Central Nervous System Regulation of Aging Physiology in Drosophila

动物知觉系统与生理动态平衡之间的动态相互作用在生物衰老中起着重要作用。感觉输入途径或营养信号成分的遗传破坏可能会对生物体的健康和寿命产生潜在的影响。同样，饮食限制模式，无论是通过减少食物摄入量或营养供应，都能提高几乎所有经过充分研究的物种的寿命。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)调节，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，以控制寿命和健康寿命。这项建议的主要目标是利用果蝇作为一种遗传易驯化的模式生物来识别和表征控制衰老进程的中枢大脑回路和神经信号底物。在我们的第一个目标中，我们将探索神经肽F和脂肪运动激素信号网络的操纵如何在不同的饮食制度下影响新陈代谢和衰老表型。在我们的第二个目标中，我们将确定化学感觉受体如何与更高级的处理中心进行通信，以调节苍蝇的寿命和健康寿命。在我们的第三个目标中，我们将识别和检查新的神经信号底物和对果蝇健康衰老进程至关重要的中央大脑区域。鉴于衰老的生物学基础和中枢神经系统跨类群的功能架构的高度保守性，我们相信这些雄心勃勃的研究将为特定的神经元电路和信号分子如何整合环境输入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。

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.