Nicotinamide and Demographic and Disease transitions: Moderation is Best

Abstract

Good health and rapid progress depend on an optimal dose of nicotinamide. Too little meat triggers the neurodegenerative condition pellagra and tolerance of symbionts such as tuberculosis (TB), risking dysbioses and impaired resistance to acute infections. Nicotinamide deficiency is an overlooked diagnosis in poor cereal-dependant economies masquerading as 'environmental enteropathy' or physical and cognitive stunting. Too much meat (and supplements) may precipitate immune intolerance and autoimmune and allergic disease, with relative infertility and longevity, via the tryptophan-nicotinamide pathway. This switch favours a dearth of regulatory T (Treg) and an excess of T helper cells. High nicotinamide intake is implicated in cancer and Parkinson's disease. Pro-fertility genes, evolved to counteract high-nicotinamide-induced infertility, may now be risk factors for degenerative disease. Moderation of the dose of nicotinamide could prevent some common diseases and personalised doses at times of stress or, depending on genetic background or age, may treat some other conditions.

Keywords: Flynn effect; IQ; Parkinson’s disease; TB; Tregs; antagonistic pleiotropy; cancer; dementia; disposable soma; environmental enteropathy; hypervitaminosis B3; immune intolerance; pellagra; thrifty phenotype.

Figure 1.

Nicotinamide switch. Higher doses shift the immune system from tolerance of infection to intolerance of antigens with consequences for both disease and fertility. Many modern therapies try to rebalance the immune system but moderation of the nicotinamide dose might have prevented the problem. AHR indicates aryl hydrocarbon receptor; BD, Behçet disease; IL, interleukin; MS, multiple sclerosis; NAD, nicotinamide adenine dinucleotide; RA, rheumatoid arthritis; SLE, systemic lupus erythematosus; TGF, transforming growth factor; TRYP, Tryptophan.

Figure 2.

A well-balanced diet is the base from which all else follows. Formulae for success had emphasised the necessity of the higher tiers, although without much agreement. Superstructure is however important as positive feedback loops further secure a high-quality diet.

Figure 3.

After the Black Death (triggered by famines), the population remained remarkably stable as did the supply of meat helped by increased wages. This period is generally agreed to have been a take-off for the industrial revolution.

Figure 4.

After the Black Death, the meat supply remained affordable and in step with the price of grain until around 1650. Then in the ‘little ice-age’ (perhaps triggered by population collapse in the new world) with harvest failures, and wars, meat became very expensive and with the exception of the wealthy the population became virtually vegetarian. Consistent with our hypothesis, fertility and population took off as did TB in the period just before the United Kingdom’s demographic transition around 1850 and the decline of TB as meat became more available, largely thanks to the wealth to pay for imports. TB indicates tuberculosis.

Figure 5.

The poor diet in pellagra-ridden American southern states delayed economic progress, despite being the source of the international cotton industry.

Figure 6.

Comparison of birth rates between the industrial North and the South of the United States. Southern states prone to pellagra maintained high fertility for a lot longer as did the pellagra-prone province around Venice a century earlier – both examples lengthening their demographic transitions.

Figure 7.

Fertility rates fell after the death rate and as meat intake rose in the United Kingdom’s demographic transition. This is the opposite of what happened in the pellagra-prone provinces of Italy and the United States.

Figure 8.

Conventional demographic transition joined to the Neolithic transition. Lower meat drove the Neolithic, whereas an increase in the meat/cereal ratio drove recent transitions. Natural increase = excess of birth after deaths. NAD indicates nicotinamide adenine dinucleotide.

Figure 9.

Koch’s postulates need revision for nutritional symbiotic relationships. Symbionts, such as TB, enhance the supply of nicotinamide when the diet is poor but become dysbiotic if the diet becomes extremely poor. Improving diet, a preventive in the early stages, may no longer be enough to reverse pathology later. TB indicates tuberculosis.

Figure 10.

Many pathogens import niacin. TB (and some gut microbes) can export nicotinic acid. On a high-nicotinamide diet, both classic pathogens and symbionts are less virulent or dysbiotic. NAD indicates nicotinamide adenine dinucleotide; TB, tuberculosis;

Figure 11.

NAD(H) recycles (not shown) in redox and dehydrogenase reactions and supplies mitochondria to generate ATP. Here we show consumption reactions and salvage pathways that conserve the supply of nicotinamide. When the dietary supply is poor, the ‘de novo’ pathway needs a dietary supply of tryptophan. ATP indicates adenosine triphosphate; NA, nicotinamide; NAD, nicotinamide adenine dinucleotide; NAD(H), nicotinamide adenine dinucleotide plus hydrogen; NAM, nicotinamide; NAMPT, nicotinamide phosphoribosyltransferase; NMN, nicotinamide mononucleotide; NMNAT, nicotinamide mononucleotide adenylyltransferase; NNMT, nicotinamide N-methyltransferase; NR, nicotinamide-riboside; PARP, poly(ADP-ribose) polymerase.

Figure 12.

Structure of nicotinamide showing its detoxification pathway that consumes methyl groups and produces N-methyl-nicotinamide that is metabolically active but then excreted. MNAM indicates N1-methylnicotinamide; NAM, nicotinamide; NNMT, nicotinamide N-methyltransferase; SAH, S-adenosylhomocysteine; SAM, S-adenosylmethionine.

Figure 13.

Striking time linked correlations between the fall in TB and the rise of cancer at a time when meat intake doubled. The same was true of the rise, particularly after 1900, in allergic and autoimmune diseases, as well as Parkinson’s disease. TB indicates tuberculosis.

Figure 14.

High nicotinamide in diet has consequences. The switch from infections to inflammation and autoimmunity can be explained by several overlapping mechanisms as can relative infertility and longevity alongside the metabolic syndrome and cancer. MNAM indicates N1-methylnicotinamide; NMN, nicotinamide mononucleotide; NNMT, nicotinamide N-methyltransferase; SAM, S-adenosylmethionine; PD, Parkinson’s disease.

Figure 15.

Nicotinamide dose matters from conception to cradle to grave. PD is a good example. An optimal dose induces NNMT and supplies NAD to mitochondria and NAD consumers and is enough to regulate DNA methylation and stimulate autophagy to keep organelles in good repair. Too much (or too little) nicotinamide and all fails, exacerbated by genetic mutations that affect autophagy known to be important in PD. MPTP indicates 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine; NAD, nicotinamide adenine dinucleotide; NNMT, nicotinamide N-methyltransferase; PARP, poly(ADP-ribose) polymerase; PD, Parkinson’s disease; SAM, S-adenosylmethionine.