Hierarchy and intersection of hallmarks of aging using genetic, pharmacologic, and dietary life span extending interventions in flies and mice.

项目摘要/摘要：（最多30行） 该提案的总体目标是开发遗传、药理和饮食干预措施， 与年龄有关的疾病的发生和发展，保持健康和功能，直到晚年。我们将测试 假设老化的标志具有相互联系和层次结构-一些标志 是一系列事件的启动者，有些标志是下游效应者。这些知识将 用于制定合理的治疗干预措施，以提高健康寿命。基因组完整性丧失， 随后的转录沉默的丧失是诱导损伤相关分子的起始标志， 包括逆转录转座子（RTEs）在内的DAMP模式，反过来通过线粒体激活先天免疫 机制和代谢重组。这种级联反应导致中枢代谢中的能量平衡缺陷， 脂滴（LD）的积累和失调，反过来又与许多年龄相关， 相关疾病包括肥胖、糖尿病、肝脏和神经退行性疾病。我们推测 LD的积累最终包括导致老化的关键下游和近端生理损伤 与年龄有关的疾病。我们将直接测试我们的假设，即存在相互联系和层次结构 衰老的标志，LD的积累是衰老的一个重要的近端因素， 选择性影响果蝇衰老的特定标志的遗传、药理和饮食干预， 老鼠.这些研究的目标是阐明健康衰老的机制，并确定新的和新颖的 遗传、药理和饮食干预措施，转化为增加健康人 寿命 我们将使用遗传和药理学延长寿命的干预措施，专门针对逆转 果蝇基因组完整性丧失和转录沉默丧失（RTE激活）的起始标志， 检查这些是否导致改善下游标志的激活，如先天性免疫缺陷的激活， 免疫力和LD在果蝇和小鼠衰老过程中的积累。我们还将测试遗传、药理和 饮食干预，以减少下游效应标志，LD在苍蝇中的积累， 小鼠，用于其对LD形成的影响，健康寿命的改善，并评估其逆转上游 激活剂事件，如RTE和先天免疫激活。我们将检验这些干预措施是否 通过改善衰老动物的下游代谢发挥作用，并：（1）延长苍蝇的寿命;（2）延迟 果蝇和小鼠模型中年龄相关表型的发生和发展（寿命、运动性（果蝇）、虚弱 （小鼠）和神经行为测试（苍蝇和小鼠）（3）减少LD的积累（组织染色; LipiTOX 和油红）和（4）使RTE活化和先天免疫正常化或稳定化（蝇和小鼠中的qPCR;报告基因 果蝇中的基因;小鼠中免疫细胞因子和激活剂的抗体）。

Project Summary/Abstract: (30 lines maximum) The overall goal of this proposal is to develop genetic, pharmacologic and dietary interventions that will delay the onset and progression of age-related diseases, preserving health and function until late in life. We will test the hypothesis that hallmarks of aging possess interconnectedness and hierarchical structure — some hallmarks are initiators in a cascade of events, and some hallmarks are downstream effectors. This knowledge will be utilized to develop rational therapeutic interventions to improve healthy longevity. Loss of genomic integrity and consequent loss of transcriptional silencing are initiator hallmarks that induce damage-associated molecular patterns (DAMPs) including retrotransposons (RTEs), that in turn activate innate immunity through mitochondrial mechanisms and metabolic rewiring. This cascade results in defective energy balance in central metabolism and the accumulation of and dysregulation of lipid droplets (LDs) that in turn are associated with a number of age- related ailments including obesity, diabetes, liver and neurodegenerative diseases. We postulate that accumulation of LDs ultimately comprises a critical downstream and proximal physiological insult leading to aging and age-related disease. We will directly test our hypothesis that there is an interconnectedness and hierarchy to the hallmarks of aging and that the accumulation of LDs is an essential proximal element in aging using genetic, pharmacologic and dietary interventions that selectively affect specific hallmarks of aging in the fly and mouse. The goal of these studies is to shed light on mechanisms of healthy aging and identify new and novel genetic, pharmacological and dietary interventions for translation into interventions that increase healthy human life span. We will use genetic and pharmacological life span extending interventions directed specifically at reversing initiator hallmarks of loss of genomic integrity and loss of transcriptional silencing (RTE activation) in flies to examine whether these lead to ameliorating the activation of downstream hallmarks such as activation of innate immunity and LD accumulation in aging in the fly and mouse. We will also test genetic, pharmacological and dietary interventions for their potential to reduce a downstream effector hallmark, LD accumulation in flies and mice, for their effects on LD formation, improvement in health span, and assess their ability to reverse upstream activator events such as RTE and innate immunity activation. We will test the hypotheses that these interventions act through improved downstream metabolism in the aging animals and: (1) extend life span in flies; (2) delay the onset and progression of age-related phenotypes in fly and mouse models (life span, motility (fly), frailty (mouse) and neurobehavioral tests (flies and mice) (3) reduce the accumulation of LDs (tissue staining; LipiTOX and Oil-Red) and (4) normalize or stabilize RTE activation and innate immunity (qPCR in flies and mice; reporter genes in flies; antibodies to immune cytokines and activators in mice).