TFEB-mediated lysosome-to-nucleus signaling in aging and lifespan regulation

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Abstract Aging is characterized by the progressive inability of cells, tissues, and organs to maintain their functional integrity and is accompanied by an increased susceptibility to morbidity—the odds to develop neurodegeneration, cancer, or cardiovascular disease increase continuously with age. There is currently no general, actionable strategy to slow down dysregulation of cell and tissue homeostasis in the aging organism. As a result, advances in healthcare in the modern era have paradoxically increased frailty and morbidity among the elderly by increasing lifespan without significantly impacting on age-related homeostasis dysregulation. Owing to a continuously aging world population, there is therefore an urgent and unmet need to identify actionable cellular and molecular targets for the development of treatments aimed at increasing healthspan along with lifespan. Hallmarks of aging are a decline in lysosome-mediated degradation pathways and chromatin dysregulation. This proposal focuses on a transcription factor EB-mediated lysosome-to-nucleus signaling pathway, the modulation of which extends mouse lifespan by 30% in males. We will systematically and mechanistically investigate the three components of this signaling pathway—namely the lysosome, the signaling transducers, and chromatin regulators—during aging by leveraging unique tools that we have developed to study lysosomal content and signaling components. Results from this study will provide the first age-associated atlas of the lysosomal content in the mammalian brain and will pioneer the investigation of lysosome-to-nucleus signaling in aging. Knowledge resulting from this study could lay the foundation for future translational investigations of clinical treatment of aging and age-related neurodegenerative disease.