Cell Sub-Journal: Revealed – The "Anti-Aging 'Miracle Supplement'" NMN Also Helps Restore Fertility

No matter how much you focus on aging, it still affects you in unexpected ways. Aging is a continuous, all-encompassing process. In a sense, our bodies enter a phase of overall aging the moment puberty ends in our teens or twenties[1]. Due to physiological complexity, different parts, organs, and cells have unique aging patterns and rates.

For example, if used properly, nerve cells in the brain will not experience significant overall functional decline even at 100 years old[2]. However, some cells begin to suffer severe functional decline from the age of 30, no matter how carefully you live—such as oocytes, which are closely linked to fertility.

Oocytes are essentially the precursor of female egg cells. A core prerequisite for female fertility is healthy egg cells, and the health (and even existence) of egg cells is determined by oocyte quality.

A 2014 study published in the renowned medical journal The Lancet showed that female oocytes are extremely vulnerable to aging. Generally, a woman’s oocytes start to experience severe quality decline around the age of 30, leading to fertility issues[3]—and current clinical practices have no solutions for this.

However, a new study conducted by a collaborative team from the University of New South Wales, Harvard University, and other institutions found that in mice, age-related oocyte quality decline can be reversed by NMN intake, and fertility can be significantly restored[4].

This study was officially published in Cell Reports (a sub-journal of Cell) on February 18, 2020.

First, the study sought to clarify how aging causes oocyte quality decline.

Through controlled experiments, researchers found that NAD+ (nicotinamide adenine dinucleotide) levels in oocytes of old mice were significantly reduced. After 4 weeks of NMN intake via drinking water (2g/L), NAD+ levels rebounded markedly. Meanwhile, multiple indicators reflecting oocyte quality also showed significant reversal—proving a close link between NAD+ levels and oocyte quality.

Figure C Note: Differences in NAD+ levels in oocytes between young (1 month old) and old (14 months old) mice (indirect measurement).
Figure D Note: Differences in NAD+ levels in oocytes between old mice with no NMN intake (ctrl) and old mice with NMN intake (indirect measurement).

After confirming the above conclusion, the study focused on whether NAD+ could reverse oocyte quality in old mice and improve the fertility of elderly female mice.

Elderly mice were given NMN via drinking water (2g/L) for different durations. Researchers then collected the mice’s oocytes and performed in vitro fertilization.

Results showed that the longer the mice took NMN, the more significant the improvement in two key indicators: blastocyst formation rate and development of the inner cell mass of blastocysts. These two indicators are critical for predicting pregnancy success—their improvement indirectly indicates enhanced fertility.

Figure G Note: Comparison of blastocyst formation rates (Day 6) between oocytes from old mice with no NMN intake (12 mo. ctrl) and old mice with NMN intake (12 mo. NMN).
Figure H Note: Comparison of inner cell mass quality of blastocysts between oocytes from old mice with no NMN intake and old mice with NMN intake.

After confirming that NMN intake (2g/L) significantly improves oocyte quality and restores fertility in elderly mice at the cellular level, the study tested whether NMN could truly restore fertility in elderly female mice at the "clinical" level.

Scientists divided elderly mice into three groups:

After 4 weeks of intake, the three groups of elderly female mice were allowed to mate with male mice with healthy fertility.

Data showed that compared with the no-NMN group, the 0.5g/L NMN group experienced a massive increase in pregnancy rate, live birth rate, and number of pups per animal. However, the 2g/L NMN dose—repeatedly proven effective in previous cellular experiments—had no effect on the fertility of elderly female mice at the clinical level.

Figures J & K Note: Live birth rate – The 0.5g/L group showed a significant increase, while the 2g/L group had no significant difference from the control group of elderly mice.
Figures L & M Note: Number of pups per animal – Same trend as live birth rate.

This data suggests a hypothesis: While NMN improves the quality of elderly oocytes, it may have adverse effects on other fertility-related functions. The underlying mechanism will likely become a key focus of future research in this field.

From the experimental data, a clear conclusion emerges: There is an optimal dose of NMN. Only when this optimal dose is reached can NMN significantly help restore fertility in the elderly from a clinical perspective.

Thus, the clinical application of NMN for age-related fertility issues in middle-aged and elderly women still has a long way to go.

Further experiments showed that even at a high dose (2g/L), the offspring mice showed no adverse effects in terms of physiological indicators or behavioral performance. The only "benefit" was a very subtle increase in muscle mass—proving that maternal NMN intake has no negative impact on offspring development.

After confirming that moderate NMN intake can significantly improve oocyte quality in elderly female mice and help restore their fertility, the study entered its final phase: exploring the underlying mechanism.

Unfortunately, no breakthrough was made in this area. Based on existing knowledge, researchers hypothesized that NAD+ exerts these effects through its interaction with SIRT2 (a well-studied "longevity protein"). Although overexpressing the SIRT2 gene increased the pregnancy rate of elderly female mice from 25% to 75%, subsequent experiments failed to confirm that SIRT2 is the key to restoring fertility in elderly female mice.

In in vitro experiments on elderly female mice, the study confirmed that NAD+ levels are a key factor in age-related oocyte quality decline. Building on this, subsequent "clinical" experiments found that moderate intake of NMN (a NAD+ precursor) can significantly reverse oocyte quality in elderly female mice, thereby restoring fertility. Further experiments confirmed that maternal NMN intake has no negative impact on the health or development of offspring.

As a direct precursor of NAD+, NMN has multiple functions. Due to its anti-aging effects widely reported in various studies, it is colloquially known as an "anti-aging 'miracle supplement'." However, the study ultimately failed to confirm NMN’s mechanism of action, leaving many key questions unanswered: Can other NAD+ precursors achieve the same effect? How to determine the optimal dose of NMN?

In conclusion, while many key questions about the relationship between NMN (and other NAD+-related substances) and age-related fertility decline remain to be answered, the results of this study are highly promising. 😉😉

[1] Thompson, Joseph J., et al. “Over the Hill at 24: Persistent Age-Related Cognitive-Motor Decline in Reaction Times in an Ecologically Valid Video Game Task Begins in Early Adulthood.” PLoS ONE, vol. 9, no. 4, Sept. 2014, doi:10.1371/journal.pone.0094215.
[2] Mattson, Mark P, and Tim Magnus. “Ageing and neuronal vulnerability.” Nature Reviews Neuroscience, vol. 7, no. 4, 2006, pp. 278–294, doi:10.1038/nrn1886.
[3] De Vos MD, Michel, et al. “Fertility Preservation in Women with Cancer.” The Lancet, vol. 384, no. 9950, Oct. 10, 2014, pp. 1302–1310, doi:https://doi.org/10.1016/S0140-6736(14)60834-5.
[4] Bertoldo, Michael J., et al. “NAD Repletion Rescues Female Fertility during Reproductive Aging.” Cell Reports, vol. 30, no. 6, 2020, doi:10.1016/j.celrep.2020.01.058.