Scientists from China and the USA have used non-human primate ovaries to improve understanding of why female fertility declines with age.
The team identified several genes, which have potential use as biomarkers, as therapeutic targets for drug discovery, or as diagnostics for age-associated infertility in humans. The mechanisms relating to ovarian ageing and female age-related fertility decline in humans are poorly understood.
'Our research is enabling the identification of new biomarkers for the diagnosis and treatment of female infertility as well as ageing-associated human ovarian disorders,' said co-author Concepcion Rodriguez Esteban from the Salk institute in La Jolla, California, 'These genes could possibly be targeted for the development of therapies to assist with fertility preservation.'
The research, published in Cell, was carried out in non-human primates and claims to have discovered the mechanisms of ovarian ageing at a single-cell resolution. The researchers identified seven ovarian cell types with distinct gene expression signatures.
Scientists first compared 2601 ovarian cells from young and old non-human primates, which led to the identification of gene activity patterns for every type of non-human primate ovarian cell, including oocytes and granulosa cells, which surround the oocytes as they grow. As these cells age, some genes that fight cellular stress become less active, which leads to damage and functional impairment.
'We found that oxidative stress, the cellular stress that damages cells, is a key player in ovarian ageing. This discovery provides valuable insight into the mechanisms by which ovaries age and eventually become infertile.' said corresponding author Professor Juan Carlos Izpisua Belmonte, also from the Salk Institute.
The second stage of the study compared data from the non-human primates with granulosa cells from healthy women between the age of 21 and 46. Age-associated damage from cellular stress as well as cell death in the women's cells were observed. Scientists discovered two key antioxidant genes (IDH1 and NDUFB10) that showed a decrease in activity, which was also seen in the non-human primate cells.
The last stage of the study involved investigating the effect of making these antioxidant genes non-functioning in the human cells. The scientists concluded that without these antioxidant genes, the human cells appeared aged akin to the aged non-human primate cells. As such, the antioxidant genes, IDH1 and NDUFB10, appear to be critical in protecting both non-human primate and human ovarian cells from the cellular stresses that occur during ageing.
This research provides an in depth understanding of the cell-type-specific mechanisms involved in primate ovarian ageing at the single-cell level. This has important ramifications for human age-related ovarian disorders and infertility, with the potential for future research to lead to the discovery of novel diagnostic biomarkers and therapeutic targets.