The role of RNA splicing factors in the regulation of longevity

Abstract

Geroscience aims to target the aging process to extend healthspan. However, the efficacy of pro- longevity interventions is highly heterogeneous, limiting their translational potential. In my dissertation research, I discovered that activity of RNA splicing factors REPO-1 and SFA-1 early in life, modulates effectiveness of known longevity interventions in C. elegans. Inhibition of REPO-1 and SFA-1 during development blocks lifespan extension in genetic mutants of dietary restriction, reduced TORC1 signaling and reduced electron transport chain function. However, they are not required for longevity in the insulin signaling mutants. Strikingly, this is mediated through the regulation of lipid utilization via a POD- 2/ACC1 dependent mechanism. The effect on lifespan is seen only when REPO-1 and SFA-1 are inhibited early in life and in the nervous system. Finally, early inhibition of REPO-1 and SFA-1 blocks lifespan extension by late onset suppression of the TORC1 pathway. Together these data highlight how early RNA splicing changes impacts response to longevity interventions and may explain variance in efficacy between individuals.