Non-Autonomous control of aging in Drosophila

果蝇衰老的非自主控制

• 批准号: 10177832
• 负责人: BLANKA ROGINA
• 金额: $ 41万
• 依托单位: UNIVERSITY OF CONNECTICUT SCH OF MED/DNT
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-09-01 至 2023-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10177832
• 关键词: Affect; Age; Aging; Biogenesis; Cell membrane; Cell physiology; Cells; Citrates; Data; Deterioration; Development; Disease; Down-Regulation; Drosophila genus; Energy Metabolism; Evaluation; Fat Body; Female; Fertility; Foundations; Genes; Genetic Transcription; Glucose; Glycolysis; Goals; Health; Health Benefit; Homeostasis; Human; Insulin; Intestines; Knowledge; Lead; Life; Link; Lipids; Longevity; Longevity Pathway; Mediating; Metabolic; Metabolism; Midgut; Mitochondria; Modeling; Molecular; Mus; Nutritional; Organism; Outcome; Physiological; Production; Rattus; Regulation; Research; Resistance; Role; Science; Signal Pathway; Signal Transduction; Stress; Testing; Therapeutic; Tissue Model; Tissue Preservation; Tissues; Translating; Work; age related; base; citrate carrier; fly; functional decline; healthspan; insight; insulin sensitivity; insulin-like signaling; metabolic abnormality assessment; metabolomics; nonhuman primate; novel therapeutics; oxidative damage; preservation; prevent; stem cell homeostasis; stem cell proliferation; stem cells; transcriptome; transcriptome sequencing; transcriptomics

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.

项目概要： 衰老与代谢、生理、增殖和组织功能下降有关 体内平衡导致有机体水平恶化。治疗策略的确定 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紧迫目标。一把钥匙 问题是识别可以驱动机体衰老的组织。我们将测试组织特异性模型 导致机体非自主衰老的代谢、生理和分子变化。 Indy（我还没死）编码主要在果蝇中表达的质膜柠檬酸转运蛋白 代谢组织：中肠、脂肪体和卵细胞（果蝇肝）。我们已经表明，整个生物体范围内的减少 Indy 活动通过改变能量代谢来延长果蝇的健康和寿命。印地果蝇的脂质含量降低 和葡萄糖水平，增加胰岛素敏感性，增加线粒体生物合成并减少氧化 损害等影响。此外，我们已经证明 Indy 表达的下调可以保留 肠道干细胞稳态，表明中肠代谢变化之间存在重要联系， 生理稳态和机体衰老。此外，我们还获得了具体的初步数据 果蝇中肠中的 Indy 还原模拟了全身 Indy 中发现的 Indy 还原的许多有益效果 亚型包括更长的寿命。因此，我们的工作假设是中肠中 INDY 的减少 调节柠檬酸盐水平，导致代谢变化，保持组织稳态并延缓衰老 自主地。我们提出以下具体目标。确认中肠在长寿中起着关键作用 通过比较仅在中肠中减少 INDY 时对果蝇健康和寿命的影响来进行调节， 脂肪体，或卵细胞（目标 1）。通过使用集成的方法确定 Indy 减少的效果和机制 涉及代谢研究以及转录组学和靶向代谢组学测定的方法 印地飞翔（目标 2）中的个人资料。确定中肠 Indy 减少的生理机制 在机体水平上减缓衰老（目标 3）。我们提出的研究将提高我们的基础知识 对有机体衰老的非自主效应的分子和生理机制。减少 INDY 同源物在蠕虫、小鼠、大鼠和非人类灵长类动物中产生相似的代谢结果，表明 我们的发现可以转化为哺乳动物有机体。