The Role of the Lysosome in Aging

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PROJECT SUMMARY/ABSTRACT Lysosomes (vacuoles in yeast) are acidic organelles that are well known for their role in degradation of cellular material through pathways such as autophagy. In addition to their role in degradation, it is also becoming clear that the lysosome is a central hub for cellular metabolism. Nutrients such as amino acids and ions are stored in the lysosome or vacuole at high levels, and nutrient-sensing pathways important for lifespan regulation such as the Target of Rapamycin (TOR) Pathway sense nutrients at the lysosomal surface. Impaired lysosomal function has been linked to the aging process and development of age-associated diseases for quite some time. However, how lysosomal dysfunction contributes to organismal aging is still unclear. Using the yeast replicative aging model system, we recently shed light on this topic by discovering a new metabolic connection between the lysosome/vacuole and mitochondria that is central to the aging process. Lysosomal function requires acidification by the evolutionarily conserved Vacuolar H+-ATPase. We found that lysosomal acidity declines at an early replicative age (defined by number of divisions) in yeast, and this change in lysosomal acidity leads to mitochondrial dysfunction and lifespan limitation. Direct suppression of lysosomal acidification loss through overexpression of V-ATPase subunits is sufficient to prevent mitochondrial dysfunction and extend lifespan, suggesting that lysosomal acidity is a critical regulator of lifespan and mitochondrial function. Consistent with this idea, we also found that lysosomal acidity is regulated by glucose levels. Calorie restriction (CR) enhances lysosomal acidity, and this enhancement is required for CR-induced lifespan extension. Collectively, these studies establish budding yeast as an excellent model to understand the role of the lysosome in aging, and support our central hypothesis that lysosomal acidity is a critical determinant of lifespan through its metabolic connection to mitochondrial function. Our previous work also raises two important unanswered questions that we will address in this proposal: how are lysosomes and mitochondria functionally connected (Aim 1), and how does CR regulate acidification of the lysosome/vacuole to promote lifespan extension (Aim 2). The experiments outlined in this proposal will define the functions of the lysosome that are important for its role in aging and disease, and identify new avenues for lifespan extension that function through enhancement of lysosomal acidity. The activity of the lysosome is highly conserved across species, including its metabolic link to the mitochondria. Thus, our long-term plan is to translate our results from the yeast experiments proposed here to determine the effects of lysosome modulation on aging and disease in mammalian systems.