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 ?-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.