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
Affiliations
Rosalba Perrone
Buck Institute for Research on Aging, Novato, CA, USA
Prasanna Vadhana Ashok Kumaar
Buck Institute for Research on Aging, Novato, CA, USA
Lauren Haky
Buck Institute for Research on Aging, Novato, CA, USA; The Dominican University of California, San Rafael, CA, USA
Cosmo Hahn
Buck Institute for Research on Aging, Novato, CA, USA
Rebeccah Riley
Buck Institute for Research on Aging, Novato, CA, USA
Julia Balough
Buck Institute for Research on Aging, Novato, CA, USA
Giuliana Zaza
Buck Institute for Research on Aging, Novato, CA, USA
Bikem Soygur
Buck Institute for Research on Aging, Novato, CA, USA
Kaitlyn Hung
Buck Institute for Research on Aging, Novato, CA, USA
Leandro Prado
Buck Institute for Research on Aging, Novato, CA, USA
Herbert G. Kasler
Buck Institute for Research on Aging, Novato, CA, USA
Ritesh Tiwari
Buck Institute for Research on Aging, Novato, CA, USA
Hiroyuki Matsui
Buck Institute for Research on Aging, Novato, CA, USA
Genesis Vega Hormazabal
Buck Institute for Research on Aging, Novato, CA, USA
Indra Heckenbach
Center for Healthy Aging, Department of Cellular and Molecular Medicine, University of Copenhagen, Copenhagen, Denmark
Morten Scheibye-Knudsen
Center for Healthy Aging, Department of Cellular and Molecular Medicine, University of Copenhagen, Copenhagen, Denmark
Francesca E. Duncan
Buck Institute for Research on Aging, Novato, CA, USA; Department of Obstetrics and Gynecology, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA; Corresponding author
Eric Verdin
Buck Institute for Research on Aging, Novato, CA, USA; Corresponding author
Summary: 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.
