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
• 负责人: Diana Jurk
• 金额: $ 39.75万
• 依托单位: MAYO CLINIC ROCHESTER
• 依托单位国家: 美国
• 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: https://reporter.nih.gov/project-details/10651688
• 关键词: Abeta synthesis; Acceleration; Age-associated memory impairment; Aging; Alzheimer' s Disease; Alzheimer' s disease model; Alzheimer' s disease pathology; Anxiety; Area; Astrocytes; Attenuated; Brain; Brain region; CDKN2A gene; Cell Aging; Cells; Chronic; Clinical Treatment; Cognitive aging; Data; Dementia; Deposition; Development; Encephalitis; Excision; Fatty acid glycerol esters; Foundations; Genetic; Goals; Imaging Device; Impaired cognition; Impairment; Inflammation; Intervention; Knowledge; LOX gene; Link; Lipids; Mass Spectrum Analysis; Measures; Mediating; Mental Depression; Mental disorders; Microglia; Modeling; Molecular; Mus; Nerve Degeneration; Neurodegenerative Disorders; Neuroglia; Neurons; Obesity; Parkinson Disease; Phenotype; Play; Pre-Clinical Model; Process; Reporting; Risk; Risk Factors; Role; Testing; Tissues; Transgenic Mice; Transgenic Model; aged; aging brain; anxiety-like behavior; brain cell; cell type; diet-induced obesity; functional improvement; genetic approach; global health; healthy aging; imaging approach; impaired driving performance; innovation; interest; lipid biosynthesis; lipid metabolism; lipidomics; mouse model; neurogenesis; neuroinflammation; neuropsychiatric disorder; novel; oxidation; pharmacologic; premature; senescence

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.

项目摘要/摘要 该应用调查了肥胖，感应，大脑衰老与 阿尔茨海默氏病（AD）的发展。蜂窝感应是一个完善的驱动程序 组织和有机老化，这一过程被认为是通过诱导的部分介导的 慢性衰老相关秘书表型（SASP）。因此，很棒 对选择性靶向感觉细胞作为促进健康衰老的策略的兴趣。我们有 发现在不同大脑区域的神经细胞和神经元中积累的感觉标记 肥胖和老年小鼠。重要的是，我们证明了使用两者的感觉清除 遗传和药理学方法，恢复的神经发生并显着改善 肥胖引起的类似动画的行为。此外，我们发现感觉细胞是一个 促进脂肪沉积在大脑中的积累的贡献者，这是一种常见的表型 衰老，肥胖和广告。这导致我们通过诱发的感应来假设肥胖 大脑，加剧与年龄相关的认知下降，并导致神经退行性疾病 例如广告。 为了检验我们的假设，我们将使用创新的鼠标模型，以允许紧急 P21CIP1或P16INK4A阳性感觉细胞（P21-ATTAC和INK-ATTAC）以及 新型转基因模型Lox-Attac（我们将与表达不同CRE的小鼠交叉） 允许我们清除专门在神经元，小胶质细胞和星形胶质细胞中的P16INK4A感觉细胞。 使用这些模型，我们将能够阐明Senscent Cell的功能影响 衰老和肥胖期间的清除率，特别是不同细胞类型的相对贡献 （AIM1）。此外，我们将检查介导脂质代谢受损的机制 在感应期间，尤其是脂质导入，脂肪生成和β氧化对细胞的作用 通过结合遗传和成像方法以及质量的结合 光谱脂质对学研究。最后，我们将研究小鼠饮食诱导的肥胖症是否 AD模型通过增加的细胞感染以及 在肥胖期间去除感觉细胞对AD病理的影响。 我们的最终目标是确定靶向感官细胞以减轻认知的新干预措施 衰老和广告期间下降。