Redox-mediated regulation of aging and healthspan by an evolutionarily conserved transcription factor HLH-2/Tcf3/E2A

Leonid Rozanov; Meenakshi Ravichandran; Giovanna Grigolon; Maria Clara Zanellati; Johannes Mansfeld; Kim Zarse; Nir Barzilai; Gil Atzmon; Fabian Fischer; Michael Ristow

doi:10.1016/j.redox.2020.101448

Redox-mediated regulation of aging and healthspan by an evolutionarily conserved transcription factor HLH-2/Tcf3/E2A

Leonid Rozanov, Meenakshi Ravichandran, Giovanna Grigolon, Maria Clara Zanellati, Johannes Mansfeld, Kim Zarse, Nir Barzilai, Gil Atzmon, Fabian Fischer, Michael Ristow

Department of Human Biology

Research output: Contribution to journal › Article › peer-review

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.

Original language	English
Article number	101448
Journal	Redox Biology
Volume	32
DOIs	https://doi.org/10.1016/j.redox.2020.101448
State	Published - May 2020

Bibliographical note

Funding Information:
We thank Dr. Malene Hansen for exchange of materials and performing experiments on argk-1 RNAi (see Discussion section), and for important comments on the manuscript. We thank Dr. Marco Groth for the primary analysis of the raw RNASeq data. C. elegans strains used in this work were provided by the Caenorhabditis Genetics Centre (Univ. of Minnesota, USA), which is funded by NIH Office of Research Infrastructure Programs ( P40 OD010440 ). This study was funded by the following grants: The Swiss National Science Foundation ( 31003A_176127 ) (Mi.R.), the Nathan Shock Center of Excellence for the Basic Biology of Aging ( P30AG038072 ) (N.B.), the Einstein-Paul Glenn Foundation for Medical Research Center for the Biology of Human Aging (N.B.), NIH/NIA-1 R01 AG044829 (N.B.), NIH/NIA-1 R01 AG042188-01 (N.B., G.A.), NIH-1 R01 AG 046949–01 (N.B.). The Ristow laboratory is supported by the Horizon 2020 program of the European Union (Ageing with Elegans, grant 633589 ).

Funding Information:
We thank Dr. Malene Hansen for exchange of materials and performing experiments on argk-1 RNAi (see Discussion section), and for important comments on the manuscript. We thank Dr. Marco Groth for the primary analysis of the raw RNASeq data. C. elegans strains used in this work were provided by the Caenorhabditis Genetics Centre (Univ. of Minnesota, USA), which is funded by NIH Office of Research Infrastructure Programs (P40 OD010440). This study was funded by the following grants: The Swiss National Science Foundation (31003A_176127) (Mi.R.), the Nathan Shock Center of Excellence for the Basic Biology of Aging (P30AG038072) (N.B.), the Einstein-Paul Glenn Foundation for Medical Research Center for the Biology of Human Aging (N.B.), NIH/NIA-1 R01 AG044829 (N.B.), NIH/NIA-1 R01 AG042188-01 (N.B. G.A.), NIH-1 R01 AG 046949?01 (N.B.). The Ristow laboratory is supported by the Horizon 2020 program of the European Union (Ageing with Elegans, grant 633589).

Publisher Copyright:
© 2020 The Authors

Keywords

Aging
Arginine kinase
Creatine kinase
ROS
Redox
Transcription

ASJC Scopus subject areas

Organic Chemistry
Clinical Biochemistry

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10.1016/j.redox.2020.101448

Cite this

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title = "Redox-mediated regulation of aging and healthspan by an evolutionarily conserved transcription factor HLH-2/Tcf3/E2A",

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.",

keywords = "Aging, Arginine kinase, Creatine kinase, ROS, Redox, Transcription",

author = "Leonid Rozanov and Meenakshi Ravichandran and Giovanna Grigolon and Zanellati, {Maria Clara} and Johannes Mansfeld and Kim Zarse and Nir Barzilai and Gil Atzmon and Fabian Fischer and Michael Ristow",

note = "Funding Information: We thank Dr. Malene Hansen for exchange of materials and performing experiments on argk-1 RNAi (see Discussion section), and for important comments on the manuscript. We thank Dr. Marco Groth for the primary analysis of the raw RNASeq data. C. elegans strains used in this work were provided by the Caenorhabditis Genetics Centre (Univ. of Minnesota, USA), which is funded by NIH Office of Research Infrastructure Programs ( P40 OD010440 ). This study was funded by the following grants: The Swiss National Science Foundation ( 31003A_176127 ) (Mi.R.), the Nathan Shock Center of Excellence for the Basic Biology of Aging ( P30AG038072 ) (N.B.), the Einstein-Paul Glenn Foundation for Medical Research Center for the Biology of Human Aging (N.B.), NIH/NIA-1 R01 AG044829 (N.B.), NIH/NIA-1 R01 AG042188-01 (N.B., G.A.), NIH-1 R01 AG 046949–01 (N.B.). The Ristow laboratory is supported by the Horizon 2020 program of the European Union (Ageing with Elegans, grant 633589 ). Funding Information: We thank Dr. Malene Hansen for exchange of materials and performing experiments on argk-1 RNAi (see Discussion section), and for important comments on the manuscript. We thank Dr. Marco Groth for the primary analysis of the raw RNASeq data. C. elegans strains used in this work were provided by the Caenorhabditis Genetics Centre (Univ. of Minnesota, USA), which is funded by NIH Office of Research Infrastructure Programs (P40 OD010440). This study was funded by the following grants: The Swiss National Science Foundation (31003A_176127) (Mi.R.), the Nathan Shock Center of Excellence for the Basic Biology of Aging (P30AG038072) (N.B.), the Einstein-Paul Glenn Foundation for Medical Research Center for the Biology of Human Aging (N.B.), NIH/NIA-1 R01 AG044829 (N.B.), NIH/NIA-1 R01 AG042188-01 (N.B. G.A.), NIH-1 R01 AG 046949?01 (N.B.). The Ristow laboratory is supported by the Horizon 2020 program of the European Union (Ageing with Elegans, grant 633589). Publisher Copyright: {\textcopyright} 2020 The Authors",

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language = "English",

volume = "32",

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T1 - Redox-mediated regulation of aging and healthspan by an evolutionarily conserved transcription factor HLH-2/Tcf3/E2A

AU - Rozanov, Leonid

AU - Ravichandran, Meenakshi

AU - Grigolon, Giovanna

AU - Zanellati, Maria Clara

AU - Mansfeld, Johannes

AU - Zarse, Kim

AU - Barzilai, Nir

AU - Atzmon, Gil

AU - Fischer, Fabian

AU - Ristow, Michael

N1 - Funding Information: We thank Dr. Malene Hansen for exchange of materials and performing experiments on argk-1 RNAi (see Discussion section), and for important comments on the manuscript. We thank Dr. Marco Groth for the primary analysis of the raw RNASeq data. C. elegans strains used in this work were provided by the Caenorhabditis Genetics Centre (Univ. of Minnesota, USA), which is funded by NIH Office of Research Infrastructure Programs ( P40 OD010440 ). This study was funded by the following grants: The Swiss National Science Foundation ( 31003A_176127 ) (Mi.R.), the Nathan Shock Center of Excellence for the Basic Biology of Aging ( P30AG038072 ) (N.B.), the Einstein-Paul Glenn Foundation for Medical Research Center for the Biology of Human Aging (N.B.), NIH/NIA-1 R01 AG044829 (N.B.), NIH/NIA-1 R01 AG042188-01 (N.B., G.A.), NIH-1 R01 AG 046949–01 (N.B.). The Ristow laboratory is supported by the Horizon 2020 program of the European Union (Ageing with Elegans, grant 633589 ). Funding Information: We thank Dr. Malene Hansen for exchange of materials and performing experiments on argk-1 RNAi (see Discussion section), and for important comments on the manuscript. We thank Dr. Marco Groth for the primary analysis of the raw RNASeq data. C. elegans strains used in this work were provided by the Caenorhabditis Genetics Centre (Univ. of Minnesota, USA), which is funded by NIH Office of Research Infrastructure Programs (P40 OD010440). This study was funded by the following grants: The Swiss National Science Foundation (31003A_176127) (Mi.R.), the Nathan Shock Center of Excellence for the Basic Biology of Aging (P30AG038072) (N.B.), the Einstein-Paul Glenn Foundation for Medical Research Center for the Biology of Human Aging (N.B.), NIH/NIA-1 R01 AG044829 (N.B.), NIH/NIA-1 R01 AG042188-01 (N.B. G.A.), NIH-1 R01 AG 046949?01 (N.B.). The Ristow laboratory is supported by the Horizon 2020 program of the European Union (Ageing with Elegans, grant 633589). Publisher Copyright: © 2020 The Authors

PY - 2020/5

Y1 - 2020/5

N2 - 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.

AB - 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.

KW - Aging

KW - Arginine kinase

KW - Creatine kinase

KW - ROS

KW - Redox

KW - Transcription

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DO - 10.1016/j.redox.2020.101448

M3 - Article

C2 - 32203922

AN - SCOPUS:85081935850

SN - 2213-2317

VL - 32

JO - Redox Biology

JF - Redox Biology

M1 - 101448

ER -

Redox-mediated regulation of aging and healthspan by an evolutionarily conserved transcription factor HLH-2/Tcf3/E2A

Abstract

Bibliographical note

Keywords

ASJC Scopus subject areas

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