Research Paper Volume 9, Issue 4 pp 1153ā€”1185

The age- and sex-specific decline of the 20s proteasome and the Nrf2/CncC signal transduction pathway in adaption and resistance to oxidative stress in Drosophila melanogaster

Laura C.D. Pomatto 1, , Sarah Wong 1, , Caroline Carney 1, , Brenda Shen 1, , John Tower 1, 2, , Kelvin J. A. Davies 1, 2, ,

  • 1 Ethel Percy Andrus Gerontology Center, Leonard Davis School of Gerontology, University of Southern California, Los Angeles, CA 90089, USA
  • 2 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

received: January 17, 2016 ; accepted: March 9, 2017 ; published: April 3, 2017 ;

https://doi.org/10.18632/aging.101218
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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 (Drosophila Nrf2 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 the de novo expression and proteolytic activity/capacity of the 20S proteasome in female D. 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 H2O2 adaptation, 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.

Abbreviations

D. melanogaster: Drosophila melanogaster; C. elegans: Caenorhabditis elegans; H2O2: hydrogen peroxide; Nrf2: the transcriptional regulator, nuclear factor ethyroid 2-related factor 2; Cnc-C: D. melanogaster cap ā€˜nā€™ collar transcription factor (ortholog of mammalian Nrf2); Skn-1: C. elegans skinhead-1 transcription factor (ortholog of mammalian Nrf2); AMC: 7-amino-4-methylcoumarin.