Lifespan extension by peroxidase and dual oxidase-mediated ROS signaling through pyrroloquinoline quinone in C. elegans

Reactive oxygen species (ROS), originally characterized based on their harmful effects on cells or organisms, are now recognized as important signal molecules regulating various biological processes. In particular, low levels of ROS released from mitochondria extend lifespan. Here, we identified a novel mechanism of generating appropriate levels of ROS at the plasma membrane through a peroxidase/dual oxidase system, which could extend lifespan in Caenorhabditis elegans (C. elegans). A redox co-factor, pyrroloquinoline quinone (PQQ), activates dual oxidase (DUOX)/BLI-3 to produce the ROS H2O2 at the plasma membrane, which is subsequently degraded by peroxidase/MLT-7, eventually ensuring the adequate levels of ROS. These ROS signals are mediated mainly by the oxidative stress transcriptional factors SKN-1/Nrf2 and JUN-1, and partially by DAF-16/FOXO. Cell biology experiments demonstrated a similarity between the mechanisms of PQQ-induced activation of human DUOX1 and 2 and C. elegans BLI-3, suggesting that DUOXs are potential targets of intervention for lifespan extension. We propose that low levels of ROS, fine-tuned by the peroxidase/dual oxidase system at the plasma membrane, act as second messengers, to extend lifespan by the effect of hormesis.