CD38 regulates ovarian function and fecundity via NAD+ metabolism

Rosalba Perrone; Prasanna Vadhana Ashok Kumaar; Lauren Haky; Cosmo Hahn; Rebeccah Riley; Julia Balough; Giuliana Zaza; Bikem Soygur; Kaitlyn Hung; Leandro Prado; Herbert G Kasler; Ritesh Tiwari; Hiroyuki Matsui; Genesis Vega Hormazabal; Indra Heckenbach; Morten Scheibye-Knudsen; Francesca E Duncan; Eric Verdin

doi:10.1016/j.isci.2023.107949

CD38 regulates ovarian function and fecundity via NAD⁺ metabolism

iScience. 2023 Sep 16;26(10):107949. doi: 10.1016/j.isci.2023.107949. eCollection 2023 Oct 20.

Authors

Rosalba Perrone¹, Prasanna Vadhana Ashok Kumaar¹, Lauren Haky^{1

2}, Cosmo Hahn¹, Rebeccah Riley¹, Julia Balough¹, Giuliana Zaza¹, Bikem Soygur¹, Kaitlyn Hung¹, Leandro Prado¹, Herbert G Kasler¹, Ritesh Tiwari¹, Hiroyuki Matsui¹, Genesis Vega Hormazabal¹, Indra Heckenbach³, Morten Scheibye-Knudsen³, Francesca E Duncan^{1

4}, Eric Verdin¹

Affiliations

¹ Buck Institute for Research on Aging, Novato, CA, USA.
² The Dominican University of California, San Rafael, CA, USA.
³ Center for Healthy Aging, Department of Cellular and Molecular Medicine, University of Copenhagen, Copenhagen, Denmark.
⁴ Department of Obstetrics and Gynecology, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA.

Abstract

Mammalian female reproductive lifespan is typically significantly shorter than life expectancy and is associated with a decrease in ovarian NAD+ levels. However, the mechanisms underlying this loss of ovarian NAD+ are unclear. Here, we show that CD38, an NAD+ consuming enzyme, is expressed in the ovarian extrafollicular space, primarily in immune cells, and its levels increase with reproductive age. Reproductively young mice lacking CD38 exhibit larger primordial follicle pools, elevated ovarian NAD+ levels, and increased fecundity relative to wild type controls. This larger ovarian reserve results from a prolonged window of follicle formation during early development. However, the beneficial effect of CD38 loss on reproductive function is not maintained at advanced age. Our results demonstrate a novel role of CD38 in regulating ovarian NAD+ metabolism and establishing the ovarian reserve, a critical process that dictates a female's reproductive lifespan.

Keywords: Biochemistry; Biological sciences; Physiology.