereby playing a pivotal role in the regulation of ion channels, and converts to NADPH and oxidant defences and synthetic anabolism.34,35 A good diet and nicotinamide supply would be expected both to improve robustness against acute microbial attack and to optimize brain function. In addition it is increasingly recognized that NAD(H)-based metabolism is the “engine” that not only sustains all cellular activities but can also “steer” and control cellular processes including differentiation. 36 Recently described effects on the survival and programming of stem cells by nicotinamide and tryptophan/ serotonin put them in a position to benefit brain development and maintenance, and enable the initial evolution of big brains as a single unit. Specifically, only a few extra cycles of cortical neurogenesis affect the proliferation of cells migrating to the prefrontal and parietal cortex, with enhanced differentiation of post-mitotic offspring (such as large cortical pyramidal neurons, which are affected in pellagra). These cycles could lead to a bigger neocortex and, after a series of environmentally-sensitive selective culls during development, could produce plastic and adapted cortico-basal ganglia, forming the better connected and neurochemically modulated mosaic brain that ultimately shapes our actions and minds.3742

NAD serves as a precursor of adenosine diphosphate (ADP)–ribose-containing messenger molecules, as well as deacetylation messenger molecules that respond to stress and drive many cell and social processes (Fig. 1). NAD consumer hubs involve sirtuins (SIRTs) and poly(ADP-ribose) polymerases (PARPs), that are inhibited by nicotinamide and have natural diet-derived agonists such as resveratrol (used by plants to cope with stress). These integrate a number of external interactions such as foraging, exercise, social interactions, and learning. They are also involved in internal regulatory roles that have pervasive effects on the immune-system, cell fates, and cycles such as differentiation, growth, autophagy, chromatin regulation with epigenetic gene silencing, microtubule organization, somatic mutation rate, and DNA repair.43,44 All of these link with pathophysiological stress mechanisms that are relevant to repairs, regeneration, survival, aging, and disease; there are many examples of these NAD circuits being at the nexus of metabolic homeostasis, and a “NAD or hydrogen world” has been proposed, dating from the geothermal origins of life.4547 Indeed NAD homeostasis could, in part, replace the five factors that Cannon envisaged as the “Wisdom of the Body,” as it incorporates environmental information (initially through NAD-dependent circadian rhythms) and physiological needs with NAD(H)-powered brains to adapt to stress and prevailing circumstances in such a way as to niche construct and eco-engineer future “NAD worlds.”48

This metabolic, behavioral, and immunological cross-road centers on the tryptophan to NAD de novo pathway—whose initiating and rate-limiting enzymes, indoleamine 2,3-dioxygenases (IDO-1 and IDO-2) or tryptophan 2,3 dioxygenase (TDO) are induced by cytokines—are usually affected by interferons (predominantly in professional antigen-presenting cells, or directly by infections such as human immunodeficiency virus [HIV]) that, in turn, affect immune function via kynurenines, which influence the population of T-cells (favoring regulatory T-cells over cytotoxic T-cells). Largely acting via excitotoxic and pro-oxidant quinolinic acid (picolinic acid is a neuroprotective chelating agent, but is not on the final path to NAD), the kynurenine pathway is implicated in many metabolic disorders (including insulin-resistance states), (neuro)degenerative disorders, inflammatory disorders, infectious disorders, and cancer.4952 This tryptophan path links with protein mammalian target of rapamycin (mTOR) paths, which senses tryptophan deprivation and also plays a pivotal part in immunity and aging.53

The nicotinamide- and tryptophan-to-NAD pathway is a “tolerance” link with the immune system, allowing selected symbionts to prosper—we do not think that these links are always simply tolerated because the immune response to eliminate them would be too energetically expensive, or would involve too much collateral damage. It also interfaces with the “social” neurotransmitters (notably serotonin), allowing group activities that benefit the food supply.54 It is likely that this as the de novo pathway for NAD with synthesis from tryptophan (normally a minor contributor to the NAD pool), and all these activities work hand-in- hand over the short-term to improve the vital NAD supply—but at a longer-term cost. NAD deficiency resulting from dietary sources activating this pathway has, in recent times, been underemphasized relative to cytokine induction. Many infections (for example, Toxoplasma gondii, Leishmania donovanii, and Clamydia sp.) activate this pathway and may stimulate NAD production to the host’s benefit at times, but these infections often consume tryptophan, as it is important for their own growth; more importantly, however, they also produce toxic compounds. Therefore, it is hard to see much human benefit in these infections (except perhaps when dietary tryptophan is too high), unless the microbe simultaneously increases the supply of tryptophan or nicotinamide—as we argue happens with TB.55

Nicotinamide Switches—Recent
A switch away from the de novo pathway, which occurs when there is adequate nicotinamide via diet, could lead to less chronic symbiotic infection and degeneration, with increased longevity. However, if the nicotinamide dose rises too high, immune intolerance may develop. For example, it may cause infertility(or at least to lower numbers); it may cause allergies including to our own tissues, leading to autoimmune diseases; and it may extend to commensals, causing inflammatory disorders), perhaps in part driven by molecular mimicry.56 These conditions are now common, with many novel versions still being described, but they first emerged amongst the wealthy as “sneezes and wheezes” in the early 19th century, coinciding with reductions in many infections—sanatoria changed quickly from focusing on TB cases to offering fashionable cures for hayfever, asthma, and allergies.57,58 Nowadays, these immune intolerance syndromes are often treated with immunosuppression, but that comes with many long-term side-effects; more subtle and safer manipulations might include less dietary nicotinamide but more tryptophan (as its substrate it induces IDO).59 Molecular mimicry may be driven by antigenic overlap with “old friends” or “old foes,” and an “epidemic of absence” but on this hypothesis is driven proximally from a diet with more nicotinamide rather than better hygiene.60 Cancers from nicotinamide (vide infra) and tryptophan/serotonin toxicity (perhaps even autism, anxiety, or hypochondriasis and narcissism) may follow, as all these conditions increase in incidence with increasing affluence.61 Global maps show a mosaic pattern of disease biogeography (and corresponding changes over time) with migrants rapidly acquiring the local incidence of various diseases. These maps show striking environmental mirror images. In the north–south gradients for TB and childhood diarrhea the rates are high in the southern hemisphere (excluding wealthier Australasia) but, in contrast, autoimmune diseases, including multiple sclerosis, asthma, Crohn’s disease, diabetes and allergies, are high in the wealthier north and in the west.62 A powerful and quick-acting environmental factor (with minor input from genetic variation) has to be responsible and could be the same factor with biphasic toxicity at low and high doses and an optimal middle range.
 

bertiedog

Senior Member
Messages
1,738
Location
South East England, UK
@Little Bluestem Well it hasn't lasted but I do still use an oxygen concentrator 3 times daily for 30 minutes. I tend to use it after meals when I slump a bit or after a walk with my dog if necessary.

I was diagnosed by Breakspear in the UK with their basic autonomic testing. I had less than 50% of the normal oxygen in my cells when all I had to do was to take 6 breaths over one minute whilst lying down in order to stress my body.

Since then I have been diagnosed through Infectolab with lyme disease and Ehrlichia so this probably explains why I couldn't stay feeling better. I am not doing too badly but still have problems with energy running out everytime I do anything physical so I can only ever walk for a maximum of 30 minutes.
 

Kimsie

Senior Member
Messages
397
I found the following study interesting. It describes how the balance of B3 and methyl groups ultimately determine health status and aging.



An illustration from the study:
CGGR2012-302875.003.jpg

I must admit that I really don't have the knowledge to understand the implications of the article in depth. I'm hoping someone more knowledgeable than me will chime in.

But as I understand it, both under- or overdosing B3 and methyl groups will lead to serious health problems. The question is, how do we find the right balance? From the full text:


So what does this tell the many of us who are essentially megadosing on B vitamins and methyl donors? Is it safe at all? Or should we not supplement them? Are the problems related to ratio, dose or both? How would supplementing NAD or NADH change the picture?

If I seem confused, it's because I am.
Hi Adreno,
I will think about this article some more, but I do have a couple of comments right away. For one thing, the majority of the methyl groups in the body come from serine (which is synthesized from glucose) or glycine and so many are used every second in the body that the miniscule amount that a person takes when they take "methyl donors" is insignificant. The only thing I can find that can cause high SAMe levels is insufficient activity of glycine N-methyltransferase, which occurs in the liver.

As the mother of a person with schizophrenia, I have read many, many articles which try to pin schizophrenia on something that begins during pregnancy, and I just don't buy it. I have 4 children, and only one with schizophrenia, and during his pregnancy I ate more meat (but not a huge amount more) than I did during the other 3 which is the opposite of what this article suggests, and there was nothing else different during that pregnancy that could account for him having schizophrenia.

My research these last few days is centering on NAD synthesis and understanding the folate cycle, which is compartmentalized and has somewhat different enzymes in the matrix, cytosol and the nucleus (and liver), and so NMNT is one of the enzymes I am looking at. I think that these two processes and the interaction between them are major players in these illnesses and I am trying to get a handle on how they work together.
 

jepps

Senior Member
Messages
519
Location
Austria
http://medicalxpress.com/news/2016-04-vitamin-aging.html

Nicotinamide riboside (NR) is pretty amazing. It has already been shown in several studies to be effective in boosting metabolism. And now a team of researchers at EPFL's Laboratory of Integrated Systems Physiology (LISP), headed by Johan Auwerx, has unveiled even more of its secrets. An article written by Hongbo Zhang, a PhD student on the team, was published today in Science and describes the positive effects of NR on the functioning of stem cells. These effects can only be described as restorative.

Parallel studies have revealed a comparable effect on stem cells of the brain and skin. "This work could have very important implications in the field of regenerative medicine," said Auwerx. "We are not talking about introducing foreign substances into the body but rather restoring the body's ability to repair itself with a product that can be taken with food." This work on the aging process also has potential for treating diseases that can affect - and be fatal - in young people, like muscular dystrophy (myopathy).

This supplement is available from Thorne http://uk.iherb.com/Thorne-Research-Niacel-Nicotinamide-Riboside-60-Veggie-Caps/57082 or supersmart http://www.supersmart.com/en--Anti-aging--Nicotinamide-Riboside-125-mg--0632
 

CCC

Senior Member
Messages
457
As the mother of a person with schizophrenia, I have read many, many articles which try to pin schizophrenia on something that begins during pregnancy, and I just don't buy it. I have 4 children, and only one with schizophrenia, and during his pregnancy I ate more meat (but not a huge amount more) than I did during the other 3 which is the opposite of what this article suggests, and there was nothing else different during that pregnancy that could account for him having schizophrenia.

I've had a bit of contact with metal illness in the pas few decades. While mental illness and spectrum disorders seem to run in families (so genetics and susceptibility is obviously involved), it is not the mother's fault.

I soooo hate it when they blame the mother.
 

heyitisjustin

Senior Member
Messages
162
@Little Bluestem Well it hasn't lasted but I do still use an oxygen concentrator 3 times daily for 30 minutes. I tend to use it after meals when I slump a bit or after a walk with my dog if necessary.

I was diagnosed by Breakspear in the UK with their basic autonomic testing. I had less than 50% of the normal oxygen in my cells when all I had to do was to take 6 breaths over one minute whilst lying down in order to stress my body.
Have you heard of Wim Hof? His breathing method might help with your oxygen issue