Shin-ichiro Imai, M.D., Ph.D.
Developmental, Regenerative and Stem Cell Biology Program
Molecular Genetics and Genomics Program
Molecular Cell Biology Program
Computational and Systems Biology Program
Rm362A (Office) & Rm362, 366 (Lab), McDonnell Medical Sciences Building
aging, longevity, hypothalamus, metabolism, NAD biosynthesis, Sirt1, NAMPT, NAD World
Understanding the molecular mechanism of aging and longevity in mammals
My laboratory focuses on the molecular mechanisms of aging and longevity in mammals. Recent studies in worms and flies have suggested that systemic interplay between multiple tissues regulates aging and longevity. In mammals, however, the complexity of tissue interplay is multiplied, and a systemic network that regulates aging and longevity has still been poorly understood. To dissect such a complex network for the systemic control of aging and longevity in mammals, 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 regulatory mechanisms of mammalian aging 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) They 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
Last Updated: 1/7/2015 8:56:38 AM