Researchers have discovered that a naturally occurring compound reverses age-related germ cell decline, improving fertility in older female mice and allowing them to give birth to more offspring. The discovery could one day help develop treatments to improve fertility in humans.
As women age, the immature egg cells (called oocytes) in women's ovaries degenerate and decrease in number, making it more difficult for them to become pregnant naturally or through assisted reproductive treatments such as IVF. A woman has a fixed number of oocytes, which mature within follicles in the outer layer of the ovary. During each reproductive cycle, several follicles begin to develop, and typically one oocyte becomes a mature egg and is expelled from the follicle each cycle.
Spermidine is a compound originally isolated from sperm, but is now known to have functions in many types of cells. Research on spermidine has shown that it extends the lifespan of yeast, flies, worms and human immune cells. Studies in animal models have shown that spermine has anti-aging properties, reducing age-related problems such as cardiovascular disease in mice and cognitive decline in fruit flies.
However, the effects of spermidine on oocytes are not known. So in a new study, researchers tested the compound on older female mice to see if it produced any benefits. First, they compared ovarian tissue from young and middle-aged mice and found that older mice had much less spermidine in their tissues. They also have poorer oocyte quality and more degenerated follicles.
To find out whether the condition of the oocytes was related to reduced spermine levels, the researchers injected some old mice with the compound. Oocytes from mice in the spermine-enhanced group developed faster and had fewer defects than those in the control group. The mice also had more follicles, a method commonly used in humans to estimate oocyte number and quality. Adding spermidine as an oral supplement to the drinking water of mice had the same results.
The researchers observed that spermine increased the success rate in the formation of blastocysts, the group of dividing cells that develop into embryos. Older mice that were naturally conceived after taking spermine had about twice as many mice per litter as control mice of the same age.
After in-depth research, they sequenced RNA from oocytes of mice of different ages and found that genes related to cellular energy production and the process of clearing cellular debris had different expression patterns in young mice, old mice, and old mice that had taken spermidine.
Oocytes from mice given spermine restored their ability to clear cellular debris and had enhanced mitochondrial function. Similar effects were seen in porcine oocytes under oxidative stress, a major feature of aging, suggesting that spermidine's mechanism of action is similar across species.
When the researchers treated laboratory-cultured oocytes with a molecule that inhibits the clearance of damaged mitochondria (mitophagy), they found that spermidine-treated cells matured much more slowly than untreated cells, further suggesting that the compound works with the cell's cleanup process to produce anti-aging effects.
"Although we already knew that spermidine has anti-aging properties, its significant effect surprised us," said Xiong Bo, the corresponding author of the study.
The study's findings have sparked considerable interest in the medical community.
"These findings are profound," said Alex Polyakov, a gynecology and fertility specialist at Melbourne's IVF and Royal Women's Hospital. "There have been tremendous advances in infertility treatment over the past few decades, and IVF success rates have increased dramatically, but women's age remains a major barrier to success because IVF cannot counteract the effects of age on oocyte quality and quantity. The holy grail of reproductive medicine is a technology or treatment that can reverse the effects of age on the ovary. Zhang et al. appear to have discovered it."
The next step for the researchers is to see if these results translate to humans. They plan to test spermidine's fertility-promoting effects on human oocytes in the laboratory to determine what doses of spermidine are safe and effective and whether the compound affects other body processes.
"We need precise clinical trials to resolve these issues before spermidine can be applied to improve human fertility," Xiong said.
The research was published in the journal Nature Aging.