Four nicotinamide adenine dinucleotide (NAD) coenzymes are the central catalysts of metabolism that allow us to convert everything we eat into everything we are and everything we do. Cells make and interconvert these coenzymes in order to allow us to keep the electrons flowing. NAD coenzymes are at the essential core of all vital processes.
Though one could consider NAD+, NADH, NADP+ and NADPH the crown jewels of metabolism, they are unlike crown jewels that are locked inside a vault inside a castle patrolled by armed guards. We discovered that NAD coenzymes are exposed to the elements of metabolic stress.
Dozens of conditions of metabolic stress including overnutrition, alcoholism, DNA damage, free radical damage, heart failure, central and peripheral neurodegeneration, postpartum, and coronavirus infection disturb the NAD system, thereby challenging a tissue’s ability to self-repair, conduct fundamental bioenergetic processes, and convert biosynthetic inputs into working structures.
Our approach to NAD metabolism was initially based on enzyme characterization and gene discovery, particularly of the eukaryotic nicotinamide riboside (NR) kinase pathway to NAD, and identification of NR and nicotinic acid riboside as NAD precursors. Since then, we developed quantitative targeted NAD metabolomic technologies to identify and characterize conditions of metabolic stress that disturb the NAD system.
We have repeatedly identified pathological and developmental conditions in which
– NAD+ and/or NADPH are under attack;
– low abundance, stress-signaling metabolites such as NMN, cADPR or NAADP accumulate; and/or
– the NAD gene set is altered at the transcriptional level.
Significantly, we have found that bioenergetic crises, such as occur in heart failure and neurodegeneration, involve a simultaneous attack on NAD+ and induction of the NMRK1 and/or NMRK2 genes. This is evidence for an endogenous system that releases NR for the benefit of damaged cells. Moreover, in these conditions, we have found that oral provision of NR repletes the NAD metabolome and results in substantial protection from the underlying insult.
We have also identified malignancies with specific disturbances in NAD metabolism that makes them vulnerable to biomarker-informed targeting of particular NAD pathways. The lab is expanding. Please read our publications and be in touch.