Researchers Find Link Between NAD+ and Impaired Women’s Fertility

A woman’s fertility normally decreases by her late 30s with reproductive function eventually ceasing at menopause. Science has shown that a biochemical called nicotinamide adenine dinucleotide (NAD+), present in all cells in the body, plays a critical role in fertility decline. Researchers have revealed how this happens and have identified potential new approaches to enhance reproductive longevity.

“Studying ovarian biology and reproductive aging is not just about trying to increase fertility, but really about the overall health of females,” said Study Senior Author Eric Verdin, MD. “We want to understand the processes that lead to decreased fertility that are linked to menopause and therefore linked to overall lifespan and health span of women. This is a perspective shift that needs to happen.”

Study Co-first Author Rosalba Perrone, PhD, commented, “We really made a step forward in understanding the role of NAD in ovarian function and how a female’s reproductive lifespan progresses. What makes this research exciting is demonstrating we can modulate NAD+ to affect fertility.”

It is known that NAD+ production subsides with age and maintaining optimal levels is vital for key cellular functions and healthy aging, said Perrone.

Recently, she explained, it became clear that the same decline was occurring in the ovaries, contributing to the natural diminishing of egg numbers along with reduced egg quality, both of which contribute to decreased fertility in females. “So, we knew that NAD was really important in promoting ovarian function, but what we didn’t know is why it declines in the first place, what is the driver of this decline?” Perrone said.

To uncover the molecular mechanisms regulating ovarian NAD+ loss, first the researchers began by adding another piece of the puzzle: CD38, an enzyme known to be one of the main culprits in degrading NAD+.

Perrone explained that during aging, more CD38 is expressed, leading to increased degradation of NAD+, which accelerates the aging processes. However, CD38’s role in female reproductive function had not been clearly established until their study. “We realized nobody had even looked at where this protein was located in the ovaries, so we really started from scratch,” she said.

According to the team, CD38 is primarily found in ovarian immune cells and located in specific structures outside the ovarian follicles. “We also saw that CD38 increases with age within the ovaries, which is the first time this has been shown,” she said, noting that the more CD38 in the body the less NAD+ there was. “Discovering the missing link in the literature, showing that CD38 expression led to NAD+ decline, was the most exciting part.”

Another aspect of the study which used mouse models that lacked CD38 also had more primordial follicles able to mature to release an egg. Females are born with a finite number of primordial follicles which determine the length of the ovarian lifespan, and therefore the fertility of the female. “We were amazed to see that the increased number of primordial follicles was associated with more offspring, reinforcing the biological relevance of our observations,” said Perrone.

The team asserted that showing that CD38 regulates ovarian function and fertility through NAD+ metabolism means that targeting this molecule may offer new approaches to enhance reproductive longevity. “What made this research rewarding is knowing that we can potentially modulate how CD38 consumes NAD+ and increase fertility when conception is desired.”