Shin-ichiro Imai, M.D., Ph.D.
Departments of Developmental Biology and Internal Medicine
My laboratory studies the systemic control of aging and longevity in mammals. To dissect such a complex network for mammalian aging/longevity control, our lab has addressed the following three questions:
1) Are there any dominant organs/tissues that regulate the process of aging and longevity in mammals?
2) How do these "control centers" communicate with other organs/tissues to control aging and longevity in mammals?
3) What signaling pathways or molecules regulate such communications at a systemic level?
We are particularly focusing on the tissue-specific functions of the mammalian NAD+-dependent deacetylase SIRT1, a key mediator that coordinates various metabolic responses in multiple tissues, and NAD+ biosynthesis mediated by nicotinamide phosphoribosyltransferase (NAMPT), a critical pacemaker that comprises a novel circadian regulatory feedback loop through the regulation of Sirt1 activity in peripheral tissues.
Most recently, we have obtained critical clues to these three questions from our study on brain-specific SIRT1-overexpressing (BRASTO) transgenic mice. We have clearly demonstrated that BRASTO mice exhibit a significant delay in the aging process and extension of life span in both males and females. SIRT1-dependent neural activation in the dorsomedial and lateral hypothalamic nuclei (DMH and LH, respectively) protects against age-related declines in skeletal muscle mitochondrial function, physical activity, body temperature, oxygen consumption, and quality of sleep. SIRT1 and its novel partner Nk2 homeobox 1 (Nkx2-1) regulate these physiological functions through the upregulation of orexin type 2 receptor (Ox2r) expression in the DMH and LH, and their colocalization identifies a specific subset of neurons in these hypothalamic regions. These findings provide critical insight into the importance of hypothalamic SIRT1 and also suggest a fundamental role of the hypothalamus as a high-order “control center of aging” in the systemic regulation of mammalian aging and longevity.
Currently, we have three main projects: 1) The function of the hypothalamus as a "control center of aging" in mammals. We are trying to characterize a novel subset of neurons in the DMH and LH, the Sirt1/Nkx2-1-double positive neurons, to better understand Sirt1-mediated aging/longevity control in mammals. 2) The importance of skeletal muscle as an "effector" to control the process of aging. Skeletal muscle responds to the stimulation that the hypothalamus mediates through the sympathetic nervous system. We are interested in this intertissue communication between the hypothalamus and skeletal muscle. 3) Systemic regulation of mammalian NAD+ biosynthesis. We are currently studying systemic NAD biosynthesis mediated by intra- and extracellular nicotinamide phosphoribosyltransferase (iNampt and eNampt). We speculate that adipose tissue functions as a "modulator" for aging/longevity control in mammals. Understanding the system dynamics of these intertissue communications among the hypothalamus, skeletal muscle, and adipose tissue will allow us to develop an intervention to control the process of aging, and even longevity, in mammals.
- Satoh, A., Brace, C. S., Rensing, N., and Imai, S. (2014) Deficiency of Prdm13, a dorsomedial hypothalamus-enriched gene, mimics age-associated changes in sleep quality and adiposity. Epub on December 25, 2014, Aging Cell.
- Stein, L. R. and Imai, S. (2014) Specific ablation of Nampt in adult neural stem cells recapitulates their functional defects during aging (accompanied with a featured preview article). EMBO J. 33: 1321-1340. PMCID: PMC4194122
- Stein, L. R., Wozniak, D. F., Dearborn, J. T., Kutabo, S., Apte, R. S., Izumi, Y., Zorumski, C. F. and Imai S. (2014) Expression of Nampt in hippocampal and cortical excitatory neurons is critical for cognitive function (A featured article). J. Neurosci. 34: 5800-5815. PMCID: PMC3996209
- Satoh, A. and Imai, S. (2014) Systemic regulation of mammalian ageing and longevity by brain sirtuins. Nat. Commun. doi: 10.1038/ncomms5211.
- Imai, S. and Guarente, L. (2014) NAD+ and sirtuins in aging and disease. Trends Cell Biol. 24: 464-471. PMCID: PMC4112140
- Satoh, A., Brace, C. S., Rensing, N., Clifton, P., Wozniak, D. F., Herzog, E. G., Yamada, K. A., and Imai, S. (2013) Sirt1 extends life span and delays aging in mice through the regulation of Nk2 homeobox 1 in the DMH and LH (Among the most-downloaded articles from Cell Press in September 2013). Cell Metab. 18: 416-430. PMCID: PMC3794712
- Imai, S. and Yoshino, J. (2013) The importance of NAMPT/NAD/SIRT1 in the systemic regulation of metabolism and ageing. Diabetes, Obesity, and Metabolism. 15 (Suppl.3): 26-33. PMCID: PMC3819727
- Stein, L. R. and Imai, S. (2012) The dynamic regulation of NAD metabolism in mitochondria. Trends Endocrinol. Metab. 23: 420-428. PMCID: PMC3683958
- Yoshino, J.*, Mills, K. F.*, Yoon, M. J., and Imai, S. (2011) Nicotinamide mononucleotide, a key NAD+ intermediate, treats the pathophysiology of diet- and age-induced diabetes. Cell Metab. 14: 528-536. (The “Featured Article” in the October 2011 issue; Currently “Most-Read Article” in Cell Metabolism; *equally contributing authors) PMCID: PMC3204926
- 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. PMCID: PMC2922851
- 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 contributing authors, *Co-correspondence) PMCID: PMC2738420
For a complete list of Dr. Imai's publications, click here
Education and Professional Experience
Department of Developmental Biology
Department of Medicine (Joint)
Washington University School of Medicine, 2013-present
- Associate Professor (tenured), Department of Developmental Biology, Department of Medicine (joint), Washington University School of Medicine, 2008-2013
- 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.â€¨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
- 2013 Vincent J. Cristofalo, PhD, Annual Lectureship, Institute on Aging, University of Pennsylvania
- 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
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