Central Nervous System Regulation of Aging Physiology in Drosophila

描述（由申请人提供）：动物的感知系统与其生理稳态之间的动态相互作用在生物衰老中起重要作用。感官输入途径或营养信号成分的遗传破坏可以对生物体的适应性和寿命产生潜在的影响。同样，饮食限制的范例，无论是通过减少食物摄入量或营养的可用性，提高寿命几乎所有物种充分审查。由于感觉输入和营养水平的综合处理主要由中枢神经系统（CNS）介导，因此大脑已成为了解环境输入对衰老生物学基础的贡献的一个有吸引力的前沿。然而，目前尚不清楚中枢神经系统如何协调这些输入与生理系统，以控制寿命和健康。本提案的主要目的是使用果蝇作为遗传上易处理的模式生物来鉴定和表征控制衰老进程的中枢脑回路和神经信号传导底物。在我们的第一个目标，我们将探讨如何操纵神经肽F和脂肪动力激素信号网络影响代谢和衰老表型下的各种饮食制度。在我们的第二个目标中，我们将确定化学感受器如何与高阶处理中心进行通信，以调节苍蝇的寿命和健康寿命。在我们的第三个目标中，我们将识别和研究新的神经信号底物和对果蝇健康衰老进程至关重要的中枢脑区。考虑到 我们相信，这些雄心勃勃的研究将为特定的神经元回路和信号分子如何整合环境输入以直接影响无脊椎动物模型、哺乳动物和人类的衰老提供有价值的见解。

DESCRIPTION (provided by applicant): The dynamic interplay between an animal's perceptual system and its physiological homeostasis plays an important role in biological aging. Genetic disruption of sensory input pathways or nutrient signaling components can induce potent effects on organismal fitness and lifespan. Likewise, dietary restriction paradigms, whether through reduction of food intake or nutrient availability, enhance longevity in nearly all species sufficiently examined. Since integrative processing of sensory inputs and nutrient levels is primarily mediated by the central nervous system (CNS), the brain has emerged as an attractive frontier for understanding the contribution of environmental inputs to the biological basis of aging. However, it remains unclear how the CNS coordinates these inputs with physiological systems to control longevity and healthspan. The primary objective of this proposal is to identify and characterize central brain circuits and neural signaling substrates tha control the progression of aging using the fruit fly Drosophila melanogaster as a genetically- tractable model organism. In our first aim, we will explore how manipulation of neuropeptide F and adipokinetic hormone signaling networks influences metabolism and aging phenotypes under various dietary regimes. In our second aim, we will determine how chemosensory receptors communicate with higher-ordered processing centers to regulate fly longevity and healthspan. In our third aim, we will identify and examine novel neural signaling substrates and central brain regions critical for the progression of healthy aging in flies. Given the high degree of conservation in both the biological basis of aging and the functional architecture of the CNS across taxa, we believe these ambitious studies will provide valuable insight into how specific neuronal circuits and signaling molecules integrate environmental inputs to directly affect aging in invertebrate models, mammals, and humans.