Human ovarian ageing is characterized by oxidative damage and mitochondrial dysfunction

Abstract

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.

Equine maternal aging affects the metabolomic profile of oocytes and follicular cells during different maturation time points

“…The metabolomic analyses from single oocytes and the associated cumulus and granulosa cells allowed us to correlate metabolite abundance between the different cell types. Overall, many of our age-related findings point to impaired mitochondrial metabolic function and the associated oxidative stress in oocytes and follicular cells from old mares, reinforcing previous reports in mares and other females ( Bentov et al, 2011 ; Sessions-Bresnahan and Carnevale, 2015 ; Liu et al, 2017 ; Catandi et al, 2021 ; Alberico and Woods, 2022 ; Lu et al, 2022 ; Smits et al, 2023 ). Supporting findings include higher abundance of glutamic acid and triglycerides and lower abundance of ceramides in oocytes and somatic follicular cells from old than young mares ( Figure 8 ).…”

“…Glutamine abundance is greater in germinal vesicle and metaphase I oocytes from older women (35–42 years) than women 23–34 years ( Smits et al, 2023 ). The authors postulated the findings in women were associated with impaired mitochondrial tricarboxylic acid cycle efficiency and reduced glutathione synthesis, promoting mitochondrial dysfunction and oxidative stress in oocytes from advanced maternal age women ( Smits et al, 2023 ). This would be consistent with the altered oocyte metabolic function and positive response to dietary antioxidants that we have observed for old mares in a previous study ( Catandi et al, 2021 ; Catandi et al, 2022 ).…”

Ovarian aging: energy metabolism of oocytes

“…The TCA cycle is a crucial component in signaling pathways and metabolic disorders associated with aging, making it an important target for anti-aging treatment strategies [19,20]. The TCA cycle takes place in oocytes, and its activity is inhibited with age [7,11,21]. Specifically, as age increases, the cross-regional transport of substances such as pyruvate and lactate salts from granulosa cells to oocytes decreases, but metabolites such as pyruvate, lactate salts, and glutamine gradually accumulate in the oocytes [7,22].…”

“…The TCA cycle takes place in oocytes, and its activity is inhibited with age [7,11,21]. Specifically, as age increases, the cross-regional transport of substances such as pyruvate and lactate salts from granulosa cells to oocytes decreases, but metabolites such as pyruvate, lactate salts, and glutamine gradually accumulate in the oocytes [7,22]. Glucose [7], glucose-6-phosphate [7], sorbitol [13], mannitol [13], urea cycle intermediates such as aspartate [7], ornithine [7], and arginine [7] increase in oocytes of older mothers, indicating that energy substrates are diverted to the pentose phosphate pathway, hexosamine synthesis pathway, and urea cycle; the TCA cycle cannot process available substrates.…”

“…1). Although cumulus cells produce ATP and provide it to oocytes [7], a decrease in ATP, a decrease in energy production capacity, and a decline in mitochondrial function are all part of the aging of the oocytes [8][9][10][11][12][13][14][15]. Reduced ATP production leads to a decline in oocyte quality, specifically resulting in decreased metabolic activity, which may affect cell cycle regulation, spindle formation during mitosis, chromosome segregation, fertilization, embryo development, and implantation, as discussed in other literature [16][17][18].…”