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) 这项提案的总体目标是开发遗传、药理和饮食干预措施，以延迟 与年龄有关的疾病的发生和发展，直到晚年才能保持健康和功能。我们将测试 假设衰老的特征具有相互联系和等级结构--一些特征 是一系列事件的发起者，而一些标志是下游的效应者。这一知识将是 用来开发合理的治疗干预措施，以提高健康长寿。基因组完整性的丧失和 随之而来的转录沉默的丧失是导致损伤相关分子的启动者特征 包括反转录转座子(RTES)在内的模式(DAMP)，这些模式(DAMP)通过线粒体激活先天免疫 机制和新陈代谢重新布线。这种级联反应导致中枢新陈代谢的能量平衡受损 脂滴(LDs)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。我们假定 LDS的积累最终包括导致衰老的关键下游和近端生理损害 以及与年龄相关的疾病。我们将直接测试我们的假设，即存在相互关联和等级 对于衰老的特征，LDS的积累是衰老过程中必不可少的近端元素 遗传、药物和饮食干预，选择性地影响苍蝇衰老的特定特征 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 用于将遗传、药物和饮食干预转化为增加健康人体健康的干预措施 寿命。 我们将使用遗传和药物延长寿命的干预措施，专门针对逆转 苍蝇TO基因组完整性丧失和转录沉默(RTE激活)丧失的启动子特征 检查这些是否导致改善下游标志的激活，如先天激活 苍蝇和小鼠衰老过程中的免疫和LD蓄积。我们还将测试遗传、药理学和 饮食干预，以减少下游效应标志，果蝇体内LD积累和 小鼠，观察它们对LD形成的影响，改善健康寿命，并评估它们逆转上游的能力 激活事件，如RTE和先天免疫激活。我们将检验这些干预措施的假设 通过改善衰老动物的下游代谢起作用：(1)延长果蝇的寿命；(2)延缓 苍蝇和小鼠模型中与年龄相关的表型的发生和发展(寿命、能动性(苍蝇)、虚弱 (小鼠)和神经行为测试(苍蝇和小鼠)(3)减少LDS(组织染色；LipiTOX)的积累 和油红)和(4)正常化或稳定RTE激活和天然免疫(苍蝇和小鼠的qPCR；报道 苍蝇的基因；小鼠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).