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、药理学和饮食干预措施，以延迟 我们将测试与年龄相关的疾病的发生和进展，保持健康和功能直到晚年。 衰老特征具有相互关联性和等级结构的假设——一些特征 是一系列事件的发起者，并且某些特征是下游效应器。 用于开发合理的治疗干预措施以延长健康寿命和基因组完整性的丧失。 随后转录沉默的丧失是诱导损伤相关分子的起始标志 模式（DAMP），包括逆转录转座子（RTE），反过来通过线粒体激活先天免疫 这种级联导致中枢代谢和代谢的能量平衡缺陷。 脂滴 (LD) 的积累和失调又与许多年龄相关 我们假设相关疾病包括肥胖、糖尿病、肝脏和神经退行性疾病。 LD 的积累最终构成了导致衰老的关键下游和近端生理损伤 我们将直接检验我们的假设，即存在相互关联性和层次结构。 衰老的标志，LDs 的积累是衰老过程中一个重要的近端元素 遗传、药理学和饮食干预措施选择性地影响果蝇衰老的特定特征 这些研究的目的是揭示健康衰老的机制并确定新的和新颖的机制。 遗传、药理学和饮食干预措施转化为提高人类健康水平的干预措施 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（RTE激活）丧失的起始标志 检查这些是否会导致改善下游标志的激活，例如先天性的激活 我们还将测试果蝇和小鼠衰老过程中的免疫和 LD 积累。 饮食干预有可能减少下游效应标志、果蝇中 LD 的积累以及 小鼠，因其对 LD 形成、改善健康寿命的影响，并评估其逆转上游的能力 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代谢来发挥作用，并且：（1）延长果蝇的寿命；（2）延迟； 果蝇和小鼠模型中与年龄相关的表型的发生和进展（寿命、运动性（果蝇）、虚弱 （小鼠）和神经行为测试（果蝇和小鼠）(3) 减少 LD 的积累（组织染色；LipiTOX 和油红）和（4）使 RTE 激活和先天免疫正常化或稳定（果蝇和小鼠中的 qPCR；记者 果蝇基因；小鼠免疫细胞因子和激活剂抗体）。