harmine and Prediabetic-State

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.

Topics: Adipose Tissue, Brown; Aging; AMP-Activated Protein Kinase Kinases; Animals; Antidepressive Agents; Caenorhabditis elegans; Drosophila melanogaster; Fatty Liver; Female; Frailty; Glucose Intolerance; Harmine; Insulin Resistance; Liver; Longevity; Male; Mice; Mitochondria; Mitophagy; Models, Animal; Monoamine Oxidase; Muscle Fibers, Skeletal; Muscle, Skeletal; Physical Conditioning, Animal; Prediabetic State; Receptors, GABA-A