In our previous article, we explored the use and constraints of existing clinical approaches to mitigate the two primary impacts of ovarian aging – assisted reproductive technology (ART) for age-related infertility and hormone replacement therapy (HRT) for countering the loss of health-protective effects from sex hormones.
However, both methods fail to address the underlying cause of ovarian aging and come with their own side effects or complications. To develop new treatment strategies against ovarian aging, research has used various longevity-enhancing techniques exhibiting life-extending effects in animal models. The goal is to extend both reproductive years and overall health.
This research covers a range of molecules and compounds focusing on specific pathways. Such compounds include antioxidants, mitochondrial boosters, polyphenol derivatives, components of specific metabolic pathways, isoflavones, and plant-derived compounds. Additionally, commonly used medications, such as metformin and, more recently, inhibitors of the mammalian target of rapamycin (mTOR), have been closely examined.
This is the third article in our three-part “Fertility in Focus” series, where we explore the mechanisms driving reproductive aging, look at the latest treatments, debunk common misconceptions, and examine promising drug candidates and lifestyle interventions.
- Understanding Reproductive Aging
- Reproductive Treatments and Common Misconceptions
- Promising Drug Candidates and Lifestyle Strategies
In the following sections, we will explore some of these promising drug candidates and their respective positive outcomes and limitations.
Drug Candidates Targeting Female Reproductive Aging
As previously discussed, oxidative stress has been suggested as a contributing factor to ovarian aging. Consequently, compounds with antioxidant properties, such as Vitamins C and E, coenzyme Q10 (CoQ10), N-acetyl-L-cysteine (NAC), and certain flavonoids, have been evaluated in rodent models. Antioxidants have shown potential pro-longevity effects in the female reproductive system, leading to varying degrees of improvement in primordial and healthy ovarian follicle counts, preservation of ovarian reserve and ovulatory cycles, and increased offspring number. (Abdollahifar et al. 2019) (Al‐Khudairy et al. 2017) (Bjelakovic et al. 2012)(Lee et al. 2018) (Liu et al. 2012) (Liu et al. 2013) (Ochiai et al. 2019) (Xian et al. 2018)
Yet, antioxidants have also been linked to adverse effects, including disruptions to ovarian and uterine functions with pharmacological doses of Vitamins C and E (Tarin et al., 2002). Furthermore, only a limited number of antioxidants have undergone clinical study in women with age-related assisted reproductive technology (ART) failure, and the results have proven to be highly inconsistent. Surprisingly, in some of these investigations, oral supplementation of certain antioxidants like resveratrol was even associated with reduced pregnancy rates (Ochiai et al., 2019), contrary to anticipated outcomes. It’s worth noting that many of these antioxidants exhibit multiple actions associated with the aging process, complicating the interpretation of their effects. Hence, the effectiveness of antioxidants is not uniform, and both the dosage and treatment duration necessitate further optimization to ensure their safe and effective usage.
We cover the rarely discussed topic of antioxidants and how most of them don’t slow down overall aging in this article.
2. Hormones (other than estrogens and progestogens)
In addition to estrogens and progestogens, which directly address hormone loss resulting from ovarian aging, research has also explored the use of other hormones. Some hormones aim to amplify or imitate estrogen’s effects, such as dehydroepiandrosterone (DHEA), a precursor to estrogen in peripheral tissue, and genistein, an isoflavone naturally present in products possessing antioxidative and phytoestrogenic (estrogen-like) properties.
Based on multiple previous clinical studies, DHEA supplementation for 2-3 months has shown potential in enhancing egg and embryo quality for women with diminished ovarian reserve or those of advanced age. DHEA is a promising candidate for “rejuvenating” ovaries in IVF procedures. However, while several studies have reported these improvements, most have not found a significant increase in pregnancy rates, and a comprehensive assessment of the subjects’ overall health was lacking. (Zhang et al., 2015) (Yuan et al., 2023) Larger randomized control trials are necessary to establish the true efficacy of DHEA.
Genistein, recognized as a major phytoestrogen due to its capacity to interact with estrogen receptors, exhibits structural and functional similarity to estradiol. In rodent studies, genistein has been observed to notably slow follicular development, resulting in enhanced ovarian reserve and maintenance of ovulatory cycles. (Zhuang et al., 2010) However, no conclusive pregnancy outcomes have been reported.
Another hormone of interest, melatonin, known for its sleep-promoting and antioxidant properties, has displayed promising results in extending reproductive lifespan and/or improving ovarian markers in both animal and clinical studies. Although melatonin has consistently demonstrated positive effects on egg quality and quantity in rodents, clinical studies in women with infertility or a history of IVF failures have yielded conflicting results. (Batioglu, Sahin et al. 2012) (Bellipanni et al. 2001) (Chen et al. 2010) (Espino et al. 2019) (Fernández et al. 2013) (Fernando et al. 2018) (Gleicher et al. 2010)(Meredith et al. 2000) (Narkwichean et al. 2013) (Song et al. 2016) (Takasaki et al. 2003)(Tamura et al. 2017) In addition, the wide-ranging metabolic and physiological impacts of melatonin on the body could complicate its translation into practical clinical applications as concerns arise about potential unanticipated adverse effects due to prolonged administration.
3. Mitochondrial Boosters
As outlined in our second article, mitochondrial dysfunction has prominently surfaced as a notable hallmark of the aging process, and its association with ovarian aging and infertility is well established. Many drug candidates with the potential for extending lifespan also exhibit protective effects on mitochondria. At the same time, the content of mitochondria serves as a significant marker for assessing egg quality. (Camacho-Pereira et al., 2016)
In addition to the antioxidant treatments mentioned earlier, which include CoQ10, Vitamins C and E, and flavonoids, new approaches that aim to boost nicotinamide adenine dinucleotide (NAD+), an essential cofactor and enzyme-substrate crucial for important chemical reactions and metabolic processes, have shown promising results in improving ovarian aging. Recent investigations into NAD+ supplementation, utilizing compounds such as nicotinamide riboside (NR) or nicotinamide mononucleotide (NMN, contained in NOVOS Boost), conducted on young and middle-aged mice, have showcased remarkable rejuvenation of eggs. This rejuvenation has led to enhanced fertility, attributed to reduced reactive oxygen species (ROS) levels and improved ovarian mitochondrial metabolism. (Bertoldo et al. 2020) (Yang et al. 2020)
Consequently, the spotlight on mitochondrial boosters is anticipated to intensify in the future. This is particularly significant given the emerging discovery of the connection between mitochondrial dysfunction and female reproductive aging, which revolves around perturbed NADH/NAD+ redox functions.
4. Glucose Metabolism Modulators
The investigation of modulators of glucose metabolism, notably metformin, has captured substantial attention in longevity research. While earlier studies primarily concentrated on its application in polycystic ovarian syndrome (PCOS), recent research in normal mice has shown metformin’s potential in counteracting age-associated ovarian fibrosis, improving follicle quantity, and establishing regular ovulatory cycles.
Additionally, this treatment has been found to enhance follicle quantity and establish regular ovulatory cycles. Notably, a study involving IVF repeaters who received low-dose metformin reported an improved pregnancy rate (Jinno et al., 2010). Metformin has also demonstrated protective effects in the ovaries of female rodents facing infertility challenges stemming from factors beyond aging, such as chemotherapy. (Barilovits et al., 2014) (Qin et al., 2019) (Landry et al., 2022) However, it’s worth noting that an alternate animal study did not yield concordant findings, as it revealed similar follicle counts between metformin-fed rats and their control counterparts (Oner et al., 2011). These differences, possibly due to variations in how treatments are given, highlight the necessity for more research to assess metformin’s effects on ovarian function thoroughly.
Similar limitations extend to a study (Barilovits et al. 2014) exploring the effects of 2-deoxyglucose (2-DG), a glucose derivative that competitively inhibits glycolysis and was proposed as a mimic of caloric restriction. This study, conducted on young mice and employing a brief treatment duration, revealed that 2-DG inhibits primordial follicle activation, suggesting its potential for preserving ovarian reserve. However, it’s important to note that chronic use of 2-DG has demonstrated cardiotoxicity and increased mortality in male rodents (Minor et al., 2010). Although its impact on females remains uncertain, these adverse effects have hindered the clinical advancement of 2-DG as a potential treatment option.
5. Other Drug Candidates: α-ketoglutarate (AKG) and Rapamycin
In addition to the previously discussed compounds, two other drug candidates, α-ketoglutarate (AKG) found in NOVOS Core and rapamycin, have exhibited promising effects in promoting ovarian longevity, with multiple lines of supporting evidence in rodent models. AKG plays a pivotal role as an intermediary in the Krebs cycle and serves as a fundamental building block for the synthesis of glutamate and glutamine. Beyond its metabolic functions, AKG has the capacity to enhance protein synthesis, support bone growth (and the calcium form of AKG, provided in NOVOS Core, offers a double boost), improve antioxidant systems, and bolster immune responses. Its anti-apoptotic and antioxidant properties have been found to enhance the quality of pig eggs (Gupta et al., 2022). At the same time, long-term use of AKG has been shown to preserve ovarian function, maintain follicle pool, and sustain fertility in aged mice, coupled with a reduction in telomere shortening. (Zhang et al., 2021)
Interestingly, AKG’s pro-longevity effects have been attributed, at least in part, to its inhibitory impact on the target of rapamycin (TOR). AKG’s mechanism of action in ovarian aging has also been proposed to involve the delay of ovarian follicle activation through mTOR inhibition. Recent studies have also indicated positive effects on egg maturation and embryo development when supplementing with potential longevity-enhancing substances such as fisetin, which is present in NOVOS Core.
Similarly, rapamycin, from which the name TOR is derived, has been extensively studied for its potential to delay ovarian aging. TOR, is a serine/threonine protein complex highly responsive to rapamycin and governs critical cellular signaling and metabolic pathways implicated in follicular development and ovarian aging. In various species, lifespan extension has been linked to mTOR suppression. Several rodent studies have demonstrated that inhibiting mTOR signaling can enhance ovarian reserve by increasing primordial follicle counts, thereby extending reproductive lifespan. (Adhikari et al. 2010) (Yu et al. 2011) (Zhang et al. 2013) (Luo, Xu et al. 2013) (Dou et al. 2017) (Guo et al., 2019)
However, the prolonged use of rapamycin has exhibited certain drawbacks, including disruptions to ovulatory cycles and loss of fertility due to halted follicle activation. Recent research has introduced a more targeted approach (Dou et al. 2017), employing a brief rapamycin treatment. This transient intervention successfully restored follicular development and ovulatory cycles in post-treatment mice, leading to improved reproductive capacity and extended ovarian lifespan, regardless of the age at which treatment was initiated. This strategy aligns with the overarching effects of TOR inhibition on longevity, suggesting that even a brief intervention at a relatively later stage can promote an extended period of health and lifespan.
While mTOR inhibition holds promise for addressing reproductive aging, further investigation is warranted to explore the potential of these compounds as short-term treatments with enduring protective effects against ovarian aging in women.
It’s important to note that much of this research has been conducted using rodent models, and we need to consider potential discrepancies between these models and human outcomes. While rodent models offer valuable insights into potential human interventions, further human studies are imperative.
Useful Lifestyle Tips To Promote Ovarian Health
Ovarian aging (in a physiological way) has not been officially established as a medical indication requiring treatment. Moreover, some of these compounds, such as rapamycin and metformin, are available only by prescription, potentially limiting accessibility. Beyond considering the use of supplements or compounds that have shown promise in research, slowing ovarian aging would necessitate the adoption of a combination of healthy lifestyle practices.
It’s important to remember that while these strategies may contribute to maintaining ovarian health, they may not entirely halt the aging process.
1. Avoid Smoking
Cigarette smoking has been linked to unfavorable reproductive outcomes, including compromised IVF outcomes and pregnancy complications. Most clinical studies indicate a dose-response relationship between smoking and the risk of early menopause. To safeguard ovarian functions, it is advised to refrain from smoking. (Kinney et al. 2007) (Oladipupo et al. 2022) (Whitcomb et al. 2018)
2. Limit Alcohol
Drinking alcohol, even in moderation (3-13 drinks per week), has been linked to accelerated ovarian aging. Most clinical studies support this, although a few have different findings. In general, it’s wise to limit alcohol consumption, especially if you’re planning to become pregnant. (Choi et al. 2017) (Freeman et al. 2021) (Kinney et al. 2007) (Li et al. 2013). We cover the topic of drugs and alcohol here.
3. Eat Healthy
It is always advisable to maintain a balanced and nutrient-rich diet that includes ample whole grains, lean proteins, healthy fats, fruits, and vegetables, not only to promote ovarian longevity but also overall well-being. (Choe and Sung 2020) (Eskew et al. 2022) (Jefferson 2010) (Qiang et al. 2023). You can incorporate antioxidant-rich foods like berries and nuts to counteract oxidative stress potentially. The scientifically designed NOVOS Longevity Diet is a valuable resource for optimizing your diet for longevity.
Furthermore, the consumption of soybean products has demonstrated protective effects on the female reproductive system. It may lower the risk of breast cancer, as suggested by certain animal and clinical studies, although findings remain contradictory. However, there is a concern that excessive consumption of soy protein (>100 mg soy isoflavones/day), as a source of phytoestrogens, could disrupt hormone cycles. It is advised to avoid excessive soy intake, although this level is notably lower than what is typically consumed in a traditional Asian diet (10–25 mg/day isoflavones). Given the potential benefits of soy products, such as cardiovascular protection, you can consider adding them to your diet moderately.
Interestingly, a study has indicated that the dietary pattern may have a more significant impact on overweight and obese women. Those who adhered to a “pro-fertility” diet, characterized by the inclusion of whole grains, soy products, seafood, produce with minimal pesticide residues, and supplementation with folic acid, vitamin B12, and vitamin D, exhibited improved markers of ovarian reserve.
4. Maintain a Healthy Weight
You should strive to maintain a healthy body weight, as extremes of weight can affect hormonal balance and ovulation. Research has shown that obese women may experience reduced chances of live births after IVF, and they often exhibit altered levels of anti-Mullerian hormone (AMH), a marker of ovarian reserve. Similarly, studies involving obese mice have revealed disruptions in ovulatory cycles alongside changes in ovarian inflammatory and hormone-related genes. (Fedorcsák et al. 2004) (Kiranmayee et al. 2017) (Su et al. 2008).
While being underweight appears to have a milder impact on ovarian health, it is commonly associated with issues like malnutrition or low body fat, leading to irregular hormone secretion and ovulation. For personalized weight management advice, it’s recommended to consult a healthcare professional. Combining a healthy diet with regular exercise is important for effective weight management.
5. Exercise Regularly
Participating in regular physical activity, which includes aerobic exercises, strength training, and flexibility exercises, has been associated with enhanced overall health. Numerous studies, encompassing both pre-clinical and clinical research, have indicated that engaging in moderate exercise has a positive influence on the ovarian reserve profile and outcomes of assisted reproductive technology (ART). While the potential impact of intense exercise on ovarian function has been a topic of debate, research has revealed that athletic women maintain ovarian reserve levels that are at least as favorable as those seen in the general population. (Falone et al. 2016) (Miller et al. 2022) (Rahayu et al. 2021)
6. Consider Suitable Medical Interventions
Age remains a significant determining factor for the success of assisted reproductive technology (ART). It’s advisable to plan proactively and explore suitable medical options before time becomes a constraint. If the idea of delaying pregnancy is under consideration, fertility preservation methods like egg or embryo freezing could be viable choices for potential future use. While there isn’t a universally defined upper age limit for in vitro fertilization (IVF), achieving successful conception through IVF becomes rare for women over 50. Generally, if a couple has been unsuccessful in conceiving after a year of trying, IVF might be a recommended consideration.
If you are grappling with symptoms related to menopause, Hormone Replacement Therapy (HRT) could be a potential avenue, though it’s typically administered for periods shorter than five years. Importantly, seeking guidance from a healthcare professional is paramount to evaluating the potential advantages and drawbacks of any new interventions.
Lu DONG is a reproductive aging scientist affiliated with the Centre for Healthy Longevity at the National University of Singapore (NUS). She is currently pursuing her PhD in the field of drug repurposing and natural products for female reproductive longevity, working under the supervision of Prof. Brian Kennedy.
Lu was honored with the Singapore Agency for Science, Technology, and Research (A*STAR) Undergraduate Scholarship and earned her Bachelor of Science (Pharmacy) degree with first-class honors from the National University of Singapore in 2020. Upon graduation, she was awarded the prestigious Integrative Sciences and Engineering Programme Scholarship in NUS for her PhD journey. Lu has given talks on female reproductive aging at international conferences such as the Bia-Echo Asia Centre for Reproductive Longevity and Equality (ACRLE) Conference 2022. She has also published a review article: “Unraveling female reproductive senescence to enhance healthy longevity” in Cell Research.
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