Activation of DAF-16/FOXO by reactive oxygen species contributes to longevity in long-lived mitochondrial mutants in Caenorhabditis elegans

Abstract

Mild deficits in mitochondrial function have been shown to increase lifespan in multiple species including worms, flies and mice. Here, we study three C. elegans mitochondrial mutants ( clk-1, isp-1 and nuo-6) to identify overlapping genetic pathways that contribute to their longevity. We find that genes regulated by the FOXO transcription factor DAF-16 are upregulated in all three strains, and that the transcriptional changes present in these worms overlap significantly with the long-lived insulin-IGF1 signaling pathway mutant daf-2. We show that DAF-16 and multiple DAF-16 interacting proteins (MATH-33, IMB-2, CST-1/2, BAR-1) are required for the full longevity of all three mitochondrial mutants. Our results suggest that the activation of DAF-16 in these mutants results from elevated levels of reactive oxygen species. Overall, this work reveals an overlapping genetic pathway required for longevity in three mitochondrial mutants, and, combined with previous work, demonstrates that DAF-16 is a downstream mediator of lifespan extension in multiple pathways of longevity.

Author summary

The use of genetic model organisms has permitted the identification of a large number of genes that influence longevity. These genes have been grouped into different pathways of lifespan extension, which have been proposed to modulate longevity by distinct mechanisms. In this work, we explore the mechanisms underlying longevity in three long-lived mitochondrial mutants in C. elegans. We find that all three mutants show upregulation of DAF-16/FOXO target genes and that DAF-16 as well as multiple proteins that function with DAF-16 are required for their longevity. Since DAF-16 has previously been shown to be responsible for the increase in lifespan resulting from decreasing insulin-IGF1 signaling, this indicates that different pathways of lifespan extension have overlapping mechanisms, and that DAF-16/FOXO is a common downstream mediator of longevity.