eNAMPT-mediated adipo-hypothalamic communication for NAD+ production and aging

eNAMPT 介导的脂肪-下丘脑通讯促进 NAD 产生和衰老

基本信息

批准号：
10160728
负责人：
SHIN-ICHIRO IMAI
金额：
$ 32.29万
依托单位：
WASHINGTON UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-08-15 至 2024-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10160728
关键词：
Address Adipose tissue Affect Age Aging Anabolism Animal Model Behavioral Binding Biological Biological Aging Blood Circulation Cognitive Communication Consumption Development Diphosphates Encapsulated Energy Metabolism Enzymes Event Exhibits Female Functional disorder Funding Genetic Engineering Genetically Engineered Mouse Goals Hippocampus (Brain)Homeostasis Human Hypothalamic structure Intervention Knock-in Knock-out Knowledge Learning Longevity Mammals Mediating Memory Metabolism Molecular Mus Neurons Niacinamide Nicotinamide Mononucleotide Nicotinamide adenine dinucleotide Outcome Pancreas Phenotype Photoreceptors Physical activity Physiological Play Poly(ADP-ribose) Polymerases Process Production Proteins Research Research Proposals Retina Role Running SIRT1 gene Signal Transduction Societies System Testing Tissues Translating aged anti aging cognitive function effective intervention exosome extracellular functional decline genetic manipulation glucose metabolism healthspan human old age (65+)in vivo mutant nicotinamide phosphoribosyltransferase novel prevent protein structure receptor sleep quality

项目摘要

TITLE OF PROJECT eNAMPT-mediated adipo-hypothalamic communication for NAD+ production and aging ABSTRACT In recent years, nicotinamide adenine dinucleotide (NAD+) metabolism has emerged as a central topic in the field of aging and longevity research. It has been established that NAD+ availability declines over age at a systemic level, triggering a variety of age-associated pathophysiological changes in diverse model organisms. In mammalian NAD+ biosynthesis, nicotinamide phosphoribosyltransferase (NAMPT) is the key enzyme that converts nicotinamide and 5’-phosphoribosyl-pyrophosphate to nicotinamide mononucleotide (NMN), an important NAD+ intermediate. Interestingly, there are two distinct forms of NAMPT in mammals: intra- and extracellular NAMPT (iNAMPT and eNAMPT, respectively). We have previously demonstrated that eNAMPT mediates a novel intertissue communication system between adipose tissue and the hypothalamus, regulating hypothalamic NAD+ levels and functions. We have now found that eNAMPT is carried in exosomes through the circulation in mice and humans. Exosomal eNAMPT is internalized into primary hypothalamic neurons and enhances NAD+ biosynthesis intracellularly. The genetically engineered mice that can maintain higher levels of exosomal eNAMPT at old ages exhibit a variety of anti-aging phenotypes and a significant extension of healthspan. These new findings demonstrate a novel systemic mechanism that regulates the process of aging and determines healthspan/lifespan, driven by an exosome-mediated delivery of eNAMPT. Thus, we hypothesize that exosomal eNAMPT is delivered to specific tissues through the interaction with a specific receptor-like protein and regulates various tissue functions, including the hippocampus-dependent cognitive functions. The K53R mutant of NAMPT, whose secretion is enhanced, could be used as a genetically engineered biologic that mitigates age-associated functional decline in mice. We will address this hypothesis by the following specific aims: 1) To elucidate the mechanism of exosomal eNAMPT targeting, we will examine the requirement of the NAMPT protein structure and also test a potential receptor candidate for exosomal eNAMPT to be internalized, 2) to further analyze the effects of supplementing eNAMPT-containing exosomes in aged mice, we will analyze their effect on the hippocampus-mediated cognitive functions, and 3) to test eNAMPT as an anti-aging biologic, we will examine the effects of eNAMPT mutants encapsulated into exosomes on cognitive, behavioral, and other tissue functions in aged mice. Thus, the anticipated outcome of the proposed research will open a new avenue to understand how systemic NAD+ homeostasis regulates aging and longevity and develop a novel anti-aging intervention by using exosomal eNAMPT as a biologic.

项目标题 ENAMPT介导的NAD+生产和衰老的adipo-Hypothalamic通讯抽象的近年来，烟酰胺腺嘌呤二核苷酸（NAD+）代谢已成为中心主题衰老和寿命研究领域。已经确定NAD+可用性在年龄上下降系统性水平，引发了潜水员模型生物的各种年龄相关的病理生理变化。在哺乳动物NAD+生物合成中，烟酰胺磷酸蛋白酶基转移酶（NAMPT）是关键酶将烟酰胺和5'-磷酸氨基磷酸转化为烟酰胺单核苷酸（NMN），A 重要的NAD+中级。有趣的是，哺乳动物中有两种不同形式的NAMPT：细胞外NAMPT（分别为INAMPT和ENAMPT）。我们以前已经证明了Enampt 介导脂肪组织和下丘脑之间的新型互助系统，调节下丘脑NAD+水平和功能。我们现在发现，eNampt通过外泌体携带小鼠和人类的循环。外泌体eNAMPT被内部化为原发性下丘脑神经元和细胞内增强NAD+生物合成。可以维持更高水平的一般工程小鼠老年时代的外泌体陶器的陶器表现出多种抗衰老表型和显着的延伸 HealthSpan。这些新发现展示了一种新型的系统机制，可以调节衰老的过程并确定由外部介导的ENAMPT递送的驱动的HealthSpan/寿命。那，我们假设外泌体eNAMPT通过与特定的相互作用传递到特定组织接收器样蛋白质并调节各种组织功能，包括海马依赖性认知功能。 NAMPT的K53R突变体的分泌得到了增强，可以用作一般的工程生物学，可减轻小鼠与年龄相关的功能下降。我们将解决这个假设通过以下具体目的：1）阐明外泌体eNAMPT靶向机理，我们将检查 NAMPT蛋白结构的需求，还测试了外泌体的潜在接收器候选者陶瓷被内在化，2）进一步分析补充含ENAMP的外泌体的影响老年小鼠，我们将分析它们对海马介导的认知功能的影响，3）测试 ENAMPT是一种抗衰老生物学，我们将研究封装在老年小鼠认知，行为和其他组织功能的外泌体。那，预期的结果拟议的研究将为了解系统性NAD+体内稳态如何调节衰老的新途径和寿命并通过使用外泌体eNAMP作为生物学来发展新型的抗衰老干预措施。