Much of our understanding of aging derives from studies in model organisms, including yeasts, worms and mice. However, to date the causes of aging and determinants of lifespan are not fully understood. SKN-1 is the C. elegans ortholog of the mammalian Nrf proteins, which defend against oxidative and proteotoxic stress. SKN-1 is important in several scenarios of lifespan extension, including reduced TORC1/2 or insulin/IGF-1 signaling, and dietary restriction. Much remains to be learned about how specific phosphorylation events regulate SKN-1, and that little is understood about how SKN-1 activity might be regulated by specific phosphatases. To investigate how SKN-1 activity might influenced by phosphatases, we performed RNAi against predicted C. elegans phosphatases. We first monitored expression of a transgene in which the promoter for the SKN-1 target gene
gcs-1 (?-glutamyl cysteine synthetase) is fused to GFP. Among phosphatases we have tested, RNAi against calcineurin (TAX-6) upregulated
gcs-1p::GFP in the anterior intestine. Calcineurin is a highly conserved Ca2+/calmodulin-dependent serine/threonine protein phosphatase that regulates cellular Ca2+ signaling responses. We next investigated whether TAX-6 knockdown influences the localization of SKN-1. TAX-6 knockdown dramatically increased SKN-1 accumulation in intestinal nuclei. We further show that TAX-6 RNAi causes an increase of mean lifespan, reduced both brood size and body length. Lifespan extension by TAX-6 RNAi requires SKN-1 but does not depend on the DAF-16/FoxO transcription factor. However, surprisingly, TAX-6 RNAi animals show reduced resistance to thermal- and oxidative stress. We are currently investigating how calcineurin affects lifespan and oxidative stress resistance through SKN-1.