title: Declining signal dependence of Nrf2-MafS-regulated gene expression correlates with aging phenotypes.
abstract: Aging is a degenerative process characterized by declining molecular, cell and organ functions, and accompanied by the progressive accumulation of oxidatively damaged macromolecules. This increased oxidative damage may be causally related to an age-associated dysfunction of defense mechanisms, which effectively protect young individuals from oxidative insults. Consistently, older organisms are more sensitive to acute oxidative stress exposures than young ones. In studies on the Drosophila Nrf2 transcription factor CncC, we have investigated possible causes for this loss of stress resistance and its connection to the aging process. Nrf2 is a master regulator of antioxidant and stress defense gene expression with established functions in the control of longevity. Here, we show that the expression of protective Nrf2/CncC target genes in unstressed conditions does not generally decrease in older flies. However, aging flies progressively lose the ability to activate Nrf2 targets in response to acute stress exposure. We propose that the resulting inability to dynamically adjust the expression of Nrf2 target genes to the organism's internal and external conditions contributes to age-related loss of homeostasis and fitness. In support of this hypothesis, we find the Drosophila small Maf protein, MafS, an Nrf2 dimerization partner, to be critical to maintain responsiveness of the Nrf2 system: overexpression of MafS in older flies preserves Nrf2/CncC signaling competence and antagonizes age-associated functional decline. The maintenance of acute stress resistance, motor function, and heart performance in aging flies overexpressing MafS supports a critical role for signal responsiveness of Nrf2 function in promoting youthful phenotypes.
authors.affiliation: Department of Biomedical Genetics, University of Rochester Medical Center, Rochester, NY 14642, USA.
authors.forename: Mohammed Mahidur
authors.initials: MM
authors.lastname: Rahman
authors.forename: Gerasimos P
authors.initials: GP
authors.lastname: Sykiotis
authors.forename: Mayuko
authors.initials: M
authors.lastname: Nishimura
authors.forename: Rolf
authors.initials: R
authors.lastname: Bodmer
authors.forename: Dirk
authors.initials: D
authors.lastname: Bohmann
mesh_terms: D000222:Adaptation, Physiological; D000375:Aging / Q000235:genetics / Q000502:physiology*; D000818:Animals; D002460:Cell Line; D004330:Drosophila / Q000235:genetics / Q000378:metabolism* / Q000502:physiology; D029721:Drosophila Proteins / Q000235:genetics / Q000378:metabolism*; D005260:Female; D018507:Gene Expression Regulation, Developmental; D006321:Heart / Q000502:physiology; D050978:Maf Transcription Factors, Small / Q000235:genetics / Q000378:metabolism*; D008297:Male; D009043:Motor Activity; D018384:Oxidative Stress; D010641:Phenotype; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D012097:Repressor Proteins; D015398:Signal Transduction; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D014158:Transcription, Genetic
chemical_list: D029721:Drosophila Proteins; D050978:Maf Transcription Factors, Small; D012333:RNA, Messenger; D012097:Repressor Proteins; D014157:Transcription Factors; C116463:cnc protein, Drosophila
keywords: Drosophila; Keap1; Nrf2; aging; oxidative stress; small Maf