NAD+ link to fertility problems uncovered by buck researchers

CD38 controls ovarian function and fertility through NAD+ metabolism.


A woman’s fertility usually starts decreasing in her late 30s and stops at menopause. Researchers at the Buck Institute have discovered that a tiny molecule called NAD+ is crucial in this process. They’ve uncovered how it works and found new ways to extend a woman’s reproductive years potentially.

Buck President and Chief Executive Officer Eric Verdin, MD, senior author of the study in iScience, published by Cell Press, said, “Studying ovarian biology and reproductive aging is not just about trying to increase fertility but about the overall health of females. We want to understand the processes that lead to decreased fertility that are linked to menopause and, therefore, linked to women’s overall lifespan and health span. This is a perspective shift that needs to happen.”

Rosalba Perrone, Ph.D., co-first author of the study and a senior research scientist in the Verdin lab, said, “We 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.”

NAD+, found in all cells in our bodies, starts decreasing as we age. Maintaining healthy NAD+ levels is crucial for proper cell function and aging. Recently, researchers discovered this NAD+ decline in the ovaries, contributing to reduced egg quantity and quality and lower female fertility.

The mystery was why NAD+ levels dropped in the first place and what caused it. To find out, researchers added another piece to the puzzle: CD38, an enzyme responsible for breaking down NAD+.

As we age, more CD38 is produced, which breaks down NAD+ and speeds up aging. However, CD38’s role in female reproductive function was unknown. The research team discovered that CD38 is mainly in ovarian immune cells and specific structures outside the ovarian follicles. They also found that CD38 increases in the ovaries with age, leading to less NAD+. The most exciting part was connecting CD38 to NAD+ decline, filling a gap in the research.

The research team also studied mice that don’t have CD38 and discovered that these mice have more “primordial follicles,” which are essential for egg maturation. Females are born with a limited number of these follicles, determining their ovarian lifespan and fertility. Interestingly, having more primordial follicles led to more offspring in the mice, underlining the importance of their findings.

This study reveals that CD38 controls ovarian function and fertility by affecting NAD+ metabolism. Targeting CD38 could be a way to improve reproductive longevity. Perrone says CD38 is a potential drug target, as small molecules and antibodies can specifically inhibit its NAD+-degrading function. This research opens the possibility of modulating CD38 to enhance fertility when needed.

This research helps to understand how CD38 affects NAD+ and fertility, but it goes beyond that. Menopause, often connected with losing reproductive ability, is linked to overall lifespan and health. So, studying how reproductive organs function better is crucial for understanding the aging process, especially in women.

The research conducted by Buck Institute researchers provides valuable insights into the role of NAD+ and CD38 in regulating ovarian function and fertility. These findings have broader implications for understanding the aging process and overall health, particularly in women. The study opens the door to potential interventions targeting CD38 to enhance fertility. It offers new avenues for research in reproductive health and aging.

Journal reference:

  1. Rosalba Perrone, Prasanna Vadhana Ashok Kumaar et al., CD38 regulates ovarian function and fecundity via NAD+ metabolism. iScience. DOI: 10.1016/j.isci.2023.107949.
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