Big brains, meat, tuberculosis, and the nicotinamide switches: co-evolutionary relationships with modern repercussions?

Abstract

Meat-eating was a game changer for human evolution. We suggest that the limiting factors for expanding brains earlier were scarcities of nicotinamide and tryptophan. In humans and some other omnivores, lack of meat causes these deficiencies. Nicotinamide adenine dinucleotide (NADH) is necessary to synthesize adenosine triphosphate (ATP) via either glycolysis or via the mitochondrial respiratory chain. NAD consumption is also necessary for developmental and repair circuits. Inadequate supplies result in "de-evolutionary" brain atrophy, as seen with pellagra. If trophic nicotinamide/tryptophan was a "prime mover" in building bigger brains, back-up mechanisms should have evolved. One strategy may be to recruit extra gut symbionts that produce NADH precursors or export nicotinamide (though this may cause diarrhea). We propose a novel supplier TB that co-evolved early, which did not originally and does not now inevitably cause disease. TB has highly paradoxical immunology for a pathogen, and secretes and is inhibited by nicotinamide and its analogue, isoniazid. Sharp declines in TB and diarrhea correlated with increased meat intake in the past, suggesting that dietary vitamin B3 and tryptophan deficiencies (also associated with poor cognition and decreased lifespans) are still common where meat is unaffordable.

Keywords: Parkinson’s; cancer; dementia; diarrhea; hypervitaminosis B3; pellagra; serotonin.

Figure 1

The de novo pathway for the semi-vitamin nicotinamide is also the immune tolerance pathway, and is closely connected to serotonin synthesis and social signaling. This may be a homeostatic circuit that supports energy and nicotinamide/tryptophan acquisition, and responsive internal solutions such as autophagy and symbionts that supply nicotinamide and NAD(H), or, pseudo-symbionts such as cancer that sink nicotinamide excesses, as do metabolic and inflammatory syndromes, but they lead to longer term toxicity. Abbreviations: SIRTs, sirtuins; PARPs, poly(ADP ribose polymerase); cADP, cyclic adenosine diphosphate; ARTs, T-cell ADP ribosyl-transferase; NNMT, nicotinamide-N-methyl-transferase.

Figure 2

Meat consumption (kg per capita) plotted against the decline of TB between 1840 and 1960 in the UK.

Figure 3

Frequency of current TB cases plotted against meat consumption for individual countries. The graph (not shown) for diarrheal illnesses looks very similar. Note the very high variances between countries in meat consumption in the contemporary world.

Figure 4

Nicotinamide: the devil may be in the dosage. Too low and symptoms of pellagra emerge, even if rarely diagnosed as the rash may frequently not be expressed. Higher doses than usually recommended may be necessary for individuals carrying certain mutations and when under genotoxic or infectious or traumatic stresses that require temporary boosts of repair circuits. Too high a dose chronically from supplemented food-stuffs or too much meat causing nicotinamide overload (an experiment whose long-term effectiveness or toxicity has never been monitored) may express itself phenotypically in many ways covering many common diseases, as does pellagra.