Enoxacin extends lifespan of C. elegans by inhibiting miR-34-5p and promoting mitohormesis
Alterations in microRNA (miRNA) processing have been previously linked to aging. Here we used the small molecule enoxacin to pharmacologically interfere with miRNA biogenesis and study how it affects aging in C. elegans. Enoxacin extended worm lifespan and promoted survival under normal and oxidativ...
Main Authors: | , , , , , , , , , , , , , |
---|---|
Format: | Article |
Language: | English |
Published: |
Elsevier
2018-09-01
|
Series: | Redox Biology |
Online Access: | http://www.sciencedirect.com/science/article/pii/S2213231718304646 |
id |
doaj-e2472728753c41be9c28092b2a0a0932 |
---|---|
record_format |
Article |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Silas Pinto Vitor N. Sato Evandro A. De-Souza Rafael C. Ferraz Henrique Camara Ana Paula F. Pinca Diego R. Mazzotti Michael T. Lovci Guilherme Tonon Camila M. Lopes-Ramos Raphael B. Parmigiani Martin Wurtele Katlin B. Massirer Marcelo A. Mori |
spellingShingle |
Silas Pinto Vitor N. Sato Evandro A. De-Souza Rafael C. Ferraz Henrique Camara Ana Paula F. Pinca Diego R. Mazzotti Michael T. Lovci Guilherme Tonon Camila M. Lopes-Ramos Raphael B. Parmigiani Martin Wurtele Katlin B. Massirer Marcelo A. Mori Enoxacin extends lifespan of C. elegans by inhibiting miR-34-5p and promoting mitohormesis Redox Biology |
author_facet |
Silas Pinto Vitor N. Sato Evandro A. De-Souza Rafael C. Ferraz Henrique Camara Ana Paula F. Pinca Diego R. Mazzotti Michael T. Lovci Guilherme Tonon Camila M. Lopes-Ramos Raphael B. Parmigiani Martin Wurtele Katlin B. Massirer Marcelo A. Mori |
author_sort |
Silas Pinto |
title |
Enoxacin extends lifespan of C. elegans by inhibiting miR-34-5p and promoting mitohormesis |
title_short |
Enoxacin extends lifespan of C. elegans by inhibiting miR-34-5p and promoting mitohormesis |
title_full |
Enoxacin extends lifespan of C. elegans by inhibiting miR-34-5p and promoting mitohormesis |
title_fullStr |
Enoxacin extends lifespan of C. elegans by inhibiting miR-34-5p and promoting mitohormesis |
title_full_unstemmed |
Enoxacin extends lifespan of C. elegans by inhibiting miR-34-5p and promoting mitohormesis |
title_sort |
enoxacin extends lifespan of c. elegans by inhibiting mir-34-5p and promoting mitohormesis |
publisher |
Elsevier |
series |
Redox Biology |
issn |
2213-2317 |
publishDate |
2018-09-01 |
description |
Alterations in microRNA (miRNA) processing have been previously linked to aging. Here we used the small molecule enoxacin to pharmacologically interfere with miRNA biogenesis and study how it affects aging in C. elegans. Enoxacin extended worm lifespan and promoted survival under normal and oxidative stress conditions. Enoxacin-induced longevity required the transcription factor SKN-1/Nrf2 and was blunted by the antioxidant N-acetyl-cysteine, suggesting a prooxidant-mediated mitohormetic response. The longevity effects of enoxacin were also dependent on the miRNA pathway, consistent with changes in miRNA expression elicited by the drug. Among these differentially expressed miRNAs, the widely conserved miR-34-5p was found to play an important role in enoxacin-mediated longevity. Enoxacin treatment down-regulated miR-34-5p and did not further extend lifespan of long-lived mir-34 mutants. Moreover, N-acetyl-cysteine abrogated mir-34(gk437)-induced longevity. Evidence also points to double-stranded RNA-specific adenosine deaminases (ADARs) as new targets of enoxacin since ADAR loss-of-function abrogates enoxacin-induced lifespan extension. Thus, enoxacin increases lifespan by reducing miR-34-5p levels, interfering with the redox balance and promoting healthspan. Keywords: Enoxacin, MicroRNA, Aging, miR-34, Mitohormesis, ADAR |
url |
http://www.sciencedirect.com/science/article/pii/S2213231718304646 |
work_keys_str_mv |
AT silaspinto enoxacinextendslifespanofcelegansbyinhibitingmir345pandpromotingmitohormesis AT vitornsato enoxacinextendslifespanofcelegansbyinhibitingmir345pandpromotingmitohormesis AT evandroadesouza enoxacinextendslifespanofcelegansbyinhibitingmir345pandpromotingmitohormesis AT rafaelcferraz enoxacinextendslifespanofcelegansbyinhibitingmir345pandpromotingmitohormesis AT henriquecamara enoxacinextendslifespanofcelegansbyinhibitingmir345pandpromotingmitohormesis AT anapaulafpinca enoxacinextendslifespanofcelegansbyinhibitingmir345pandpromotingmitohormesis AT diegormazzotti enoxacinextendslifespanofcelegansbyinhibitingmir345pandpromotingmitohormesis AT michaeltlovci enoxacinextendslifespanofcelegansbyinhibitingmir345pandpromotingmitohormesis AT guilhermetonon enoxacinextendslifespanofcelegansbyinhibitingmir345pandpromotingmitohormesis AT camilamlopesramos enoxacinextendslifespanofcelegansbyinhibitingmir345pandpromotingmitohormesis AT raphaelbparmigiani enoxacinextendslifespanofcelegansbyinhibitingmir345pandpromotingmitohormesis AT martinwurtele enoxacinextendslifespanofcelegansbyinhibitingmir345pandpromotingmitohormesis AT katlinbmassirer enoxacinextendslifespanofcelegansbyinhibitingmir345pandpromotingmitohormesis AT marceloamori enoxacinextendslifespanofcelegansbyinhibitingmir345pandpromotingmitohormesis |
_version_ |
1725075391101534208 |
spelling |
doaj-e2472728753c41be9c28092b2a0a09322020-11-25T01:33:50ZengElsevierRedox Biology2213-23172018-09-01188492Enoxacin extends lifespan of C. elegans by inhibiting miR-34-5p and promoting mitohormesisSilas Pinto0Vitor N. Sato1Evandro A. De-Souza2Rafael C. Ferraz3Henrique Camara4Ana Paula F. Pinca5Diego R. Mazzotti6Michael T. Lovci7Guilherme Tonon8Camila M. Lopes-Ramos9Raphael B. Parmigiani10Martin Wurtele11Katlin B. Massirer12Marcelo A. Mori13Department of Biophysics, Program in Molecular Biology, São Paulo School of Medicine, Federal University of São Paulo (UNIFESP), São Paulo, SP, Brazil; Laboratory of Aging Biology (LaBE), Department of Biochemistry and Tissue Biology, Program in Genetics and Molecular Biology, Institute of Biology, University of Campinas (UNICAMP), Campinas, SP, BrazilDepartment of Biophysics, Program in Molecular Biology, São Paulo School of Medicine, Federal University of São Paulo (UNIFESP), São Paulo, SP, BrazilDepartment of Biophysics, Program in Molecular Biology, São Paulo School of Medicine, Federal University of São Paulo (UNIFESP), São Paulo, SP, Brazil; Laboratory of Aging Biology (LaBE), Department of Biochemistry and Tissue Biology, Program in Genetics and Molecular Biology, Institute of Biology, University of Campinas (UNICAMP), Campinas, SP, BrazilDepartment of Biophysics, Program in Molecular Biology, São Paulo School of Medicine, Federal University of São Paulo (UNIFESP), São Paulo, SP, BrazilDepartment of Biophysics, Program in Molecular Biology, São Paulo School of Medicine, Federal University of São Paulo (UNIFESP), São Paulo, SP, Brazil; Laboratory of Aging Biology (LaBE), Department of Biochemistry and Tissue Biology, Program in Genetics and Molecular Biology, Institute of Biology, University of Campinas (UNICAMP), Campinas, SP, BrazilDepartment of Biophysics, Program in Molecular Biology, São Paulo School of Medicine, Federal University of São Paulo (UNIFESP), São Paulo, SP, Brazil; Laboratory of Aging Biology (LaBE), Department of Biochemistry and Tissue Biology, Program in Genetics and Molecular Biology, Institute of Biology, University of Campinas (UNICAMP), Campinas, SP, BrazilDepartment of Psychobiology. São Paulo School of Medicine. Federal University of São Paulo (UNIFESP), São Paulo, SP, BrazilCenter for Molecular Biology and Genetic Engineering (CBMEG), University of Campinas (UNICAMP), Campinas, SP, BrazilLaboratory of Aging Biology (LaBE), Department of Biochemistry and Tissue Biology, Program in Genetics and Molecular Biology, Institute of Biology, University of Campinas (UNICAMP), Campinas, SP, BrazilMolecular Oncology Center, Hospital Sírio-Libanês, São Paulo, SP, BrazilMolecular Oncology Center, Hospital Sírio-Libanês, São Paulo, SP, BrazilInstitute of Science and Technology, Federal University of Sao Paulo (UNIFESP), São Paulo, SP, BrazilCenter for Molecular Biology and Genetic Engineering (CBMEG), University of Campinas (UNICAMP), Campinas, SP, BrazilDepartment of Biophysics, Program in Molecular Biology, São Paulo School of Medicine, Federal University of São Paulo (UNIFESP), São Paulo, SP, Brazil; Laboratory of Aging Biology (LaBE), Department of Biochemistry and Tissue Biology, Program in Genetics and Molecular Biology, Institute of Biology, University of Campinas (UNICAMP), Campinas, SP, Brazil; Corresponding author at: Department of Biochemistry and Tissue Biology, Institute of Biology, University of Campinas, Rua Monteiro Lobato, 255, 13083-862 Campinas, SP, Brazil.Alterations in microRNA (miRNA) processing have been previously linked to aging. Here we used the small molecule enoxacin to pharmacologically interfere with miRNA biogenesis and study how it affects aging in C. elegans. Enoxacin extended worm lifespan and promoted survival under normal and oxidative stress conditions. Enoxacin-induced longevity required the transcription factor SKN-1/Nrf2 and was blunted by the antioxidant N-acetyl-cysteine, suggesting a prooxidant-mediated mitohormetic response. The longevity effects of enoxacin were also dependent on the miRNA pathway, consistent with changes in miRNA expression elicited by the drug. Among these differentially expressed miRNAs, the widely conserved miR-34-5p was found to play an important role in enoxacin-mediated longevity. Enoxacin treatment down-regulated miR-34-5p and did not further extend lifespan of long-lived mir-34 mutants. Moreover, N-acetyl-cysteine abrogated mir-34(gk437)-induced longevity. Evidence also points to double-stranded RNA-specific adenosine deaminases (ADARs) as new targets of enoxacin since ADAR loss-of-function abrogates enoxacin-induced lifespan extension. Thus, enoxacin increases lifespan by reducing miR-34-5p levels, interfering with the redox balance and promoting healthspan. Keywords: Enoxacin, MicroRNA, Aging, miR-34, Mitohormesis, ADARhttp://www.sciencedirect.com/science/article/pii/S2213231718304646 |