The antimicrobial peptide pileup promotes enterocyte shedding to maintain gut homeostasis in aging Drosophila.

Pileup, a novel age-associated antimicrobial peptide in Drosophila, is a genetic marker and key regulator of aging enterocyte shedding, linked to membrane compromise and JNK activation.

• Why it matters: Replacing aging enterocytes requires shedding, but the mechanisms controlling enterocyte removal are poorly understood compared with intestinal stem cell regulation.
• What they did: Age-related mitochondrial dysfunction generates ROS via ATG1 kinase, activating hypoxia-inducible factor 1α to induce pileup specifically in aging enterocytes; pileup then compromises membranes and triggers JNK activation.
• The result: Pileup has three homologs, and loss of all four genes causes tumorous cell accumulation, gut barrier dysfunction, microbiome dysbiosis, and premature death, implying essential roles for AMP-driven shedding in gut homeostasis during aging.