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

Luis Filipe Costa-Machado, Esther Garcia-Dominguez, Rebecca L. McIntyre, Jose Luis Lopez-Aceituno, Álvaro Ballesteros-Gonzalez, Andrea Tapia-Gonzalez, David Fabregat-Safont, Tobias Eisenberg, Jesús Gomez, Adrian Plaza, Aranzazu Sierra-Ramirez, Manuel Perez, David Villanueva-Bermejo, Tiziana Fornari, María Isabel Loza, Gonzalo Herradon, Sebastian J. Hofer, Christoph Magnes, Frank Madeo, Janet S. Duerr, Oscar J. Pozo, Maximo-Ibo Galindo, Isabel Pino, Riekelt H. Houtkooper, Diego Megias, Jose Viña, Mari Carmen Gomez-Cabrera and Pablo J. Fernandez-Marcos ()
Additional contact information
Luis Filipe Costa-Machado: Metabolic Syndrome Group – BIOPROMET. Madrid Institute for Advanced Studies - IMDEA Food, CEI UAM + CSIC
Esther Garcia-Dominguez: Fundación Investigación Hospital Clínico Universitario/INCLIVA, University of Valencia
Rebecca L. McIntyre: University of Amsterdam
Jose Luis Lopez-Aceituno: Metabolic Syndrome Group – BIOPROMET. Madrid Institute for Advanced Studies - IMDEA Food, CEI UAM + CSIC
Álvaro Ballesteros-Gonzalez: Centro de Investigación Príncipe Felipe
Andrea Tapia-Gonzalez: Centro de Investigación Príncipe Felipe
David Fabregat-Safont: Hospital del Mar Medical Research Institute - (IMIM)
Tobias Eisenberg: University of Graz, Humboldtstraße 50
Jesús Gomez: Spanish National Cancer Research Centre (CNIO), Melchor Fernández Almagro 3
Adrian Plaza: Metabolic Syndrome Group – BIOPROMET. Madrid Institute for Advanced Studies - IMDEA Food, CEI UAM + CSIC
Aranzazu Sierra-Ramirez: Metabolic Syndrome Group – BIOPROMET. Madrid Institute for Advanced Studies - IMDEA Food, CEI UAM + CSIC
Manuel Perez: Spanish National Cancer Research Centre (CNIO), Melchor Fernández Almagro 3
David Villanueva-Bermejo: Institute of Food Science Research (CIAL UAM-CSIC), C/ Nicolás Cabrera, 9
Tiziana Fornari: Institute of Food Science Research (CIAL UAM-CSIC), C/ Nicolás Cabrera, 9
María Isabel Loza: Kaertor Foundation, EMPRENDIA Building, Floor 2, Office 4, Campus Vida, E-15706, Santiago de Compostela, Spain
Gonzalo Herradon: Universidad CEU San Pablo, Urb. Montepríncipe
Sebastian J. Hofer: University of Graz, Humboldtstraße 50
Christoph Magnes: Joanneum Research Forschungsgesellschaft mbH
Frank Madeo: University of Graz, Humboldtstraße 50
Janet S. Duerr: Ohio University
Oscar J. Pozo: Hospital del Mar Medical Research Institute - (IMIM)
Maximo-Ibo Galindo: Centro de Investigación Príncipe Felipe
Isabel Pino: Centro de Investigación Príncipe Felipe
Riekelt H. Houtkooper: University of Amsterdam
Diego Megias: Spanish National Cancer Research Centre (CNIO), Melchor Fernández Almagro 3
Jose Viña: Fundación Investigación Hospital Clínico Universitario/INCLIVA, University of Valencia
Mari Carmen Gomez-Cabrera: Fundación Investigación Hospital Clínico Universitario/INCLIVA, University of Valencia
Pablo J. Fernandez-Marcos: Metabolic Syndrome Group – BIOPROMET. Madrid Institute for Advanced Studies - IMDEA Food, CEI UAM + CSIC

Nature Communications, 2023, vol. 14, issue 1, 1-22

Abstract: Abstract 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.

Date: 2023
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DOI: 10.1038/s41467-023-38410-y

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