Sex Differences in the Response to Genetic and Chemical Pro-Longevity Interventions in Caenorhabditis elegans

Women often live longer than men yet suffer worse health outcomes in old age. This sexual dimorphism in lifespan and aging trajectories is robust and has been frequently observed and comprehensively documented. Sex differences extend beyond natural aging and are additionally seen in the response to pro-longevity interventions. Despite that, our understanding of the mechanisms underlying such differences remains limited. In this dissertation, I utilize the model organism Caenorhabditis elegans to explore sex differences in aging. I leverage a healthspan(definition) measure that is unique to male C. elegans: mating. Males display a complex mating behavior that strongly declines with age due to physiological deterioration, making it an ideal screening phenotype to investigate the efficacy of pro-longevity interventions. Using male reproductive success as a complex healthspan measure, I investigate the effects of DAF-2/ IGF-1 insulin receptor degradation on male longevity and whether the effects of this intervention are sexually dimorphic. Additionally, I examine the effects of several pro-longevity chemical compounds on male lifespan and contrast them to previously published hermaphrodite data to determine whether their effects on longevity are sexually dimorphic or sex shared. Finally, I characterize the transcriptomic signatures of two chemical pro-longevity interventions, metformin and Thioflavin T, on aging C. elegans and determine whether the effects at the transcriptional level are sexually dimorphic or sex shared. This work provides a new experimental paradigm for the study of sex differences in aging using the model organism C. elegans and offers new mechanistic targets for future research. Understanding the mechanistic basis of sex differences in aging will aid in the development of interventions that can benefit individuals of any sex. This dissertation includes previously unpublished coauthored material.