1. Peripheral modulation of antidepressant targets MAO-B and GABAAR by harmol induces mitohormesis and delays aging in preclinical models.
- Author
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Costa-Machado LF, Garcia-Dominguez E, McIntyre RL, Lopez-Aceituno JL, Ballesteros-Gonzalez Á, Tapia-Gonzalez A, Fabregat-Safont D, Eisenberg T, Gomez J, Plaza A, Sierra-Ramirez A, Perez M, Villanueva-Bermejo D, Fornari T, Loza MI, Herradon G, Hofer SJ, Magnes C, Madeo F, Duerr JS, Pozo OJ, Galindo MI, Del Pino I, Houtkooper RH, Megias D, Viña J, Gomez-Cabrera MC, and Fernandez-Marcos PJ
- Subjects
- Muscle Fibers, Skeletal drug effects, AMP-Activated Protein Kinase Kinases metabolism, Muscle, Skeletal drug effects, Liver drug effects, Insulin Resistance, Glucose Intolerance metabolism, Prediabetic State metabolism, Longevity drug effects, Caenorhabditis elegans, Drosophila melanogaster, Frailty prevention & control, Physical Conditioning, Animal, Models, Animal, Male, Female, Animals, Mice, Fatty Liver metabolism, Adipose Tissue, Brown drug effects, Harmine analogs & derivatives, Harmine pharmacology, Antidepressive Agents pharmacology, Mitochondria drug effects, Mitophagy drug effects, Aging drug effects, Monoamine Oxidase metabolism, Receptors, GABA-A metabolism
- 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., (© 2023. The Author(s).)
- Published
- 2023
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