Research Interests
In our current society, achieving productive aging, which aims to keep people as productive as possible with good health and spirit for their private and social activities as they grow older, will be urgent to maximize the duration of high quality of life and to promote a stable economy and solvent social security in health care systems. To achieve this ultimate goal, our laboratory is studying the fundamental mechanisms of aging and longevity in mammals, focusing on the physiological importance of the mammalian nicotinamide adenine dinucleotide (NAD)-dependent protein deacetylase SIRT1 and systemic NAD biosynthesis mediated by nicotinamide phosphoribosyltransferase (NAMPT) for the regulation of metabolism and aging.
Through our research, we have proposed a comprehensive concept of a novel systemic regulatory network, named NAD World, for the intricate connection between metabolism and aging. This new concept of the NAD World provides important insights into the systemic regulation of mammalian aging and longevity and also conveys ideas of functional hierarchy and frailty for the induction of aging. Understanding the system dynamics of the NAD World will enable us to develop therapeutic and preventive interventions for age-associated diseases, such as type 2 diabetes and Alzheimer™s disease.
Here are three burning questions that we are trying to answer:
1) Which organs/tissues play a major role in the regulation of aging and longevity in mammals? Is there any control center of aging?
2) What hormones/factors mediate the communication between the â€control center of aging and other modulatory organs/tissues?
3) What molecules/signaling pathways coordinate the regulation of mammalian aging at a systemic level?
We are currently hypothesizing that the brain, particularly the hypothalamus, might play a central role in the regulation of mammalian aging and longevity. Systemic feedback loops involved in the hypothalamus and peripheral tissues, such as stomach and adipose tissue, might determine the pace of aging and eventually longevity. We are also trying to manipulate this system using a key NAD intermediate, nicotinamide mononucleotide (NMN).
Biosketch
Education and Professional
Experience:
- Associate Professor (tenured), Department of Developmental Biology, Department of Medicine (joint), Washington University School of Medicine, 2008-present
- Assistant Professor, Department of Developmental Biology (Formerly, Molecular Biology and Pharmacology), Department of Medicine (joint), Washington University School of Medicine, 2001-2008.
- Postdoctoral Fellow/Associate, Massachusetts Institute of Technology, Department of Biology, 1997-2001.
Postdoctoral Adviser: Dr. Leonard Guarente
- Instructor, Keio University School of Medicine, Department of Microbiology, 1993-1997.
- Ph.D., Keio University Graduate School of Medicine, Tokyo, Japan, 1995. Thesis Supervisor: Dr. Toshiya Takano
- M.D., Keio University School of Medicine, Tokyo, Japan, 19
Honors and Awards
- The Ellison Medical Foundation Senior Scholar in Aging Award, 2008-2012
- The Longer Life Foundation Pilot & Feasibility Award, 2008-2010
- WUSM 2008 Distinguished Investigator Award, 2007
- The Glenn Award for Research in Biological Mechanisms of Aging, 2007-2008
- The Juvenile Diabetes Research Foundation Innovation Award, 2006-2007
- The American Diabetes Association Innovation Award, 2006-2008
- Special Recognition for Excellence in Mentoring in the 7th Annual Outstanding Faculty Mentor Awards, 2006
- Washington University Clinical Nutrition Research Unit (CNRU) Pilot & Feasibility Award, 2005-2007
- The Ellison Medical Foundation New Scholar in Aging Award, 2003-2007
- Washington University Center for Aging Pilot Project Award, 2002
- Leukemia & Lymphoma Society Special Fellowship, 2001-2004
- Medal from the Tokyo Society of Medical Sciences and Faculty of Medicine, Tokyo University, Japan, 2000
Selected Publications
Grimm, A. A., Brace, C. S., Wang, T., Stormo, G., and Imai, S. 2010. A nutrient-sensitive interaction between Sirt1 and HNF-1alpha regulates Crp expression. Aging Cell, In press.
Yoshino, Y and Imai, S. 2010. A clock ticks in pancreatic beta cells. Cell Metab. 12: 107-108.
Satoh, A, Brace, C. S., Ben-Josef, G., West, T., Wozniak, D. F., Holtzman, D. M., Herzog, E. D., and Imai, S. 2010. SIRT1 promotes the central adaptive response to diet restriction through activation of the dorsomedial and lateral nuclei of the hypothalamus. J. Neurosci. 30: 10220-10232.
Imai, S. and Guarente, L. 2010. Ten years of NAD-dependent SIR2 family deacetylases: implications for metabolic diseases. Trends Pharmacol. Sci. 31: 212-220.
Imai, S. 2010. "Clocks" in the NAD World: NAD as a metabolic oscillator for the regulation of metabolism and aging. Biochim. Biophys. Acta. 1804: 1584-1590.
Ramsey, K. M., Yoshino, J., Brace, C. S., Abrassart, D., Kobayashi, Y., Marcheva, B., Hong, H.-K., Chong, J. L., Buhr, E. D., Lee, C., Takahashi, J. S., Imai, S., and Bass, J. 2009. Circadian clock feedback cycle through NAMPT-mediated NAD+ biosynthesis. Science 324: 651-654. (§equally contributed authors, *Co-correspondence)
Imai, S. 2009. From heterochromatin islands to the NAD World: A hierarchical view of aging through the functions of mammalian Sirt1 and systemic NAD biosynthesis. Biochim. Biophys. Acta. 1790: 997-1004.
Moynihan Ramsey, K., Mills, K. F., Satoh, A., and Imai, S. 2008. Age-associated loss of Sirt1-mediated enhancement of glucose-stimulated insulin secretion in BESTO mice. Aging Cell 7, 78-88.
Revollo, J. R., Kärner, A., Mills, K. F., Satoh, A., Wang, T., Garten, A., Dasgupta, D., Sasaki, Y., Wolberger, C., Townsend, R. R., Milbrandt, J., Kiess, W., and Imai, S. 2007. Nampt/PBEF/visfatin regulates insulin secretion in beta cells as a systemic NAD biosynthetic enzyme. Cell Metab. 6, 363-375. (accompanied with a featured preview article in the November 2007 issue)
Wang, T., Zhang, X., Bheda, P., Revollo, J. R., Imai, S., and Wolberger, C. 2006. Structure of Nampt/PBEF/visfatin, a mammalian NAD+ biosynthetic enzyme. Nat. Struct. Mol. Biol. 13:661-662.
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