Researchers have found that a naturally occurring compound enhanced fertility in older female mice by reversing age-related reproductive cell decline, causing them to produce larger litters. The discovery could one day aid in developing treatments to improve human fertility.
As women age, the immature egg cells in their ovaries, called oocytes, deteriorate and decrease in number, making it more difficult for them to fall pregnant naturally or with assisted reproductive treatment like IVF. A woman is born with a fixed number of oocytes, which mature from within a follicle found in the outside layer of the ovaries. During each reproductive cycle, several follicles begin to develop and, typically, one oocyte each cycle will become a mature egg and be ovulated from its follicle.
Previous studies into spermidine, a compound that was first isolated from sperm but is now known to have functions in many types of cells, have shown that it lengthens lifespan in yeast, flies, worms and human immune cells. Research on animal models demonstrated anti-aging properties, reducing age-related problems like cardiovascular disease in mice and cognitive decline in fruit flies.
However, the effect of spermidine on oocytes was unknown. So, in a new study, researchers tested the compound on older female mice to see whether it produced any benefits. First, they compared ovarian tissue from young and middle-aged mice and found that the tissue from older mice contained far less spermidine. They also had poorer-quality oocytes and more degraded follicles.
To see whether the oocytes’ condition was related to reduced spermidine levels, the researchers injected some older mice with the compound. Compared to a control group, oocytes in the spermidine-boosted mice developed more quickly and had fewer defects. The mice also had more follicles, a measure often used in humans to estimate the number and quality of oocytes. The results were the same when spermidine was provided as an oral supplement in the mice’s drinking water.
The researchers observed that spermidine improved the success rate of the formation of blastocysts, the cluster of dividing cells that develop into embryos, and that older mice who’d been given spermidine and then conceived naturally had around twice as many young per litter as control mice of the same age.
Digging deeper, they sequenced the RNA from the oocytes of differently aged mice and found that the genes linked to cell energy production and processes that clear away cellular debris had different expression patterns in young mice, older mice, and older mice that had received spermidine.
The oocytes of spermidine-treated mice had recovered their ability to clear cellular debris, and mitochondrial function was enhanced. A similar effect was seen in pig oocytes placed under oxidative stress, a dominant feature of aging, suggesting that spermidine’s mechanism of action was similar across species.
When the researchers treated lab-cultured oocytes with a molecule that inhibits the removal of damaged mitochondria (mitophagy), they found the spermidine-treated cells matured much slower than the untreated ones, further suggesting that the compound works with the cell’s clean-up processes to produce its anti-aging effects.
“Although we have known about the anti-aging properties of spermidine, we were still surprised by its remarkable effects,” said Bo Xiong, corresponding author of the study.
The study’s findings have already generated a lot of interest in the medical community.
“The implications of these findings are far-reaching,” said Alex Polyakov, gynecologist and fertility specialist at Melbourne IVF and the Royal Women’s Hospital. “While tremendous advances in fertility treatments over the past few decades resulted in drastically improved IVF success rates, female age remains the main obstacle to success since IVF cannot counteract the effects of age on the quality and quantity of oocytes that can be obtained. The holy grail of reproductive medicine would be a technique or treatment that could reverse the effect of age on the ovaries. Zhang et al. appear to have discovered such a holy grail.”
The next step for the researchers is to see whether these results translate to humans. They plan to test spermidine fertility-enhancing properties on human oocytes in the lab to see what doses are safe and effective and whether other bodily processes are affected by the compound.
“We need precise clinical trials to address these concerns before spermidine can be applied to boost fertility in humans,” Xiong said.
The study was published in the journal Nature Aging.
Source: Nanjing Agricultural University via Nature, Scimex