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

Fecha de publicación: 15/05/2023 Fecha Ahead of Print: 15/05/2023

Autores de INCLIVA

• Esther Garcia Dominguez

  Autor

• 

  Jose Viña Ribes

  Autor

• 

  Maria Carmen Gomez Cabrera

  Autor

Participantes ajenos a INCLIVA

• Costa-Machado, Luis Filipe
• McIntyre, Rebecca L
• Lopez-Aceituno, Jose Luis
• Ballesteros-Gonzalez, Alvaro
• Tapia-Gonzalez, Andrea
• Fabregat-Safont, David
• Eisenberg, Tobias
• Gomez, Jesus
• Plaza, Adrian
• Sierra-Ramirez, Aranzazu
• Perez, Manuel
• Villanueva-Bermejo, David
• Fornari, Tiziana
• Loza, Maria 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
• Fernandez-Marcos, Pablo J

Grupos y Plataformas de I+D+i

• Grupo de Investigación en Ejercicio, Nutrición y Estilo de Vida Saludable

  

  Established Researcher

  Maria Carmen Gomez Cabrera

• Grupo de investigación en envejecimiento y ejercicio físico

  

  Leading Researcher

  Jose Viña Ribes

Abstract

Reversible mitochondrial stress leading to improved mitochondrial function (mitohormesis) has been reported as an anti-aging mechanism. Here the authors report that harmol (a beta-carboline compound) induces mitohormesis in peripheral organs, alleviates aging-related phenotypes in mice, and extends lifespan in invertebrate 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, 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.

© 2023. The Author(s).