Critical Genes Regulated by FoxO Transcription Factors in Life Span Control

Abstract

FoxO transcription factors (TFs) control metabolism, development, and aging in diverse species. Mouse models implicate FoxO dysregulation in the pathogenesis of age-related disease, including type 2 diabetes, cancer, osteoporosis, and cardiovascular disease. In the nematode C. elegans, the FoxO ortholog DAF-16 extends life span more than 2-fold in response to reduced signaling from the insulin-like growth factor receptor (IGFR) ortholog DAF-2. However, DAF-16/FoxO regulates numerous target genes, posing a significant challenge to understanding the mechanistic details of life span extension.

Here, we have developed a logical framework to prioritize functional testing of DAF-16/FoxO target genes highly associated with longevity. Multiple DAF-16/FoxO isoforms are expressed in C. elegans, and we dissected the contributions of individual isoforms to life span control using novel isoform-specific daf-16/FoxO mutants. Whole-transcriptome profiling (RNA-seq) revealed the sets of target genes regulated by each DAF-16/FoxO isoform. An integrative analysis of the life span phenotypes and gene expression profiles of daf-16/FoxO isoform-specific mutants yielded an experimentally tractable list of high-priority genes likely to influence life span. We then screened these genes using a novel method and discovered critical longevity targets of DAF-16/FoxO. These findings suggest that a small subset of DAF-16/FoxO target genes may play a disproportionate role in life span control. Furthermore, most of the genes we identified are conserved in humans and may be involved in human age-related disease. Our approach integrating genetics, phenotypic analysis, and gene expression profiling may be generally useful in dissecting the mechanisms by which transcription factors influence complex processes like aging.