A new mouse study published in Cell Reports has shown that a metabolic precursor of the coenzyme NAD+ rejuvenates oocytes (egg cells), restoring fertility .
The oldest cells
In humans, female fertility begins to decline near the end of the third decade of life, long before other markers of aging appear. This age-related decline is mostly associated with poor oocyte quality. Germ cells exhibit the same aging-related symptoms as somatic cells, including epigenetic dysfunction and genomic instability. Oocytes are among the oldest cells in the body, only produced during the fetal stage, unlike somatic cells, which are constantly being replaced by new ones. Therefore, it is no wonder that aging catches up with oocytes early. On the other hand, anti-aging solutions that work for somatic cells should also be expected to work for oocytes.
NAD+ to the rescue
According to the study, the loss of oocyte quality with age correlates with the declining levels of NAD+ (nicotinamide adenine dinucleotide) and treatment with the NAD+ metabolic precursor NMN (nicotinamide mononucleotide) restores it.
NAD+, a coenzyme responsible for many cellular functions, was discovered in the early 20th century as an alcoholic fermentation enhancer. Later, it was revealed that NAD+ acts as a crucial component of the electron transport chain, which is the main intracellular energy-producing mechanism. In the 1990s, NAD+ made headlines again when it was found that sirtuins depend on it to do their highly important deacetylation job. For additional information on NAD+, you are encouraged to check this two-article series. Levels of NAD+ in cells decline with age, and their replenishment has long been a target of longevity research.
The researchers had managed to gauge NAD+ levels in individual oocytes and found that they were indeed much lower than in surrounding tissues, which is likely due to their age. When induced to complete their meiosis (the cellular division that results in functional reproductive cells), oocytes in aged mice often revealed severe deficiencies in spindle assembly and chromosome segregation, leading to aneuploidy (the presence of an abnormal number of chromosomes in a cell) and other complications. By administering NMN orally, the researchers had succeeded in alleviating these problems to such a degree that they describe the result as “rescuing” mouse fertility. Notable improvements were observed in ovulation rate and in birth rates as well. The authors had also been able to extend the age-defying benefits of NMN to the embryos derived from oocytes of older animals. Adding NMN to the culture in which the embryos were developing increased blastocyst cell count, an important indicator of transplantation success in in-vitro fertilization.
Are sirtuins involved?
To determine whether the benefits were actually achieved via NAD+ dependent sirtuin activity, the researchers had manipulated the sirtuin levels in mice via transgenic overexpression of Sir2. By doing so, they were able to largely recapitulate the benefits of in vivo NMN treatment. On the other hand, deletion of Sir2 had no adverse impact on oocyte quality. However, this was only tested in young mice. The authors concede that using older animals could have revealed the true impact of Sir2 deletion on fertility. As of now, the authors hypothesize that increased NAD+ levels could be affecting oocytes by simply enhancing energy metabolism rather than by assisting sirtuins.
Don’t try this at home
Self-treatment with NMN and other NAD+ precursors is becoming increasingly popular, but if you are thinking about experimenting with NMN at home, the researchers have a warning for you:
One unexpected aspect of this study was that treatment with a lower dose of NMN resulted in improved functional fertility. This could suggest that there is an optimum range for dosing of NAD+ precursors beyond which other aspects of fertility could be adversely affected, lowering functional fertility. This will be an important concern to the clinical translation of this work, especially given that NAD+ precursors such as NR are freely available as supplements. Out of caution, we suggest that these supplements should not be taken by women wishing to become pregnant until further studies have been completed.
Addressing aging-related decline in fertility is a noble and important goal. Today, it is done with limited success via assisted reproduction technologies (ARTs), which can be invasive, expensive, and, at times, risky. Although major steps towards oogenesis in vitro from stem cells are being made , until this technology has matured, treatment with NMN, a well-known compound, could potentially provide a simple and safe way of improving and restoring fertility in women.
 Bertoldo, M. J., Listijono, D. R., Ho, W. H. J., Riepsamen, A. H., Goss, D. M., Richani, D., … & Loh, W. G. N. (2020). NAD+ Repletion Rescues Female Fertility during Reproductive Aging. Cell Reports, 30(6), 1670-1681.
 Morohaku, K., Tanimoto, R., Sasaki, K., Kawahara-Miki, R., Kono, T., Hayashi, K., … & Obata, Y. (2016). Complete in vitro generation of fertile oocytes from mouse primordial germ cells. Proceedings of the National Academy of Sciences, 113(32), 9021-9026.