Neuronal Orchestration of Metabolic State and Longevity

项目摘要/摘要 老年人将不成比例地受到代谢性疾病引起的并发症的影响，包括 糖尿病、心脏病和神经变性，预计从现在到2050年将翻一番。然而， 将肥胖和代谢性疾病与长寿联系起来的基本机制仍然知之甚少。这个 中枢神经系统是脂肪代谢和寿命的主要驱动力。然而，神经内分泌信号表明 具体地控制新陈代谢和寿命在任何系统中都知之甚少，并且不能在 细胞培养。我的实验室的长期目标是破译神经回路和神经内分泌 调节新陈代谢和寿命的机制，并定义支配其 两性关系。我们已经发现了一种整合的神经代谢系统，它是 线虫模型系统中的神经系统和肠道，其中古老和保守的方面 神经内分泌生物学的研究可以用最先进的分子工具来发现。我们定义了两个关键节点 神经内分泌系统的调节：一个神经元，一个新陈代谢。神经元结节整合 来自环境的食物和氧气感官信息，代谢节点将脂肪损失与 线粒体应激。我们的中心假设是神经元和新陈代谢节点抵消了一个 另一种是维持神经内分泌平衡的完整性，以及这种平衡的破坏 任何一个节点上的机制都会改变寿命。这项提议的目标是确定分子 调节神经元和代谢节点之间的动态平衡的机制，并识别 保护长寿的关键驱动力。因此，我们的神经内分泌途径定义了一个独特而强大的模型 研究神经刺激的脂代谢对寿命的影响。目标1将定义神经 整合神经内分泌信号、脂肪代谢和寿命的电路机制。我们的目标是扩大规模 从分子、电路和生物属性的多个层次进行分析，以实现机械化 洞察多模式神经回路的活动如何引起协调的生理变化 新陈代谢和长寿。目标2将确定神经驱动的脂肪减少之间的机械相互作用 以及肠道中的线粒体压力感应通路，最终决定了寿命。使用分子 遗传方法，生化分析，代谢和寿命分析，我们将揭开分子 减脂机制与压力保护机制相结合，共同决定寿命。一位少校 我们提出的研究的预期结果是，长寿是一种突发属性，由长寿的程度决定 代谢组织中的线粒体应激可以抵消神经元对脂肪丢失的驱动力。这个 目标1和目标2中提出的实验有望在分子水平上精确定位 神经内分泌动态平衡的机制。这些知识对于未来的设计是至关重要的 安全有效的药物来对抗伴随衰老而来的代谢性疾病。

PROJECT SUMMARY/ABSTRACT Older adults will be disproportionately affected by the complications arising from metabolic diseases including diabetes, heart disease and neurodegeneration, predicted to double between now and 2050. However, the fundamental mechanisms that link obesity and metabolic disease with longevity remain poorly understood. The central nervous system is a major driver of lipid metabolism and lifespan. However neuroendocrine signals that specifically control metabolism and lifespan are poorly understood in any system, and cannot be modeled in cell culture. The long-term goal of my laboratory is to decipher the neural circuits and neuroendocrine mechanisms that regulate metabolism and lifespan, and to define the key regulatory principles that govern their relationship. We have uncovered an integrated neuro-metabolic system that underlies communication between the nervous system and the intestine in the C. elegans model system, in which ancient and conserved aspects of neuroendocrine biology can be discovered with state-of-the-art molecular tools. We define two critical nodes for the regulation of this neuroendocrine system: one neuronal, one metabolic. The neuronal node integrates food and oxygen sensory information from the environment, and the metabolic node integrates fat loss with mitochondrial stress. Our central hypothesis is that the neuronal and metabolic nodes counterbalance one another to maintain the integrity of neuroendocrine homeostasis, and that disruption of this counterbalancing mechanism at either node alters lifespan. The objective of this proposal is to determine the molecular mechanisms that regulate the homeostatic balance between the neuronal and metabolic nodes, and to identify the key drivers that protect longevity. Thus, our neuroendocrine pathway defines a unique and powerful model to study the consequences of neuronally-stimulated lipid metabolism, on longevity. Aim 1 will define the neural circuit mechanisms that integrate neuroendocrine signaling, fat metabolism and lifespan. Our goal is to scale multiple levels of analysis from molecular, circuit-level and organismal properties to achieve mechanistic insights how the activity of a multimodal neural circuit gives rise to coordinated physiological shifts in metabolism and longevity. Aim 2 will identify the mechanistic interactions between neuronally-driven fat loss and mitochondrial stress-sensing pathways in the intestine, which ultimately drive lifespan. Using molecular genetic approaches, biochemical analyses, metabolic and lifespan assays, we will uncover the molecular mechanisms that couple fat loss with stress-protective mechanisms that together determine longevity. A major expected outcome of our proposed studies is that longevity is an emergent property, determined by the extent to which mitochondrial stress in metabolic tissues can counterbalance the neuronal drive for fat loss. The experiments proposed in Aims 1 and 2 are expected to pinpoint, at a molecular level, the integrative mechanisms that underlie this neuroendocrine homeostasis. This knowledge is critical for the future design of safe and effective drugs to combat metabolic diseases that accompany aging.