Mechanisms linking pre-mRNA splicing to longevity in C. elegans

Abstract

Geroscience aims to target the fundamental biology of aging to address the increasing prevalence of age-related diseases. However, a comprehensive understanding of molecular mechanisms underlying longevity interventions and inter-individual variability remains elusive. Prior work in C. elegans determined a critical role of splicing factors SFA-1 and REPO-1 as pathway-specific modulators of longevity, and postulated lipid metabolism, particularly through POD-2, as a downstream effector mechanism. My PhD thesis characterized pre-mRNA splicing and lipidomic changes associated with REPO-1 loss, and determined that POD-2 phenocopies REPO-1 in the regulation of lipid deposits and lifespan extension by dietary restriction, reduced TORC1 and mutant ETC. This work also defined the spatial and temporal effects of REPO-1 loss. These data elucidate molecular mechanisms of responses to longevity interventions. Additionally, my dissertation work demonstrated that differences in Oleic acid concentration underly variation in lifespan expectancy using the ret-1 splicing reporter. This work exemplifies the utility of multi-staged assessment of lifespan variation, thereby significantly contributing to the advancement of precision Geroscience. Altogether, my dissertation substantiates the role of pre-mRNA splicing in both the regulation of response to longevity interventions and the prediction of lifespan expectancy.