Impact of Ovarian Aging in Reproduction: From Telomeres and Mice Models to Ovarian Rejuvenation

Abstract

The trend in our society to delay procreation increases the difficulty to conceive spontaneously. Thus, there is a growing need to use assisted reproduction technologies (ART) to form a family. With advanced maternal age, ovaries not only produce a lower number of oocytes after ovarian stimulation but also a lower quality-mainly aneuploidies-requiring further complex analysis to avoid complications during implantation and pregnancy. Although there are different options to have a child at advanced maternal age (like donor eggs), this is not the preferred choice for most patients. Unless women had cryopreserved their eggs at a younger age, reproductive medicine should try to optimize their opportunities to become pregnant with their own oocytes, when chances of success are reasonable. Aging has many causes, but telomere attrition is ultimately one of the main pathways involved in this process. Several reports link telomere biology and reproduction, but the molecular reasons for the rapid loss of ovarian function at middle age are still elusive. This review will focus on the knowledge acquired during the last years about ovarian aging and disease, both in mouse models of reproductive senescence and in humans with ovarian failure, and the implication of telomeres in this process. In addition, the review will discuss recent results on ovarian rejuvenation, achieved with stem cell therapies that are currently under study, or ovarian reactivation by tissue fragmentation and the attempts to generate oocytes in vitro.

Keywords: Telomeres; iPS cells; ovary; reproduction; stem cells.

Figure 1

Ovarian aging. Molecular mechanisms that lead to aneuploidy. The top panel represents the follicular decay in the ovary during aging. At 16/20 weeks of fetal development, follicular quantity is maximum. Due to atresia, the number of follicles falls from 7 million to 1 million at birth. At the time of menarche, women have 300,000 to 400,000 follicles, which are recruited cyclically until menopause (1,000 follicles). The lower panel depicts the molecular mechanisms that lead to aneuploidies in the aged ovary. External factors can aggravate molecular alterations promoting aneuploidies. Chromosomes are represented in blue, telomeres in orange, spindles in dark blue and chiasmas are drawn in red. Cohesins are represented in black line and altered cohesins in broken lines.

Figure 2

Telomeres and follicle dynamics in the ovary. Telomere length decreases as primordial follicles mature to ovulatory follicles. The aged ovary (also prematurely aged) presents a decrease in the total number of follicles. Different genetic causes can be involved in premature ovarian aging. Primordial follicles that remain in the menopause ovaries do not show the ability to resume their development, but upon stem cell therapy (SCT), they are reactivated for maturation and ovulation.

Figure 3

Methods for the in vitro production of germ cells. Several strategies, from spontaneous differentiation to the supplementation of the culture media, have been used to generate PGC like cells. Yamashiro and colleagues have made a further step to build xenogeneic ovaries. Orange dots indicates studies carried out with hESC, and blue dots specify studies with hiPSC. BMPs: Bone Morphogenetic Proteins; DAZL: Deleted in Azoospermia-like; GSK3: Glycogen Synthase Kinase 3; JNK: c-Jun N-terminal Kinase; MAPK: Mitogen-Activated Protein Kinase iMeLCs: incipient Mesoderm-Like Cells; hPGCLCs: human Primordial Germ Cell like Cells.