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, 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).

Citation

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 Del Pino, Riekelt H Houtkooper, Diego Megias, Jose Viña, Mari Carmen Gomez-Cabrera, Pablo J Fernandez-Marcos. Peripheral modulation of antidepressant targets MAO-B and GABAAR by harmol induces mitohormesis and delays aging in preclinical models. Nature communications. 2023 May 15;14(1):2779

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PMID: 37188705

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