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

项目摘要。 据估计，到2050年，65岁以上的美国公民人数将达到近1亿， 是现在的两倍多。随着现代世界的人口结构继续向老年人倾斜， 并且减缓衰老过程在生物医学研究中变得越来越重要。老化 在过去的25年里，研究人员有了许多发现，并证明了减缓衰老可以 预防或延缓许多疾病的形成，改善整体健康。其中许多保存 “长寿途径”最初是使用线虫秀丽隐杆线虫发现的， 操纵和短暂的寿命有益于衰老研究。 许多这些高度重视的出版物已经确定了多种遗传途径， 神经系统对压力的感知具有不同的信号网络和下游效应器， 改善健康和长寿。虽然这些研究提供了大量的证据， 调节衰老，是常见的多种长寿途径，他们缺乏特定的信号，受体，神经 电路和下游效应器。其中一些研究报告了重要的 神经递质5-羟色胺作为一种必要的信号分子上游的代谢变化，发生在 外周组织，这证实了我将在本提案中提出的初步数据。更具体地说，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。 非自主信号通路，被食物的气味抑制。优雅我们还发现，DR 导致肠基因，含黄素单加氧酶-2（FMO-2）的诱导，这是必需的， 足以改善健康、抗压和长寿。我们还观察到fmo-2和 寿命的延长既依赖于肾上腺素能信号传导，也可以被5-羟色胺 拮抗药米安色林。 这个项目将阐明由缺乏食物引起的细胞非自主途径的组成部分， 最终导致肠道FMO-2诱导和寿命延长。为此，我将确定 启动信号级联反应（Aim 1）的多巴胺能神经元，并决定哪个神经元接受该信号级联反应。 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 缺乏）使用多种筛选方法（目标3）。总的来说，这些目标将加强我们的 了解一个高度保守的信号通路，修改老化。我研究的最终目标 是利用在这里获得的生物学见解来开发增加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.