Reproductive aging: biological pathways and potential interventive strategies

With the widespread participation of women in work, postponing pregnancy has become an increasing trend for professional women in many countries. However, this is linked with increased reproductive problems. As women age, the number and quality of oocytes in the ovary decrease (Sherman et al., 1994; Broekmans et al., 2004), accompanied by the impaired endocrine function of the ovary (Fitzgerald et al., 1998) and other phenotypes (Table 1). A number of studies have shown that compared with young women, women over the age of 35 have significantly reduced ovarian function and have a significantly increased probability of infertility, miscarriage, premature delivery, pregnancy complications, and birth defects (Crawford and Steiner, 2015; Miller et al., 2022). Around the age of 45–55, women enter menopause and ultimately lose their fertility. This age-related decline in fertility is known as reproductive aging.

The limited follicle pool in the ovary established in early life and its depletion rate determine reproductive lifespan in females. In contrast, sperms are continuously produced throughout adulthood in males. Such difference makes women more vulnerable to reproductive aging in most cases. However, a gradual decrease in male reproductive function with age is also a conserved phenomenon observed in mammals, birds, and flies (Fricke and Koppik, 2019). Studies in males have noted that aging results in smaller testes (Mahmoud et al., 2003), a significant decrease in the average number of Sertoli cells (Johnson et al., 1984), and lower testosterone levels (Pines, 2011). A retrospective analysis of semen parameters (e.g., ejaculate volume, sperm concentration, and sperm motility) in over 5000 men aged 16–72 years suggests semen parameters start to decline after 34 years of age (Stone et al., 2013). In addition, the probabilities of miscarriage (Belloc et al., 2008), preterm birth (Zhu et al., 2005), and various birth defects (McIntosh et al., 1995) are significantly increased among the offspring of aged males. A meta-analysis suggests that the offspring of older fathers (≥30 years old) also show a significantly higher risk of schizophrenia than those of younger fathers (25–29 years old) (Miller et al., 2011).

This review summarizes the phenotypes, causes, and interventive strategies of reproductive aging for both females and males. The recognized causes of reproductive aging include oxidative stress, mitochondrial dysfunction, telomere shortening, chromosome errors, and gene mutations (Fig. 1). These factors can impair gamete quality and quantity through various biological pathways. Although practical and effective methods to deal with reproductive aging remain to be developed, some interventive strategies have been tested in animal models and in vitro systems.

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