Shin-ichiro Imai, M.D., Ph.D.
Project Overview:
This proposal aims to understand the importance of a new metabolic regulatory system termed systemic NAD biosynthesis in predicting and extending the health span in humans and to explore the potential of nicotinamide mononucleotide (NMN), a key chemical in this systemic NAD biosynthesis system, as a biomarker of aging and a therapeutic agent to prevent and treat age-associated metabolic complications, such as obesity and type 2 diabetes, in humans. Nicotinamide adenine dinucleotide (NAD) is an important chemical that functions as an essential currency for cellular energy metabolism in all living organisms. In mammals, nicotinamide (a form of vitamin B3) is a major substrate to synthesize NAD, and NMN is an intermediate compound that is synthesized from nicotinamide. Nicotinamide phosphoribosyltransferase (Nampt) is the key enzyme that catalyzes the conversion from nicotinamide to NMN. We have recently demonstrated that Nampt functions both inside and outside the cells and plays a critical role in maintaining normal insulin secretion in pancreatic β cells. Strikingly, NMN, a product of the Nampt reaction, circulates in mouse and human blood, and βcells depend on circulating NMN to maintain their function. We have also found that plasma NMN levels decrease over age in mice and that NMN administration improves glucose metabolism in aged, diabetic mice. In this proposal, therefore, we hypothesize that plasma NMN levels might serve as a novel functional biomarker to predict the risks of age-associated metabolic complications, such as obesity and type 2 diabetes, and that NMN administration might be an effective intervention to prevent/treat those age-associated complications in mice and humans. To address this hypothesis, we will 1) examine whether a genetic manipulation that decreases Nampt levels accelerates the development of metabolic complications over age or under a high-fat diet (HFD) in mice and 2) examine whether plasma NMN levels can be used as an effective biomarker to assess the risk of age-associated metabolic complications by measuring NMN levels in plasma samples from human obese non-diabetic subjects at the age of 30s-60s and analyzing the relationship between systemic NAD biosynthesis and metabolic parameters in those human subjects. These studies should provide new, critical insight into the physiological significance of systemic NAD biosynthesis and therapeutic applications of NMN for metabolism and aging in mice and humans.
