Non-Autonomous control of aging in Drosophila

项目摘要： 衰老与代谢、生理、增殖和组织的功能下降有关。 体内平衡导致生物体水平的恶化。确定治疗策略， 预防或延缓与年龄相关的衰退已成为生物医学科学研究的迫切目标。一个关键 问题是可以驱动生物体老化的组织的识别。我们将测试一种组织特异性 代谢、生理和分子变化，非自主地驱动生物体衰老。 Indy（I'm not dead yet）编码一种主要在果蝇中表达的质膜柠檬酸转运蛋白 代谢组织：中肠、脂肪体和卵母细胞（蝇肝）。我们已经证明，整个组织范围内的减少 在Indy，活动通过改变能量代谢延长了苍蝇的健康和寿命。印第蝇的血脂降低 和葡萄糖水平，增加胰岛素敏感性，增加线粒体生物合成和减少氧化 损害以及其他影响。此外，我们已经表明，下调Indy表达保留了 肠干细胞的稳态，表明中肠代谢变化之间的重要联系， 生理稳态和有机体老化。此外，我们还获得了初步数据， 在苍蝇中肠中的Indy减少模仿了在全身Indy中发现的Indy减少的许多有益效果 包括更长的寿命。因此，我们的工作假设是中肠的INDY减少 调节柠檬酸盐水平，导致代谢变化，保持组织稳态，减缓衰老， 自主地。我们提出以下具体目标。证实中肠在长寿中起着关键作用 通过比较当INDY仅在中肠减少时对苍蝇健康和寿命的影响， 脂肪体或卵母细胞（Aim 1）。用综合分析方法确定Indy还原的效果和机理 涉及代谢研究、转录组学和靶向代谢组学测定的方法 Indy flies中的配置文件（目标2）。确定中肠中Indy减少的生理机制 在生物体水平上延缓衰老（目标3）。我们提出的研究将增进我们对 分子和生理机制的非自主效应的有机体老化。减少 蠕虫、小鼠、大鼠和非人类灵长类动物中的INDY同源物导致类似的代谢结果，这表明 我们的发现可以应用到哺乳动物身上

Project Summary: Aging is associated with functional decline in metabolic, physiological, proliferative, and tissue homeostasis leading to deterioration on the organismal level. The identification of therapeutic strategies that prevent or postpone age-related decline has become an urgent goal of biomedical science research. A key issue is the identification of tissue(s) that can drive organismal ageing. We will test a model of tissue-specific metabolic, physiological and molecular changes that drive organismal aging non-autonomously. Indy (I'm not dead yet) encodes a plasma membrane citrate transporter predominantly expressed in fly metabolic tissues: the midgut, fat body and oenocytes (fly liver). We have shown that organism-wide reduction in Indy activity extends fly health and longevity by altering energy metabolism. Indy flies have decreased lipid and glucose levels, increased insulin sensitivity, increased mitochondrial biogenesis and reduced oxidative damage, among other effects. Additionally, we have shown that down-regulation of Indy expression preserves intestinal stem cell homeostasis, suggesting an important link between metabolic changes in the midgut, physiological homeostasis and organismal aging. Moreover, we have obtained preliminary data that specific Indy reduction in fly midgut mimics many beneficial effects of Indy reduction found in whole body Indy hypomorphs including longer lifespan. Therefore, our working hypothesis is that INDY reduction in the midgut regulates citrate levels leading to metabolic changes that preserve tissue homeostasis and slows aging non- autonomously. We propose the following specific aims. Confirm that the midgut has a key role in longevity regulation by comparing the effects on fly health and lifespan when INDY is reduced solely in the midgut, the fat body, or the oenocytes (Aim 1). Determine effects and mechanism of Indy reduction by using an integrated approach involving study of metabolism, and determination of the transcriptomic and targeted metabolomics profile in Indy flies (Aim 2). Determine the physiological mechanism by which Indy reduction in the midgut slows aging on organismal level (Aim 3). Our proposed study will advance our basic knowledge on the molecular and physiological mechanisms underlying non-autonomous effects on organismal aging. Reducing INDY homologs in worms, mice, rats and non-human primates leads to similar metabolic outcome, suggesting that our findings could be translated to mammalian organisms.