Research Abstract:
My laboratory focuses on the molecular mechanisms of aging and longevity in mammals. Recent studies have revealed critical regulators and pathways for the metabolic regulation of aging and longevity in model organisms. Our questions are three-fold: 1) Is there any “control center” to regulate the pace of aging and longevity? 2) Is there any specific hormone(s) that is secreted from the “control center” and regulates aging? and 3) Is there any “universal regulatory factor” to regulate the production and/or secretion of such hormones? We are addressing these questions by focusing on the function of the mammalian NAD-dependent deacetylase Sirt1 (Imai et al., Nature 403:795-800, 2000). Sir2 orthologs have been demonstrated to play key roles in regulating aging and longevity in lower eukaryotes and also implicated to be a mediator for caloric restriction, which retards aging and extends longevity in a variety of organisms. Currently, we have two main projects: 1) Tissue-specific functions of Sirt1 in the regulation of metabolism and aging. We are examining whether Sirt1 controls the pace of aging through the regulation of key metabolic responses to nutrient availability in different tissues by employing integrated physiology and mouse genetics. Our current focuses are on the roles of Sirt1 in pancreatic beta cells, hepatocytes, and hypothalamic neurons. 2) Systemic regulation of mammalian NAD biosynthesis. We speculate that systemic NAD biosynthesis might play an essential role in aging by regulating Sirt1 activity. We are currently studying systemic NAD biosynthesis mediated by intra- and extracellular nicotinamide phosphoribosyltransferase (iNampt and eNampt). These studies will set the stage for subsequent genetic and pharmacological manipulations of Sirt1 activity and/or NAD biosynthesis and assessment of the impact of such interventions on mammalian aging and longevity.
Selected Publications:
Revollo JR, Grimm AA and Imai S. The regulation of nicotinamide adenine dinucleotide biosynthesis by Nampt/PBEF/visfatin in mammals. Curr. Opin. Gastroenterol 2007 23:164-170.
Moynihan KA and Imai S. Sirt1 as a key regulator orchestrating the response to caloric restriction. Drug Discovery Today. Dis Mechan 2006 3:11-17.
Wang T, Zhang X, Bheda P, Revollo JR, Imai S, and Wolberger C. Structure of Nampt/PBEF/visfatin, a mammalian NAD+ biosynthetic enzyme. Nat Struct Mol Biol 2006 13:661-662.
Moynihan KA, Grimm AA, Plueger MM, Bernal-Mizrachi E, Ford E, Cras-Mneur C, Permutt MA, and Imai S. Increased dosage of mammalian Sir2 in pancreatic beta cells enhances glucose-stimulated insulin secretion in mice. Cell Metab 2005 2:105-117. (Cover art for the August 2005 issue)
Revollo JR, Grimm AA, Imai S. The NAD biosynthesis pathway mediated by nicotinamide phosphoribosyltransferase regulates Sir2 activity in mammalian cells. J Biol Chem 2004 279:50754-50763.
Last Updated: 09/12/2007 |