title: SKN-1/Nrf, stress responses, and aging in Caenorhabditis elegans.
abstract: The mammalian Nrf/CNC proteins (Nrf1, Nrf2, Nrf3, p45 NF-E2) perform a wide range of cellular protective and maintenance functions. The most thoroughly described of these proteins, Nrf2, is best known as a regulator of antioxidant and xenobiotic defense, but more recently has been implicated in additional functions that include proteostasis and metabolic regulation. In the nematode Caenorhabditis elegans, which offers many advantages for genetic analyses, the Nrf/CNC proteins are represented by their ortholog SKN-1. Although SKN-1 has diverged in aspects of how it binds DNA, it exhibits remarkable functional conservation with Nrf/CNC proteins in other species and regulates many of the same target gene families. C. elegans may therefore have considerable predictive value as a discovery model for understanding how mammalian Nrf/CNC proteins function and are regulated in vivo. Work in C. elegans indicates that SKN-1 regulation is surprisingly complex and is influenced by numerous growth, nutrient, and metabolic signals. SKN-1 is also involved in a wide range of homeostatic functions that extend well beyond the canonical Nrf2 function in responses to acute stress. Importantly, SKN-1 plays a central role in diverse genetic and pharmacologic interventions that promote C. elegans longevity, suggesting that mechanisms regulated by SKN-1 may be of conserved importance in aging. These C. elegans studies predict that mammalian Nrf/CNC protein functions and regulation may be similarly complex and that the proteins and processes that they regulate are likely to have a major influence on mammalian life- and healthspan.
authors.affiliation: Research Division, Joslin Diabetes Center, One Joslin Place, Boston, MA 02215, USA; Department of Genetics and Harvard Stem Cell Institute, Harvard Medical School, Boston, MA 02215, USA. Electronic address: keith.blackwell@joslin.harvard.edu.
authors.forename: T Keith
authors.initials: TK
authors.lastname: Blackwell
authors.affiliation: Research Division, Joslin Diabetes Center, One Joslin Place, Boston, MA 02215, USA; Department of Genetics and Harvard Stem Cell Institute, Harvard Medical School, Boston, MA 02215, USA.
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Steinbaugh
authors.affiliation: Research Division, Joslin Diabetes Center, One Joslin Place, Boston, MA 02215, USA; Department of Genetics and Harvard Stem Cell Institute, Harvard Medical School, Boston, MA 02215, USA.
authors.forename: John M
authors.initials: JM
authors.lastname: Hourihan
authors.affiliation: Research Division, Joslin Diabetes Center, One Joslin Place, Boston, MA 02215, USA; Department of Genetics and Harvard Stem Cell Institute, Harvard Medical School, Boston, MA 02215, USA.
authors.forename: Collin Y
authors.initials: CY
authors.lastname: Ewald
authors.affiliation: Research Division, Joslin Diabetes Center, One Joslin Place, Boston, MA 02215, USA; Department of Genetics and Harvard Stem Cell Institute, Harvard Medical School, Boston, MA 02215, USA.
authors.forename: Meltem
authors.initials: M
authors.lastname: Isik
mesh_terms: D000375:Aging / Q000502:physiology*; D000818:Animals; D017173:Caenorhabditis elegans / Q000502:physiology*; D029742:Caenorhabditis elegans Proteins / Q000378:metabolism*; D004268:DNA-Binding Proteins / Q000378:metabolism*; D008136:Longevity / Q000502:physiology*; D013312:Stress, Physiological / Q000502:physiology*; D014157:Transcription Factors / Q000378:metabolism*
chemical_list: D029742:Caenorhabditis elegans Proteins; D004268:DNA-Binding Proteins; D014157:Transcription Factors; C073702:skn-1 protein, C elegans
keywords: Aging; C. elegans; Detoxification; Metabolism; Proteasome; SKN-1/Nrf; Stress response