DAF-18 is required for the age-dependent increase in DAF-16 activity in Caenorhabditis elegans

ABSTRACT The insulin/insulin-like growth factor signaling (IIS) pathway modulates growth, survival, and lifespan by regulating FOXO transcription factors. In Caenorhabditis elegans , IIS maintains DAF-16/FOXO in an inactive state unless animals are challenged by environmental stress. Recent evidence suggests that DAF-16 becomes activated as part of normal aging in C. elegans , yet the regulatory module responsible for this phenomenon is largely undefined. Embedded within IIS is phospholipid signaling in which PIP 3 produced by the PI3 kinase AGE-1 is an upstream event in DAF-16 inhibition. Countering AGE-1 is DAF-18, an ortholog of human PTEN phosphatase that dephosphorylates PIP 3 . Although it is required for normal lifespan in C. elegans , functional characterization of DAF-18 has primarily focused on its roles during development in the germline and neurons. In this study we asked whether DAF-18 plays a role in the age-dependent activation of DAF-16, and specifically in DAF-16-mediated immunity. Our data show that DAF-18 is expressed in multiple tissues during adulthood. We found that DAF-18 contributes to host defense in adult animals by functioning in the neurons and intestine, likely working through DAF-16 which acts in those same tissues to confer immunity. Supporting this possibility, DAF-18 was required for increased DAF-16 transcriptional activity during aging. Post-translational modifications including ubiquitination and sumoylation appear to be required for the function of DAF-18 during aging in C. elegans , indicating that strategies to modulate PTEN activity are evolutionarily conserved. Our results establish an important role for DAF-18 later in life and imply that it is a critical component of a neuroendocrine signaling circuit that governs the dynamic activity of DAF-16.