The Interconnections Between Somatic and Ovarian Aging in Murine Models

Abstract

The mammalian female is born with a limited ovarian reserve of primordial follicles. These primordial follicles are slowly activated throughout the reproductive lifecycle, thereby determining lifecycle length. Once primordial follicles are exhausted, women undergo menopause, which is associated with several metabolic perturbations and a higher mortality risk. Long before exhaustion of the reserve, females experience severe declines in fertility and health. As such, significant efforts have been made to unravel the mechanisms that promote ovarian aging and insufficiency. In this review, we explain how long-living murine models can provide insights in the regulation of ovarian aging. There is now overwhelming evidence that most life-span-extending strategies, and long-living mutant models simultaneously delay ovarian aging. Therefore, it appears that the same mechanisms that regulate somatic aging may also be modulating ovarian aging and germ cell exhaustion. We explore several potential contributing mechanisms including insulin resistance, inflammation, and DNA damage-all of which are hallmarks of cellular aging throughout the body including the ovary. These findings are in alignment with the disposable soma theory of aging, which dictates a trade-off between growth, reproduction, and DNA repair. Therefore, delaying ovarian aging will not only increase the fertility window of middle age females, but may also actively prevent menopausal-related decline in systemic health parameters, compressing the period of morbidity in mid-to-late life in females.

Keywords: Calorie restriction; Fertility; Follicle; IGF; Menopause.

Figure 1.

Schematic representation of pathways that regulate primordial follicle activation, which are simultaneously regulated by life-extending therapies. Calorie restriction (CR) and rapamycin inhibit the mTOR pathway in granulosa cells, which in turns regulates oocyte activation of the Pi3K/Akt/FOXO3a pathway. FOXO3a phosphorylation results in its nuclear extrusion and activation of the primordial follicle. Reduced IGF-I and insulin signaling in metformin-treated mice, GH-deficient Ames dwarf, and GH receptor knockout (GHRKO) mice also contribute to reduced Pi3K/Akt activation and reduced FOXO3a phosphorylation, maintaining primordial follicle in the quiescent stage.