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Hyperactivation of Nrf2 increases stress tolerance at the cost of aging acceleration due to metabolic deregulation

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 tha...

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Autores principales: Tsakiri, Eleni N., Gumeni, Sentiljana, Iliaki, Kalliopi K., Benaki, Dimitra, Vougas, Konstantinos, Sykiotis, Gerasimos P., Gorgoulis, Vassilis G., Mikros, Emmanuel, Scorrano, Luca, Trougakos, Ioannis P.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: John Wiley and Sons Inc. 2018
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6351879/
https://www.ncbi.nlm.nih.gov/pubmed/30537423
http://dx.doi.org/10.1111/acel.12845
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author Tsakiri, Eleni N.
Gumeni, Sentiljana
Iliaki, Kalliopi K.
Benaki, Dimitra
Vougas, Konstantinos
Sykiotis, Gerasimos P.
Gorgoulis, Vassilis G.
Mikros, Emmanuel
Scorrano, Luca
Trougakos, Ioannis P.
author_facet Tsakiri, Eleni N.
Gumeni, Sentiljana
Iliaki, Kalliopi K.
Benaki, Dimitra
Vougas, Konstantinos
Sykiotis, Gerasimos P.
Gorgoulis, Vassilis G.
Mikros, Emmanuel
Scorrano, Luca
Trougakos, Ioannis P.
author_sort Tsakiri, Eleni N.
collection PubMed
description 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.
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spelling pubmed-63518792019-02-07 Hyperactivation of Nrf2 increases stress tolerance at the cost of aging acceleration due to metabolic deregulation Tsakiri, Eleni N. Gumeni, Sentiljana Iliaki, Kalliopi K. Benaki, Dimitra Vougas, Konstantinos Sykiotis, Gerasimos P. Gorgoulis, Vassilis G. Mikros, Emmanuel Scorrano, Luca Trougakos, Ioannis P. Aging Cell Original Papers 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. John Wiley and Sons Inc. 2018-12-10 2019-02 /pmc/articles/PMC6351879/ /pubmed/30537423 http://dx.doi.org/10.1111/acel.12845 Text en © 2018 The Authors. Aging Cell published by the Anatomical Society and John Wiley & Sons Ltd. This is an open access article under the terms of the http://creativecommons.org/licenses/by/4.0/ License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.
spellingShingle Original Papers
Tsakiri, Eleni N.
Gumeni, Sentiljana
Iliaki, Kalliopi K.
Benaki, Dimitra
Vougas, Konstantinos
Sykiotis, Gerasimos P.
Gorgoulis, Vassilis G.
Mikros, Emmanuel
Scorrano, Luca
Trougakos, Ioannis P.
Hyperactivation of Nrf2 increases stress tolerance at the cost of aging acceleration due to metabolic deregulation
title Hyperactivation of Nrf2 increases stress tolerance at the cost of aging acceleration due to metabolic deregulation
title_full Hyperactivation of Nrf2 increases stress tolerance at the cost of aging acceleration due to metabolic deregulation
title_fullStr Hyperactivation of Nrf2 increases stress tolerance at the cost of aging acceleration due to metabolic deregulation
title_full_unstemmed Hyperactivation of Nrf2 increases stress tolerance at the cost of aging acceleration due to metabolic deregulation
title_short Hyperactivation of Nrf2 increases stress tolerance at the cost of aging acceleration due to metabolic deregulation
title_sort hyperactivation of nrf2 increases stress tolerance at the cost of aging acceleration due to metabolic deregulation
topic Original Papers
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6351879/
https://www.ncbi.nlm.nih.gov/pubmed/30537423
http://dx.doi.org/10.1111/acel.12845
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