Molecular Mechanisms and Genetic Basis of Human Ovarian Aging

This research proposal is in response to the NOT-OD-24-079 “Notice of Special Interest: Women’s Health Research” focused on health conditions that are female-specific. The ovary is the first organ to age in the human body. Ovarian aging negatively influences lifespan and a broad range of health outcomes in cardiovascular, skeletal, metabolic, immune, and neurocognitive systems in women. However, as with so many aspects of women’s health, ovarian aging has received limited scientific attention, even in large genomic survey projects, and the biological mechanisms underlying human ovarian aging and that may have broad implications for women’s healthspan remain poorly understood. The objective of this proposal is to investigate the molecular mechanisms that control the remarkably complex processes of ovarian aging and that are causally linked to human genetic factors influencing ovarian aging. In our preliminary studies, by performing a coupled single nucleus (sn)RNA-seq and snATAC-seq (Assay for Transposase-Accessible Chromatin using sequencing) analysis of flash-frozen ovary tissues from young (age 20s) and reproductively old (age ~50s) women, we made an interesting discovery that aging in the ovary proceeds through the conserved hallmark pathways of aging in each cell type, such as activation of mTOR signaling, but in an accelerated manner compared to other human tissue types, and there is a remarkable coordination of transcriptome and regulatory changes across all cell types in the ovary. These findings raise the hope that known geroprotectors that target the hallmarks of aging can be used to delay aging in the ovary in women. However, they also raise important new questions: how early aging starts in the ovary which is important to understand if we want to delay ovarian aging and its negative health outcomes; and what mechanisms underlie the dynamic and coordinated transcriptional and regulatory changes in the ovary and how they influence interactions between oocytes and their surrounding somatic cells during ovarian aging. Furthermore, we found that the great majority (94%) of the genetic variants associated with age at natural menopause (ANM), a proxy for female reproductive aging, as well as a trustworthy indicator of postmenopausal health, reside in non-coding regions of the genome, indicating that regulatory changes contribute to ovarian aging. However, elucidating the functional role of these non-coding regulatory variants and identification of their target genes is challenging and difficulties in GWAS interpretation has been the major barrier to understanding the genetic basis of ovarian aging in women and translation of human genetic discovery. By addressing the new questions and filling the knowledge gaps in the molecular mechanisms and genetic basis of human ovarian aging through integrated in silico analysis and unbiased genomic profiling at single cell level, and CRISPR-mediated genome editing and data-driven functional assays, our long-term goal is to define and validate regulatory drivers of the “premature” aging in the ovary and identify potential targets for therapeutic interventions in women.