Abstract The overarching goal of this Program Project Grant (PPG) application is to investigate signaling pathways regulating lysosomal homoeostasis in aging and Alzheimer’s disease (AD). Although the etiology of AD remains elusive, age is the greatest risk factor. Therefore, an advanced understanding of aging biology will reveal crucial mechanistic insights and novel therapeutic targets for Alzheimer’s disease. The lysosome plays a critical role in the clearance of protein aggregates whose function declines with aging. Thus enhancing lysosomal function may promote healthy aging and combat age-associated pathological protein accumulation. While the lysosome has been traditionally regarded as a passive organelle for terminal degradation, emerging evidence including the groundbreaking work done by our PPG investigators, demonstrates that the lysosome is an active participant in multiple cellular processes, including stress responses, nutrient sensing, and cellular metabolism. Each of these functions involve coordinated signaling between the lysosome and the nucleus. We propose three innovative research projects aimed at elucidating the lysosome-to-nucleus signaling pathways that regulate lysosomal homeostasis in aging and disease, with a focus on tau pathogenesis. Our studies are enabled by several powerful experimental tools we have created for this work, and by state-of-the- art technologies offered by our proposed proteomics and metabolomics cores. Our PPG will have a lasting impact on the field in several ways. First, we address critical barriers to understanding lysosomal biology in aging and AD, particularly in the context of pathological tau which is increasingly recognized as a key disease- driving factor in AD. Second, our study holds promise for intervention in AD and other protein aggregate pathologies by uncovering molecular pathways to harness innate lysosomal sensing mechanisms and clearance capacity. Third, our work will produce a first-in-class Aging- and Tauopathy-associated Lysosomal atlas (ATLas) of the lysosomal proteome and metabolome from mouse cortex and hippocampus to be shared through a web-based open-access platform. This will broadly support research beyond our PPG to understand the biological function and therapeutic targeting of the lysosome in aging, Alzheimer’s disease and neurodegeneration. Overall, our PPG is substantially greater than the sum of its parts through the complementary expertise and close interactions among the PPG investigators, the coherent and multidisciplinary nature of the research projects, the powerful technical platforms offered by the cores, and the valuable ATLas to be shared to the research community at large.