Regulation of enterocyte cell death by dMyc modulates intestinal barrier function and lifespan in D. melanogaster. Kazutaka Akagi, Subhash Katewa, Kenneth Wilson, Subir Kapuria, Amit Sharma, Arshad Ayyaz, Heinrich Jasper, Pankaj Kapahi. Buck Inst Research Aging, Novato, CA.

   Loss of gut integrity has been associated with various human diseases like inflammatory bowel disease, however, the mechanisms which lead to loss of barrier function remain poorly understood. Here we identify a critical role for intestinal cell survival mediated by dMyc in the regulation of intestinal barrier function in Drosophila melanogaster. We demonstrate that dietary restriction (DR) slows the age-related decline in intestinal integrity by reducing enterocytes cell death through up-regulation of dmyc in the intestinal epithelium. Reduction of dmyc in gut enterocytes enhances cell death through JNK signaling and leads to enhanced gut permeability. This also increases vulnerability to pathogenic bacteria and abrogates DR-mediated lifespan extension due to systemic infection. The effects of loss of dmyc in the gut can be rescued by inhibiting Caspase activity or antibiotic treatment. Furthermore, knockdown of caspase-9 (dronc) or overexpression of dmyc in the intestinal cells is sufficient to extend lifespan under rich nutrient conditions. We propose that dMyc in gut enterocytes plays a critical role in extending organismal lifespan by maintaining intestinal barrier function in response to nutritional changes.