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

项目名称 eNAMPT介导的脂肪-下丘脑通讯对NAD+产生和衰老的影响 摘要 近年来，烟酰胺腺嘌呤二核苷酸（NAD+）代谢已成为研究的中心课题。 老龄化和长寿研究领域。已经确定，NAD+的可用性随着年龄的增长而下降， 系统水平，在不同的模式生物中引发各种年龄相关的病理生理变化。 在哺乳动物NAD+生物合成中，烟酰胺磷酸核糖基转移酶（NAMPT）是 将烟酰胺和5 '-磷酸核糖基-焦磷酸转化为烟酰胺单核苷酸肽（NMN）， NAD+中间体。有趣的是，在哺乳动物中有两种不同形式的NAMPT：内部和 细胞外NAMPT（分别为iNAMPT和eNAMPT）。我们之前已经证明了eNAMPT 介导脂肪组织和下丘脑之间的一种新的组织间通讯系统， 下丘脑NAD+水平和功能。我们现在已经发现eNAMPT通过以下途径携带在外泌体中： 老鼠和人类的血液循环。外泌体eNAMPT内化到原代下丘脑神经元中， 增强细胞内NAD+生物合成。基因工程小鼠可以维持较高的水平， 外泌体eNAMPT在老年表现出多种抗衰老表型，并显着延长 healthspan.这些新发现证明了一种新的调节衰老过程的系统机制 并决定健康跨度/寿命，由外泌体介导的eNAMPT递送驱动。因此我们 假设外泌体eNAMPT通过与特定的 受体样蛋白，并调节各种组织功能，包括依赖于海马的认知功能， 功能协调发展的NAMPT的K53 R突变体，其分泌增强，可用作遗传学上的 工程生物，减轻年龄相关的功能下降的小鼠。我们将讨论这一假设 通过以下具体目标：1）为了阐明外泌体eNAMPT靶向的机制，我们将研究 NAMPT蛋白质结构的要求，并测试外泌体的潜在受体候选物 2）为了进一步分析补充含有eNAMPT的外泌体对ENAMPT细胞的影响， 老年小鼠，我们将分析其对海马介导的认知功能的影响，3）测试 eNAMPT作为一种抗衰老的生物，我们将研究eNAMPT突变体的影响， 外泌体对老年小鼠认知、行为和其他组织功能的影响。因此， 这项研究将为理解系统性NAD+稳态如何调节衰老开辟一条新的途径 和长寿，并通过使用外泌体eNAMPT作为生物制剂来开发新的抗衰老干预。

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.