Degrading intestinal DAF-2 nearly doubles Caenorhabditis elegans lifespan without affecting development or reproduction

Abstract

Twenty-eight years following the breakthrough discovery that a single-gene mutation of daf-2 can double the lifespan of Caenorhabditis elegans, it remains unclear where this gene, which encodes an insulin/IGF-1 receptor, is expressed and where it acts to regulate aging. Here, by inserting DNA sequences of fluorescent tags into the genomic locus of daf-2 and that of its downstream transcription factor daf-16, we determined that both genes are expressed in most or all tissues from embryos through adulthood, in line with their diverse functions. Using tissue-specific auxin-induced protein degradation, we determined that both DAF-2 and DAF-16 act in the intestine to regulate organismal aging. Strikingly, loss of DAF-2 in the intestine nearly doubled C. elegans lifespan but did not produce the adverse developmental or reproductive phenotypes associated with genetic daf-2 mutants. These findings unify the mechanism of lifespan regulation by genes and that by dietary restriction, and begin to focus anti-aging research on nutrient supply. HighlightsO_LIdaf-2 and daf-16 are expressed in most or all cells of C. elegans using genome editing. C_LIO_LIDAF-2 and DAF-16 both regulate lifespan from the intestine as determined using auxin-induced protein degradation. C_LIO_LIReduced insulin signaling in the intestine nearly doubles C. elegans lifespan without adverse effects on development or reproduction. C_LIO_LILifespan regulation by genes and dietary restriction are unified by intestinal supply of nutrients and metabolism. C_LI