A PTEN variant uncouples longevity from impaired fitness in C. elegans via tuning the activity of FOXO and NRF

Insulin/IGF-1 signaling (IIS) regulates various physiological aspects in many species. In C. elegans, mutations in daf-2/insulin/IGF-1 receptor dramatically increase lifespan and pathogen resistance, but generally impair motility, development, and reproduction. Whether these pleiotropic effects can be dissociated at a specific step in the IIS pathway remains unknown. Here we show that a single amino acid change in DAF-18, PTEN phosphatase, allows worms to maintain longevity and enhanced immunity in daf-2 mutants compared to wild-type, without defects in growth and motility. Through performing a mutagenesis screen, we identified a missense mutation in daf-18 [daf-18(yh1)], which suppressed developmental defects in daf-2 mutants with small effects on pathogen resistance. We showed that the daf-18(yh1) caused a reduction in its function, but maintained long lifespan, motility span, and resistance against various stresses in daf-2 mutants. We further showed that daf-18(yh1) retained the activity of DAF-16/FOXO but restricted detrimental upregulation of SKN-1/NRF, for exerting beneficial physiological consequences. Our study will provide important insights into how one evolutionarily conserved component, PTEN coordinates healthy longevity and fitness. Four samples each of daf-2(e1370), daf-2(e1370); daf-18(yh1), and daf-2(e1370); daf-18(nr2037) mutants