Nicotinamide, NAD(P)(H), and Methyl-Group Homeostasis Evolved and Became a Determinant of Ageing Diseases: Hypotheses and Lessons from Pellagra

Abstract

Compartmentalized redox faults are common to ageing diseases. Dietary constituents are catabolized to NAD(H) donating electrons producing proton-based bioenergy in coevolved, cross-species and cross-organ networks. Nicotinamide and NAD deficiency from poor diet or high expenditure causes pellagra, an ageing and dementing disorder with lost robustness to infection and stress. Nicotinamide and stress induce Nicotinamide-N-methyltransferase (NNMT) improving choline retention but consume methyl groups. High NNMT activity is linked to Parkinson's, cancers, and diseases of affluence. Optimising nicotinamide and choline/methyl group availability is important for brain development and increased during our evolution raising metabolic and methylome ceilings through dietary/metabolic symbiotic means but strict energy constraints remain and life-history tradeoffs are the rule. An optimal energy, NAD and methyl group supply, avoiding hypo and hyper-vitaminoses nicotinamide and choline, is important to healthy ageing and avoids utilising double-edged symbionts or uncontrolled autophagy or reversions to fermentation reactions in inflammatory and cancerous tissue that all redistribute NAD(P)(H), but incur high allostatic costs.

Figure 1

NAD(H)—the electron donor to complex I translocating protons across the membrane by a “steam engine” like mechanism producing ATP: the most important function of mitochondria alongside proton leaks for heat and energy dissipation and signals for autophagy and apoptosis. Many mutations that affect mitochondrial complex 1, or, microtubular function and kinases and autophagy/mitophagy and radical production contribute to rare forms of ageing diseases such as PD in a vicious cycle subverting normal quality controls that affect proteosomal homeostasis. In the case of Parkinsons', increasing NADH levels may drive excessive dopamine synthesis to toxic levels by enhancing the recycling of the cofactor for tyrosine hydroxylase.

Figure 2

Direct redox regulation apart NAD-consuming pathways influences a prodigious number of pathways involved in internal metabolism and connections with the external world. Survival at the cellular level and of viable interactions with each other and diet and symbionts means that NAD and Nicotinamide are at the hub of the survival of superorganisms such as ourselves. Key: FoxO—forkhead transcription factors; Sirt2 and PARP in text; CD38 cluster differentiation 38; TNF—tumor necrosis factor; E2 Prostaglandin E2; cADP—cyclic adenosine di-phosphate; ART2—T-cell ADPribosyltransferase; ADPR protein—adenosine di-phosphate ribose protein.

Figure 3

NAD(H) availability is key to good brain evolution and development. An inherent weak link is poor supply or a potential imbalance between induction of NNMT and nicotinamide and choline intake in early and later life with a risk of late degenerations such as Alzheimer's and Parkinson's disease. Overinduction of NNMT by nicotinamide could paradoxically cause intracellular pellagra perhaps explaining why nicotinamide can appear to help short-term even though nicotinamide may be a long-term toxin. In addition, poor diet or induction of NNMT disturbs the methylome and the epigenome creating cancer promoting epimutations.