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

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 PIP3 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 PIP3. 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.