Dissecting the role of reproduction in regulating lysosomal function in C. elegans

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Reproduction and aging are linked processes in eukaryotes. Across different species, aging is synchronized with the reproductive cycle such that progeny generation coincides with the time when the animal is the fittest. Mutations in C. elegans that prevent germ cell proliferation also increase longevity, pointing to a genetically regulated cross talk between the gonad and the soma to influence fitness. How this cross-tissue signaling functions during the reproductive cycle, and through which cellular processes it acts in somatic cells, remains unclear. My research group is studying the molecular underpinning of the synchrony between reproduction and somatic fitness. We have recently identified a functional link between reproduction and lysosomal pH in somatic cells that provides a plausible model to explain how C. elegans integrates signals from the gonad to delay aging via improved proteolysis: in animals that have ceased reproduction, lysosomal-mediated proteolysis in the soma collapses and tissue deterioration ensues. The overarching goal of this research is to understand the genetic mechanisms that connect life history traits, such as reproduction and aging. Specifically, the proposed research aims to dissect the genes necessary to regulate lysosomal function, and consequently protein homeostasis, as animals age. In Objective 1, we will extend our efforts to isolate and characterize the genes required to trigger gonad-to-soma signaling at the transition between reproductive and non-reproductive periods through genome-wide genetic screens. We will use our expertise in developing transgenic sensors and pH-sensitive assays to detect dynamic changes in lysosomal pH in intestine and muscle of live worms as a phenotypic readout for these experiments. In Objective 2, we will address the chemical composition of intestinal cells that are influenced by signaling from the gonad following the end of reproduction. We will take a spectroscopic approach to quantitatively measure endogenous changes in the molecular signatures of live intestinal cells using Fourier-Transform Infrared Spectroscopy (FTIR) analysis. This work will take advantage of our previous experience in Mid-IR imaging of live C. elegans oocytes at the Canadian Light Source (CLS) and is expected to generate a detailed chemical map of aging-associated markers. Finally, in Objective 3, we will investigate the specific impact of lysosomal function in aging by using transgenic interventions to control lysosomal pH, followed by lifespan analyses. To this end, we will use transgenic and optogenetic tools that allow for in vivo vesicle acidification. In summary, these experiments will reveal novel genes that integrate reproductive information to modulate aging. Considering the evolutionary conservation of aging networks, we expect this research to be relevant to vertebrate systems as well.