Does obesity exacerbate age-related cognitive decline via senescence?
肥胖是否会通过衰老加剧与年龄相关的认知能力下降?
基本信息
- 批准号:10040045
- 负责人:
- 金额:$ 39.75万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2020
- 资助国家:美国
- 起止时间:2020-09-10 至 2025-05-31
- 项目状态:未结题
- 来源:
- 关键词:Age-associated memory impairmentAgingAlzheimer&aposs DiseaseAlzheimer&aposs disease modelAlzheimer&aposs disease pathologyAmyloid beta-ProteinAnxietyAreaAstrocytesAttenuatedBrainBrain regionCDKN2A geneCell AgingCellsChronicClinical TreatmentCognitive agingDataDepositionDevelopmentDietEncephalitisExcisionFatty acid glycerol estersFoundationsGeneticGoalsImaging DeviceImpaired cognitionImpairmentInflammationInterventionKnowledgeLOX geneLeadLinkLipidsMass Spectrum AnalysisMeasuresMediatingMental disordersMicrogliaModelingMolecularMusNerve DegenerationNeurodegenerative DisordersNeurogliaNeuronsObesityParkinson DiseasePharmacologyPhenotypePlayPre-Clinical ModelProcessReportingRiskRisk FactorsRoleTestingTissuesTransgenic MiceTransgenic Modelagedaging brainanxiety-like behaviorbrain cellcell typefunctional improvementgenetic approachglobal healthhealthy agingimaging approachimpaired driving performanceinnovationinterestlipid biosynthesislipid metabolismmouse modelneurogenesisneuroinflammationneuropsychiatric disordernoveloxidationprematuresenescence
项目摘要
PROJECT SUMMARY/ABSTRACT
This application investigates the relationship between obesity, senescence, brain aging and the
development of Alzheimer’s disease (AD). Cellular senescence is a well-established driver of
tissue and organismal aging, a process thought to be partly mediated via the induction of a
chronic Senescence-associated secretory phenotype (SASP). Consequently, there is great
interest in selectively targeting senescent cells as a strategy to promote healthy aging. We have
found that senescent markers accumulated in glia cells and neurons in different brain regions of
obese and aged mice. Importantly, we showed that clearance of senescent cells, using both
genetic and pharmacological approaches, restored neurogenesis and significantly decreased
obesity-induced anxiety-like behavior. Additionally, we found that senescent cells were a
contributor to the accumulation of fat deposits in the brain, a phenotype common between
aging, obesity and AD. This led us to hypothesize that obesity, by inducing senescence in the
brain, exacerbates age-related cognitive decline and contributes to neurodegenerative diseases
such as AD.
In order to test our hypothesis, we will use innovative mouse models which allow the elimination
of either p21Cip1 or p16Ink4a positive senescent cells (p21-ATTAC and INK-ATTAC), as well as a
novel transgenic model LOX-ATTAC (which we will cross with different Cre-expressing mice)
allowing us to clear p16Ink4a senescent cells specifically in neurons, microglia and astrocytes.
Using these models, we will be able to elucidate the functional impact of senescent cell
clearance during aging and obesity, in particular, the relative contribution of different cell-types
(aim1). Additionally, we will examine the mechanisms mediating impaired lipid metabolism
during senescence in particular the role of lipid import, lipogenesis and β-oxidation to cellular
senescence by using a combination of genetic and imaging approaches as well as mass
spectrometry lipidomics studies. Finally, we will investigate if diet-induced obesity in mouse
models of AD exacerbates neurodegeneration via increased cellular senescence as well as the
impact of removal of senescent cells to the pathology of AD during obesity.
Our ultimate goal is to identify new interventions that target senescent cells to alleviate cognitive
decline during aging and AD.
项目总结/摘要
本申请研究肥胖、衰老、脑老化和脑老化之间的关系。
阿尔茨海默病(AD)的发展。细胞衰老是一个公认的驱动因素,
组织和有机体衰老,这一过程被认为部分是通过诱导
慢性衰老相关分泌表型(SASP)。因此,
选择性靶向衰老细胞作为促进健康衰老的策略。我们有
发现衰老标记物在大脑不同区域的神经胶质细胞和神经元中积累,
肥胖和老年小鼠。重要的是,我们表明,清除衰老细胞,使用
通过遗传和药理学方法,恢复了神经发生,
肥胖引起的焦虑样行为此外,我们发现衰老细胞是一种
在大脑中脂肪沉积的积累的贡献者,一种常见的表型之间
衰老、肥胖和AD。这使我们假设,肥胖,通过诱导衰老,
大脑,加剧与年龄相关的认知能力下降,并导致神经退行性疾病
例如AD。
为了验证我们的假设,我们将使用创新的小鼠模型,
p21 Cip 1或p16 Ink 4a阳性衰老细胞(p21-ATTAC和INK-ATTAC),以及
新的转基因模型LOX-ATTAC(我们将与不同的Cre表达小鼠杂交)
使我们能够清除p16 Ink 4a衰老细胞,特别是在神经元,小胶质细胞和星形胶质细胞。
利用这些模型,我们将能够阐明衰老细胞的功能影响,
衰老和肥胖期间的清除,特别是不同细胞类型的相对贡献
(aim1)。此外,我们还将研究介导脂质代谢受损的机制
在衰老过程中,特别是脂质输入、脂肪生成和β-氧化对细胞的作用,
衰老通过使用遗传和成像方法的组合以及质量
光谱脂质组学研究。最后,我们将研究饮食诱导的小鼠肥胖是否
AD模型通过增加的细胞衰老以及
去除衰老细胞对肥胖期间AD病理学的影响。
我们的最终目标是确定针对衰老细胞的新干预措施,以减轻认知功能。
在衰老和AD期间下降。
项目成果
期刊论文数量(0)
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专利数量(0)
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Diana Jurk其他文献
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{{ truncateString('Diana Jurk', 18)}}的其他基金
Does obesity exacerbate age-related cognitive decline via senescence?
肥胖是否会通过衰老加剧与年龄相关的认知能力下降?
- 批准号:
10413219 - 财政年份:2020
- 资助金额:
$ 39.75万 - 项目类别:
Does obesity exacerbate age-related cognitive decline via senescence?
肥胖是否会通过衰老加剧与年龄相关的认知能力下降?
- 批准号:
10259705 - 财政年份:2020
- 资助金额:
$ 39.75万 - 项目类别:
Does obesity exacerbate age-related cognitive decline via senescence?
肥胖是否会通过衰老加剧与年龄相关的认知能力下降?
- 批准号:
10651688 - 财政年份:2020
- 资助金额:
$ 39.75万 - 项目类别:
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