OVERALL PROJECT SUMMARY Aging is by far the most important driver and risk factor for developing a variety of neurodegenerative diseases, including Alzheimer’s disease (AD) and related dementias. These devastating diseases exact an enormous emotional, social and economic toll on patients and their families, yet to date there are no effective treatments that delay, much less reverse, the onset or progression of these diseases. Clearly, new approaches to understanding and treating age-related neurodegeneration are needed. This Program Project Grant (PPG) proposal aims to fill this serious gap in our knowledge and treatment approaches. The proposed PPG consists of three research projects, each focused on an aspect of brain aging that is known to be crucial for brain function: 1) cell fate decisions, particularly cell death and cellular senescence; 2) metabolism, particularly responses leading to metabolic reprogramming and inflammation; and 3) cell-cell interactions, particularly interactions between neurons and non-neuronal cells in the brain. We propose to support the projects by an administrative core, which will also provide statistical and bioinformatics support, and three scientific cores: 1) an iPSC/Organoid core; 2) a Proteomics and Metabolism core; and 3) a Single Cell and Spatial Transcriptomics core. The PPG benefits from the exceptionally diverse expertise of the Project and Core leaders and co-leaders, all of whom are acknowledged leaders in contemporary aging research. Each of the projects is a close collaboration among several PPG members, many of whom have a history of productive collaboration. Each of the scientific cores will provide state-of-the art support to the projects, enabling conceptual and technical advances that would be difficult to achieve in isolation. Together, the Projects and Cores have the potential to uncover new mechanisms of AD and related dementias, which will be tested in human cells and organoids and mice. Importantly, these mechanisms can be developed into interventions that can be used treat human patients.