The mechanisms of serotonin-based signaling in food perception and DR-mediated longevity

项目摘要。 据估计，到2050年，65岁以上的美国公民数量将达到近1亿，更多 是今天的两倍还多。随着现代世界的人口结构继续向老的方向倾斜，理解 在生物医学研究中，减缓衰老过程变得越来越重要。老龄化 研究人员在过去的25年里取得了许多发现，并证明了延缓衰老可以 预防或延缓多种疾病的形成，改善整体健康状况。其中许多是保守的 “长寿途径”最初是使用线虫秀丽线虫发现的，在这种线虫中很容易遗传 操控和短暂的寿命有利于衰老研究。 其中一些备受推崇的出版物已经确定了多条遗传途径，这些途径将 神经系统通过不同的信号网络和下游效应器感知压力 增进健康和长寿。虽然这些研究提供了大量证据表明细胞间信号 调节衰老是多种长寿途径的共同之处，它们缺乏特定的信号、受体、神经 电路，以及涉及的下游效应器。其中一些研究已经报道了重要的 神经递质5-羟色胺作为代谢变化上游的必要信号分子 外周组织，这证实了我将在本提案中提出的初步数据。更确切地说，我们的 数据显示，研究最充分的长寿干预措施，饮食限制(DR)，部分是通过细胞起作用的 线虫中受食物气味抑制的非自主信号通路。我们进一步发现，Dr 导致一种肠道基因的诱导，含有黄素的单加氧酶-2(FMO-2)，这是必要的和 足以提高健康寿命、抗应激能力和寿命。我们还观察到FMO-2和 寿命的延长既依赖于5-羟色胺能信号，也可以通过5-羟色胺来实现 拮抗剂米安色林。 该项目将阐明由于缺乏食物而启动的细胞非自主途径的组成部分 最终导致肠道FMO-2的诱导和寿命的延长。为此，我将确定 启动信号级联的5-羟色胺能神经元(目标1)，并确定哪个神经元接收该信号 信号(目标2)。从这里，我将发现发生在血清素释放下游的信号事件(或 使用多种筛查方法(目标3)。总的来说，这些目标将加强我们的 对调节衰老的高度保守的信号通路的理解。我研究的最终目标是 是利用在这里获得的生物学洞察力来开发提高人类健康寿命的疗法。

Project Summary. It is estimated that by 2050 the number of US citizens over the age of 65 will reach nearly 100 million, more than twice as many as today. As the demographics of the modern world continue to skew older, understanding and mitigating the aging process has become increasingly important within biomedical research. Aging researchers have made many discoveries in the past 25 years and have demonstrated that slowing aging can prevent or delay the formation of many diseases and improve overall health. Many of these conserved “longevity pathways” were initially discovered using the nematode Caenorhabditis elegans, where easy genetic manipulation and brief lifespans benefit aging research. A number of these highly regarded publications have identified multiple genetic pathways that link the perception of stress by the nervous system with distinct signaling networks and downstream effectors that improve health and longevity. While these studies provide substantial evidence that cell to cell signaling regulates aging and is common to multiple longevity pathways, they lack the specific signals, receptors, neural circuits, and downstream effectors involved. Some of these studies have reported the important neurotransmitter serotonin as a necessary signaling molecule upstream of the metabolic changes that occur in peripheral tissues, which corroborates the preliminary data I will present in this proposal. More specifically, our data show that the most well-studied longevity intervention, dietary restriction (DR), acts in part through a cell non-autonomous signaling pathway that is inhibited by the smell of food in C. elegans. We further find that DR leads to induction of an intestinal gene, flavin-containing monooxygenase-2 (fmo-2), that is both necessary and sufficient to improve healthspan, stress resistance, and longevity. We also observe that induction of fmo-2 and extension of lifespan both depend on the serotonergic signaling and can be recapitulated by the serotonin antagonist drug, mianserin. This project will elucidate components of the cell non-autonomous pathway initiated by the lack of food that eventually leads to intestinal fmo-2 induction and extension of lifespan. To that end I will identify the serotonergic neuron which initiates the signaling cascade (Aim 1), and determine which neuron receives that signal (Aim 2). From here, I will discover the signaling events that occur downstream of serotonin release (or absence) using a number of screening methods (Aim 3). Collectively, these aims will enhance our understandings of a highly conserved signaling pathway that modifies aging. The ultimate goal of my research is to exploit the biological insights gained here to develop therapeutics that increase human healthspan.