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

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State: Public
Version: Final published version
License: Not specified
Serval ID
serval:BIB_5F0FC273FD9C
Type
Article: article from journal or magazin.
Collection
Publications
Institution
Title
Hyperactivation of Nrf2 increases stress tolerance at the cost of aging acceleration due to metabolic deregulation.
Journal
Aging cell
Author(s)
Tsakiri E.N., Gumeni S., Iliaki K.K., Benaki D., Vougas K., Sykiotis G.P., Gorgoulis V.G., Mikros E., Scorrano L., Trougakos I.P.
ISSN
1474-9726 (Electronic)
ISSN-L
1474-9718
Publication state
Published
Issued date
02/2019
Peer-reviewed
Oui
Volume
18
Number
1
Pages
e12845
Language
english
Notes
Publication types: Journal Article ; Research Support, Non-U.S. Gov't
Publication Status: ppublish
Abstract
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.
Keywords
Adaptation, Physiological, Aging/physiology, Animals, Cytoprotection, Drosophila Proteins/metabolism, Drosophila melanogaster/metabolism, Drosophila melanogaster/physiology, Energy Metabolism, Insulin/metabolism, Metabolic Networks and Pathways, Mitochondria/metabolism, Mitochondrial Dynamics, NF-E2-Related Factor 2/metabolism, Phenotype, Signal Transduction, Somatomedins/metabolism, Stress, Physiological, Nrf2, aging, insulin/IGF-like, metabolism, mitostasis, proteostasis
Pubmed
Web of science
Open Access
Yes
Create date
05/01/2019 16:45
Last modification date
05/04/2020 6:20
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