| Autor: |
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 |
| Jazyk: |
angličtina |
| Rok vydání: |
2023 |
| Předmět: |
|
| Zdroj: |
Nature Communications, Vol 14, Iss 1, Pp 1-22 (2023) |
| Druh dokumentu: |
article |
| ISSN: |
2041-1723 |
| DOI: |
10.1038/s41467-023-38410-y |
| Popis: |
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. |
| Databáze: |
Directory of Open Access Journals |
| Externí odkaz: |
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Full text from SpringerLink