TY - JOUR
TI - Hyperactivation of Nrf2 increases stress tolerance at the cost of aging acceleration due to metabolic deregulation
AU - Tsakiri, E.N.
AU - Gumeni, S.
AU - Iliaki, K.K.
AU - Benaki, D.
AU - Vougas, K.
AU - Sykiotis, G.P.
AU - Gorgoulis, V.G.
AU - Mikros, E.
AU - Scorrano, L.
AU - Trougakos, I.P.
JO - Aging Cell
PY - 2019
VL - 18
TODO - 1
SP - null
PB - Wiley-Blackwell Publishing Ltd
SN - 1474-9718, 1474-9726
TODO - 10.1111/acel.12845
TODO - cyclin C;  cytochrome c oxidase;  Drosophila protein;  fatty acid synthase;  glycogen synthase;  insulin;  proteasome;  proteome;  pyruvate kinase;  reactive oxygen metabolite;  somatomedin;  transcription factor Nrf2;  tubulin;  Drosophila protein;  insulin;  somatomedin;  transcription factor Nrf2, adult;  animal cell;  animal experiment;  animal tissue;  Article;  cell aging;  cell death;  cell protection;  cell survival;  controlled study;  down regulation;  Drosophila;  gene knockdown;  gene ontology;  gene overexpression;  genomic instability;  insect larva;  insulin dependent diabetes mellitus;  insulin signaling;  larvistatic activity;  metabolic regulation;  mitochondrial biogenesis;  mitochondrial dynamics;  mitochondrial gene;  mitochondrial respiration;  negative feedback;  nonhuman;  oxidative stress;  priority journal;  protein degradation;  protein expression level;  protein homeostasis;  proteomics;  ubiquitination;  upregulation;  adaptation;  aging;  animal;  Drosophila melanogaster;  energy metabolism;  metabolism;  mitochondrion;  phenotype;  physiological stress;  physiology;  signal transduction, Adaptation, Physiological;  Aging;  Animals;  Cytoprotection;  Drosophila melanogaster;  Drosophila Proteins;  Energy Metabolism;  Insulin;  Metabolic Networks and Pathways;  Mitochondria;  Mitochondrial Dynamics;  NF-E2-Related Factor 2;  Phenotype;  Signal Transduction;  Somatomedins;  Stress, Physiological
TODO - Metazoans viability depends on their ability to regulate metabolic processes and also to respond to harmful challenges by mounting anti-stress responses; these adaptations were fundamental forces during evolution. Central to anti-stress responses are a number of short-lived transcription factors that by functioning as stress sensors mobilize genomic responses aiming to eliminate stressors. We show here that increased expression of nuclear factor erythroid 2-related factor (Nrf2) in Drosophila activated cytoprotective modules and enhanced stress tolerance. However, while mild Nrf2 activation extended lifespan, high Nrf2 expression levels resulted in developmental lethality or, after inducible activation in adult flies, in altered mitochondrial bioenergetics, the appearance of Diabetes Type 1 hallmarks and aging acceleration. Genetic or dietary suppression of Insulin/IGF-like signaling (IIS) titrated Nrf2 activity to lower levels, largely normalized metabolic pathways signaling, and extended flies’ lifespan. Thus, prolonged stress signaling by otherwise cytoprotective short-lived stress sensors perturbs IIS resulting in re-allocation of resources from growth and longevity to somatic preservation and stress tolerance. These findings provide a reasonable explanation of why most (if not all) cytoprotective stress sensors are short-lived proteins, and it also explains the build-in negative feedback loops (shown here for Nrf2); the low basal levels of these proteins, and why their suppressors were favored by evolution. © 2018 The Authors. Aging Cell published by the Anatomical Society and John Wiley & Sons Ltd.
ER -