Longevity Genes Revealed by Integrative Analysis of Isoform-Specific daf-16/FoxO Mutants of Caenorhabditis elegans

摘要

FoxO transcription factors promote longevity across taxa. How they do so is poorly understood. In the nematode Caenorhabditis elegans , the A- and F-isoforms of the FoxO transcription factor [DAF-16][1] extend life span in the context of reduced [DAF-2][2] insulin-like growth factor receptor (IGFR) signaling. To elucidate the mechanistic basis for [DAF-16][1]/FoxO-dependent life span extension, we performed an integrative analysis of isoform-specific [daf-16][1]/FoxO mutants. In contrast to previous studies suggesting that DAF-16F plays a more prominent role in life span control than DAF-16A, isoform-specific [daf-16][1]/FoxO mutant phenotypes and whole transcriptome profiling revealed a predominant role for DAF-16A over DAF-16F in life span control, stress resistance, and target gene regulation. Integration of these datasets enabled the prioritization of a subset of 92 [DAF-16][1]/FoxO target genes for functional interrogation. Among 29 genes tested, two DAF-16A-specific target genes significantly influenced longevity. A loss-of-function mutation in the conserved gene [gst-20][3] , which is induced by DAF-16A, reduced life span extension in the context of [daf-2][2]/IGFR RNAi without influencing longevity in animals subjected to control RNAi. Therefore, [gst-20][3] promotes [DAF-16][1]/FoxO-dependent longevity. Conversely, a loss-of-function mutation in [srr-4][4] , a gene encoding a seven-transmembrane-domain receptor family member that is repressed by DAF-16A, extended life span in control animals, indicating that [DAF-16][1]/FoxO may extend life span at least in part by reducing [srr-4][4] expression. Our discovery of new longevity genes underscores the efficacy of our integrative strategy while providing a general framework for identifying specific downstream gene regulatory events that contribute substantially to transcription factor functions. As FoxO transcription factors have conserved functions in promoting longevity and may be dysregulated in aging-related diseases, these findings promise to illuminate fundamental principles underlying aging in animals. [1]: http://www.wormbase.org/db/get?name=WBGene00000912;class=Gene [2]: http://www.wormbase.org/db/get?name=WBGene00000898;class=Gene [3]: http://www.wormbase.org/db/get?name=WBGene00001768;class=Gene [4]: http://www.wormbase.org/db/get?name=WBGene00005655;class=Gene