RT Journal Article
SR Electronic
T1 Recapitulating Human Ovarian Aging Using Random Walks
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 2022.05.31.494088
DO 10.1101/2022.05.31.494088
A1 Joshua Johnson
A1 John W. Emerson
A1 Sean D. Lawley
YR 2022
UL http://biorxiv.org/content/early/2022/06/01/2022.05.31.494088.abstract
AB Mechanism(s) that control whether individual human primordial ovarian follicles (PFs) remain dormant, or begin to grow, are all but unknown. One of our groups has recently shown that activation of the Integrated Stress Response (ISR) pathway can slow follicular granulosa cell proliferation by activating cell cycle checkpoints. Those data suggest that the ISR is active and fluctuates according to local conditions in dormant PFs. Because cell cycle entry of (pre)granulosa cells is required for PF growth activation (PFGA), we propose that rare ISR checkpoint resolution allows individual PFs to begin to grow. Fluctuating ISR activity within individual PFs can be described by a random process. In this paper, we model ISR activity of individual PFs by one-dimensional random walks (RWs) and monitor the rate at which simulated checkpoint resolution and thus PFGA threshold crossing occurs. We show that that the simultaneous recapitulation of i) the loss of PFs over time within simulated subjects, and ii) the timing of PF depletion in populations of simulated subjects equivalent to the distribution of the human age of natural menopause can be produced using this approach. In the RW model, the probability that individual PFs grow is influenced by regionally fluctuating conditions, that over time manifests in the known pattern of PFGA. Considered at the level of the ovary, randomness appears to be a key, purposeful feature of human ovarian aging.Competing Interest StatementThe authors have declared no competing interest.