Unraveling female reproductive senescence to enhance healthy longevity

Abstract

In a society where women often want successful careers and equal opportunities to men, the early nature of ovarian aging often forces women to make difficult life choices between career and family development. Fertility in women begins to decline after the age of 37 years and it is rare for pregnancies to occur after 45. This reproductive decline in women is inevitable and culminates in menopause, which is a major driver of age-related diseases. In a world where biomedical advances are leading to modifiable biological outcomes, it is time to focus on mitigating female reproductive senescence to maintain fertility and preserve age-related hormonal functions, with the goal of providing increased life choices and enhancing healthspan. To date, reproductive longevity research remains an understudied field. More needs to be done to unravel the biology of the ovarian follicles, which are the functional units of reproductive lifespan and are comprised of cell types including the oocyte (female gamete) and a group of specialized supporting somatic cells. Biological attempts to maintain the quality and quantity of follicles in animal models through manipulating pathways involved in aging can potentially prolong female reproductive lifespan and healthspan. Here, we summarize the molecular events driving ovarian aging and menopause and the interventional strategies to offset these events. Developing solutions to female reproductive senescence will open doors to discover ways to enhance true healthy longevity for both men and women.

Fig. 1. Ovarian follicles: the functional units of ovary for reproductive lifespan.

Along the hypothalamic-pituitary-ovarian axis, the hypothalamus secretes gonadotropin-releasing hormone (GnRH) which travels down to stimulate the pituitary gland which in turn secretes follicle stimulating hormone (FSH) and luteinizing hormone (LH). FSH and LH reach the ovaries in the bloodstream to signal the development of ovarian follicles to produce estrogen and progesterone during the follicular and luteal phase of the menstrual cycle. Estrogen rises steadily via a positive feedback loop to result in LH surge from the anterior pituitary gland, leading to ovulation. In a “young ovary”, in each cycle, several resting primordial follicles with immature ova are activated. They develop during folliculogenesis and normally only one ovarian follicle will be “selected” as the dominant follicle and eventually releases the mature ovum (ovulation). The ruptured follicle then transforms into the corpus luteum and degenerates to form the corpus albicans if no implantation occurred. Follicular supporting cells such as the granulosa and theca cells, and the corpus luteum provide endocrine support necessary for ovulation, preparation for implantation and pregnancy, with the release of estrogen and progesterone (symbolized as blue dots). As a woman ages, the finite pool of primordial follicles depletes during each ovulatory cycle and along with constant follicular atresia, results in the degeneration and loss of ovarian follicles and their oocytes, becoming the “aged ovary”. The “aged ovary” shrinks due to age-related fibrosis and releases little estrogen and progesterone due to the extremely low number of viable ovarian follicles.

Fig. 2. Post-reproductive lifespan across species.

The human female is one of a few selected species of mammals with a significant post-reproductive lifespan. The significance of menopause is extensively being debated on whether it is a vestigial evolutionary inheritance or has crucial implication in conferring evolutionary survival of the fittest to our early days’ ancestors as been reproduced from Ellis et al. (Open access license: https://creativecommons.org/licenses/by/4.0/. Image legend has been shifted to the top left of the image from the original image).

Fig. 3. The post-reproductive lifespan is a result of a hypoestrogenic environment that has pleiotropic health effects.

However, the biological significance of the post-reproductive lifespan in women remains unknown.