Mechanisms to Regulate Aging through Neurosensory and Reward Circuits

描述(申请人提供)：中枢神经系统(CNS)调节我们的健康和幸福感的能力得到了广泛的赞赏，最近的研究表明中枢神经系统在调节衰老过程中的重要性。通过基因或环境手段改变对大脑的感觉输入，能够调节抗应激、新陈代谢和寿命，但这些输入如何通过中枢神经系统整合才刚刚开始解开。在我们最近发表的结果中，我们发现了一组感觉神经元，一种特定的信息素受体(Ppk23)，以及大脑中一组表达保守神经肽(NPF)的神经元，这些神经元是能够快速且可逆地调节果蝇的抗逆性、脂肪储存和寿命的电路的组成部分。这项提议的主要目标是完全定义一个神经回路，从输入到最终的效应器信号通路，能够调节衰老过程。在我们的第一个目标中，我们将确定交配奖励是否作为调节衰老的同一神经回路的输入，它部分抵消了信息素感觉对寿命和新陈代谢的影响。在我们的第二个目标中，我们将确定负责调节整个有机体衰老和生理的中间神经元以及神经内分泌细胞的亚群，作为这一神经回路的一部分。我们的最终目标将阐明这条神经通路是如何与能够调节衰老的已知通路相互作用的。由于衰老的生物学基础和中枢神经系统的功能结构在不同的类群中都高度保守，本提案中进行的研究将阐明大脑如何处理和整合环境输入，以直接调节衰老过程。我们相信，这些雄心勃勃的研究将推动成功的抗衰老干预措施的发展。

DESCRIPTION (provided by applicant): The power of the central nervous system (CNS) to modulate our health and well-being is widely appreciated, and recent studies have demonstrated the importance of the CNS in regulating the aging process. Alteration of sensory input to the brain by genetic or environmental means is capable of regulating stress resistance, metabolism, and longevity, but how these inputs are integrated by the CNS is only beginning to be unraveled. In our recently published results, we discovered a set of sensory neurons, a specific pheromone receptor (ppk23), and a group of neurons in the brain expressing a conserved neuropeptide (NPF) that are components of a circuit capable of quickly and reversibly regulating stress resistance, fat storage, and lifespan in the fruit fly, Drosophlia melanogaster. The primary objective of this proposal is to completely define a neural circuit, from inputs to the ultimate effector signaling pathways, capable of regulating the aging process. In our first aim we will determine if mating-reward, which partially negates the effects of pheromone sensation on lifespan and metabolism, acts as an input to the same neural circuit to regulate aging. In our second aim, we will identify subsets of interneurons as well as neuroendocrine cells that are responsible for modulating whole-organism aging and physiology as a part of this neural circuit. Our final aim will elucidate how this neural pathway interacts wih known pathways that are capable of regulating aging. As both the biological basis of aging and the functional architecture of the CNS are highly conserved across taxa, the studies performed in this proposal will elucidate how the brain processes and integrates environmental inputs to directly regulate the aging process. We believe that these ambitious studies will push forward the development of successful anti-aging interventions.