NAD+

Research NAD⁺ is a vital coenzyme involved in more than 500 redox reactions and plays crucial roles in non-redox enzymatic processes, including cell signaling (CD38), DNA repair (PARPs), and epigenetic modifications (Sirtuins). The decline of NAD⁺ levels has been linked to various health issues, such as aging and obesity-related metabolic disorders like non-alcoholic fatty liver disease and type 2 diabetes. Replenishing NAD⁺ levels, often through NAD⁺ precursors like NR or NMN, has shown promise in extending lifespan and improving metabolic disorders. Our own research has uncovered a remarkable NR derivative compound called dihydronicotinamide riboside (NRH), which exhibits unparalleled efficacy in augmenting NAD⁺ levels, surpassing the increase achieved by NR in cell and animal models. Additionally, we have elucidated the NRH-induced NAD⁺ biosynthesis pathway, involving the phosphorylation of NRH into NMNH by adenosine kinase, followed by conversion to NAD⁺. Importantly, by administering adenosine kinase inhibitors, we successfully inhibited the NRH-induced NAD⁺ increases in cells and animal tissues. Presently, our investigation aims to further characterize the physiological effects of NRH and other novel NAD⁺ precursors, as well as their underlying mechanisms in metabolic disease and aging models, to evaluate their therapeutic potential.

Research Area 1: NAD Metabolism in Pancreatic Beta Cell Health.

NAD is essential for regulating insulin secretion and survival pathways in pancreatic beta cells, particularly during the progression of Type 2 Diabetes. We found that, in obese mice with established hyperglycemia, NRH treatment improved pancreatic beta cell function and insulin secretion. The underlying mechanisms are currently being investigated under an R01 grant sponsored by NIDDK.

Research Area 2: NAD Dysregulation in Cardiac Aging.

NAD levels decline in the heart with age, leading to an increased burden of cellular senescence, hypertrophy, and fibrosis, which contribute to myocardial remodeling and age-related cardiac dysfunction. We are specifically interested in understanding how cardiomyocyte senescence can be regulated by NAD depletion and replenishment, and how NAD precursors can be applied as therapeutic agents to interrupt the progression of cardiac aging.