The Aging Ovary and the Tales Learned Since Fetal Development

Abstract

Background: While the term "aging" implies a process typically associated with later life, the consequences of ovarian aging are evident by the time a woman reaches her forties, and sometimes earlier. This is due to a gradual decline in the quantity and quality of oocytes which occurs over a woman's reproductive lifespan. Indeed, the reproductive potential of the ovary is established even before birth, as the proper formation and assembly of the ovarian germ cell population during fetal life determines the lifetime endowment of oocytes and follicles. In the ovary, sophisticated molecular processes have been identified that regulate the timing of ovarian aging and these are critical to ensuring follicular maintenance.

Summary: The mechanisms thought to contribute to overall aging have been summarized under the term the "hallmarks of aging" and include such processes as DNA damage, mitochondrial dysfunction, telomere attrition, genomic instability, and stem cell exhaustion, among others. Similarly, in the ovary, molecular processes have been identified that regulate the timing of ovarian aging and these are critical to ensuring follicular maintenance. In this review, we outline critical processes involved in ovarian aging, highlight major achievements for treatment of ovarian aging, and discuss ongoing questions and areas of debate.

Key messages: Ovarian aging is recognized as what may be a complex process in which age, genetics, environment, and many other factors contribute to the size and depletion of the follicle pool. The putative hallmarks of reproductive aging outlined herein include a diversity of plausible processes contributing to the depletion of the ovarian reserve. More research is needed to clarify if and to what extent these putative regulators do in fact govern follicle and oocyte behavior, and how these signals might be integrated in order to control the overall pattern of ovarian aging.

Keywords: Germ cell; Oocyte; Ovarian aging; Ovary; Primordial follicle.

Figure 1.. The major signaling pathways and the molecules regulating primordial follicle growth activation (PFA).

Both inhibitory and activating pathways are known to function to regulate primordial follicle recruitment; these are summarized in the accompanying Figure. (Left panel) The “on switch” results in PFA, and the “off switch” to dormancy (e.g. preservation of the ovarian reserve). The PI3K/AKT/mTOR pathway includes the binding of growth factors to tyrosine kinase receptors. This binding leads to a phosphorylation cascade resulting in phosphorylation of PIP2 into PIP3 by PI3K. This promotes PDK1 recruitment to the cell membrane and activates Akt by phosphorylation. Akt can then translocate to the nucleus and phosphorylate the FOXO3 transcription factor, as well as regulate rapamycin (mTOR) activity through phosphorylation of tuberous sclerosis complex 2 (TSC2). PTEN serves an inhibitory role, dephosphorylating PIP3 to PIP2 and blocking follicle activation. (Right panel) Mechanical fragmentation can activate the Hippo signaling pathway. This process starts with the polymerization of globular actin (G-actin) to filamentous actin (F-Actin), which leads to MTS1/2 and SAV1 complex. Phosphorylation of the large tumor suppressor 1 and 2 (LATS1/2) by the complex MTS1/2 and SAV1 prevents YAP and TAZ’s phosphorylation and promotes their entry into the nucleus. Inside the nucleus, YAP/TAZ stimulates downstream growth factors and stimulators that result in primordial follicle activation. From a therapeutic standpoint, putative pharmacologic approaches aimed at blocking PFA and protecting the ovarian reserve include mTOR and FOXO3, which can be targeted with small molecule inhibitors, as well as exogenous delivery of AMH, which sequesters FOXO3 in the nucleus. Conversely, PTEN-specific inhibitors, as well as mechanical activation of the Hippo pathway, have been trialed as therapeutic strategies for PFA, but true therapeutic successes have not yet been realized. Figure created with BioRender.com.