Promising therapies like mitochondrial treatments and experimental technologies offer hope for overcoming fertility challenges as parenthood is increasingly delayed.
Study: Emerging therapeutic strategies to mitigate female and male reproductive aging. Image Credit: BGStock72 / Shutterstock
In a recent study published in the journal Nature Aging, a group of authors explored and summarized emerging experimental strategies and methodologies to reduce reproductive aging and improve fertility in the context of advanced reproductive age.
Background
The global trend of delayed parenthood has resulted in an increasing number of individuals attempting to conceive in their late 30s and 40s when fertility naturally declines. Female fertility begins to decrease significantly after age 30, with an exponential drop in pregnancy rates between 30 and 40 years and miscarriage rates exceeding 90% by age 45.
Male fertility also declines, with reduced conception rates and heightened miscarriage risk when fathers are over 40. Despite the public perception that supplements and assisted reproductive technologies can fully restore fertility, evidence supporting their effectiveness is limited, particularly in humans. The authors emphasize that robust clinical trials validating these interventions are urgently needed, especially for individuals of advanced reproductive age.
Mechanisms of reproductive aging
Female reproductive aging
Several interconnected factors drive the decline in female fertility. One of the most significant is the progressive depletion of ovarian follicles. Women are born with a finite number of oocytes (egg cells), and this reserve diminishes over time due to apoptosis and ovulation. Moreover, the quality of the remaining oocytes declines, primarily due to mitochondrial dysfunction and chromosomal abnormalities.
With age, mitochondrial activity in oocytes decreases, leading to impaired energy production, increased oxidative stress, and defective meiotic division. Chromosomal missegregation during meiosis becomes more frequent, resulting in higher rates of meiotic aneuploidy (abnormal chromosome numbers) and lower chances of successful pregnancies.
Another key factor is ovarian fibrosis, a condition characterized by excessive collagen deposition and inflammation in the ovarian stroma. This fibrotic environment disrupts follicular growth and contributes to gonadotropin resistance, further impairing reproductive potential. Collectively, these changes culminate in a steep decline in fertility for women in their mid-30s, with natural conception becoming rare by the mid-40s.
Male reproductive aging
Although male fertility declines more gradually, aging induces significant changes in sperm quality and testicular function. Sperm motility and morphology deteriorate with age, and the accumulation of DNA damage in sperm increases the risk of chromosomal abnormalities. This DNA damage is associated with poorer embryo quality and reduced implantation success. Testosterone levels also decline, negatively affecting spermatogenesis.
Oxidative stress plays a major role in male reproductive aging, causing cellular damage in spermatozoa and Leydig cells, which are essential for testosterone production. These changes result in reduced fertility and an increased risk of adverse pregnancy outcomes, even when conception occurs.
Therapeutic interventions for female reproductive aging
A range of supplements is marketed to improve fertility, but strong clinical evidence for their efficacy is lacking. Some promising candidates include Coenzyme Q10 (CoQ10), melatonin, and Nicotinamide Adenine Dinucleotide (NAD+) boosters like Nicotinamide Mononucleotide (NMN) and Nicotinamide Riboside (NR). CoQ10 improves mitochondrial function, reducing oxidative stress and enhancing oocyte quality.
Melatonin, a potent antioxidant, has been shown to improve oocyte maturation and embryo development in preclinical models. NAD+ boosters restore mitochondrial activity, increasing ovulation and reducing oxidative damage in aged oocytes.
Another promising compound is spermidine, a cellular metabolite that reduces reactive oxygen species (ROS) and improves spindle alignment in oocytes. However, despite their potential in animal studies, the authors stress that large-scale human clinical trials are required to validate these findings and determine their true effectiveness.
Pharmaceutical approaches
Pharmaceutical interventions targeting reproductive aging have shown encouraging results in preclinical studies. Metformin and rapamycin, known for their roles in regulating cellular metabolism, have demonstrated efficacy in delaying follicular depletion and improving mitochondrial function. The Gonadotropin-Releasing Hormone (GnRH) antagonist cetrorelix has been found to enhance follicle growth and ovulation in aged mice. Additionally, BGP-15, a compound with antioxidant properties, has shown promise in reducing ovarian fibrosis and restoring mitochondrial bioenergetics in oocytes.
Assisted reproductive technologies (ART)
ART, such as in vitro fertilization (IVF) and intracytoplasmic sperm injection (ICSI), remains a cornerstone for individuals with age-related infertility. However, the success of ART decreases significantly with age due to poor oocyte quality and higher rates of aneuploidy. Emerging techniques aim to address these challenges. Mitochondrial Replacement Therapy (MRT) replaces defective oocyte mitochondria with healthy donor mitochondria, potentially rejuvenating egg quality. While MRT shows promise, ethical considerations and long-term safety must be addressed before widespread clinical use.
In Vitro Gametogenesis (IVG) is another promising technology that reprograms somatic cells to create new oocytes. While MRT and IVG are still experimental, they offer hope for overcoming age-related reproductive decline in the future.
Addressing male reproductive aging
Therapeutic strategies for male reproductive aging are less developed but equally important. Antioxidants like idebenone and melatonin have shown potential in reducing oxidative stress and improving sperm motility. Idebenone, a CoQ10 analog, enhances mitochondrial function and reduces ROS levels in sperm. Preclinical studies indicate that these interventions can enhance embryo quality and implantation rates.
Hormonal therapies targeting testosterone production are also under investigation. Treatments such as melatonin and sildenafil improve Leydig cell function, restoring testosterone levels and enhancing spermatogenesis.
Conclusions
To summarize, the study highlights the urgent need to address reproductive aging as delayed parenthood becomes increasingly common. Despite promising preclinical evidence, effective clinical interventions for reducing age-related fertility decline remain limited. Emerging therapeutic strategies, including antioxidants, mitochondrial therapies, and advanced reproductive technologies, show potential but require rigorous validation through well-designed clinical trials, particularly for individuals of advanced reproductive age.
The authors also emphasize the need for a cautious approach to emerging technologies like MRT and IVG, ensuring that ethical concerns and long-term safety for offspring are thoroughly addressed.