NMN and Fertility: Can Boosting NAD+ Support Female Fertility?
As women are now waiting longer to have children than in generations past, infertility rates in those over age 35 are more noticeable and have increased in recent decades. Although infertility occurs for many reasons—such as excess weight, hormonal imbalances, and excessive toxin exposure, to name a few—advanced maternal age is a leading cause of the inability to become or stay pregnant.
Typically, once a woman reaches her early-to-mid-30s, both the number of viable egg cells and chances of becoming pregnant naturally and easily decrease year after year. But it’s not a lost cause, and new research shows that several lifestyle changes or supplements may be able to help—including NMN.
NAD+ and Female Fertility: What’s the Link?
Oocytes—immature egg cells before they fully mature into eggs that can be fertilized—are not self-renewing cells. As many people have heard, the number of eggs that a woman has at birth will be the highest number she ever has. Due to this finite number of egg cells that decrease with each passing year, a woman's fertility is largely based on the quantity and quality of oocytes she has left.
But, while there's no way to increase the number of oocytes, research with animals shows that we may be able to improve the quality of the ones remaining to support fertility—and the compound NAD+ (nicotinamide adenine dinucleotide) is likely involved.
NMN (nicotinamide mononucleotide) is a precursor to NAD+, an essential coenzyme needed by just about every one of our cells—including oocytes. Reductions in NAD+ are linked to both accelerated aging and disease development. Conversely, maintaining healthy NAD+ stores with precursors like NMN (or NR) is associated with heart, cognitive, muscle, metabolic, and bone health—and, in turns out, reproductive function.
Alongside a reduction in NAD+ levels is a decline in the quality and number of oocytes. Aging oocytes have impaired follicular development, ovulation rates, and oocyte maturation, leading to low fertility.
Plus, women with low fertility have increased rates of mitochondrial dysfunction and oxidative damage—the buildup of harmful molecules called reactive oxygen species (ROS). Excessive ROS buildup leads to DNA damage and subsequent cell death—including oocytes—which disrupts several processes related to fertilization and pregnancy.
Recent Research: Can NMN Support Female Fertility?
The past few years have seen several studies come out about NMN and female fertility. These research studies provide compelling evidence that NMN or other NAD+ precursors may be able to stall the age-related decline in female fertility that was previously thought to be irreversible.
A 2022 study published in Biomedicines used a combination of deep learning and AI models to detect cellular changes in oocytes in young and older mice, with some of the older mice receiving supplemental NMN. At 12 months old, the mice were considered middle-aged, or approximately early 40s if translated to human years.
The research team, based out of the University of New South Wales in Sydney, used their model to identify a cellular signature of the oocytes, finding that 60% of the oocytes from older NMN-treated mice were classified as having a “young” morphology. This means that the shape, structure, form, and size of their oocytes were the same as the young mice after receiving NMN.
Using oocyte morphology to determine fertility is reminiscent of using biological age to assess internal health rather than chronological age, and this research suggests that boosting NAD+ levels can partially restore oocytes to their younger forms.
Another study that was published in 2020 in the journal Cell Reports also produced promising results regarding NMN and female fertility.
In this research, female mice between 16 and 17 months of age—translating to about 50 to 54 in human years—received supplemental NMN for 10 days. Unsurprisingly, the oocytes from the older mice were of lower quality compared to those from young mice, including having much lower numbers of oocytes able to become mature eggs and greater numbers of fragmented oocytes, which are less likely to mature and fertilize successfully.
However, adding NMN to the mix significantly improved several aspects of the aged mice’s fertility, including:
- Increased the number of antral follicles, the fluid-like sacs that house oocytes and are a measure of ovarian reserve (future egg supply)
- Improved the spindle-chromosome structure, which prevents genetic chromosomal conditions
- Improved cortical granule (CG) distribution, which prevents the fatal condition of polyspermy (when an egg is fertilized by more than one sperm)
- Increased ovastacin levels, which helps with sperm binding
- Improved mitochondrial function, as seen by a reduction in “mislocalized mitochondria” (an indication of compromised function) from 40% to 24%, and increased mitochondrial membrane potential, which is essential for producing ATP.
- Increased ATP production within oocytes
- Reduced oxidative stress and lower ROS levels in oocytes
- Increased activity of SIRT1, a sirtuin protein linked to longevity whose low levels are thought to affect infertility.
As if that wasn’t enough, and perhaps most importantly, the NMN-treated aged mice had a greater number of pups in their litter.
Although NMN did not increase the older females’ birth rates to that of the young mice (it’s not a time machine, after all), it led to significantly higher live births than the unsupplemented aged mice.
The authors note that NMN treatment only increased the number of pups during the first litter, indicating that the short, 10-day treatment used in this study only benefited oocytes for approximately one month. However, it isn’t exactly clear how these results translate to humans—after all, women don’t birth successions of litters (or litters at all, for that matter—unless we’re talking OctoMom, that is).
One important thing to note with this study is that initial experiments found lower doses of NMN to be more beneficial than higher doses. The greatest number of mature oocytes were obtained at lower doses (200 mg/kg/day) compared to mice receiving 1,000 mg/kg/day. This is consistent with previous research that also found that lower doses of NMN improved fertility markers and oocyte quality in mice more than higher doses.
What Happens to Oocytes in Aging?
Changes in human oocytes during aging involve a variety of mechanisms and cycles of activity versus stasis, significantly impacting reproductive outcomes. Advanced maternal age (AMA) and elevated gonadotrophin levels contribute to decreased oocyte viability, increased ootoxicity, and higher rates of chromosomal and spindle misalignments, suggesting aging oocytes are more susceptible to adverse effects.
The "FSH OOToxicity Hypothesis" and "2-Hit Hypothesis" propose explanations for infertility related to high FSH levels and aging, emphasizing the decline in oocyte quality. Aging also results in a decreased abundance of proteins critical for meiosis and proteostasis in oocytes, affecting reproductive success.
Moreover, oocyte aging is accelerated by stress conditions in vivo, influenced by factors like oviductal apoptosis and female stress. Energy metabolism decline due to Krebs cycle dysfunction, compensated by increased NADPH dehydrogenation and DNA repair mechanisms, is another aspect of aging in oocytes, aiming to maintain developmental competence.
Furthermore, aging involves decreased translational efficiency, influenced by alterations in epigenetic modification regulators, impacting oocyte maturation and aging-associated maternal factors. These changes highlight the complex interplay between genetic, environmental, and physiological factors in the aging of human oocytes, underscoring the critical need for understanding these processes for reproductive success and interventions.
There are many unanswered questions, including why humans and a very small number of other animals have a post-reproductive lifespan (as noted in the “Grandmother Hypothesis”) and how much metabolic activity oocytes engage in, contributing to potential DNA damage in these reproductive cells. This is a highly active area of research, and many labs are interested in elucidating the mechanisms behind the degradation of oocytes and the impact on ovarian function. Ovarian senescence may be another driver of reproductive ability loss, and we have some partial solutions to senescence now, with better protocols being developed in labs worldwide.
Key Takeaways:
Although infertility can occur for a myriad of reasons (both on the male and female sides of things), high-quality and healthy oocytes are a prerequisite for successful fertilization and subsequent pregnancy. Therefore, focusing on supporting this area of female fertility with NAD+ precursors like low-to-moderate doses of NMN may be one simple solution for the millions of people dealing with unsuccessful pregnancies.
Not only that, but if these results were to translate to humans, it would imply that supplemental NMN could help women in their 40s and potentially even 50s to maintain healthy pregnancies. In the future, we may see that using NAD+ precursors like NMN or NR could be a low-risk way to support fertility and pregnancies with increasing maternal age. While animal studies are encouraging, we’ll have to wait for clinical trials to see if NMN or other NAD+ precursors do indeed benefit fertility in the middle-aged and beyond.
References:
Bernstein LR, Mackenzie ACL, Durkin K, Kraemer DC, Chaffin CL, Merchenthaler I. Maternal age and gonadotrophin elevation cooperatively decrease viable ovulated oocytes and increase ootoxicity, chromosome-, and spindle-misalignments: ‘2-Hit’ and ‘FSH-OoToxicity’ mechanisms as new reproductive aging hypotheses. Molecular Human Reproduction. 2023;29(10):gaad030. doi:10.1093/molehr/gaad030
Galatidou S, Petelski A, Sabater L, et al. P-710 Single-cell proteomic analysis of human oocytes reveals a decreased abundance of meiosis and proteostasis regulators with advanced maternal age. Human Reproduction. 2023;38(Supplement_1):dead093.1032. doi:10.1093/humrep/dead093.1032
Habibalahi A, Campbell JM, Bertoldo MJ, et al. Unique Deep Radiomic Signature Shows NMN Treatment Reverses Morphology of Oocytes from Aged Mice. Biomedicines. 2022;10(7):1544. Published 2022 Jun 29. doi:10.3390/biomedicines10071544
Huang J, Chen P, Jia L, et al. Multi‐omics analysis reveals translational landscapes and regulations in mouse and human oocyte aging. Advanced Science. 2023;10(26):2301538. doi:10.1002/advs.202301538
Kong QQ, Wang GL, An JS, et al. Effects of postovulatory oviduct changes and female stress on aging of mouse oocytes. Reproduction. Published online May 2021. doi:10.1530/REP-21-0160
Miao Y, Cui Z, Gao Q, Rui R, Xiong B. Nicotinamide Mononucleotide Supplementation Reverses the Declining Quality of Maternally Aged Oocytes. Cell Rep. 2020;32(5):107987.
Tatone C, Di Emidio G, Vitti M, et al. Sirtuin Functions in Female Fertility: Possible Role in Oxidative Stress and Aging. Oxid Med Cell Longev. 2015;2015:659687.
Zhao H, Li T, Zhao Y, et al. Single-cell transcriptomics of human oocytes: environment-driven metabolic competition and compensatory mechanisms during oocyte maturation. Antioxidants & Redox Signaling. 2019;30(4):542-559. doi:10.1089/ars.2017.7151
