Targeting Cellular Senescence to Extend Healthspan

项目总结/摘要 本研究旨在探讨代谢功能障碍、衰老、 脑老化和阿尔茨海默病（AD）的发展。 细胞衰老是组织和有机体衰老的一个公认的驱动因素， 被认为是部分介导的诱导慢性衰老相关的分泌 表型（SASP）。因此，人们对选择性靶向衰老细胞产生了极大的兴趣 作为促进健康老龄化的战略。我的实验室发现衰老细胞 在肥胖和老年小鼠不同脑区的神经胶质细胞和神经元中积累。 重要的是，我们表明，清除衰老细胞，使用遗传和 药理学方法，恢复神经发生，并显着减少肥胖- 引起类似焦虑的行为此外，我们发现衰老细胞是一个贡献者， 大脑中脂肪沉积的积累，这是衰老，肥胖和肥胖之间常见的表型。 AD.这使我们假设肥胖通过诱导大脑衰老， 与年龄相关的认知能力下降，并导致神经退行性疾病，如AD。 该项目将是柯克兰博士领导的项目1的补充：“细胞衰老和 代谢功能障碍”，马约/UMN P01 AG 62413的一部分，旨在研究 衰老疗法对肥胖和年龄相关疾病的影响。因此，调查 在脑老化和AD的背景下，肥胖和衰老之间的机械联系是一个 这是一个自然和逻辑的延伸。 为了验证我们的假设，我们将使用创新的小鼠模型， P01，其允许消除p21 Cip 1或p16 Ink 4a阳性衰老细胞（p21 ATTAC 和INK-ATTAC）。使用这些模型，我们将能够阐明功能的影响， 衰老和肥胖期间的衰老细胞清除，特别是， 不同衰老亚型（AIM 1）。此外，我们将能够评估 在AD的小鼠模型中新鉴定的senescin化合物（目的2）。这些新颖 候选药物（包括几种FDA批准的化合物和天然产物） 被确定为药物发现和开发核心的一部分，由保罗罗宾斯博士领导 （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，以减轻认知功能。 在衰老和AD期间下降。

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.