title: The Indirubin Derivative 6-Bromoindirubin-3'-Oxime Activates Proteostatic Modules, Reprograms Cellular Bioenergetic Pathways, and Exerts Antiaging Effects.
abstract: OBJECTIVE
  Organismal aging can be delayed by mutations that either activate stress responses or reduce the nutrient-sensing pathway signaling; thus, by using Drosophila melanogaster as an in vivo experimental screening platform, we searched for compounds that modulate these pathways.
  
  
  RESULTS
  We noted that oral administration of the glycogen synthase kinase 3 (Gsk-3) inhibitor 6-bromoindirubin-3'-oxime (6BIO) in Drosophila flies extended healthy life span. 6BIO is not metabolized in fly tissues, modulated bioenergetic pathways, decreased lipid and glucose tissue load, activated antioxidant and proteostatic modules, and enhanced resistance to stressors. Mechanistically, we found that the effects on the stress-responsive pathways were largely dependent on the activity of the transcription factor nuclear factor erythroid 2-related factor (Nrf-2). Genetic inhibition of Gsk-3 largely phenocopied the 6BIO-mediated effects, while high levels of Gsk-3 expression and/or kinase activity suppressed proteostatic modules and reduced flies' longevity; these effects were partially rescued by 6BIO. Also, 6BIO was found to partially reduce the 3-phosphoinositide-dependent protein kinase-1 (Pdpk1) activity, a major effector of the insulin/insulin-like growth factor-1 cell signaling pathways.
  
  
  METHODS
  6BIO exerts the unique property of increasing stress tolerance and in parallel partially suppressing the nutrient-sensing pathway signaling.
  
  
  CONCLUSIONS
  Our findings suggest that the 6BIO scaffold can be used for the development of novel antiaging compounds. Antioxid. Redox Signal. 27, 1027-1047.
authors.affiliation: 1 Department of Cell Biology and Biophysics, Faculty of Biology, National and Kapodistrian University of Athens , Athens, Greece .
authors.forename: Eleni N
authors.initials: EN
authors.lastname: Tsakiri
authors.affiliation: 2 Department of Pharmacognosy and Natural Products Chemistry, Faculty of Pharmacy, National and Kapodistrian University of Athens , Athens, Greece .
authors.forename: Nicolas
authors.initials: N
authors.lastname: Gaboriaud-Kolar
authors.affiliation: 1 Department of Cell Biology and Biophysics, Faculty of Biology, National and Kapodistrian University of Athens , Athens, Greece .
authors.forename: Kalliopi K
authors.initials: KK
authors.lastname: Iliaki
authors.affiliation: 2 Department of Pharmacognosy and Natural Products Chemistry, Faculty of Pharmacy, National and Kapodistrian University of Athens , Athens, Greece .
authors.forename: Job
authors.initials: J
authors.lastname: Tchoumtchoua
authors.affiliation: 1 Department of Cell Biology and Biophysics, Faculty of Biology, National and Kapodistrian University of Athens , Athens, Greece .
authors.forename: Eleni-Dimitra
authors.initials: ED
authors.lastname: Papanagnou
authors.affiliation: 1 Department of Cell Biology and Biophysics, Faculty of Biology, National and Kapodistrian University of Athens , Athens, Greece .
authors.forename: Sofia
authors.initials: S
authors.lastname: Chatzigeorgiou
authors.affiliation: 1 Department of Cell Biology and Biophysics, Faculty of Biology, National and Kapodistrian University of Athens , Athens, Greece .
authors.forename: Konstantinos D
authors.initials: KD
authors.lastname: Tallas
authors.affiliation: 3 Department of Pharmaceutical Chemistry, Faculty of Pharmacy, National and Kapodistrian University of Athens , Athens, Greece .
authors.forename: Emmanuel
authors.initials: E
authors.lastname: Mikros
authors.affiliation: 2 Department of Pharmacognosy and Natural Products Chemistry, Faculty of Pharmacy, National and Kapodistrian University of Athens , Athens, Greece .
authors.forename: Maria
authors.initials: M
authors.lastname: Halabalaki
authors.affiliation: 2 Department of Pharmacognosy and Natural Products Chemistry, Faculty of Pharmacy, National and Kapodistrian University of Athens , Athens, Greece .
authors.forename: Alexios-Leandros
authors.initials: AL
authors.lastname: Skaltsounis
authors.affiliation: 1 Department of Cell Biology and Biophysics, Faculty of Biology, National and Kapodistrian University of Athens , Athens, Greece .
authors.forename: Ioannis P
authors.initials: IP
authors.lastname: Trougakos
mesh_terms: D000284:Administration, Oral; D000375:Aging / Q000187:drug effects* / Q000378:metabolism; D000818:Animals; D004195:Disease Models, Animal; D029721:Drosophila Proteins / Q000378:metabolism; D004331:Drosophila melanogaster / Q000187:drug effects* / Q000378:metabolism; D004734:Energy Metabolism / Q000187:drug effects*; D005260:Female; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism; D006801:Humans; D007211:Indoles / Q000008:administration & dosage* / Q000494:pharmacology; D008297:Male; D053858:Metabolic Networks and Pathways / Q000187:drug effects; D051267:NF-E2-Related Factor 2 / Q000378:metabolism; D010091:Oximes / Q000008:administration & dosage* / Q000494:pharmacology; D000074702:Proteostasis / Q000187:drug effects*
chemical_list: C483321:6-bromoindirubin-3'-oxime; D029721:Drosophila Proteins; D007211:Indoles; D051267:NF-E2-Related Factor 2; D010091:Oximes; D038362:Glycogen Synthase Kinase 3
keywords: 6-bromoindirubin-3′-oxime; Gsk-3; Nrf-2; Pdpk1; aging; proteostasis