Direct and Indirect Gene Regulation by a Life-Extending FOXO Protein in C. elegans: Roles for GATA Factors and Lipid Gene Regulators

SummaryIn long-lived C. elegans insulin/IGF-1 pathway mutants, the life-extending FOXO transcription factor DAF-16 is present throughout the animal, but we find that its activity in a single tissue can delay the aging of other tissues and extend the animal’s life span. To better understand the topography of DAF-16 action among the tissues, we analyzed a collection of DAF-16-regulated genes. DAF-16 regulated most of these genes in a cell-autonomous fashion, often using tissue-specific GATA factors to direct their expression to specific tissues. DAF-16 could also act cell nonautonomously to influence gene expression. DAF-16 affected gene expression in other cells, at least in part, via the lipid-gene regulator MDT-15. DAF-16, and probably MDT-15, could act cell nonautonomously in the endoderm to ameliorate the paralysis caused by expressing Alzheimer’s Aβ protein in muscles. These findings suggest that MDT-15-dependent intercellular signals, possibly lipid signals, can help to coordinate tissue physiology, enhance proteostasis, and extend life in response to DAF-16/FOXO activity.

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► DAF-16 regulates genes both cell autonomously and cell nonautonomously
► DAF-16 can act at in the endoderm to delay muscle aging
► DAF-16 can act at a distance to protect animals from amyloid paralysis
► Cell-non-autonomous gene regulation by DAF-16 involves the lipid-gene regulator MDT-15