German women are now around five and a half years older when they give birth to their first child, on average at 30 years of age, than they were 50 years ago. This presents medicine with completely new problems regarding issues such as successful pregnancy, fertility and family planning. A successful pregnancy depends primarily on the quality of the egg cells, and this quality decreases with age. Fertility decreases on the one hand, and abortions and the likelihood of congenital abnormalities increase on the other. Despite the high demand, a truly effective non-invasive ("non-penetrating") therapy has not yet been developed. For this reason, we are now taking a closer look at whether and how NMN can improve fertility.
In this study, Bertoldo et al. show that this declining egg quality is caused by stagnating NAD + (nicotinamide adenine dinucleotide) levels and how this point promises a potential therapeutic approach through the NAD+ precursor NMN (nicotinamide mononucleotide).
Why does the quality of eggs decline with age?
Most tissue types are continuously treated by our stem Cells repaired. Egg cells are a little different. They are produced during human development in the womb, after which a finite pool of eggs is available that is no longer renewed. It is therefore obvious that this indispensable cell type is particularly susceptible to malfunctions over the years.
What are the NAD+ levels in the eggs?
For the study, mice, whose fertility declines at about 8 months in a similar way to humans, were divided into three groups:
- Young mice (4-5 weeks old)
- Old mice (12 months old)
- Old mice with NMN (12 months old)
To measure the NAD+ levels of the eggs, the researchers used hyperspectral microscopy imaging, which takes advantage of the autofluorescence of NADH and NADPH.
The 12-month-old mice were treated with NMN-supplemented drinking water (2 g/l) for four weeks. The oocytes were then examined using hyperspectral microscopy imaging and compared across groups.
Results of NMN supplementation
There was a significantly reduced NAD+ level in the old mice. At the same time, however, there was an increased NAD+ level in the old mice treated with NMN. (see figure)
So far so good, but do high NAD+ levels really support fertility?
To investigate this question, 14-month-old mice were treated with drinking water containing NMN. One group received 2 g/l and the other 0,5 g/l. The control group had to make do with regular water.
Treatment with the NAD+ precursor NMN led to a significant improvement in egg quality and regained fertility. The findings also extended to embryo development, with the negative effects of advanced gestational age being eliminated (only at 0,5 g/l).
Further results of treatment with NMN:
- It seemed to make a difference how long the mice were treated with NMN. The mice that were treated the longest also showed the best results.
- No negative effect of NMN supplementation was observed in the mother or offspring.
Discussion
Surprisingly, the improvements in pregnancy and birth were only seen in the “low-dose” 0,5g/l group. These findings indicate an optimal dosage of NMN and show that high-dose NMN improves egg quality but not pregnancy outcome. According to the authors, this could be due to an as yet unknown upper limit of NMN tolerance or too high levels of NMN metabolites such as nicotinamide. In the right Dosage, NMN could indeed improve fertility.
All in all, treatment with NAD+ precursors could be an exciting non-invasive therapy option for women of advanced reproductive age in the future. Further prospective studies are needed to confirm and evaluate these assumptions. Only scientific findings from research on humans allow concrete conclusions to be drawn about the human benefit.
Sources
Books
Bertoldo, MJ, Listijono, DR, Ho, WJ, Riepsamen, AH, Goss, DM, Richani, D., Jin, XL, Mahbub, S., Campbell, JM, Habibalahi, A., Loh, WN, Youngson, NA , Maniam, J., Wong, A., Selesniemi, K., Bustamante, S., Li, C., Zhao, Y., Marinova, MB, Kim, LJ, … Wu, LE (2020). NAD+Repletion rescues female fertility during reproductive aging.Cell reports,30(6), 1670–1681.e7.https://doi.org/10.1016/j.celrep.2020.01.058
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