title: MicroRNAs mediate dietary-restriction-induced longevity through PHA-4/FOXA and SKN-1/Nrf transcription factors.
abstract: BACKGROUND
  Dietary restriction (DR) has been shown to prolong longevity across diverse taxa, yet the mechanistic relationship between DR and longevity remains unclear. MicroRNAs (miRNAs) control aging-related functions such as metabolism and lifespan through regulation of genes in insulin signaling, mitochondrial respiration, and protein homeostasis.
  
  
  RESULTS
  We have conducted a network analysis of aging-associated miRNAs connected to transcription factors PHA-4/FOXA and SKN-1/Nrf, which are both necessary for DR-induced lifespan extension in Caenorhabditis elegans. Our network analysis has revealed extensive regulatory interactions between PHA-4, SKN-1, and miRNAs and points to two aging-associated miRNAs, miR-71 and miR-228, as key nodes of this network. We show that miR-71 and miR-228 are critical for the response to DR in C. elegans. DR induces the expression of miR-71 and miR-228, and the regulation of these miRNAs depends on PHA-4 and SKN-1. In turn, we show that PHA-4 and SKN-1 are negatively regulated by miR-228, whereas miR-71 represses PHA-4.
  
  
  CONCLUSIONS
  Based on our findings, we have discovered new links in an important pathway connecting DR to aging. By interacting with PHA-4 and SKN-1, miRNAs transduce the effect of dietary-restriction-mediated lifespan extension in C. elegans. Given the conservation of miRNAs, PHA-4, and SKN-1 across phylogeny, these interactions are likely to be conserved in more-complex species.
authors.affiliation: Department of Molecular, Cellular and Developmental Biology, Yale University, P.O. Box 208103, New Haven, CT 06520, USA.
authors.forename: Thalyana
authors.initials: T
authors.lastname: Smith-Vikos
authors.affiliation: Department of Molecular, Cellular and Developmental Biology, Yale University, P.O. Box 208103, New Haven, CT 06520, USA.
authors.forename: Alexandre
authors.initials: A
authors.lastname: de Lencastre
authors.affiliation: Department of Molecular, Cellular and Developmental Biology, Yale University, P.O. Box 208103, New Haven, CT 06520, USA.
authors.forename: Sachi
authors.initials: S
authors.lastname: Inukai
authors.affiliation: Department of Molecular, Cellular and Developmental Biology, Yale University, P.O. Box 208103, New Haven, CT 06520, USA.
authors.forename: Mariel
authors.initials: M
authors.lastname: Shlomchik
authors.affiliation: Department of Molecular, Cellular and Developmental Biology, Yale University, P.O. Box 208103, New Haven, CT 06520, USA.
authors.forename: Brandon
authors.initials: B
authors.lastname: Holtrup
authors.affiliation: Department of Molecular, Cellular and Developmental Biology, Yale University, P.O. Box 208103, New Haven, CT 06520, USA. Electronic address: fslack@bidmc.harvard.edu.
authors.forename: Frank J
authors.initials: FJ
authors.lastname: Slack
mesh_terms: D000375:Aging; D000818:Animals; D017173:Caenorhabditis elegans / Q000235:genetics / Q000502:physiology*; D029742:Caenorhabditis elegans Proteins / Q000235:genetics* / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000235:genetics* / Q000378:metabolism; D035683:MicroRNAs / Q000235:genetics* / Q000378:metabolism; D016133:Polymerase Chain Reaction; D015534:Trans-Activators / Q000235:genetics* / Q000378:metabolism; D014157:Transcription Factors / Q000235:genetics* / Q000378:metabolism
chemical_list: D029742:Caenorhabditis elegans Proteins; D004268:DNA-Binding Proteins; C000598472:MIRN228 microRNA, C elegans; C575438:MIRN71 microRNA, C elegans; D035683:MicroRNAs; C113277:Pha-4 protein, C elegans; D015534:Trans-Activators; D014157:Transcription Factors; C073702:skn-1 protein, C elegans