Shin-ichiro Imai, MD, PhD

Research interests

Our major interest is to understand the systemic regulation of aging and longevity in mammals and translate that knowledge into an effective anti-aging intervention that makes our later lives as healthy and productive as possible (“productive aging”).

Three key tissues have been identified as basic elements in mammalian aging and longevity control: the hypothalamus as the control center, skeletal muscle as an effector and adipose tissue as a modulator.

In the dorsomedial hypothalamus (DMH), the mammalian NAD+-dependent deacetylase SIRT1 and its binding partner Nkx2-1 cooperate to counteract age-associated physiological decline and promote longevity in mice (Satoh et al., Cell Metab., 2013).  Adipose tissue remotely promotes NAD+ biosynthesis, SIRT1 activity and neural activity in the hypothalamus through the secretion of nicotinamide phosphoribosyltransferase (NAMPT), a key NAD+ biosynthetic enzyme (Yoon et al., Cell Metab., 2015).  Skeletal muscle secretes myokines in response to the signal from the hypothalamus, possibly affecting other tissue functions (under investigation).  These findings are integrated into a comprehensive concept of mammalian aging and longevity control, named the NAD World 2.0 (Imai, npj Systems Biology and Applications, 2016).

To dissect the system dynamics of the NAD World 2.0, our lab is currently conducting the following projects:

1. The function of the hypothalamus as the “control center of aging” in mammals: We are characterizing a novel subset of neurons in the DMH, the Sirt1/Nkx2-1-double positive neurons, to understand Sirt1-mediated aging and longevity control in mammals. We have identified Prdm13 as one of the critical genes specifically expressed in the Sirt1/Nkx2-1-double positive neurons (Satoh et al., Aging Cell 2015). We are trying to genetically manipulate Prdm13 expression in these neurons and examine what happens to the process of aging and longevity.
2. The function of extracellular NAMPT (eNAMPT) secreted by adipose tissue: We are currently studying the importance of systemic NAD+ biosynthesis mediated by eNAMPT in mammalian aging and longevity control. We speculate that adipose tissue functions as a “modulator” for the function of the control center, namely, the hypothalamus. We are studying the aging phenotypes of adipose tissue-specific Nampt-knockin (ANKI) mice that have higher eNAMPT levels in their blood circulation.
3. The anti-aging effect of nicotinamide mononucleotide (NMN): In the concept of the NAD World 2.0, NMN, a key product of the NAMPT reaction, is important as a potential systemic signaling molecule.  NAMPT-mediated NAD+ biosynthesis declines during aging and in age-associated diseases, such as type 2 diabetes (Yoshino et al., Cell Metab., 2011). We have recently demonstrated that the long-term administration of NMN mitigates age-associated physiological decline in mice (Mills et al., Cell Metab., 2016). To elucidate the pathophysiological significance of NMN, we are currently characterizing a newly identified NMN transporter and conducting human clinical trials.
4. The function of skeletal muscle as an “effector” for aging and longevity control: Skeletal muscle responds to the signal from the hypothalamus through the sympathetic nervous system and secretes a myokine. We are interested in the function of this myokine, speculating that this myokine mediates other inter-tissue communications.

Through these projects, we aim to understand the importance of these critical inter-tissue communications among the hypothalamus, skeletal muscle and adipose tissue in mammalian aging and longevity control. The anticipated outcome of these studies will allow us to develop effective anti-aging interventions to achieve “productive aging” in the world.

Education and Professional Experience

Theodore and Bretha Bryan Distinguished Professor in Environmental Medicine
Washington School of Medicine, 2023-Present

Professor
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. 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, 1989

Honors and Awards

2016 The Most Influential 100 People for JAPAN 2017, Nikkei Business

2016 Glenn/AFAR Breakthroughs in Gerontology (BIG) Award

2016 Keynote Lecture, “The PARP Family and ADP-ribosylation”, Cold Spring Harbor Laboratory Meeting, New York.

2013 Vincent J. Cristofalo, PhD, Annual Lectureship, Institute on Aging, University of Pennsylvania

2008-2012 The Ellison Medical Foundation Senior Scholar in Aging Award

2008-2010 The Longer Life Foundation Pilot & Feasibility Award

2007 WUSM 2008 Distinguished Investigator Award

2007-2008 The Glenn Award for Research in Biological Mechanisms of Aging

2006-2007 The Juvenile Diabetes Research Foundation Innovation Award

2006-2008 The American Diabetes Association Innovation Award

2006 Special Recognition for Excellence in Mentoring in the Seventh Annual Outstanding Faculty Mentor Awards

2005-2007 Washington University Clinical Nutrition Research Unit (CNRU) Pilot & Feasibility Award

2003-2007 The Ellison Medical Foundation New Scholar in Aging Award

2002 Washington University Center for Aging Pilot Project Award

2001-2004 Leukemia &Lymphoma Society Special Fellowship

2000 Medal from the Tokyo Society of Medical Sciences and Faculty of Medicine, Tokyo University, Japan

Selected publications

• Mills, K. F., Yoshida, S., Stein, L. R., Grozio, A., Kubota, S., Sasaki, Y., Redpath, P., Miguard, M. E., Apte, R. S., Uchida, K., Yoshino, J.*, and Imai, S.*  (2016)  Long-term administration of nicotinamide mononucleotide mitigates age-associated physiological decline in mice.  Cell Metab.  24:795-806.  (*Co-correspondance)
• Lin, J. B.§, Kubota, S.§, Ban, N., Yoshida, M., Santeford, A., Sene, A., Nakamura, R., Zapata, N., Kubota, M., Tsubota, K., Yoshino, J., Imai, S.*, and Apte, R. S.*  (2016) NAMPT-mediated NAD+ biosynthesis is essential for vision in mice.  Cell Rep.  17: 69-85.  (§equally contributing authors; *co-correspondence).  PMCID: PMC5104206
• Stromsdorfer, K. L.*, Yamaguchi, S.*, Yoon, M. J.*, Moseley, A. C., Franczyk, M. P., Kelly, S. C., Qi, N., Imai, S., and Yoshino, J.  (2016)  NAMPT-mediated NAD+ biosynthesis in adipocytes regulates adipose tissue function and multi-organ insulin sensitivity in mice.  Cell Rep.  16: 1851-1860.  (*equally contributing authors)  PMCID: PMC5094180
• Imai, S.  (2016)  The NAD World 2.0: The Importance of the Inter-Tissue Communication Mediated by NAMPT/NAD+/SIRT1 in Mammalian Aging/Longevity Control.  npj Systems Biology and Applications.  doi:10.1038/npjsba.2016.18
• Imai, S. and Guarente, L.  (2016)  It takes two to tango: NAD+ and sirtuins in aging/longevity control.  npj Aging and Mechanisms of Disease.  doi:10.1038/npjamd.2016.17
• Yoon, M. J., Yoshida, M., Johnson, S., Takikawa, A., Usui, I., Tobe, K., Nakagawa, T., Yoshino, J., and Imai, S.  (2015)  SIRT1-mediated eNAMPT secretion from adipose tissue regulates hypothalamic NAD+ and function in mice.  Cell Metab.  21: 706-717.  PMCID: PMC4426056
• Satoh, A., Brace, C. S., Rensing, N., and Imai, S.  (2015)  Deficiency of Prdm13, a dorsomedial hypothalamus-enriched gene, mimics age-associated changes in sleep quality and adiposity. Aging Cell  14: 209-218.  PMCID: PMC4364833
• Satoh, A. and Imai, S.  (2014)  Systemic regulatory mechanisms of mammalian aging and longevity by brain sirtuins.  Nat. Commun.  5: 4211. doi: 10.1038/ncomms5211.
• 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
• 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

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