Nicotinamide mononucleotide (NMN) deamidation and indirect regulation of the NAD metabolome

Abstract Treatment with nicotinamide mononucleotide (NMN) is a prominent strategy to address the age-related decline in nicotinamide adenine dinucleotide (NAD+) levels for maintaining aspects of late-life health. It is assumed that exogenous NMN is directly incorporated into the NAD+ metabolome in mammals via the canonical recycling pathway. Here, we show that NMN can undergo direct deamidation and incorporation via the de novo pathway, which is in part mediated by the gut microbiome. Surprisingly, isotope labelling studies revealed that exogenous NMN treatment potently increased the endogenous production of unlabelled NAD metabolites, suggesting that exogenous NMN impacts the NAD metabolome through indirect means, rather than through its direct incorporation. This included a striking increase in endogenous production of the metabolites nicotinic acid riboside (NaR) and nicotinamide riboside (NR) which was amplified in antibiotics treated animals, suggesting the production of endogenous NaR/NR through altered metabolic flux, enzyme kinetics and/or an as-yet unidentified pathway that interacts with the gut microbiome.