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Título: | Peripheral modulation of antidepressant targets MAO-B and GABAAR by harmol induces mitohormesis and delays aging in preclinical models |
Autor: | 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 CSIC ORCID; Fornari, Tiziana CSIC ; Loza, María Isabel; Herradón, Gonzalo; Hofer, Sebastian J.; Magnes, Christoph; Madeo, Frank; Duerr, Janet S.; Pozo, Oscar J.; Galindo, Maximo-Ibo; Pino, Isabel del CSIC ORCID; Houtkooper, Riekelt H.; Megías, Diego; Viña, José; Gómez-Cabrera, Mari Carmen; Fernández-Marcos, Pablo José | Fecha de publicación: | 2023 | Editor: | Springer Nature | Citación: | Nature Communications 14(1): 2779 (2023) | Resumen: | 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. | Versión del editor: | https://doi.org/10.1038/s41467-023-38410-y | URI: | http://hdl.handle.net/10261/341803 | DOI: | 10.1038/s41467-023-38410-y | E-ISSN: | 2041-1723 |
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