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dc.contributor.author
Rozanov, Leonid
dc.contributor.author
Ravichandran, Meenakshi
dc.contributor.author
Grigolon, Giovanna
dc.contributor.author
Zanellati, Maria C.
dc.contributor.author
Mansfeld, Johannes
dc.contributor.author
Zarse, Kim
dc.contributor.author
Barzilai, Nir
dc.contributor.author
Atzmon, Gil
dc.contributor.author
Fischer, Fabian
dc.contributor.author
Ristow, Michael
dc.date.accessioned
2020-03-26T09:30:39Z
dc.date.available
2020-03-26T02:56:39Z
dc.date.available
2020-03-26T09:30:39Z
dc.date.issued
2020-05
dc.identifier.other
10.1016/j.redox.2020.101448
en_US
dc.identifier.uri
http://hdl.handle.net/20.500.11850/406666
dc.identifier.doi
10.3929/ethz-b-000406666
dc.description.abstract
Physiological aging is a complex process, influenced by a plethora of genetic and environmental factors. While being far from fully understood, a number of common aging hallmarks have been elucidated in recent years. Among these, transcriptomic alterations are hypothesized to represent a crucial early manifestation of aging. Accordingly, several transcription factors (TFs) have previously been identified as important modulators of lifespan in evolutionarily distant model organisms. Based on a set of TFs conserved between nematodes, zebrafish, mice, and humans, we here perform a RNA interference (RNAi) screen in C. elegans to discover evolutionarily conserved TFs impacting aging. We identify a basic helix-loop-helix TF, named HLH-2 in nematodes (Tcf3/E2A in mammals), to exert a pronounced lifespan-extending effect in C. elegans upon impairment. We further show that its impairment impacts cellular energy metabolism, increases parameters of healthy aging, and extends nematodal lifespan in a ROS-dependent manner. We then identify arginine kinases, orthologues of mammalian creatine kinases, as a target of HLH-2 transcriptional regulation, serving to mediate the healthspan-promoting effects observed upon impairment of hlh-2 expression. Consistently, HLH-2 is shown to epistatically interact with core components of known lifespan-regulating pathways, i.e. AAK-2/AMPK and LET-363/mTOR, as well as the aging-related TFs SKN-1/Nrf2 and HSF-1. Lastly, single-nucelotide polymorphisms (SNPs) in Tcf3/E2A are associated with exceptional longevity in humans. Together, these findings demonstrate that HLH-2 regulates energy metabolism via arginine kinases and thereby affects the aging phenotype dependent on ROS-signaling and established canonical effectors.
en_US
dc.format
application/pdf
en_US
dc.language.iso
en
en_US
dc.publisher
Elsevier
en_US
dc.rights.uri
http://creativecommons.org/licenses/by-nc-nd/4.0/
dc.subject
Aging
en_US
dc.subject
Transcription
en_US
dc.subject
ROS
en_US
dc.subject
Redox
en_US
dc.subject
Arginine kinase
en_US
dc.subject
Creatine kinase
en_US
dc.title
Redox-mediated regulation of aging and healthspan by an evolutionarily conserved transcription factor HLH-2/Tcf3/E2A
en_US
dc.type
Journal Article
dc.rights.license
Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International
dc.date.published
2020-02-04
ethz.journal.title
Redox Biology
ethz.journal.volume
32
en_US
ethz.pages.start
101448
en_US
ethz.size
11 p.
en_US
ethz.version.deposit
publishedVersion
en_US
ethz.grant
Spezies-unabhängige globale Regulatoren systemischer Alterung
en_US
ethz.identifier.scopus
ethz.publication.place
Amsterdam
en_US
ethz.publication.status
published
en_US
ethz.leitzahl
ETH Zürich::00002 - ETH Zürich::00012 - Lehre und Forschung::00007 - Departemente::02070 - Dep. Gesundheitswiss. und Technologie / Dep. of Health Sciences and Technology::02540 - Institut für Translationale Medizin / Institute of Translational Medicine::03976 - Ristow, Michael / Ristow, Michael
ethz.leitzahl.certified
ETH Zürich::00002 - ETH Zürich::00012 - Lehre und Forschung::00007 - Departemente::02070 - Dep. Gesundheitswiss. und Technologie / Dep. of Health Sciences and Technology::02540 - Institut für Translationale Medizin / Institute of Translational Medicine::03976 - Ristow, Michael / Ristow, Michael
ethz.grant.agreementno
176127
ethz.grant.fundername
SNF
ethz.grant.funderDoi
10.13039/501100001711
ethz.grant.program
Projekte Lebenswissenschaften
ethz.date.deposited
2020-03-26T02:56:39Z
ethz.source
SCOPUS
ethz.eth
yes
en_US
ethz.availability
Open access
en_US
ethz.rosetta.installDate
2020-03-26T09:30:51Z
ethz.rosetta.lastUpdated
2022-03-29T01:39:00Z
ethz.rosetta.versionExported
true
ethz.COinS
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