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

使用遗传、药理学和饮食延长果蝇和小鼠寿命的干预措施，研究衰老标志的层次结构和交叉点。

• 批准号: 10901046
• 负责人: STEPHEN L HELFAND
• 金额: $ 39.58万
• 依托单位: BROWN UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-20 至 2024-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10901046
• 关键词: Affect; Age; Aging; Alzheimer' s Disease; Animals; Antibodies; Behavioral Assay; Cerulenin; Chromatin; Chromatin Structure; DNA Sequence Alteration; Dementia; Diabetes Mellitus; Dietary Intervention; Disease; Elements; Event; FASN gene; Feedback; Gene Silencing; Genetic; Goals; Health; Histology; Human; Immune; Intervention; Knowledge; Lead; Life; Link; Lipids; Liver diseases; Longevity; Maps; Measures; Metabolic; Metabolism; Mitochondria; Modification; Molecular; Motor; Mus; Mutation; Natural Immunity; Neurodegenerative Disorders; Obesity; Oils; Pattern; Phenotype; Physiological; Production; Reporter Genes; Retrotransposon; Structure; Testing; Therapeutic Intervention; Time-restricted feeding; Tissue Stains; Transgenes; Translations; age related; cell motility; cytokine; dietary; energy balance; epigenome; experimental study; fly; frailty; gene therapy; genetic testing; genome integrity; healthspan; healthy aging; immune activation; improved; knock-down; mouse model; neurobehavior; neurobehavioral test; novel; pharmacologic; preservation; response; therapy development; tool

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).

项目摘要/摘要：（最多30行） 该提案的总体目标是开发遗传，药物和饮食干预措施，以延迟 与年龄有关的疾病的发作和进展，保留健康和功能，直到生命后期。我们将测试 衰老标志具有相互联系和等级结构的假设 - 一些标志 是一系列级联的发起人，一些标志是下游效果。这些知识将是 用于开发合理的治疗干预措施以改善健康的寿命。基因组完整性的丧失和 随之而来的转录沉默丧失是引发损伤相关分子的引发剂标志 图案（湿）包括逆转座子（RTE），进而通过线粒体激活先天免疫力 机制和代谢重新布线。这种级联导致中央代谢和 脂质液滴（LDS）的积累和失调，而脂质液滴（LDS）又与许多年龄有关 相关疾病，包括肥胖，糖尿病，肝脏和神经退行性疾病。我们假设 LD的积累最终包括关键的下游和近端身体损伤，导致衰老 和与年龄有关的疾病。我们将直接检验我们存在相互联系和层次结构的假设 符合衰老的标志，LDS的积累是使用衰老的近端元素 遗传，药理学和饮食干预措施有选择地影响垂直衰老的特定标志，并且 老鼠。这些研究的目的是阐明健康衰老的机制并识别新的和新颖的 遗传，药物和饮食干预措施，用于将健康人类的干预措施转化为干预措施 寿命。 我们将使用遗传和药物寿命跨度直接延长干预措施，以逆转 基因组完整性丧失和转录沉默丧失（RTE激活）的启动标志 检查这些是否会改善下游标志的激活，例如先天性的激活 免疫力和LD在苍蝇和小鼠衰老中的积累。我们还将测试遗传学，药理和 饮食干预措施，以减少下游效应子标志，LD积累的潜力 小鼠对LD形成的影响，健康跨度的改善并评估其上游的能力 RTE和先天免疫激活等激活剂事件。我们将测试这些干预措施的假设 通过改善衰老动物的下游新陈代谢采取行动，并：（1）在苍蝇中延长寿命； （2）延迟 苍蝇和鼠标模型中与年龄相关的表型的发作和进展（寿命，运动性（苍蝇），脆弱 （小鼠）和神经行为测试（苍蝇和小鼠）（3）减少LDS的积累（组织染色； Lipitox 和油红色）和（4）正常或稳定RTE激活和先天免疫（蝇和小鼠的QPCR；记者 果蝇中的基因；小鼠免疫细胞因子和活化剂的抗体）。