Regulation of Age-Related Cognitive Decline by the C. elegans Adult Neuronal IIS/FOXO Transcriptome

Abstract

Elucidating the molecular factors and signaling pathways responsible for age-related cognitive decline remains one of the most important goals in the aging field. The insulin/insulin-like growth factor-1 signaling (IIS) pathway has been implicated in cellular activities ranging from longevity to stress response and is conserved from C. elegans to mammals. Previous work has found that mutation of the IIS receptor homolog DAF-2 doubles the lifespan and extends the memory capabilities of C. elegans. These longevity phenotypes are dependent on the activity of DAF-16, a forkhead box O (FOXO) protein transcription factor. While the Murphy Lab has identified the entire suite of neuronal IIS/FOXO targets in both daf-2 and daf-2;daf-16 young adult worms, the neuronal IIS/FOXO targets in aged worms have yet to be characterized. Neuronal IIS/FOXO targets in aged worms are of particular interest as they may reveal candidate genes that can slow down cognitive decline with age. This thesis investigates the differential gene expression between aged daf-2 and daf-2;daf-16 neuronal transcriptomes in order to identify and validate candidate genes that may be responsible for extended learning and short/intermediate-term associative memory in aged daf-2 worms. We show that genes dod-24 and F08H9.4 are involved in aged daf-2 mutants’ ability to learn; furthermore, genes alh-2, mtl-1, and C44B7.5 may be responsible for aged daf-2 mutants’ maintained intermediate-term associative memory. By identifying candidate genes potentially responsible for improved cognitive abilities with age, this study contributes to the field’s understanding of the regulation of age-related cognitive decline by the IIS pathway and provides potential therapeutic targets for maintaining cognitive abilities with age.