Enoxacin extends lifespan of C. elegans by inhibiting miR-34-5p and promoting mitohormesis

Author(s):Show less -

Pinto, Silas ^{[1, 2]} ; Sato, Vitor N. ^[1] ; De-Souza, Evandro A. ^{[1, 2]} ; Ferraz, Rafael C. ^[1] ; Camara, Henrique ^{[1, 2]} ; Pinca, Ana Paula F. ^{[1, 2]} ; Mazzotti, Diego R. ^[3] ; Lovci, Michael T. ^[4] ; Tonon, Guilherme ^[2] ; Lopes-Ramos, Camila M. ^[5] ; Parmigiani, Raphael B. ^[5] ; Wurtele, Martin ^[6] ; Massirer, Katlin B. ^[4] ; Mori, Marcelo A. ^{[1, 2]}

Affiliation

^[1] Fed Univ Sao Paulo UNIFESP, Sao Paulo Sch Med, Program Mol Biol, Dept Biophys, Sao Paulo, SP - Brazil

^[2] Univ Campinas UNICAMP, Inst Biol, Program Genet & Mol Biol, Dept Biochem & Tissue Biol, Lab Aging Biol LaBE, Campinas, SP - Brazil

^[3] Fed Univ Sao Paulo UNIFESP, Sao Paulo Sch Med, Dept Psychobiol, Sao Paulo, SP - Brazil

^[4] Univ Campinas UNICAMP, Ctr Mol Biol & Genet Engn CBMEG, Campinas, SP - Brazil

^[5] Hosp Sirio Libanes, Mol Oncol Ctr, Sao Paulo, SP - Brazil

^[6] Fed Univ Sao Paulo UNIFESP, Inst Sci & Technol, Sao Paulo, SP - Brazil

• Document type: Journal article
• Source: REDOX BIOLOGY; v. 18, p. 84-92, SEP 2018.
• Web of Science Citations: 6

Abstract

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. (AU)

• FAPESP's process: 12/04064-0 - Search for a pharmacological intervention to mimic the beneficial effects of caloric restriction in C. elegans
• Grantee: Vitor Neves Sato
• Support Opportunities: Scholarships in Brazil - Scientific Initiation
• FAPESP's process: 15/04264-8 - Phenotypic screen of nematodes C. elegans mutants for proteins necessary to systemic RNAi
• Grantee: Henrique Camara
• Support Opportunities: Scholarships in Brazil - Master
• FAPESP's process: 17/04377-2 - Study of Dicer effects on mitochondrial function, metabolism and aging in C. elegans nematodes
• Grantee: Silas Pinto da Silva
• Support Opportunities: Scholarships in Brazil - Doctorate
• FAPESP's process: 15/01316-7 - Dicer, miRNAs and the control of mitochondrial function in the context of aging and caloric restriction
• Grantee: Marcelo Alves da Silva Mori
• Support Opportunities: Regular Research Grants
• FAPESP's process: 14/10814-8 - Determination of factors that controls Dicer expression in vivo in C. elegans
• Grantee: Evandro Araújo de Souza
• Support Opportunities: Scholarships in Brazil - Master
• FAPESP's process: 17/01184-9 - CAMeLEOm: cross-species analysis of metabolic, lifespan effects and omics of dietary restriction mimetics
• Grantee: Marcelo Alves da Silva Mori
• Support Opportunities: Research Projects - Thematic Grants
• FAPESP's process: 12/24490-4 - Study of the involvement of impact in the effects of caloric restriction in C. elegans
• Grantee: Rafael Ferraz Bannitz
• Support Opportunities: Scholarships in Brazil - Master
• FAPESP's process: 10/52557-0 - Identification of mechanisms responsible for beneficial effects of calorie restriction
• Grantee: Marcelo Alves da Silva Mori
• Support Opportunities: Research Grants - Young Investigators Grants
• FAPESP's process: 14/25270-3 - Study of Dicer effects on mitochondrial function, metabolism and aging in nematodes C. elegans
• Grantee: Silas Pinto da Silva
• Support Opportunities: Scholarships in Brazil - Master
• FAPESP's process: 14/25068-0 - Unraveling new mechanisms responsible for the cell non-autonomous control of proteostasis in C. elegans
• Grantee: Ana Paula Forti Pinca
• Support Opportunities: Scholarships in Brazil - Master