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.

Bibliographic Details

Main Authors:	Costa-Machado, Luis Filipe, García-Domínguez, Esther, McIntyre, Rebecca L., López-Aceituno, José Luis, Ballesteros-González, Álvaro, Tapia-González, Andrea, Fabregat-Safont, David, Eisenberg, Tobias, Gómez, Jesús, Plaza, Adrian, Sierra-Ramírez, Aranzazu, Pérez, Manuel, Villanueva-Bermejo, David, Fornari, Tiziana, Loza, María Isabel, Herradón, Gonzalo, Hofer, Sebastian J., Magnes, Christoph, Madeo, Frank, Duerr, Janet S., Pozo, Oscar J., Galindo, Maximo-Ibo, Pino, Isabel del, Houtkooper, Riekelt H., Megías, Diego, Viña, José, Gómez-Cabrera, Mari Carmen, Fernández-Marcos, Pablo José
Other Authors:	Fundação para a Ciência e a Tecnologia (Portugal)
Format:	artículo biblioteca
Language:	English
Published:	Springer Nature 2024-01-08T10:42:55Z
Online Access:	http://hdl.handle.net/10261/341803
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