Calcineurin inhibition enhancesCaenorhabditis eleganslifespan by defecation defects-mediated calorie restriction and nuclear hormone signaling

Abstract Calcineurin is a highly conserved calcium/calmodulin-dependent serine/threonine protein phosphatase with diverse functions. Inhibition of calcineurin is known to enhance Caenorhabditis elegans lifespan via multiple signaling pathways. Aiming to study the role of calcineurin in regulating innate immunity, we discover that calcineurin is required for the rhythmic defecation motor program (DMP) in C. elegans . Calcineurin inhibition leads to defects in the DMP, resulting in intestinal bloating, rapid colonization of the gut by bacteria, and increased susceptibility to bacterial infection. We demonstrate that intestinal bloating by calcineurin inhibition mimics calorie restriction that results in enhanced lifespan. The TFEB ortholog, HLH-30, is required for calcineurin inhibition-mediated lifespan enhancement by triggering lipolysis. Finally, we show that the nuclear hormone receptor, NHR-8, is upregulated by calcineurin inhibition and is required for increased lifespan. Our studies uncover a role for calcineurin in the C. elegans DMP and provide a new mechanism for calcineurin inhibition-mediated longevity extension.