The process of ovarian aging: it is not just about oocytes and granulosa cells

Abstract

Ovarian age is classically considered the main cause of female reproductive infertility. In women, the process proceeds as an ongoing decline in the primordial follicle stockpile and it is associated with reduced fertility in the mid-thirties, irregular menstruation from the mid-forties, cessation of fertility, and, eventually, menopause in the early fifties. Reproductive aging is historically associated with changes in oocyte quantity and quality. However, besides the oocyte, other cellular as well as environmental factors have been the focus of more recent investigations suggesting that ovarian decay is a complex and multifaceted process. Among these factors, we will consider mitochondria and oxidative stress as related to nutrition, changes in extracellular matrix molecules, and the associated ovarian stromal compartment where immune cells of both the native and adaptive systems seem to play an important role. Understanding such processes is crucial to design treatment strategies to slow down ovarian aging and consequently prolong reproductive lifespan and, more to this, alleviaingt side effects of menopause on the musculoskeletal, cardiovascular, and nervous systems.

Keywords: Aging; Extracellular matrix; Follicular dynamic; Immune cells; Inflammation; Macrophages; Matrisome; Mitochondria; Ovary; Oxidative stress.

Fig. 1

Schematic depicting the factors that together with cell and tissue compartments are involved in the onset and/or progression of ovarian aging. For details, see the text. ECM extracellular matrix, PMFs primordial follicles, ROS reactive oxygen species

Fig. 2

Macrophage fusion into multinucleated giant cells is a hallmark of the ovarian stroma during reproductive aging. In these micrographs, two serial sections from an ovary of a 9-month-old 129/Sv female mouse stained with hematoxylin/eosin (A) and with PAS/Alcian (B) are shown (scale bar = 200 μm). (i), (ii), and (iii) are magnifications of three different areas in A and B, showing giant cells that stain light brown in hematoxylin/eosin (yellow dashed line) and dark red/violet in PAS/Alcian (red dashed line) (scale bar = 25 μm) (our unpublished observations)