Researchers in a 2023 study show that the supplement spermidine is effective in improving egg quality in older mice, which is related to the cellular process mitophagy. The supplement may be useful in helping older women improve egg quality, but more research is needed in humans.
Polyamines are molecules in cells that help stabilize important components like DNA and proteins, and one of them, spermidine, has been linked to longevity. Spermidine was first discovered in semen.
This study wanted to determine if spermidine has any impact on improving egg quality in aged mice.
For more background on egg quality, check out my Complete guide to egg quality.
Some notes as youโre reading:
- Most of the data here is presented in this paper as a bar graph, so Iโm estimating the values the best I can.
- One of their main metrics for egg quality is the maturity rate of eggs that they get from the mice. Higher egg maturity rates implies that the eggs matured more quickly, suggesting theyโre higher quality.
- Youโll also see โฮผMโ used here quite a bit to describe a concentration. The large M denotes molarity (a chemistry term).
๐ Original studies are referenced in this post or within the linked Remembryo posts.
๐ก Reminder: Terms underlined with a dotted black line are linked to glossary entries. Clicking these does not count toward your paywall limit.
Spermidine is decreased in the ovaries of aged mice
The researchers first compared the metabolic profiles of ovaries from young and old mice. They found that these mice had very different profiles, with one component (spermidine) being reduced by about 1/4 to 1/2 from young mouse ovaries (depending on the test used).
Spermidine administration improves egg quality in aged mice
Spermidine by intraperitoneal injection
Intraperitoneal injections involve injections into the peritoneal cavity. The peritoneum is essentially a sac that separates the skin from the abdominal organs, and the cavity inside is a common route for administering drugs in mice.
Injecting spermidine into the peritoneal cavity of older mice increased ovarian spermidine levels, resulting in a slight boost in pre-antral and antral follicles and an increase in the number of pups per litter (5 pups versus 3 in the control group, compared to about 15 in young mice).
Next, they performed ovarian stimulation on the mice to collect eggs and see if they were better quality with spermidine treatment (ie. higher maturity, improved fertilization, etc.). The mice were treated with spermidine injections before they were stimulated.
They tried different dosages of spermidine and measured egg maturity. Aged mice without spermidine showed about a 40% maturity rate, which was comparable to the 25 mg/kg dose. At 50 mg/kg, maturity increased to about 60%, while at 100 mg/kg it dropped to about 55%, suggesting a possible detrimental effect with a high dose.
They found that spermidine increased the number of eggs retrieved, their maturity and fragmentation:
- Young mice (about 25 eggs, 90% maturity, 2% fragmentation).
- Aged mice without spermidine (about 11 eggs, 60% maturity, 10% fragmentation)
- Aged mice with spermidine injection (about 18 eggs, 70% maturity, 5% fragmentation)
They also showed that fertilization and blastocyst conversion rates improved with spermidine:
- Young mice (about 90% fertilization, 70% of 2-cell embryos converted to blastocysts)
- Aged mice without spermidine (about 50% fertilization, 30% blastocyst conversion)
- Aged mice with spermidine injections (about 70% fertilization, 40% blastocyst conversion)
Additionally, aneuploidy was reduced when using spermidine. They performed karyotypes on the mouse eggs, and found that young mice showed a low amount of aneuploidy compared to aged mice (about 8% vs 30%). Injection of spermidine decreased the amount of aneuploidy from 30% to about 20%.
Spermidine by the oral route
They repeated some of the experiments above by administering spermidine by the oral route (in drinking water), and found similar results. They used a concentration of 3mM for 30 days. Note that 3mM corresponds to a spermidine concentration of 0.43575 g/L, which the mice sipped from each day. Itโs not clear how much they actually drank, or their exact weights, so giving accurate oral dosages isnโt possible.
Spermidine in the culture media during IVM
They also retrieved immature eggs from mice, then matured them by in vitro maturation and supplemented spermidine in the IVM culture media (three concentrations were used: 25 ฮผM, 50 ฮผM and 100 ฮผM.). The timing wasnโt specifically mentioned, but it seems like it was for 14 hours.
They found that 25 ฮผM resulted in improved maturity, with 50 ฮผM performing even better. However, 100 ฮผM decreased the maturity rates and was comparable to not using spermidine at all (again, suggesting that too high a dosage may be detrimental).
Aneuploidy decreased from about 40% to 25% in mature eggs from aged mice with or without spermidine supplemented.
Mitophagy is central to the effects of spermidine on aged eggs
Now that theyโre confidant that spermidine has a positive effect on improving the quality of eggs from aged mice, they wanted to better understand whatโs causing this to happen.
First, they isolated mRNA from the mice to see if there were differences in gene expression. They found that aged mice had increased expression of genes involved in autophagy and mitophagy.
Autophagy is a process that occurs in cells to breakdown and recycle unused or degrading components. When autophagy targets the mitochondria, itโs called mitophagy. Autophagy/mitophagy was reduced in aged mice, but spermidine supplementation increased the activity of these processes.
Mitophagy is an important process to remove aged and damaged mitochondria. High levels of damaged mitochondria can contribute to oxidative stress by releasing reactive oxygen species (ROS), and can trigger cell death by releasing mitochondrial DNA (Ma et al. 2020). These factors can contribute to poor egg quality, which might be reversed by using spermidine to promote mitophagy.
Spermidine is effective in pig eggs
Next, they wanted to do a couple of things: they wanted to see if spermidine works in another animal besides the mouse, and if it improves oxidative stress levels. Oxidative stress is caused by ROS, like hydrogen peroxide, which can naturally be produced in the egg. Itโs generally believed that prolonged exposure to ROS contributes to aging.
They made a model using pig eggs and subjected them to oxidative stress using hydrogen peroxide.
Using this model, they found that ROS decreased egg maturity rates. There was no improvement when they used 50 ฮผM of spermidine, but there was when they used 100 ฮผM. This shows that spermidine protects eggs from oxidative stress.
Conclusions
This study compared young mice to old mice that were treated with or without spermidine.
They looked at 2 routes of administration of spermidine: daily intraperitoneal injections, and supplementation in drinking water (oral route).
Both methods improved egg quality in older mice, such as increasing egg maturity, fertilization rates, and decreasing aneuploidy rates. There was also a higher number of eggs retrieved.
They also retrieved immature eggs from mice and matured them in the lab (in vitro maturation or IVM). Supplementing spermidine in the IVM culture media resulted in improved egg maturity rates and reduced aneuploidy.
Further experiments found that spermidine promoted a cellular process called mitophagy, where old and damaged mitochondria are recycled. Without mitophagy, damaged mitochondria could accumulate and cause stress that could contribute to low egg quality.
They also found similar results in another model, involving pig egg cells.
Overall, this is a really interesting study that shows spermidine could be an important factor for improving egg quality in older women. However, there are two major issues:
The dosage of spermidine needs to be worked out. Experiments in this study showed that dosages that were too high may be detrimental. The authors note a previous study by Jiang et al. (2021), which shows that high levels of spermidine can cause oxidative stress. Furthermore, Senekowitsch et al. (2023) showed that a dosage of 15 mg/day oral spermidine is broken down and isnโt detectable in the blood, suggesting that spermidine isnโt stable through the oral route at this dosage. The dosage needs to be examined in humans to determine the best amount.
These results were found in mice, and not humans. Besides the obvious physical differences, the reproductive biology of humans is very different from mice. However, the fact that they were able to see a benefit by supplementing spermidine in mice (intraperitoneally and orally), in culture (with IVM) and in pigs, is promising.
Nonetheless, more work needs to be done before this supplement can be used in people.
Reference
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About Embryoman
Embryoman (Sean Lauber) is a former embryologist and the founder of Remembryo, an IVF research and fertility education website. After working in an IVF lab in the US, he returned to Canada and now focuses on making fertility research more accessible. He holds a Masterโs in Immunology and launched Remembryo in 2018 to help patients and professionals make sense of IVF research. Sean shares weekly study updates on Facebook, Instagram, and Reddit regularly. He also answers questions on Reddit or in his private Facebook group.
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