A recent study published in the Journal of Nature Aging has explored emerging strategies to improve fertility and reduce reproductive aging, specifically in the context of advanced reproductive age. The study summarizes findings from research that addresses the challenges faced by individuals attempting conception later in life, particularly in women over 35 and men over 40.
The trend of delayed parenthood has led to an increasing number of individuals attempting to conceive in their late 30s and early 40s, a time when fertility naturally declines. Women’s fertility typically starts to decrease after the age of 30, with a steep drop-off in pregnancy rates between 30 and 40. By the age of 45, miscarriage rates rise dramatically, reaching over 90%.
Male fertility also declines with age, though the effects are more gradual. Reduced conception rates and a higher risk of miscarriage are observed in fathers over 40. Despite the widespread belief that supplements and assisted reproductive technologies (ART) can restore fertility, evidence supporting these claims is limited, particularly in humans. The study emphasizes the need for robust clinical trials to validate these interventions, especially for individuals in advanced reproductive age.
Aging ovaries are marked by excessive collagen deposits and inflammation, known as ovarian fibrosis. This condition restricts follicle growth and impairs ovulation, contributing significantly to fertility decline. Women are born with a finite number of oocytes (egg cells), which deplete over time due to apoptosis (programmed cell death) and ovulation. The quality of the remaining oocytes also deteriorates, primarily due to mitochondrial dysfunction and chromosomal abnormalities.
With advancing age, mitochondrial activity in oocytes decreases, leading to impaired energy production, increased oxidative stress, and defective meiotic division. This results in higher rates of chromosomal missegregation during meiosis, leading to aneuploidy (abnormal chromosome numbers) and lower chances of successful pregnancies.
Another key factor in fertility decline is ovarian fibrosis. This condition causes excessive collagen deposition in the ovarian stroma, leading to gonadotropin resistance and further impairment of reproductive potential. As a result, fertility declines rapidly for women in their mid-30s, and natural conception becomes rare by the mid-40s.
While male fertility declines more gradually than female fertility, aging still leads to significant changes in sperm quality and testicular function. Sperm motility and morphology deteriorate with age, and DNA damage in sperm increases, which in turn raises the risk of chromosomal abnormalities. This damage negatively affects embryo quality and reduces the likelihood of successful implantation.
Testosterone levels also decline with age, impacting spermatogenesis, the process by which sperm are produced. Additionally, oxidative stress plays a major role in male reproductive aging, causing cellular damage to spermatozoa and Leydig cells, which are essential for testosterone production. This leads to reduced fertility and an increased risk of adverse pregnancy outcomes, even when conception is achieved.
A variety of supplements are marketed to improve fertility, but the clinical evidence supporting their effectiveness is limited. Some promising candidates include Coenzyme Q10 (CoQ10), melatonin, and Nicotinamide Adenine Dinucleotide (NAD+) boosters such as Nicotinamide Mononucleotide (NMN) and Nicotinamide Riboside (NR). CoQ10 helps improve mitochondrial function, reducing oxidative stress and enhancing oocyte quality. Melatonin, a powerful antioxidant, has been shown to improve oocyte maturation and embryo development in preclinical models.
NAD+ boosters help restore mitochondrial activity, which in turn increases ovulation and reduces 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, these findings need large-scale human clinical trials for validation.
Pharmaceutical interventions targeting reproductive aging have shown positive results in preclinical studies. Metformin and rapamycin, known for their roles in regulating cellular metabolism, have been shown to delay follicular depletion and improve mitochondrial function. The Gonadotropin-Releasing Hormone (GnRH) antagonist cetrorelix has been found to enhance follicle growth and ovulation in aged mice. BGP-15, a compound with antioxidant properties, has also shown promise in reducing ovarian fibrosis and restoring mitochondrial function in oocytes.
ART, including in vitro fertilization (IVF) and intracytoplasmic sperm injection (ICSI), is commonly used to treat individuals with age-related infertility. However, ART success rates decline significantly with age, mainly due to poor oocyte quality and higher rates of aneuploidy. Emerging techniques, such as Mitochondrial Replacement Therapy (MRT), aim to address these challenges by replacing defective oocyte mitochondria with healthy donor mitochondria, potentially rejuvenating egg quality. Although MRT shows promise, its widespread clinical use is hindered by ethical concerns and the need for further research on its long-term safety.
In Vitro Gametogenesis (IVG), a process that reprograms somatic cells to create new oocytes, is another promising technology. While both MRT and IVG are still experimental, they offer hope for overcoming age-related reproductive decline in the future.
Therapeutic strategies for male reproductive aging are still developing but remain crucial. Antioxidants such as idebenone and melatonin show promise in reducing oxidative stress and improving sperm motility. Idebenone, a CoQ10 analog, enhances mitochondrial function and reduces ROS levels in sperm. Preclinical studies suggest that these interventions can improve embryo quality and implantation rates.
Hormonal therapies targeting testosterone production are also being explored. Treatments such as melatonin and sildenafil aim to improve Leydig cell function, restore testosterone levels, and enhance spermatogenesis.
The study underscores the urgent need to address reproductive aging as delayed parenthood becomes more 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 clinical trials, especially for individuals of advanced reproductive age.
The authors also emphasize the need for a cautious approach to experimental technologies like MRT and IVG, ensuring that ethical considerations and the long-term safety of offspring are thoroughly addressed.
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