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) Are there any “control centers” to regulate the pace of aging and longevity in mammals? 2) Are there any specific hormones or humoral factors that are secreted from the “control centers” and regulates aging? and 3) Are there any “universal regulatory factors” to regulate the production and/or the secretion of such hormones or humoral factors? 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:
Ramsey KM, Mills KF, Satoh A, Imai S. Age-associated loss of Sirt1-mediated enhancement of glucose-stimulated insulin secretion in BESTO mice. Aging Cell 2008 7:78-88.
Revollo JR, Korner A, Mills KF, Satoh A, Wang T, Garten A, Dasgupta D, Sasaki Y, Wolberger C, Townsend RR, Milbrandt J, Kiess W, Imai S. Nampt/PBEF/visfatin regulates insulin secretion in beta cells as a systemic NAD biosynthetic enzyme. Cell Metab. 2007 6:363-375. (associated with a featured preview article in the November 2007 issue)
Revollo JR, Grimm AA, Imai S. The regulation of nicotinamide adenine dinucleotide biosynthesis by Nampt/PBEF/visfatin in mammals. Curr. Opin. Gastroenterol. 2007 23:164-170.
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)
Last Updated: 10/30/2008 |