Aging is the greatest risk factor for several diseases, including neurodegenerative conditions such as Alzheimer’s disease. Our lab investigates the mechanisms responsible for brain aging, with the goal of identifying targets to improve healthy aging and treat neurodegeneration. Our work is focused on two different areas of the brain: the hippocampus and the hypothalamus. In this presentation, I will highlight our work investigating the mechanisms of hypothalamic aging and the changes that this area of the brain undergoes in neurodegeneration. The hypothalamus is a well-conserved brain region that controls homeostatic and survival-related behaviors such as sleep, circadian rhythms, metabolic homeostasis, reproduction, and hormone status. We have identified cell-type specific transcriptional and epigenetic changes with age in the mouse that correlate with loss of hypothalamic function. We have also discovered sex-specific features of the aging hypothalamus suggesting cell-intrinsic epigenetic changes that underlie differences in male and female aging. Finally, we have performed the first large-scale analysis of single cell transcriptomic changes in the hypothalamus in Alzheimer’s disease, and I will present our preliminary findings suggesting major changes in specific hypothalamic subregions and cell types. In the long term, this work may lead to new strategies to enhance healthy brain function in the context of aging and neurodegeneration and improve quality of life in the elderly.