Infertility likely stems from age-related decline of the ovaries, but the molecular mechanisms that lead to this decline have been unclear. Now, scientists have discovered, in unprecedented detail, how ovaries age in non-human primates. The findings, published in Cell, reveal several genes that could be used as biomarkers and point to therapeutic targets for diagnosing and treating female infertility and age-associated ovarian diseases, such as ovarian cancer, in humans.
“This is the first in-depth analysis of ovarian aging at a single-cell resolution in a non-human primate model,” says Juan Carlos Izpisua Belmonte, one of the co-corresponding authors, professor in Salk’s Gene Expression Laboratory and holder of the Roger Guillemin Chair. “We found that oxidative stress, the cellular stress that damages cells, is a key player in ovarian aging. This discovery provides valuable insight into the mechanisms by which ovaries age and eventually become infertile.”
The scientists compared 2,601 ovarian cells from young and old non-human primates, and identified gene activity patterns for every type of primate ovarian cell including ooctyes and granulosa cells, which surround the oocytes as they develop. The scientists then compared the primate data with granulosa cells from healthy women ranging in age from 21 to 46 years.
Two key antioxidant genes (IDH1 and NDUFB10) showed decreased function, as seen in the non-human primate cells. To better understand the connection between ovarian aging and the antioxidant genes, the scientists tested what happened to the human cells when the antioxidant genes were made non-functional. They found that without IDH1 or NDUFB10, the cells appeared old and similar to the old non-human primate cells. The results suggest that IDH1 and NDUFB10 play a critical role in protecting both human and non-human primate ovarian cells from cellular stress during aging.
“This study provides a comprehensive understanding of the specific mechanisms of primate ovarian aging at single-cell resolution,” says Guang-Hui Liu, co-corresponding author, professor at the Chinese Academy of Sciences and former Salk research associate. “Our results will hopefully lead to the development of new tools to aid in the rejuvenation of aged ovarian cells.”