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.