Aging is recognized as a process that results from the combined influence of genetic and epigenetic determinants, life-style associated events and environmental factors. In the non-senescent freshwater polyp Hydra, one of the classical model systems for evolutionary developmental biology and regeneration, transcription factor FoxO modulates both stem cell proliferation and innate immunity. This provides strong support for the role of FoxO as a critical rate-of-aging regulator. However, how environmental factors interact with FoxO remains a fundamental question in biology. Here we find that deficiency in FoxO signaling in Hydra leads to dysregulation of antimicrobial peptide expression and that FoxO loss-of-function polyps are more susceptible to colonization of foreign bacteria and impaired in selection for bacteria resembling the native microbiome. These findings reveal a key role of FoxO signaling in the communication between host and microbiota and embed the evolutionary conserved longevity factor FoxO into the holobiont concept.