Multi-omic profiling reveals impaired luteal resolution and CHK2-regulated inflammation in ovarian aging

Abstract

The ovary ages earlier than most other organs, but the molecular mechanisms that drive this decline remain unclear. To gain more insight into this process, we profiled ovaries from young and reproductively aged mice after synchronized ovulation and found that aging was marked by the accumulation of luteal cells with increased steroidogenic, antigen presentation and inflammatory gene expression. DNA methylation was globally preserved in aged ovaries but showed focal age-associated changes at gene regulatory regions. Protein profiling identified an increase in checkpoint kinase 2 (CHK2), a DNA damage response protein encoded by the CHEK2 gene associated with the timing of natural menopause in humans. CHK2 and DNA damage markers were increased in aged mice and human ovarian somatic cells. Transient CHK2 inhibition in aged mice increased the proportion of mature oocytes and blastocyst formation and reversed inflammatory signatures in granulosa cells. These findings identify defective luteal resolution and inflammation as features of ovarian aging and suggest that CHK2 induces a reversible age-associated inflammatory signature. Our results show that reproductive decline may remain pharmacologically modifiable during ovarian aging via regulation of the inflammatory response.