Recent studies have suggested that systemic interplay between multiple tissues regulates aging and longevity in model organisms. In mammals, however, the complexity of tissue interplay is multiplied, and a systemic network for mammalian aging/longevity control has been poorly understood. Our long-term goal is to understand such a systemic regulatory network for aging/longevity control in mammals, and to translate that knowledge into an effective intervention to prevent and treat age-associated pathophysiology in humans. To achieve this goal, we have particularly focused on the tissue-specific functions of the mammalian NAD+-dependent protein deacetylase SIRT1, and NAD+ biosynthesis mediated by nicotinamide phosphoribosyltransferase (NAMPT). We have recently demonstrated that the hypothalamus, particularly the dorsomedial and lateral hypothalamic nuclei (DMH and LH, respectively), is the critical place where SIRT1 regulates aging and longevity in mice. Thus, understanding how hypothalamic NAD+ levels are regulated is critical to better understand the system dynamics of mammalian aging/longevity control. Most recently, we have found that adipose tissue plays an important role in modulating NAD+ production in the hypothalamus through the SIRT1-mediated secretion of extracellular NAMPT (eNAMPT). Therefore, we hypothesize that adipose tissue-secreted eNAMPT regulates hypothalamic SIRT1 function, particularly in the DMH and LH, and also that the imbalance between eNAMPT and hypothalamic SIRT1 functions is developed during aging, causing functional defects in the hypothalamus and thereby affecting age-associated pathophysiology in mammals. To address this hypothesis, we will 1) investigate the physiological relevance of eNAMPT in the regulation of hypothalamic SIRT1 function, using loss- and gain-of-function mouse models;2) confirm the biochemical function of eNAMPT as a systemic NAD+ biosynthetic enzyme by manipulating the equilibrium of the eNAMPT enzymatic reaction in vivo;and 3) assess possible causes for the imbalance between adipose tissue and the hypothalamus during aging by examining changes in eNAMPT enzymatic activity, hypothalamic uptake/utilization of NMN, and SIRT1 protein levels in hypothalamic nuclei, in young, middle age, and old mice. Preliminary results presented in this proposal provide strong support to our hypothesis. Thus, elucidating the physiological importance of this unprecedented intertissue communication mechanism between adipose tissue and the hypothalamus will further advance our understanding of a systemic regulatory network for aging and longevity in mammals and contribute to the development of a possible intervention to achieve better health span in our aging society.
Our long-term goal is to understand a systemic regulatory network for aging/longevity control in mammals, and to translate that knowledge into an effective intervention to prevent and treat age-associated pathophysiology in humans. We have recently found that adipose tissue plays a critical role in regulating hypothalamic function through the secretion of a key enzyme that contributes to the biosynthesis of NAD+, an essential currency of cellular energy metabolism. In this research proposal, we will investigate the physiological importance of this unprecedented communication mechanism between adipose tissue and the hypothalamus. The anticipated results will further advance our understanding of a systemic regulatory network for aging and longevity in mammals and contribute to the development of a possible intervention to achieve better health span in our aging society.
|Yoshino, Jun; Baur, Joseph A; Imai, Shin-Ichiro (2017) NAD+ Intermediates: The Biology and Therapeutic Potential of NMN and NR. Cell Metab :|
|Satoh, Akiko; Imai, Shin-Ichiro; Guarente, Leonard (2017) The brain, sirtuins, and ageing. Nat Rev Neurosci 18:362-374|
|Lin, Jonathan B; Kubota, Shunsuke; Ban, Norimitsu et al. (2016) NAMPT-Mediated NAD(+) Biosynthesis Is Essential for Vision In Mice. Cell Rep 17:69-85|
|Stromsdorfer, Kelly L; Yamaguchi, Shintaro; Yoon, Myeong Jin et al. (2016) NAMPT-Mediated NAD(+) Biosynthesis in Adipocytes Regulates Adipose Tissue Function and Multi-organ Insulin Sensitivity in Mice. Cell Rep 16:1851-60|
|Imai, Shin-Ichiro (2016) The NAD World 2.0: the importance of the inter-tissue communication mediated by NAMPT/NAD+/SIRT1 in mammalian aging and longevity control. NPJ Syst Biol Appl 2:16018|
|Yoon, Myeong Jin; Yoshida, Mitsukuni; Johnson, Sean et al. (2015) SIRT1-Mediated eNAMPT Secretion from Adipose Tissue Regulates Hypothalamic NAD+ and Function in Mice. Cell Metab 21:706-17|
|Stein, Liana Roberts; Zorumski, Charles F; Imai, Shin-Ichiro et al. (2015) Nampt is required for long-term depression and the function of GluN2B subunit-containing NMDA receptors. Brain Res Bull 119:41-51|