Proteostasis and metabolism in brain aging

项目总结 阿尔茨海默病等与年龄相关的神经退行性疾病表现为神经元蛋白的分解 动态平衡(蛋白质平衡)。年龄相关性代谢功能障碍与蛋白质的关系 这类疾病的聚集性仍然知之甚少。阐明年龄相关疾病的分子基础 蛋白质平衡的丧失有望激发新的治疗方法，不仅是针对阿尔茨海默氏症这样的疾病， 但更广泛地说，它适用于一系列与年龄相关的疾病。越来越多地，“老年科学”的这个承诺正在成为 被认为是延长我们健康寿命的关键。 老年学中最有成效的实验方法之一是使用遗传可及模型 研究长寿的系统。这些模型已经能够识别单基因突变和 延长寿命的干预措施，强调衰老过程的可塑性，并提出 显著改变了它的路线。受此类干预影响并导致寿命延长的细胞事件 然而，延期在很大程度上仍不清楚。在许多情况下，对寿命的影响与变化有关 在蛋白质平衡和新陈代谢方面。 然而，要详细了解蛋白质代谢和长寿之间的关系，需要一个完整的 研究寿命延长扰动对全球蛋白质动态平衡的影响的方法 明确定义的遗传系统中的代谢流量。在这里，申请者建议通过将 使用遗传方法(Jasper)、蛋白质组学和生物信息学方法的小组的专门知识(希林和 Ghaemmaghami)和代谢组学方法(Ramanathan)来开发蛋白质和代谢模型 果蝇长寿突变体的动态平衡。 质谱学领域的最新技术进步使蛋白质的全球分析成为可能 复杂生物体的周转率和代谢流量。结合这些技术和详细的分析 延长寿命的遗传扰动有望为分子研究提供变革性的新见解 长寿所需的变化。申请者提出的目标是：(I)评估与年龄相关的变化 全球蛋白质周转和代谢通量，(Ii)决定下游能量代谢的变化 Jun-N末端激酶和胰岛素信号通路影响蛋白质周转，以及(Iii)进行遗传学研究 探讨衰老、长寿的原因。 预计将果蝇系统的优势与最先进的蛋白质组学和 代谢组学方法将极大地加速发现影响 生理和细胞功能与年龄的关系，为年龄相关疾病提供了新的治疗途径。

PROJECT SUMMARY Age-related neurodegenerative diseases like Alzheimer’s Disease exhibit a breakdown in neuronal protein homeostasis (proteostasis). The relationship between age-related metabolic dysfunctions and protein aggregation in such diseases remains poorly understood. Elucidating the molecular basis for the age-related loss of proteostasis is expected to inspire new therapeutic approaches, not only for diseases like Alzheimer’s, but more broadly for a wide range of age-related diseases. Increasingly, this promise of “Geroscience” is being recognized as critical for extending our healthspan. Among the most productive experimental approaches in Geroscience is the use of genetically accessible model systems for the study of longevity. These models have allowed the identification of single gene mutations and of interventions that extend lifespan, highlighting the plasticity of the aging process and suggesting avenues to significantly alter its course. The cellular events impacted by such interventions and causing the lifespan extension, however, remain largely unclear. In many cases, the effect on longevity is associated with changes in proteostasis and metabolism. To understand the relationship between proteostasis and longevity in detail, however, requires an integrated approach that investigates the effects of lifespan extending perturbations on global protein homeostasis and metabolic flux in a well-defined genetic system. Here, the applicants propose such integration by combining the expertise of groups using genetic approaches (Jasper), proteomic and bioinformatic approaches (Schilling and Ghaemmaghami), and metabolomic approaches (Ramanathan) to develop models for protein and metabolic homeostasis in long-lived mutants of Drosophila. Recent technological advances in the field of mass spectrometry have enabled global analyses of protein turnover rates and metabolic flux in complex organisms. Combining these technologies with detailed analysis of lifespan-extending genetic perturbations is expected to provide transformative new insights into molecular changes required for longevity. The aims proposed by the applicants are to (i) assess age-related changes in global protein turnover and metabolic flux, (ii) determine if changes in energy metabolism downstream of the Jun-N-terminal Kinase and Insulin signaling pathways influence protein turnover, and (iii) perform genetic studies to explore the causes of aging and longevity. It is anticipated that combining the strengths of the Drosophila system with state-of-the-art proteomic and metabolomic approaches will significantly accelerate the discovery of fundamental mechanisms influencing physiology and cell function with age, providing new therapeutic avenues for age-related diseases.