# Cellular senescence and epigenomic remodeling in ovarian aging

> **NIH NIH R01** · UNIVERSITY OF OKLAHOMA HLTH SCIENCES CTR · 2020 · $345,069

## Abstract

PROJECT SUMMARY/ABSTRACT
Declines in ovarian function are closely associated with reductions in healthspan and longevity. Numerous
studies have linked ovarian dysfunction to systemic organismal aging, although very little is known with regard
to the basic, intrinsic mechanisms that initiate and perpetuate age-related ovarian functional declines. These
knowledge gaps represent a critical barrier to developing treatments aimed at attenuating age-related ovarian
failure. Ovarian aging is characterized by the progressive depletion of quiescent primordial follicles, which
eventually leads to irregular patterns of ovulation and disruption of the ovarian endocrine milieu. This project will
systemically explore how cell-type specific changes in cellular senescence and epigenetics/genomic
organization contribute to age-related ovarian failure through the use of novel transgenic NuTRAP models that
allow for the isolation of nucleic acids (DNA & RNA) specifically from oocytes, granulosa cells, or theca cells
without the need for cell sorting. Successful completion of this project will determine: 1) what role cellular
senescence and epigenetic modifications play in primordial follicle exhaustion, 2) if age-related cellular
senescence and epigenetic modifications occur in a cell-type specific fashion along differing timelines, 3) if
epigenetic changes precede or follow the emergence of cellular senescence, and 4) if the removal of senescent
cells and/or the suppression of the SASP through senolytic drug treatment can extend reproductive lifespan. We
hypothesize that granulosa cells encapsulating primordial follicles accumulate deleterious cellular and epigenetic
alterations, undergo a senescence-like transition, and thereby accelerate primordial follicle growth and
maturation, thereby leading to exhaustion. We will test this hypothesis through following aims. Specific Aim 1:
Characterize cell type-specific changes in markers of cellular senescence in oocytes, granulosa, and theca cells
from the aging ovary. We predict that senescence cell burden and inflammatory mediators will increase with
advancing age and that granulosa cells are a major source of this phenotype. Specific Aim 2: Characterize cell
type-specific changes in epigenetic alterations and transcriptional profiles within oocytes, granulosa, and theca
cells from the aging ovary. We predict that the majority of age-related changes will be cell-specific and that
`epigenetic clocks' of distinct cell types advance at different rates. We also anticipate that granulosa cells will
display the greatest changes in epigenetic and transcriptional profiles and that this will correspond to declines in
ovarian primordial follicle reserve. Aim 3: Determine if the clearance of senescent cells within the ovary restores
ovarian function and prolongs reproductive fitness. We predict that senolytic treatment will increase the number
of primordial follicles and that oocytes will accumulate less DNA damage with chronolog...

## Key facts

- **NIH application ID:** 10091665
- **Project number:** 1R01AG069742-01
- **Recipient organization:** UNIVERSITY OF OKLAHOMA HLTH SCIENCES CTR
- **Principal Investigator:** Michael B Stout
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $345,069
- **Award type:** 1
- **Project period:** 2020-09-30 → 2025-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10091665

## Citation

> US National Institutes of Health, RePORTER application 10091665, Cellular senescence and epigenomic remodeling in ovarian aging (1R01AG069742-01). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10091665. Licensed CC0.

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