Costa-Machado, L.F., Garcia-Dominguez, E., McIntyre, R.L., Lopez-Aceituno, J.L., Ballesteros-Gonzalez, , Tapia-Gonzalez, A., Fabregat-Safont, D., Eisenberg, T., Gomez, J., Plaza, A., Sierra-Ramirez, A., Perez, M., Villanueva-Bermejo, D., Fornari, T., Loza, M.I., Herradon, G., Hofer, S.J., Magnes, C., Madeo, F., Duerr, J.S., Pozo, O.J., Galindo, M.I., Del Pino, I., Houtkooper, R.H., Megias, D., Viña, J., Gomez-Cabrera, M.C., Fernandez-Marcos, P.J. (2023). Peripheral modulation of antidepressant targets MAO-B and GABAAR by harmol induces mitohormesis and delays aging in preclinical models.  Nat. Commun. 14(1): 2779.

FBrf0256523

Research paper

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.

PMC10185515 (PMC) (EuropePMC)