Molecular and Structural Determinants of Ovarian Aging

Graduation Date

Spring 5-9-2026

Document Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Programs

Biochemistry & Molecular Biology

First Advisor

John S. Davis

Abstract

Women’s ovaries begin to exhibit clinically significant aging in their mid-30s, nearly a decade before other vital organs begin to age. Ovarian aging involves progressive fibrosis and inflammation, which gradually damages the ovarian structure, leading to extracellular matrix stiffening and impairing oocyte quality and steroid hormone production. Many pathways essential in ovarian development are also key pathways in fibrosis, such as the Hippo pathway. Although the Hippo signaling pathway and its effectors YAP1 and TAZ regulate follicle development and fibrosis, its exact role in ovarian aging remains unclear. This study utilized CD1 mice to examine ovarian aging across four age groups, from immature to senescent mice approximately aligning with stages of human reproductive aging. Analysis of ovarian RNA and protein showed that the Hippo pathway effectors YAP1 and TAZ decline after puberty and stay suppressed with age, suggesting that ovarian fibrosis with age occurs independently of the canonical Hippo-YAP1/TAZ activation. The increasing trend of delaying childbearing has led to a significant increase in women seeking fertility treatment and relying on IVF, which overlaps with ovarian aging. Granulosa cells (GC), which are crucial for oocyte development, play a key role in these age-related changes. In our study, IVF patients were classified as good (≥17 oocytes retrieved) or poor (≤8 oocytes retrieved) responders, and young (≤ 31years) and old viii (≥37years) patients. To better understand GC dysfunction with age, this research combined ATAC-seq and RNA-seq to analyze chromatin accessibility and gene expression in IVF patients classified by age and response to gonadal stimulation. In poor responders, GCs showed transcriptional and chromatin-accessibility signatures of premature luteinization, with notable declines in cell cycle markers, interleukins, and apoptosis markers. ATAC-seq confirmed that poor responders have highly accessible promoter regions for genes involved in cholesterol synthesis, whereas good responders showed enrichment for immune response–related accessibility and transcriptional programs. Together, these data highlight a model of ovarian aging in which both Hippo-independent stromal fibrosis and chromatin-mediated lipid metabolism occur in aging GCs. Overall, these findings could lead to new biomarkers for predicting IVF success and understanding ovarian aging.

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