The article explores the process by which certain dietary supplements may slow ovarian aging in mice.
Sirtuins and mitochondrial function are involved in this process.
Fertility and its decline with age
The decline in fertility in women occurs relatively quickly during life. Aging leads to a decrease in the quantity and quality of eggs, and the ability to fertilize declines as early as a woman's 30s.
Therefore, many research groups are trying to attack the problem of aging ovaries from several angles.
This study focuses on mitochondria
The researchers in this study specifically focused on the effect of aging on the mechanisms of mitochondrial fission and fusion in the ovaries.
These processes are essential for normal mitochondrial function and for biological processes dependent on mitochondria.
Previous studies have shown that higher levels of NAD+ can improve mitochondrial function and reverse ovarian aging.
Since NAD+ precursors, namely nicotinamide mononucleotide (NMN) and nicotinamide riboside (NR), are commonly consumed as dietary supplements and have a good safety profile, these researchers determined it was worth testing whether administering NMN or NR supplements to mice could improve ovarian aging.
Better body weight and better appearance
The researchers compared four groups of mice, with six animals in each group:
young, middle-aged,
middle-aged + NMN,
and middle-aged + NR.
The treated animals received NMN and NR for 17 days.
The next day, the researchers compared the biomarkers of the animals.
First, the researchers compared body weight to ovarian weight to calculate the ovarian index, which serves as a measure of fertility in females.
A higher ovarian index indicates better fertility.
The results showed a slight increase in the ovarian index following NMN and NR treatments.
The researchers also examined the morphology of the organ.
They saw larger amounts of corpus luteum in middle-aged mice treated with NMN and NR.
The corpus luteum is a structure formed in the ovary after ovulation.
It secretes progesterone, a hormone essential for implantation and pregnancy.
Aging leads to a decrease in the corpus luteum.
Another indication of the ovarian aging state in middle-aged mice that showed improvement following NMN and NR treatments was an increase in the number of antral follicles and a decrease in the number of atretic follicles.
Ovarian follicles are sacs containing immature eggs.
Antral follicles are large follicles preparing for ovulation, while atretic follicles are characterized by apoptotic bodies, a degenerated egg, and fragmentation of the egg nucleus.
Hormones and their effect on ovarian aging
Based on the ratio of luteinizing hormone (LH) to follicle-stimulating hormone (FSH) (LH/FSH) in the mice, the researchers learned that "ovarian aging impaired the LH/FSH balance" and increased follicular atresia in the ovaries, a process of follicle degeneration or resorption accompanied by apoptosis.
However, again, applications of NMN and NR improved these parameters: they helped rebalance the LH/FSH ratio and reduced follicular atresia.
Mitochondria and sirtuins in the service of better ovarian health
The phenotypic descriptions described earlier are the known suspects in ovarian aging.
However, in this article, the researchers also decided to investigate mitochondrial phenotypes as a measure of ovarian health because mitochondrial fission and fusion proteins are essential in oogenesis, embryogenesis, implantation, and protection of the ovarian follicle reserve.
Compared to young mice, middle-aged mice had significantly lower levels of gene transcripts for genes related to mitochondrial fusion.
Treatment with NMN and NR helped increase the expression of these genes in middle-aged mice to levels close to those observed in young mice.
Gene transcript levels related to mitochondrial fission in middle-aged mice were higher compared to those in young mice.
Treatment with NMN and NR significantly reduced the levels of these genes in the mouse ovaries. Protein analysis confirmed the positive effect of NMN and NR.
The connection between NMN, NR, and mitochondria
The observed connection between NMN, NR, and mitochondria prompted the researchers to check sirtuin levels.
Sirtuins have previously been described as helping to inhibit ovarian aging and balance mitochondrial dynamics, and they are regulated by NAD+.
Therefore, measuring their levels was essential in this experimental setup.
The researchers noted lower levels of Sirt1 transcripts in the middle-aged group compared to young mice, likely due to an aging-induced decrease in NAD+.
Treatment with NAD+ precursors, NMN and NR, increased Sirt1 levels in the ovaries. These results were confirmed by measuring SIRT1 protein levels.
Summary and future outlook
Based on the current results and previous studies, they hypothesized that the release of NAD+ from NMN and NR supplements led to the activation of SIRT1.
Activated SIRT1 led to a decrease in DRP1, one of the fission proteins, which reduced the frequency of mitochondrial fission.
The researchers note that previous studies in animal models, including humans, show that NMN and NR supplements are safe even at high doses.
These are good news for future testing of NMN and NR supplements in humans to inhibit ovarian aging.
The study shows that administration of an NAD+ precursor (NMN or NR) restores the LH/FSH balance and mitochondrial dynamics, increases SIRT1 activity, and alleviates folliculogenesis problems in middle-aged mice.
Therefore, we believe that NMN and NR may be used as a drug or dietary supplement to reduce aging-related folliculogenesis or ovulation problems.
Study limitations and suggestions for future research
It is important to note that this study was conducted on mice, and further studies are needed to confirm the results in humans.
Additionally, the study did not examine the long-term effects of NMN and NR on ovarian health and fertility.
Future research may focus on the following aspects:
- Clinical trials in humans to examine the safety and efficacy of NMN and NR in inhibiting ovarian aging and improving fertility.
- Investigating the precise molecular mechanisms through which NMN and NR affect ovarian health.
- Testing the effects of NMN and NR on other aspects of women's health, such as bone health and cardiovascular health.
Summary
This study offers a new and promising therapeutic possibility for inhibiting ovarian aging and improving fertility in women. NMN and NR are relatively safe dietary supplements already in widespread use, making them attractive candidates for further research and development.
Sources
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