Targeting Cellular Senescence to Extend Healthspan

靶向细胞衰老以延长健康寿命

• 批准号: 10117964
• 负责人: JAMES L. KIRKLAND
• 金额: $ 39.75万
• 依托单位: MAYO CLINIC ROCHESTER
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-06-01 至 2024-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10117964
• 关键词: Age-associated memory impairment; Aging; Alzheimer' s Disease; Alzheimer' s disease model; Amygdaloid structure; Anxiety; Apoptosis; Astrocytes; Biological; Biological Markers; Brain; Brain region; CDKN2A gene; Cell Aging; Cells; Characteristics; Chromatin; Chronic; Clinical Treatment; Cytometry; Data; Deposition; Development; Disease; Drug Targeting; FDA approved; Fatty acid glycerol esters; Genetic; Goals; Grant; Image; Impaired cognition; Intervention; Knowledge; Laboratories; Lead; Link; Mediating; Metabolic dysfunction; Minnesota; Modeling; Molecular; Mus; Natural Products; Nerve Degeneration; Neurodegenerative Disorders; Neuroglia; Neurons; Obesity; Pharmaceutical Preparations; Pharmacology; Phenotype; Physiology; Positioning Attribute; Process; Reporting; Resistance; Risk Factors; Role; Testing; Time; Tissues; Treatment Efficacy; Universities; Work; age related; aged; aging brain; anxiety-like behavior; cell age; cell type; cellular targeting; cognitive function; drug candidate; drug development; drug discovery; drug testing; efficacy testing; functional improvement; healthspan; healthy aging; innovation; interest; mouse model; neurogenesis; neuropsychiatric disorder; novel; promoter; senescence; suicide gene; tau Proteins; tool

PROJECT SUMMARY/ABSTRACT This project aims to investigate the relationship between metabolic dysfunction, 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. My laboratory has found that senescent cells accumulate 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, restores neurogenesis and significantly decreases 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. This project will be a supplement to Project 1 led by Dr. Kirkland on: “Cellular Senescence and Metabolic Dysfunction”, part of the Mayo/UMN P01 AG 62413, which aims to investigate the impact of senotherapies in the context of obesity and age-related diseases. Thus, investigating the mechanistic links between obesity and senescence in the context of brain aging and AD is a natural and logical extension of this project. In order to test our hypothesis, we will use innovative mouse models developed as part of the P01 which allow the elimination of either p21Cip1 or p16Ink4a positive senescent cells (p21 ATTAC and INK-ATTAC). 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 senescent sub-types (aim1). Additionally, we will be able to evaluate the efficacy of newly identified senotherapeutic compounds in a mouse model of AD (aim 2). These novel candidate drugs (which include several FDA approved compounds and natural products) have been identified as part of the Drug Discovery and Development Core led by Dr. Paul Robbins (University of Minnesota) as part of the P01. 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 该项目旨在研究代谢功能障碍、衰老、 脑老化与阿尔茨海默病(AD)的发展。 细胞衰老是组织和组织衰老的一个公认的驱动因素，这是一个过程 认为部分是通过诱导慢性衰老相关的分泌来调节的 表型(SASP)。因此，选择性地靶向衰老细胞引起了极大的兴趣 作为促进健康老龄化的一项战略。我的实验室发现衰老细胞 在肥胖和衰老小鼠不同脑区的神经胶质细胞和神经元中蓄积。 重要的是，我们展示了衰老细胞的清除，使用遗传和 药理学方法，恢复神经再生，显著减少肥胖- 诱发焦虑样行为。此外，我们发现衰老的细胞对 脂肪沉积在大脑中的积累，这是衰老、肥胖和 广告。这导致我们假设，肥胖通过诱导大脑衰老，加剧了 与年龄相关的认知能力下降，并导致神经退行性疾病，如阿尔茨海默病。 该项目将是柯克兰博士领导的项目1的补充，项目1的主题是：“细胞衰老和 代谢功能障碍“，梅奥/明尼苏达P01 AG 62413的一部分，旨在调查 老年疗法在肥胖和年龄相关疾病方面的影响。因此，调查 在大脑老化和AD的背景下，肥胖和衰老之间的机制联系是 这个项目的自然和合乎逻辑的延伸。 为了检验我们的假设，我们将使用创新的老鼠模型，作为 P01，它允许消除p21Cip1或p16INK4a阳性的衰老细胞(p21ATTAC 和INK-ATTAC)。使用这些模型，我们将能够阐明 衰老和肥胖过程中衰老细胞的清除，特别是 不同的衰老亚型(AIM1)。此外，我们将能够评估 在阿尔茨海默病小鼠模型中新发现的感官治疗化合物(目标2)。这些小说 候选药物(包括几种FDA批准的化合物和天然产品) 被确定为保罗·罗宾斯博士领导的药物发现和开发核心的一部分 (明尼苏达大学)作为P01的一部分。 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。