Tubular lysosomes in health and disease

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Project summary In the past century, the average human lifespan has increased dramatically; however, healthspan has not scaled accordingly. Moreover, neurodegenerative diseases are now the leading cause for disability adjusted life years (DALYs), a quantitative measure of “healthy” years lost. Therefore, aging, and age-related diseases have become major public health concerns. To begin addressing these concerns, we are using two genetically tractable model systems, Drosophila and C. elegans, to study mechanisms governing the natural aging process and how these processes may go awry during late age to trigger age-related diseases. Currently, we have three major areas of focus. First, we are using CRISPR/Cas9 technology to engineer human degenerative disease models in flies to study the disease pathology at a molecular, cellular, and organismal level. The models we are generating also provide a robust time- and cost-effective platform to screen potential genetic and chemical therapeutic strategies. Our second major research area is focused on studying a newly described class of degradative tubular lysosomes that exhibit pro-health capabilities when induced. Our major goal is to better understand how tubular lysosomes are induced in certain tissues naturally and utilize this information to test whether their pro-health effects can be co-opted to suppress cellular aging when induced in non-native contexts. Our third major area of focus is to better understand the relationship between sleep and aging. Reduced sleep is typically associated with many health issues and reduced lifespan; however, some natural short sleepers are able to sleep less without compromising their overall health and, in some cases, even live longer. Using a Drosophila model of a human natural short sleep mutation, we are studying how natural short sleepers are able to maintain health despite sleeping less. Further, we are exploring how increasing longevity affects sleep; namely, whether activating pro-longevity pathways reduces sleep pressure. Collectively, we anticipate that the insights from these studies will inform new strategies to improve late-age health.