Conserved neuropeptidergic regulation of intestinal integrity in invertebrate models of aging

Abstract Age-related decline in intestinal barrier function impacts survival across species, but the underlying cell intrinsic and extrinsic factors remain unclear. Here, we demonstrate a role for neuropeptides in regulating aging-associated increases in intestinal leakiness. Adult-specific knockdown of insulin-like peptides daf-28 or ins-7 in C. elegans neurons or dilp3 in D. melanogaster neurons improves intestinal integrity and lifespan of these animals, respectively. Neuropeptide knockdowns activate intestinal DAF-16/FOXO transcription factor that likely increases expression of epithelial barrier components. Furthermore, age-associated changes in neuronal DAF-28 peptide secretion mirrors C. elegans reproductive span and overexpression of this peptide suppresses the improved intestinal health in long-lived germline-less animals. Collectively, we show that intestinal integrity is subject to neuronal regulation, and this neuropeptidergic axis may be modulated by the animal’s germline.