Tissue entrainment by feedback regulation of insulin gene expression in the endoderm of <i>Caenorhabditis elegans</i>

How are the rates of aging of different tissues coordinated? In Caenorhabditis elegans, decreasing insulin/IGF-1 signaling extends lifespan by activating the transcription factor DAF-16/FOXO. If DAF-16 levels are experimentally increased in one tissue, such as the intestine, DAF-16 activity in other tissues rises. Here we test the hypothesis that this "FOXO-to-FOXO" signaling occurs via feedback regulation of ins-7 insulin gene expression. We find that DAF-16 regulates ins-7 expression in the intestine, and that preventing this regulation blocks FOXO-to-FOXO signaling from the intestine to other tissues. Our findings show that feedback regulation of insulin gene expression coordinates DAF-16 activity among the tissues, and they establish the intestine, which is the animal's entire endoderm, as an important insulin-signaling center.