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 a critical intermediate that is synthesized from nicotinamide. Nicotinamide phosphoribosyltransferase (NAMPT) is the key enzyme that catalyzes the conversion from nicotinamide to NMN.
In our previous studies, we have demonstrated that NAMPT functions both inside and outside the cells and plays a critical role in maintaining normal insulin secretion in pancreatic cells. Strikingly, NMN, a product of the NAMPT reaction, circulates in mouse and human blood, and cells 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 ages 30s-60s and analyzing the relationship between systemic NAD biosynthesis and metabolic parameters in those human subjects.
We have made important findings from mouse studies outlined in Specific Aim (1) in the first budgetary year and will therefore focus on human studies proposed in Specific Aim (2) in the second budgetary year. These studies should provide new, critical insights into the physiological significance of systemic NAD biosynthesis and therapeutic applications of NMN for metabolism and aging in mice and humans.
Final Report:
This study aimed to understand the importance of systemic NAD biosynthesis regulated by nicotinamide phosphoribosyltransferase (NAMPT), a key NAD biosynthetic enzyme, in predicting and extending the health span in humans and to explore the potential of nicotinamide mononucleotide (NMN), a product of the NAMPT reaction and a novel metabolite in mouse and human plasma, as a biomarker of aging and a therapeutic agent to prevent and treat age-associated metabolic complications, such as type 2 diabetes, in humans. In our previous studies, we have demonstrated that NAMPT functions as an intra- and extracellular NAD biosynthetic enzyme and plays a critical role in maintaining normal NAD biosynthesis and glucose-stimulated insulin secretion in pancreatic β cells. We also found that plasma NMN levels decrease over age in mice. In this study, therefore, we hypothesized that plasma NMN levels might serve as a novel functional biomarker to predict the risks of age-associated metabolic complications and that NMN administration might be an effective intervention to prevent/treat those age-associated complications, such as type 2 diabetes, in mice and humans.
To address this hypothesis, we conducted both mouse and human studies. In the mouse study [SPECIFIC AIM (1)], we examined the importance of NAMPT-mediated NAD biosynthesis in the pathogenesis of high-fat diet (HFD)- and age-induced type 2 diabetes. We successfully demonstrated that both HFD and aging compromise NAMPT-mediated NAD biosynthesis, contributing to the pathogenesis of diet- and age-induced type 2 diabetes. Short-term NMN administration dramatically ameliorated the pathophysiology of type 2 diabetes, partly through SIRT1 activation, providing proof of the concept that promoting NAD biosynthesis by administering NMN can be an effective nutriceutical anti-aging intervention.
In the human study [SPECIFIC AIM (2)], we measured plasma NMN levels in 40 obese non-diabetic human subjects and analyzed possible relationships between plasma NMN levels and various metabolic parameters. Whereas this initial assessment failed to show any significant correlations, the study provided critical information to set up the next human study that will look much deeper into the dynamics of NAMPT-mediated systemic NAD biosynthesis in humans. Therefore, these findings clearly provide new insights into the physiological significance of NAMPT-mediated systemic NAD biosynthesis and therapeutic applications of NMN for metabolism and aging in rodents and humans.
