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 lifespan-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.

Sex Differences in Myocardial and Vascular Aging

“…111,135 Although ovarian aging can promote the development of subclinical and then clinical myocardial and vascular disease, cardiovascular risk may also predispose to ovarian aging (eg, atherosclerosis involving microvasculature of the ovaries), 136 and age-related somatic mutations can affect both. 137,138 Notably, additional approaches to clarifying hormonerelated cardiovascular risk can involve examining the relative effects of sex-determining hormones in genderaffirming hormone therapy within transgender populations. Early data suggest that transgender females experience increased thromboembolic disease compared to cisgender women, whereas transgender males develop lipid profiles reflecting their gender rather than natal sex potentially without adverse cardiovascular risk.…”

“…111,135 Although ovarian aging can promote the development of subclinical and then clinical myocardial and vascular disease, cardiovascular risk may also predispose to ovarian aging (eg, atherosclerosis involving microvasculature of the ovaries), 136 and age-related somatic mutations can affect both. 137,138…”

Growth Hormone and Aging: New Findings

“…The results indicated that the slower rate of primordial follicle activation (increased ovarian reserve) in these animals is associated with reduced accumulation of DNA damage in the oocytes and reduced macrophage infiltration of the ovaries. These studies add to the evidence for association of reduced gonadal aging with slower somatic aging in these mutants [ 95 ], and identify likely mechanisms of this association.…”

A single-cell atlas of the aging murine ovary

“…It is also noteworthy that TCs upregulate cell proliferation pathways (e.g. mTOR), which increase with aging 105 , but more importantly have been linked to the activation of primordial follicles 106 .…”