RT Journal Article
T1 Peripheral modulation of antidepressant targets MAO-B and GABAAR by harmol induces mitohormesis and delays aging in preclinical models
A1 Machado, Luis Filipe Costa
A1 García-Domínguez, Esther
A1 McIntyre, Rebecca L.
A1 López-Aceituno, José Luis
A1 Ballesteros-González, Álvaro
A1 Tapia-González, Andrea
A1 Fabregat Safont, David
A1 Eisenberg, Tobias
A1 Gómez, Jesús
A1 Plaza, Adrián
A1 Sierra-Ramírez, Aranzazu
A1 Pérez, Manuel
A1 Villanueva-Bermejo, David
A1 Fornari, Tiziana
A1 Herradón, Gonzalo
A1 Hofer, Sebastian J.
A1 Magnes, Christoph
A1 Madeo, Frank
A1 Duerr, Janet S.
A1 Pozo, Oscar J.
A1 Galindo, Maximo-Ibo
A1 Pino, Isabel del
A1 Houtkooper, Riekelt H.
A1 Megías, Diego
A1 Viña, José
A1 Gómez-Cabrera, Mari Carmen
A1 Fernández-Marcos, Pablo J.
A1 Loza García, María Isabel
AB 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.
PB Springer Nature
YR 2023
FD 2023-05-15
LK https://hdl.handle.net/10347/45566
UL https://hdl.handle.net/10347/45566
LA eng
NO Costa-Machado, L.F., Garcia-Dominguez, E., McIntyre, R.L. et al. Peripheral modulation of antidepressant targets MAO-B and GABAAR by harmol induces mitohormesis and delays aging in preclinical models. Nat Commun 14, 2779 (2023). https://doi.org/10.1038/s41467-023-38410-y
DS Minerva
RD 24 abr 2026