PROJECT SUMMARY/ABSTRACT The decline of health in aging has long been associated with dysfunctional mitochondria and lysosomes, but whether the failure of these two organelles is linked remains unclear. The overall goal of this application is to delineate how mitochondria and lysosomes communicate with each other to promote health in aging. The central hypothesis is that mitochondria and lysosomes normally communicate with each other to promote health, but this becomes compromised during aging, leading the two organelles to co-devolve into dysfunction. This is supported by preliminary data showing that defective lysosomes can activate a mitochondrial stress pathway in young adult C. elegans. The rationale is that in many aging conditions like Parkinson's disease, both mitochondria and lysosomes are defective or have familial mutations. If communication between mitochondria and lysosomes is important, the health decline with aging may result from not only loss of function in the individual organelles but also from the loss of their synergistic communication. Thus, there is a critical need to understand how mitochondrial-lysosomal communication adapts to stress and organellar dysfunction in aging. The central hypothesis of this proposal will be tested by the following specific aims: 1) Identify the stress signaling pathway connecting defective lysosomes and mitochondria, 2) Define the tissue-specific roles in lysosome-to- mitochondrial signaling in the aging model organism C. elegans, 3) Determine how lysosome-to-mitochondrial signaling changes during aging and Parkinson's disease and whether boosting this signaling can rescue health. This proposed application is innovative because 1) it focuses on the inter-organellar response of mitochondria and lysosomes to aging-related stress and 2) it will delineate mitochondrial-lysosomal communication in the multi-tissue aging organism C. elegans. Previous work in mitochondrial-lysosomal interactions used single-celled systems like yeast and cell culture which cannot fully model aging. The research proposed here is significant because by defining a novel route of communication between mitochondria and lysosomes required for cellular homeostasis in stress and aging, this proposal will provide strategies for therapeutic development to restore their communication during aging. In addition to the experimental research, this application also proposes a career development plan. Dr. Shen's career goal is to become an independent, academic investigator in aging science. Completing this proposal will allow her to establish a research niche in mitochondrial-lysosomal stress communication in aging and gain technical and leadership skills that are essential for her development into an independent investigator. To help her achieve her goals, Dr. Shen has assembled a Scientific Advisory Committee to deepen her understanding of lysosomal biology, RNA-seq, and metabolomics. This award will also give her the opportunity to ...