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。
基本信息
- 批准号:10901046
- 负责人:
- 金额:$ 39.58万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 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:
- 关键词:AffectAgeAgingAlzheimer&aposs DiseaseAnimalsAntibodiesBehavioral AssayCeruleninChromatinChromatin StructureDNA Sequence AlterationDementiaDiabetes MellitusDietary InterventionDiseaseElementsEventFASN geneFeedbackGene SilencingGeneticGoalsHealthHistologyHumanImmuneInterventionKnowledgeLeadLifeLinkLipidsLiver diseasesLongevityMapsMeasuresMetabolicMetabolismMitochondriaModificationMolecularMotorMusMutationNatural ImmunityNeurodegenerative DisordersObesityOilsPatternPhenotypePhysiologicalProductionReporter GenesRetrotransposonStructureTestingTherapeutic InterventionTime-restricted feedingTissue StainsTransgenesTranslationsage relatedcell motilitycytokinedietaryenergy balanceepigenomeexperimental studyflyfrailtygene therapygenetic testinggenome integrityhealthspanhealthy agingimmune activationimprovedknock-downmouse modelneurobehaviorneurobehavioral testnovelpharmacologicpreservationresponsetherapy developmenttool
项目摘要
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)
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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STEPHEN L HELFAND其他文献
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{{ truncateString('STEPHEN L HELFAND', 18)}}的其他基金
Genetic and Functional Mechanisms in Citrate Transporter Disorder associated with SLC13A5
与 SLC13A5 相关的柠檬酸转运蛋白紊乱的遗传和功能机制
- 批准号:
10651203 - 财政年份:2023
- 资助金额:
$ 39.58万 - 项目类别:
The effect of life span modifying interventions on Alzheimer's Disease in Drosophila and Mice.
寿命改变干预措施对果蝇和小鼠阿尔茨海默病的影响。
- 批准号:
10609394 - 财政年份:2020
- 资助金额:
$ 39.58万 - 项目类别:
The effect of life span modifying interventions on Alzheimer's Disease in Drosophila and Mice.
寿命改变干预措施对果蝇和小鼠阿尔茨海默病的影响。
- 批准号:
10375432 - 财政年份:2020
- 资助金额:
$ 39.58万 - 项目类别:
Regulation of retrotransposable element activity in Drosophila.
果蝇逆转录转座元件活性的调节。
- 批准号:
9150884 - 财政年份:2016
- 资助金额:
$ 39.58万 - 项目类别:
Project 2: Role of Retrotransposable Element Activity in Drosophila Models of Alzheimer's Disease
项目2:逆转录转座元件活性在阿尔茨海默病果蝇模型中的作用
- 批准号:
10581529 - 财政年份:2016
- 资助金额:
$ 39.58万 - 项目类别:
Project 2: Role of Retrotransposable Element Activity in Drosophila Models of Alzheimer's Disease
项目2:逆转录转座元件活性在阿尔茨海默病果蝇模型中的作用
- 批准号:
10333662 - 财政年份:2016
- 资助金额:
$ 39.58万 - 项目类别:
Single Gene Mutants that Confer Longevity in Drosphila
赋予果蝇长寿的单基因突变体
- 批准号:
7919036 - 财政年份:2009
- 资助金额:
$ 39.58万 - 项目类别:
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