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Recapitulating human ovarian aging using random walks.

Joshua Johnson1, John W Emerson2, Sean D Lawley3

  • 1Department of Obstetrics and Gynecology, University of Colorado-Anschutz Medical Center, Aurora, Colorado, United States.

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|August 29, 2022
PubMed
Summary

The Integrated Stress Response (ISR) pathway regulates primordial ovarian follicle (PF) dormancy. Rare resolution of ISR checkpoints allows PFs to grow, explaining ovarian aging patterns.

Keywords:
ANMAgingDNA damageEIF2S1FertilityFollicleMathematical modelingMenopauseOvaryPrimordial follicle

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Area of Science:

  • Reproductive Biology
  • Cellular Biology
  • Ovarian Physiology

Background:

  • Mechanisms controlling human primordial ovarian follicle (PF) dormancy and growth remain largely unknown.
  • The Integrated Stress Response (ISR) pathway has been shown to inhibit granulosa cell proliferation by activating cell cycle checkpoints.
  • The ISR is hypothesized to be active and fluctuate within dormant PFs based on local conditions.

Purpose of the Study:

  • To propose and model a mechanism for primordial ovarian follicle growth activation (PFGA).
  • To investigate the role of Integrated Stress Response (ISR) checkpoint resolution in initiating PFGA.
  • To explore how fluctuating ISR activity, modeled as a random process, influences PF dynamics and ovarian aging.

Main Methods:

  • Utilizing one-dimensional random walks (RWs) to model the fluctuating ISR activity within individual PFs.
  • Simulating checkpoint resolution rates to determine the threshold crossing for PFGA.
  • Comparing simulation outputs with observed PF loss over time and the timing of natural menopause.

Main Results:

  • The RW model successfully recapitulates the loss of PFs over time in simulated subjects.
  • The model accurately reproduces the timing of PF depletion, aligning with the human age of natural menopause.
  • Individual PF growth probability is influenced by fluctuating regional conditions, manifesting as known PFGA patterns.

Conclusions:

  • Rare resolution of ISR checkpoints is proposed as the trigger for primordial ovarian follicle growth.
  • Fluctuating ISR activity, modeled by random walks, provides a framework for understanding PFGA and ovarian aging.
  • Randomness is identified as a crucial, potentially purposeful, feature of human ovarian aging at the ovarian level.