Study suggests antidepressants may help slow reproductive aging

In a new study, Northwestern University researchers exposed roundworms—a well-established model organism in biological research—to selective serotonin reuptake inhibitors (SSRIs), a class of drugs used to treat depression and anxiety. Surprisingly, this treatment improved the quality of the eggs of the aged females.

Exposure to SSRIs not only more than doubled embryonic death, but also more than doubled chromosomal abnormalities in surviving offspring. Under the microscope, the eggs also looked younger and healthier, round and plump instead of tiny and misshapen, which is common with aging.

Amazed by the results, the researchers replicated the experiment in fruit flies, another common model organism, and SSRIs demonstrated the same effect.

Although much more work is needed, the researchers say these findings provide new opportunities to explore pharmacological interventions that could combat infertility problems in humans by improving egg quality and delaying the onset of reproductive aging.

The study will be published on May 8 in the journal Developmental biology.

“There is still a long way to go between this new finding and the fertility clinic,” said Northwestern’s Ilya Ruvinsky, who led the study. “But the more we study the reproductive system, the better we understand it and the more opportunities we have to develop practical interventions.”

Ruvinsky is a Research Associate Professor in Northwestern’s Weinberg College of Arts and Sciences. Erin Aprison, a research associate in Ruvinsky’s lab, is the first author of the paper. Svetlana Dzitoyeva, a postdoctoral researcher in Ruvinsky’s lab, is a co-author of the paper.

Eliminate the middleman

Previously, Ruvinsky’s team found that male pheromones delayed the aging of female eggs. Published in the Proceedings of the National Academy of Sciences in May 2022, the above study exposed female roundworms to male pheromones, resulting in healthier offspring.

When the female roundworms sensed the male pheromones, they diverted their energy and resources away from the overall health of the body towards increasing reproductive health. “The pheromone convinces the female to send help to her eggs and disappoint the rest of her body,” Ruvinsky said. “It’s not all or nothing, it’s changing the balance.”

In the new study, Ruvinsky and his team decided to remove male pheromones from the equation entirely.

“The neurons that signal the body to change its resources rely on serotonin as a messenger,” he said. “We identified those neurons in previous work and wondered if we could directly access that system. Perhaps we could stimulate the serotonin system with pharmaceuticals, bypassing the need for male pheromones. Lo and behold, we saw better ova in every way.”

delay the decline

To carry out the study, the team added a low dose of SSRIs to the food of the aged roundworms. The researchers primarily explored the effects of fluoxetine (Prozac), but also tested citalopram (Celexa) and zimelidine.

The researchers continuously exposed the aged worms to SSRIs at concentrations comparable to those used to treat anxiety and depression in humans. Although egg quality generally drops precipitously as worms age, fluoxetine-treated worms managed to avoid the decline.

“When we only gave a temporary regimen of the drug and then withdrew it, the egg quality stayed high for a while, but then it dropped rapidly,” Ruvinsky said. “We think it’s because they need a continuous signal.”

Ruvinsky and his team also found that when exposed to fluoxetine, the roundworms produced more egg precursors. But, in a seemingly counterproductive twist, more of these cells died. However, this is also another advantage.

“How do you get the components to make higher-quality eggs? You take components from other eggs,” Ruvinsky explained. “Many eggs die and are sent to the ‘salvage yard.’ You break the parts and use them for the few eggs that survive.”

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Wondering whether or not the finding was unique to worms, Ruvinsky’s team replicated the study in fruit flies. Once again, fluoxetine exposure improved the egg quality of the older female flies.

Although worms, flies, and humans may look very different, they have more in common than most people realize.

“This neural system does more or less the same thing in various animals,” Ruvinsky said. “More serotonin in the brain causes animals to focus on food instead of exploring their environment. That’s true for mammals, flies and worms. We may not be able to extend the window of fertility to 60 years. But even if we could add a year or two to a person’s fertile window, that would make a world of difference.”

The study, “Serotonergic Signaling Plays a Deeply Conserved Role in Improving Oocyte Quality,” was supported by the National Institutes of Health (award number R01GM126125).