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 这个应用程序调查肥胖、衰老、脑老化和 阿尔茨海默病(AD)的发展。细胞衰老是一个公认的驱动因素 组织和组织的衰老，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，有很大的 有兴趣选择性地将衰老细胞作为促进健康衰老的一种策略。我们有 发现衰老标记物聚集在脑内不同区域的神经胶质细胞和神经元中 肥胖和衰老的小鼠。重要的是，我们用这两种方法证明了衰老细胞的清除 遗传学和药理学方法，恢复了神经发生，并显著减少 肥胖导致的焦虑样行为。此外，我们发现衰老的细胞是一种 大脑中脂肪沉积的贡献者，这是一种常见的 衰老、肥胖和阿尔茨海默病。这导致我们假设肥胖，通过诱导老年人衰老 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。 为了检验我们的假设，我们将使用创新的老鼠模型，这种模型允许消除 P21Cip1或p16INK4a阳性衰老细胞(p21-ATTAC和INK-ATTAC)，以及 新的转基因模型LOX-ATTAC(我们将与不同表达Cre的小鼠杂交) 使我们能够清除p16INK4a衰老细胞，特别是神经元、小胶质细胞和星形胶质细胞。 使用这些模型，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 (目标1)。此外，我们还将研究调节脂代谢受损的机制。 特别是在衰老过程中，脂质输入、脂肪生成和β氧化对细胞的作用 使用遗传和成像方法以及质量的组合来实现衰老 光谱分析类脂组学研究。最后，我们将调查饮食是否会导致小鼠肥胖 阿尔茨海默病模型通过增加细胞衰老加剧神经变性，以及 肥胖期去除衰老细胞对AD病理的影响。 我们的最终目标是确定针对衰老细胞的新干预措施，以缓解认知障碍 在衰老和阿尔茨海默病期间下降。