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Peripheral modulation of antidepressant targets MAO-B and GABAAR by harmol induces mitohormesis and delays aging in preclinical models

Reversible and sub-lethal stresses to the mitochondria elicit a program of compensatory responses that ultimately improve mitochondrial function, a conserved anti-aging mechanism termed mitohormesis. Here, we show that harmol, a member of the beta-carbolines family with anti-depressant properties, i...

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Autores principales: Costa-Machado, Luis Filipe, Garcia-Dominguez, Esther, McIntyre, Rebecca L., Lopez-Aceituno, Jose Luis, Ballesteros-Gonzalez, Álvaro, Tapia-Gonzalez, Andrea, Fabregat-Safont, David, Eisenberg, Tobias, Gomez, Jesús, Plaza, Adrian, Sierra-Ramirez, Aranzazu, Perez, Manuel, Villanueva-Bermejo, David, Fornari, Tiziana, Loza, María Isabel, Herradon, Gonzalo, Hofer, Sebastian J., Magnes, Christoph, Madeo, Frank, Duerr, Janet S., Pozo, Oscar J., Galindo, Maximo-Ibo, del Pino, Isabel, Houtkooper, Riekelt H., Megias, Diego, Viña, Jose, Gomez-Cabrera, Mari Carmen, Fernandez-Marcos, Pablo J.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10185515/
https://www.ncbi.nlm.nih.gov/pubmed/37188705
http://dx.doi.org/10.1038/s41467-023-38410-y
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author Costa-Machado, Luis Filipe
Garcia-Dominguez, Esther
McIntyre, Rebecca L.
Lopez-Aceituno, Jose Luis
Ballesteros-Gonzalez, Álvaro
Tapia-Gonzalez, Andrea
Fabregat-Safont, David
Eisenberg, Tobias
Gomez, Jesús
Plaza, Adrian
Sierra-Ramirez, Aranzazu
Perez, Manuel
Villanueva-Bermejo, David
Fornari, Tiziana
Loza, María Isabel
Herradon, Gonzalo
Hofer, Sebastian J.
Magnes, Christoph
Madeo, Frank
Duerr, Janet S.
Pozo, Oscar J.
Galindo, Maximo-Ibo
del Pino, Isabel
Houtkooper, Riekelt H.
Megias, Diego
Viña, Jose
Gomez-Cabrera, Mari Carmen
Fernandez-Marcos, Pablo J.
author_facet Costa-Machado, Luis Filipe
Garcia-Dominguez, Esther
McIntyre, Rebecca L.
Lopez-Aceituno, Jose Luis
Ballesteros-Gonzalez, Álvaro
Tapia-Gonzalez, Andrea
Fabregat-Safont, David
Eisenberg, Tobias
Gomez, Jesús
Plaza, Adrian
Sierra-Ramirez, Aranzazu
Perez, Manuel
Villanueva-Bermejo, David
Fornari, Tiziana
Loza, María Isabel
Herradon, Gonzalo
Hofer, Sebastian J.
Magnes, Christoph
Madeo, Frank
Duerr, Janet S.
Pozo, Oscar J.
Galindo, Maximo-Ibo
del Pino, Isabel
Houtkooper, Riekelt H.
Megias, Diego
Viña, Jose
Gomez-Cabrera, Mari Carmen
Fernandez-Marcos, Pablo J.
author_sort Costa-Machado, Luis Filipe
collection PubMed
description Reversible and sub-lethal stresses to the mitochondria elicit a program of compensatory responses that ultimately improve mitochondrial function, a conserved anti-aging mechanism termed mitohormesis. Here, we show that harmol, a member of the beta-carbolines family with anti-depressant properties, improves mitochondrial function and metabolic parameters, and extends healthspan. Treatment with harmol induces a transient mitochondrial depolarization, a strong mitophagy response, and the AMPK compensatory pathway both in cultured C2C12 myotubes and in male mouse liver, brown adipose tissue and muscle, even though harmol crosses poorly the blood–brain barrier. Mechanistically, simultaneous modulation of the targets of harmol monoamine-oxidase B and GABA-A receptor reproduces harmol-induced mitochondrial improvements. Diet-induced pre-diabetic male mice improve their glucose tolerance, liver steatosis and insulin sensitivity after treatment with harmol. Harmol or a combination of monoamine oxidase B and GABA-A receptor modulators extend the lifespan of hermaphrodite Caenorhabditis elegans or female Drosophila melanogaster. Finally, two-year-old male and female mice treated with harmol exhibit delayed frailty onset with improved glycemia, exercise performance and strength. Our results reveal that peripheral targeting of monoamine oxidase B and GABA-A receptor, common antidepressant targets, extends healthspan through mitohormesis.
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spelling pubmed-101855152023-05-17 Peripheral modulation of antidepressant targets MAO-B and GABAAR by harmol induces mitohormesis and delays aging in preclinical models Costa-Machado, Luis Filipe Garcia-Dominguez, Esther McIntyre, Rebecca L. Lopez-Aceituno, Jose Luis Ballesteros-Gonzalez, Álvaro Tapia-Gonzalez, Andrea Fabregat-Safont, David Eisenberg, Tobias Gomez, Jesús Plaza, Adrian Sierra-Ramirez, Aranzazu Perez, Manuel Villanueva-Bermejo, David Fornari, Tiziana Loza, María Isabel Herradon, Gonzalo Hofer, Sebastian J. Magnes, Christoph Madeo, Frank Duerr, Janet S. Pozo, Oscar J. Galindo, Maximo-Ibo del Pino, Isabel Houtkooper, Riekelt H. Megias, Diego Viña, Jose Gomez-Cabrera, Mari Carmen Fernandez-Marcos, Pablo J. Nat Commun Article Reversible and sub-lethal stresses to the mitochondria elicit a program of compensatory responses that ultimately improve mitochondrial function, a conserved anti-aging mechanism termed mitohormesis. Here, we show that harmol, a member of the beta-carbolines family with anti-depressant properties, improves mitochondrial function and metabolic parameters, and extends healthspan. Treatment with harmol induces a transient mitochondrial depolarization, a strong mitophagy response, and the AMPK compensatory pathway both in cultured C2C12 myotubes and in male mouse liver, brown adipose tissue and muscle, even though harmol crosses poorly the blood–brain barrier. Mechanistically, simultaneous modulation of the targets of harmol monoamine-oxidase B and GABA-A receptor reproduces harmol-induced mitochondrial improvements. Diet-induced pre-diabetic male mice improve their glucose tolerance, liver steatosis and insulin sensitivity after treatment with harmol. Harmol or a combination of monoamine oxidase B and GABA-A receptor modulators extend the lifespan of hermaphrodite Caenorhabditis elegans or female Drosophila melanogaster. Finally, two-year-old male and female mice treated with harmol exhibit delayed frailty onset with improved glycemia, exercise performance and strength. Our results reveal that peripheral targeting of monoamine oxidase B and GABA-A receptor, common antidepressant targets, extends healthspan through mitohormesis. Nature Publishing Group UK 2023-05-15 /pmc/articles/PMC10185515/ /pubmed/37188705 http://dx.doi.org/10.1038/s41467-023-38410-y Text en © The Author(s) 2023 https://creativecommons.org/licenses/by/4.0/Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) .
spellingShingle Article
Costa-Machado, Luis Filipe
Garcia-Dominguez, Esther
McIntyre, Rebecca L.
Lopez-Aceituno, Jose Luis
Ballesteros-Gonzalez, Álvaro
Tapia-Gonzalez, Andrea
Fabregat-Safont, David
Eisenberg, Tobias
Gomez, Jesús
Plaza, Adrian
Sierra-Ramirez, Aranzazu
Perez, Manuel
Villanueva-Bermejo, David
Fornari, Tiziana
Loza, María Isabel
Herradon, Gonzalo
Hofer, Sebastian J.
Magnes, Christoph
Madeo, Frank
Duerr, Janet S.
Pozo, Oscar J.
Galindo, Maximo-Ibo
del Pino, Isabel
Houtkooper, Riekelt H.
Megias, Diego
Viña, Jose
Gomez-Cabrera, Mari Carmen
Fernandez-Marcos, Pablo J.
Peripheral modulation of antidepressant targets MAO-B and GABAAR by harmol induces mitohormesis and delays aging in preclinical models
title Peripheral modulation of antidepressant targets MAO-B and GABAAR by harmol induces mitohormesis and delays aging in preclinical models
title_full Peripheral modulation of antidepressant targets MAO-B and GABAAR by harmol induces mitohormesis and delays aging in preclinical models
title_fullStr Peripheral modulation of antidepressant targets MAO-B and GABAAR by harmol induces mitohormesis and delays aging in preclinical models
title_full_unstemmed Peripheral modulation of antidepressant targets MAO-B and GABAAR by harmol induces mitohormesis and delays aging in preclinical models
title_short Peripheral modulation of antidepressant targets MAO-B and GABAAR by harmol induces mitohormesis and delays aging in preclinical models
title_sort peripheral modulation of antidepressant targets mao-b and gabaar by harmol induces mitohormesis and delays aging in preclinical models
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10185515/
https://www.ncbi.nlm.nih.gov/pubmed/37188705
http://dx.doi.org/10.1038/s41467-023-38410-y
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