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Human ovarian ageing is characterized by oxidative damage and mitochondrial dysfunction
Myrthe A.J. Smits, Bauke V. Schomakers, Michel van Weeghel, Eric J.M. Wever, Rob C.I. Wüst, Frederike Dijk, Georges E. Janssens, Mariëtte Goddijn, Sebastiaan Mastenbroek, Riekelt H. Houtkooper, Geert Hamer
Ageing, mitochondria, oxidative stress
Human ovarian ageing encompasses the age-related decline in female fertility. Oxidative stress and mitochondrial dysfunction in oocytes are suggested as causal, but corroborating evidence is limited. Using immunofluorescence imaging on human ovarian tissue, we found oxidative damage by protein and lipid (per)oxidation at the primordial follicle stage. Additionally, using comprehensive metabolomics and lipidomics, a cohort of 150 human germinal vesicles and metaphase I oocytes and 15 corresponding cumulus cell samples displayed a shift in glutathione to oxiglutathione ratio and depletion of phospholipids. Age-related changes in polar metabolites suggested a decrease in mitochondrial function, as demonstrated by NAD+, purine and pyrimidine depletion, while glycolysis substrates and glutamine accumulated with age. Oocytes of advanced maternal age likely used alternative energy sources like glycolysis and the adenosine salvage pathway, and possibly increased ATP production in cumulus cells. These findings indicate that oocytes of advanced maternal age suffer from oxidative damage and mitochondrial dysfunction.