Peripheral modulation of antidepressant targets MAO-B and GABAAR by harmol induces mitohormesis and delays aging in preclinical models

  • Nat Commun. 2023 May 15;14(1):2779. doi: 10.1038/s41467-023-38410-y.
Luis Filipe Costa-Machado  1  2  3 ,  Esther Garcia-Dominguez  4 ,  Rebecca L McIntyre  5 ,  Jose Luis Lopez-Aceituno  1 ,  Álvaro Ballesteros-Gonzalez  6 ,  Andrea Tapia-Gonzalez  7 ,  David Fabregat-Safont  8  9 ,  Tobias Eisenberg  10  11  12 ,  Jesús Gomez  13 ,  Adrian Plaza  1 ,  Aranzazu Sierra-Ramirez  1 ,  Manuel Perez  13 ,  David Villanueva-Bermejo  14 ,  Tiziana Fornari  14 ,  María Isabel Loza  2  3 ,  Gonzalo Herradon  15 ,  Sebastian J Hofer  10  11  12 ,  Christoph Magnes  16 ,  Frank Madeo  10  11  12 ,  Janet S Duerr  17 ,  Oscar J Pozo  8 ,  Maximo-Ibo Galindo  6  18  19 ,  Isabel Del Pino  7  20 ,  Riekelt H Houtkooper  5 ,  Diego Megias  13 ,  Jose Viña  4 ,  Mari Carmen Gomez-Cabrera  4 ,  Pablo J Fernandez-Marcos  21
Affiliations
  • 1. Metabolic Syndrome Group - BIOPROMET. Madrid Institute for Advanced Studies - IMDEA Food, CEI UAM + CSIC, E28049, Madrid, Spain.
  • 2. Kaertor Foundation, EMPRENDIA Building, Floor 2, Office 4, Campus Vida, E-15706, Santiago de Compostela, Spain, E-15706, Santiago de Compostela, Spain.
  • 3. BioFarma Research Group, Center for Research in Molecular Medicine and Chronic Diseases (CIMUS), Universidade de Santiago de Compostela, Santiago de Compostela, Spain.
  • 4. Freshage Research Group, Department of Physiology, Faculty of Medicine, CIBERFES, Fundación Investigación Hospital Clínico Universitario/INCLIVA, University of Valencia, Valencia, Spain.
  • 5. Laboratory Genetic Metabolic Diseases, Amsterdam Gastroenterology, Endocrinology, Metabolism, Amsterdam Cardiovascular Sciences, Amsterdam UMC, University of Amsterdam, Amsterdam, Netherlands.
  • 6. Developmental Biology and Disease Models Group, Centro de Investigación Príncipe Felipe, 46012, Valencia, Spain.
  • 7. Neural Plasticity Group, Centro de Investigación Príncipe Felipe, 46012, Valencia, Spain.
  • 8. Applied Metabolomics Research Group, Hospital del Mar Medical Research Institute - (IMIM), Barcelona, Spain.
  • 9. Environmental and Public Health Analytical Chemistry, Research Institute for Pesticides and Water, University Jaume I, 12006, Castelló de la Plana, Castellón, Spain.
  • 10. Institute of Molecular Biosciences, NAWI Graz, University of Graz, Humboldtstraße 50, 8010, Graz, Austria.
  • 11. BioTechMed Graz, 8010, Graz, Austria.
  • 12. Field of Excellence BioHealth - University of Graz, Graz, Austria.
  • 13. Confocal Microscopy Unit, Biotechnology Programme, Spanish National Cancer Research Centre (CNIO), Melchor Fernández Almagro 3, 28029, Madrid, Spain.
  • 14. Department of Production and Characterization of Novel Foods, Institute of Food Science Research (CIAL UAM-CSIC), C/ Nicolás Cabrera, 9, P.O. Box. 28049, Madrid, Spain.
  • 15. Lab. Pharmacology, Faculty of Pharmacy, Universidad CEU San Pablo, Urb. Montepríncipe, 28668, Boadilla del Monte, Madrid, Spain.
  • 16. HEALTH-Institute for Biomedicine and Health Sciences, Joanneum Research Forschungsgesellschaft mbH, 8010, Graz, Austria.
  • 17. Department of Biological Sciences, Ohio University, Athens, OH, 45701, USA.
  • 18. Instituto Interuniversitario de Investigación de Reconocimiento Molecular y Desarrollo Tecnológico (IDM), Universitat Politècnica de València, Universitat de València, 46022, Valencia, Spain.
  • 19. UPV-CIPF Joint Research Unit "Disease Mechanisms and Nanomedicine". Centro de Investigación Príncipe Felipe, 46012, Valencia, Spain.
  • 20. Instituto de Neurociencias, Consejo Superior de Investigaciones Científicas, Universidad Miguel Hernández, Campus de Sant Joan, 03550, Alicante, Spain.
  • 21. Metabolic Syndrome Group - BIOPROMET. Madrid Institute for Advanced Studies - IMDEA Food, CEI UAM + CSIC, E28049, Madrid, Spain. [email protected].
PMID: 37188705 DOI: 10.1038/s41467-023-38410-y
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.

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