Non-Autonomous control of aging in Drosophila

项目总结： 衰老与代谢、生理、增殖和组织的功能衰退有关 动态平衡导致生物体水平的恶化。确定治疗策略， 预防或延缓衰老已成为生物医学科学研究的迫切目标。一把钥匙 问题是识别可能导致生物衰老的组织(S)。我们将测试一种组织特异性的模型 代谢、生理和分子方面的变化，非自主地驱动生物体衰老。 Indy(我还没死)编码一种主要在苍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(苍蝇肝)。我们已经证明了生物体范围内的减少 在印地，运动通过改变能量代谢来延长苍蝇的健康和寿命。印地苍蝇能降低血脂 和血糖水平，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，我们已经证明，下调Indy表达可以保留 肠道干细胞动态平衡，表明中肠代谢变化之间存在重要联系， 生理动态平衡和生物体衰老。此外，我们已经获得了具体的初步数据， 苍蝇中肠减少Indy与全身Indy中发现的Indy减少的许多有益效果相似 亚态包括更长的寿命。因此，我们的工作假设是中肠的印地减少 调节柠檬酸水平，导致代谢变化，保持组织动态平衡，延缓衰老 自主地。我们提出了以下具体目标。确认中肠在长寿中起着关键作用 通过比较单独在中肠减少Indy对苍蝇健康和寿命的影响进行调节， 脂肪体或卵母细胞(目标1)。用一种综合的方法确定降低印染的效果和机理 涉及新陈代谢研究、转录和靶向代谢组学测定的方法 印地苍蝇的档案(目标2)。确定中肠吲哚减少的生理机制 在生物体水平上延缓衰老(目标3)。我们建议的研究将增进我们对 非自主影响生物体衰老的分子和生理机制。减少 蠕虫、小鼠、大鼠和非人类灵长类动物中的印地同系物导致相似的代谢结果，这表明 我们的发现可以被转化到哺乳动物身上。

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.