Flavin biology and its role in longevity in Caenorhabditis elegans

Abstract

While the past few decades have uncovered many of the mysteries of the molecular mechanisms of aging, new pathways, programs, and interventions continue to be discovered. Many such interventions involve the modification of cellular metabolism via dietary modification, nutrient sensing and processing, and pharmaceutical treatment, namely with the biguanide metformin, a common diabetes drug. In my thesis work, I investigated the role of a specific micronutrient, riboflavin, and a set of flavin-dependent proteins and how their modulation can robustly extend lifespan in the roundworm model organism Caenorhabditis elegans. Knockdown of the riboflavin transporter rft-1 significantly increases longevity and acts through canonical longevity pathways of nutrient sensing, stress resistance, and mitochondrial stress responses. Knockdown of the flavin-dependent enzyme cytochrome b5 reductase hpo-19 also extends lifespan in a genetic manner distinct from rft-1, revealing E2F/EFL-1 as a novel transcription factor that contributes to aging and longevity. The research in this thesis uncovers the importance of a key set of proteins in metazoan aging, and focusing on these flavoproteins and the genetic programs they activate may unveil novel approaches to fighting age-related disease and extending healthy lifespan.