Abstract
Research in model organisms including Caenorhabditis elegans has led to the discovery of a number of genetic longevity pathways that are conserved in multiple organisms. Unfortunately, many or all of these pathways have pleiotropic effects including decreased fertility, developmental defects and other side effects undesirable for human translation. Our research focuses on identifying genes downstream of the transcriptional pathways that play important roles in the promotion of longevity with a goal of increasing lifespan with minimal side effects. Our recent data focusing on the effectors downstream of the hypoxic response led to a discovery that a single enzyme is both necessary and sufficient to improve stress resistance and longevity downstream of multiple stress response pathways. This protein, flavin-containing monooxygenase-2 (FMO-2), improves multiple measures of health in addition to longevity and is part of a well-conserved family of proteins. Our current studies focus on the molecular mechanisms, signaling pathways, and stress response programs that utilize FMO proteins in C. elegans, while testing similar hypotheses in mammalian systems. We also focus on developing small molecules (drugs) that may be useful in modifying the expression or activity of these proteins in humans. Our results suggest that FMOs are conserved modulators of metabolism, stress response and perhaps longevity in multiple organisms. We conclude that flavin-containing monooxygenases have evolved as regulators of metabolism and stress response and that better understanding their molecular mechanisms will suggest ways in which they may be modulated to benefit health and longevity.