Date of Award
Later years of life are often characterized by reduced cognitive function and mobility. One contributor is the cellular accumulation of reactive oxygen species (ROS), but our understanding of how cells respond to ROS to promote health and survival is incomplete. Follicle stimulating hormone receptor-1 (FSHR-1) and sphingosine kinase-1 (SPHK-1) mediate responses to oxidative stress and regulate life history traits in the roundworm Caenorhabditis elegans. The genes encoding both proteins are conserved in humans where they are implicated in stress responses, cell survival and neuronal function. fshr-1 and sphk-1 work together to mediate responses to intestinal oxidative stress in C. elegans. Whether these genes also work in a common pathway to control lifespan or healthspan is unknown. Previous studies indicated potential phenotypic differences in life history traits based on the worms’ bacterial food source. The typical source, OP50 E. coli, is pathogenic compared to the HB101 strain. I hypothesized differences in pathogenicity between the two strains cause decreased lifespan and locomotion through oxidative stress effects that may differentially affect the mutants. Here I show sphk-1 and fshr-1 are required for normal life- and healthspan in C. elegans. I found significant reductions in mutant lifespans on both lawns versus wild type worms, but no differences within genotype across food. fshr-1, sphk-1, and double mutants had decreased swimming rates compared to wild type worms at all timepoints, but no significant difference in motor decline over time between the genotypes. This suggests the genes may not act in a timed manner to regulate accumulation of oxidative stress. I also saw non-additive effects for the genes on both lifespan and healthspan, as double mutants showed phenotypes equal to single mutants, indicating fshr-1 and sphk-1 work in a single pathway to mediate life- and healthspan. Lawn pathogenicity levels do not affect lifespan in the mutants, suggesting the potential decrease in innate immunity does not make the worms susceptible to increased OP50 pathogenicity. These data provide evidence of a common genetic pathway between sphk-1 and fshr-1 during aging, consistent with their known roles in oxidative stress mediation. Furthermore, recent overexpression experiments indicate the sufficiency of fshr-1 in increasing the mobility of the worms across the lifespan when expressed in either glial or intestinal cells. Further studies will continue exploring these pathways.
Adkins, Ryan Dennis, "The G protein-coupled receptor (GPCR) FSHR-1 and the SPHK-1 lipid kinase regulate C. elegans life- and healthspans via a common pathway" (2023). Undergraduate Honors Thesis Collection. 714.