Research Article: Can ovarian aging be delayed by pharmacological strategies?

Date Published: January 31, 2019

Publisher: Impact Journals

Author(s): Jinjin Zhang, Qian Chen, Dingfu Du, Tong Wu, Jingyi Wen, Meng Wu, Yan Zhang, Wei Yan, Su Zhou, Yan Li, Yan Jin, Aiyue Luo, Shixuan Wang.


Aging has been regarded as a treatable condition, and delaying aging could prevent some diseases. Ovarian aging, a special type of organ senescence, is the earliest-aging organ, as ovaries exhibit an accelerated rate of aging with characteristics of gradual declines in ovarian follicle quantity and quality since birth, compared to other organs. Ovarian aging is considered as the pacemaker of female body aging, which drives the aging of multiple organs of the body. Hence, anti-ovarian aging has become a research topic broadly interesting to both biomedical scientists and pharmaceutical industry. A marked progress has been made in exploration of possible anti-ovarian agents or approaches, such as calorie restriction mimetics, antioxidants, autophagy inducers etc., over the past years. This review is attempted to discuss recent advances in the area of anti-ovarian aging pharmacology and to offer new insights into our better understanding of molecular mechanisms underlying ovarian aging, which might be informative for future prevention and treatment of ovarian aging and its related diseases.

Partial Text

As human longevity has been significantly improved, aging-related problems are markedly increasing. It is predicted that the number of people over 60 years old by 2050 will be five times than that of 1950 [1]. As the world’s most populous country, China entered into the aging society 13 years ago. According to the previous population census data, the aged population in China has exceeded world average in size, growth rate and proportion. The average lifespan of Chinese people will increase to 81.9 by 2040 [2]. The primary problem of the aging population is the serious detriments caused by the aging of various organs and the decline of their functions. Organ senescence is often highly associated with a variety of diseases, such as cancer, diabetes, cardiovascular disease and obesity. The occurrence and development of these diseases lead to the decrease of the life quality and increase of the proportion of people who live with the diseases. However, fortunately, aging has been shown to be an improvable condition, and delaying aging would be a way to prevent and treat diseases [3].

The free radical theory of aging has been a classical and the most influential theory in the field of aging, since was first postulated by Denham Harman in the middle of the last century. Oxidative stress leads to changes in the ovarian microenvironment, and these changes account for ovarian senescence and the decrease of ovarian reserve [13, 14]. During the senescence process, the level of reactive oxygen species (ROS) increases, while the expression and activity of oxidative defense system related enzymes are significantly reduced. These all lead to a wide range of oxidative damage, including the cell membrane lipid peroxidation, protein oxidation and enzymes inactivation and DNA damage [15-21]. Also, ROS in follicle oocytes, corpus luteum cells and follicular fluid of elderly women who receive assisted reproductive technology (ART) increases significantly, while antioxidant enzymes decreased; this causes the low success rate of ART [22-24]. It has been shown that oxidative damage products of DNA, protein and lipid in ovarian stromal cells increase markedly with age [25]. Clinical studies have also shown that higher ROS levels exist in unfertilized eggs or low-quality embryos [23, 26]. All these studies indicate that oxidative stress plays an important role in ovarian aging. Therefore, antioxidants have been used to prevent ovarian aging

Over the past years, it has been shown that improvement of cellular and physiological metabolisms could also prevent ovarian aging. One of the approaches is caloric restriction (CR), also known as dietary restriction (DR). CR by limiting the daily diet to 25% – 50% of the normal diet ensures that the body receives sufficient nutrients without malnutrition. The ability of CR to extend lifespan and delay aging have drawn noteworthy researchers’ attention since the original work was reported by McCay and colleagues eighty years ago [47]. Since then, a number of studies have confirmed that CR is the most effective means to postpone the aging of the body and extend lifespan of many organisms. Thereby it is the most inspiring discovery in the aging field [48]. CR can not only prolong the average life expectancy of rodents, but also improve the fertility and prolong the reproductive life [49], by delaying the process of ovarian aging. Although CR is so effective, its implementation is not so easy in real life practice. Thus, alternative substances have been looked for to mimic the CR effects as further detailed below. Also, the main signaling pathways that mediate the CR effects and the most promising pharmacological substances that modulate these pathways and mimic the CR effects will be discussed in the following sections.

Over the past few years, a series of epigenetic regulators have been identified, such as small molecule inhibitors of DNA methylation and histone acetyltransferases or non-coding RNAs. These regulators have the potency of treating cancer, myelodysplastic syndrome and neural degeneration [74]. Epigenetic regulations are involved in the changes of gene or protein expressions without altering DNA sequence. Epigenetic modifications are reversible. This characteristic makes small molecule epigenetic regulators attractive as aging intervention agents [75]. In the past 20 years, the role of histone and genomic epigenetic modification regulation in ovarian aging has been gradually recognized, and has become a research hotspot in this field. Abnormal regulation of the related gene expression can lead to ovarian cell apoptosis and accelerated aging, which in turn can accelerate the aging of the ovaries [76].

Autophagy is an intracellular bulk degradation system. During the process, part of the cytoplasm is enveloped in the autophagosomes, then fused and degraded by lysosomes [82]. Several clinical trials are exploring autophagy as a therapeutic target as it plays vital roles in age-associated diseases [83].

Studies have indicated that telomere length are strongly associated with lifespan [91]. Reports on the role of the telomere and telomerase in female ovaries are still limited. Positive correlations were found between female reproductive life span, being widely accepted as ovarian reserve, and the telomere length [92]. The telomere length, serving as a biological clock, may play vital roles in limited ovarian lifespan, particularly at the cellular level [93]. Another study suggests that telomere length and telomerase activity are associated with primary ovarian insufficiency, which may indicate the progression of ovarian decline [94]. Compared to oocytes from young females, telomere length from the aged was remarkably shorter [95].

A variety of autoimmune antibodies, such as anti-nuclear antibodies and anti-ovarian tissue antibodies, have been found to be related to POF [124]. Therefore, immunotherapy is of certain significance to patients with POF. In theory, immunomodulators are effective against autoimmune POF. It has been reported that patients treated with clinical immunosuppressive agents, such as glucocorticoid can resume ovulation and pregnancy, but the effect is not so clear. Administration of the immunosuppressant diethyleneethanol and freund’s adjuvant during prepubertal provided sufficient anti-GnRH for calfs to delay the onset of puberty for 112 days [125]. Treatment with corticosteroids and testosterone can significantly improve the general condition of POF mice models by reducing the levels of lymphocytes, immune globulins, and related antibodies [126]. However, the clinical application of glucocorticoid has many adverse reactions and the long-term curative effect need to be followed-up. It was shown that the effect of androgens on autoimmune POF is significant, and their side effects are relatively less significant, so the patient’s compliance is better. Androgens may inhibit the immune system by regulating the hypothalamic-pituitary-gonad axis [127]. Since the optimal treatment time and duration of POF with glucocorticoid or androgen have not been determined, further studies are needed.

Traditional Chinese medicine holds that symptoms of perimenopausal women are related to the imbalance in the body of Yin and Yang, disturbance of viscera. Deficiency of the kidney energy is the fundamental cause, so it should be given priority to tonifying kidney and spleen, accompanied by protecting liver and calming nerves. Some can achieve satisfactory curative effect, such as Bushen Huoxue Recipe, Liu Wei Di Huang Jia Jian, Zuo Gui Wan Jia Jian and so on. The mechanisms of traditional Chinese medicine are complicated as the pharmacological ingredients are complex. Recent years, several studies have found that traditional Chinese medicine may regulate women nervous-endocrine system and immune system by removing free radicals, improving ovarian microcirculation and reducing cell apoptosis, and then delay ovarian aging [128,129]. The experiments of animals have revealed that, with age, the levels of nerve growth factor and norepinephrine (NE) in the ovaries, and the increase of sympathetic nervous activity were related to reproductive ability of rats. Electric acupuncture can promote the recovery of ovulation and increase fertility of older rats by reducing the level of NGF in ovary or blocking the activity of NE [130].

Nowadays, many young women choose to delay or avoid marriage and/or giving a birth owing to the accelerated pace of our society and various pressures from work and family. However, their ovarian reserves strictly define their best age of fertility, since a sharp decline in ovarian functions is observed after age 35, which defines a high-risk period. After 35 years-old, the rate of pregnancy markedly decreases while miscarriage and premature birth for a woman increase significantly. Consequently, the health of maternal females and child is threatened post this stage. Therefore, more systematic and careful studies of the female reproductive system, especially the mechanisms of ovarian aging and the effective delay strategies, are of great importance. Current research on ovarian aging mechanisms, such as primordial follicles activation and follicular atresia, have provided new insights into our better understanding of molecular mechanisms underlying ovarian aging delay. This rich information has been useful for development of anti-ovarian aging therapies as described above. Upon our review, some drugs may have several pharmacological actions and work through a variety of pathways (Figure 1). We believe that, upon future establishments of effective therapies, it will no longer be a fantasy to extend women’s reproductive life and delay menopause with the development of medical advances in this specific area.




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