Fighting Age-Related Female Infertility: Study Finds NMN Boosts Egg Quality

As women are now waiting longer and longer to have children, infertility rates in those over age 35 have increased in recent decades. Although infertility occurs for many reasons — hormonal imbalances, excessive toxin exposure, and too-low or too-high body weight to name a few — advanced maternal age is a leading cause of the inability to become and stay pregnant. Beginning in a woman’s mid-30s, both the number of viable egg cells and the chances of becoming pregnant naturally decrease year after year. 

With one out of every three women over age 35 experiencing trouble getting pregnant or maintaining a pregnancy, researchers and patients alike are seeking out various ways to support fertility. In contrast to the costly and invasive assisted reproductive technologies with inconsistent success rates, like in vitro fertilization (IVF), women can first try out supplements or natural compounds that may support fertility. 

New research published in Cell Reports suggests that nicotinamide mononucleotide (NMN) may just be one of those fertility-boosting compounds. In this study, Miao and colleagues provide compelling evidence that NMN may also mitigate the age-related decline in maternal fertility that was previously thought to be irreversible, providing hope for women who wish to become pregnant in their 40s and beyond.

NAD+ and female fertility: fighting the biological race against time

Oocytes, which is the term for immature egg cells before they fully mature into eggs that can be fertilized, are not self-renewing cells, and the amount of oocytes a woman has at birth will be the highest number she ever has. Due to this finite number of cells, a woman's fertility is primarily based on both the number and the quality of oocytes she has left. While there is currently no way to increase the number of oocytes, we may be able to improve the functioning of the ones remaining — and it may have to do with the compound NAD+ (nicotinamide adenine dinucleotide).

NMN is a precursor to the essential coenzyme NAD+; declines in NAD+ levels are thought to be at the root of accelerated aging and many chronic diseases. In animal and cell-based studies, NMN increases NAD+ levels rapidly and is linked to improved cardiovascular, brain, metabolic, muscle, and bone health.

Paralleling the age-related reduction in NAD+ levels is a decline in the quality and number of oocytes. Aging oocytes have significantly impaired follicular development, ovulation rates, and oocyte maturation, leading to low fertility. Knowing the parallels between declining oocyte quantity and quality and NAD+ levels, Miao and colleagues looked at the effects of supplemental NMN on fertility in aged female mice. 

Egging on optimal oocytes with NMN 

In this study, researchers used aged female mice that were between 16 and 17 months of age, which translates to 50 to 54 years old in humans. As expected with their increasing age, the oocytes from these aged mice had lower NAD+ levels and were of significantly lower quality compared to the oocytes from young, 6-week old mice. After just 10 days of receiving supplemental NMN, the aged mice showed significant reversals in these low oocyte NAD+ levels, alongside improvements in several other markers of fertility. 

As expected, the aged mice experienced drastic reductions in the number of oocytes becoming mature eggs and increases in the number of fragmented oocytes, which are less likely to successfully mature and fertilize. But NMN significantly mitigated these age-related oocyte dysfunctions, leading to increased egg quality and function. 

Notably, the highest number of mature oocytes were obtained at lower doses of NMN, with 200 mg per kg of body weight per day (mg/kg/day) boasting better results than the higher amount of 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. 

NMN treatment also increased the number of antral follicles — the fluid-like sacs that house oocytes — and improved three markers of fertility that become dysfunctional with age: the spindle-chromosome structure, cortical granule (CG) distribution, and ovastacin levels. The spindle-chromosome structure prevents chromosomal genetic conditions (like Down syndrome), while CG distribution and healthy ovastacin levels help sperm binding and prevent the fatal condition of polyspermy — when an egg is fertilized by more than one sperm.

Perhaps most importantly, the NMN-treated aged mice had increases in the number of pups in their litter. Although NMN did not boost the aged females’ birth rates to that of the young mice, it led to significantly higher live births than the untreated 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 (let alone litters in the first place).

Elevating energy production to enhance egg health 

The aged mice also experienced significant improvements in mitochondrial function after NMN supplementation. Before treatment, over 40% of the aged oocytes had mislocalized mitochondria, diminishing their function. After NMN treatment, the proportion of mislocalized mitochondria was reduced to 24%, which coincided with increased mitochondrial function. 

In tandem with these positive effects on mitochondria, NMN improved ATP (energy) production and mitigated the accumulation of inflammatory reactive oxygen species (ROS) seen in aging oocytes. Excessive ROS buildup causes oxidative stress and DNA damage that can lead to cell death (in this case, oocytes), which negatively affects several processes involving fertilization and pregnancy. Lastly, the NMN-supplemented oocytes had increased activity of the sirtuin SIRT1. Sirtuins are proteins linked to health and longevity, and researchers believe low sirtuin levels and activity are implicated with infertility. 

Key Takeaway From This Research:

In this study, supplementing aged female mice with a lower dose of 200 mg/kg NMN, as opposed to 1000 mg/kg, restored NAD+ levels in their oocytes. This improved oocyte quality and maturation, increased birth rates, recovered mitochondrial function, and reduced ROS accumulation — all of which support fertilization and healthy pregnancy.

If these results were to translate to humans, it would suggest that supplemental NMN could help women well into their 50s to maintain viable pregnancies. In the future, we may see that low-dose NMN supplementation could be a non-invasive and low-risk way to increase fertility and support pregnancies with increasing age. While promising, we’ll have to wait for the clinical trials to see if NMN does indeed benefit fertility in the middle-aged and beyond. 

References:

Bertoldo MJ, Listijono DR, Ho W-HJ, et al. NAD repletion rescues female fertility during reproductive aging. Cell Reports. February 2020:1670-1681. doi:10.1101/721985

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. doi:10.1016/j.celrep.2020.107987

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. doi:10.1155/2015/659687