title: The age- and sex-specific decline of the 20s proteasome and the Nrf2/CncC signal transduction pathway in adaption and resistance to oxidative stress inDrosophila melanogaster.
abstract: Hallmarks of aging include loss of protein homeostasis and dysregulation of stress-adaptive pathways. Loss of adaptive homeostasis, increases accumulation of DNA, protein, and lipid damage. During acute stress, the Cnc-C (DrosophilaNrf2 orthologue) transcriptionally-regulated 20S proteasome degrades damaged proteins in an ATP-independent manner. Exposure to very low, non-toxic, signaling concentrations of the redox-signaling agent hydrogen peroxide (H2O2) cause adaptive increases in thede novoexpression and proteolytic activity/capacity of the 20S proteasome in femaleD. melanogaster(fruit-flies). Female 20S proteasome induction was accompanied by increased tolerance to a subsequent normally toxic but sub-lethal amount of H2O2, and blocking adaptive increases in proteasome expression also prevented full adaptation. We find, however, that this adaptive response is both sex- and age-dependent. Both increased proteasome expression and activity, and increased oxidative-stress resistance, in female flies, were lost with age. In contrast, male flies exhibited no H2O2adaptation, irrespective of age. Furthermore, aging caused a generalized increase in basal 20S proteasome expression, but proteolytic activity and adaptation were both compromised. Finally, continual knockdown of Keep1 (the cytosolic inhibitor of Cnc-C) in adults resulted in older flies with greater stress resistance than their age-matched controls, but who still exhibited an age-associated loss of adaptive homeostasis.
authors.affiliation: Ethel Percy Andrus Gerontology Center, Leonard Davis School of Gerontology, University of Southern California, Los Angeles, CA 90089, USA.
authors.forename: Laura C D
authors.initials: LCD
authors.lastname: Pomatto
authors.affiliation: Ethel Percy Andrus Gerontology Center, Leonard Davis School of Gerontology, University of Southern California, Los Angeles, CA 90089, USA.
authors.forename: Sarah
authors.initials: S
authors.lastname: Wong
authors.affiliation: Ethel Percy Andrus Gerontology Center, Leonard Davis School of Gerontology, University of Southern California, Los Angeles, CA 90089, USA.
authors.forename: Caroline
authors.initials: C
authors.lastname: Carney
authors.affiliation: Ethel Percy Andrus Gerontology Center, Leonard Davis School of Gerontology, University of Southern California, Los Angeles, CA 90089, USA.
authors.forename: Brenda
authors.initials: B
authors.lastname: Shen
authors.affiliation: Ethel Percy Andrus Gerontology Center, Leonard Davis School of Gerontology, University of Southern California, Los Angeles, CA 90089, USA.|Molecular and Computational Biology Program, Department of Biological Sciences, Dornsife College of Letters, Arts and Sciences, University of Southern California, Los Angeles, CA 90089, USA.
authors.forename: John
authors.initials: J
authors.lastname: Tower
authors.affiliation: Ethel Percy Andrus Gerontology Center, Leonard Davis School of Gerontology, University of Southern California, Los Angeles, CA 90089, USA.|Molecular and Computational Biology Program, Department of Biological Sciences, Dornsife College of Letters, Arts and Sciences, University of Southern California, Los Angeles, CA 90089, USA.
authors.forename: Kelvin J A
authors.initials: KJA
authors.lastname: Davies
mesh_terms: D000222:Adaptation, Physiological / Q000235:genetics*; D000255:Adenosine Triphosphate / Q000378:metabolism; D000375:Aging; D000818:Animals; D029721:Drosophila Proteins / Q000096:biosynthesis* / Q000235:genetics*; D004331:Drosophila melanogaster; D005260:Female; D018507:Gene Expression Regulation, Developmental / Q000235:genetics; D055785:Gene Knockdown Techniques; D006861:Hydrogen Peroxide / Q000494:pharmacology; D000072019:Kelch-Like ECH-Associated Protein 1; D008297:Male; D018384:Oxidative Stress / Q000235:genetics*; D046988:Proteasome Endopeptidase Complex / Q000235:genetics*; D050050:Protein Carbonylation; D012097:Repressor Proteins / Q000096:biosynthesis* / Q000235:genetics*; D012727:Sex Characteristics; D015398:Signal Transduction / Q000235:genetics*
chemical_list: D029721:Drosophila Proteins; C527886:Keap1 protein, Drosophila; D000072019:Kelch-Like ECH-Associated Protein 1; D012097:Repressor Proteins; C116463:cnc protein, Drosophila; D000255:Adenosine Triphosphate; D006861:Hydrogen Peroxide; D046988:Proteasome Endopeptidase Complex
keywords: 20S proteasome; Nrf2; adaptive homeostasis; oxidative stress; protein aggregation; protein oxidation