Comprehensive investigation of the role of CD38 in ovarian NAD+ metabolism and reproductive aging

Author

Lauren Haky, Dominican University of CaliforniaFollow

Graduation Year

2023

Document Type

Master's Thesis

Degree

Master of Science

Program

Biological Science

Program Director

Meredith Protas, PhD

First Reader

Eric Verdin, PhD

Second Reader

Rosalba Perrone, PhD

Abstract

Nicotinamide adenine dinucleotide (NAD+) is a cofactor and coenzyme found in all living cells and is crucial for energy metabolism and tissue homeostasis. It is well documented that several tissues exhibit an age-related NAD+ decline which is strongly associated with aging and age-associated diseases. While the underlying cause of NAD+ decline is unknown, one possibility is that the major NAD+ consuming enzyme, CD38, may drive tissue NAD+ decline during aging. Several studies have previously reported that NAD+ precursor supplementation or CD38 inhibition increased tissue NAD+ levels, overall health, and lifespan in mice.

Women experience an irreversible decline in reproductive health with advancing age; however, the underlying mechanisms contributing are largely unknown. Recent studies report that NAD+ levels decrease with age in the ovary and may contribute to declining oocyte quality and infertility. Importantly, restoring ovarian NAD+ levels via precursor supplementation increased ovarian NAD+ levels, oocyte quality, and rescued fertility in aged female mice. These studies emphasize the importance of NAD+ within the ovarian microenvironment. However, the mechanisms responsible for the ovarian NAD+ decline remain unclear.

For the first time, we report the localization of ovarian CD38 and its impact on the immune profile during aging. Breeding trials, follicular counts, and NAD+ measurements comparing CD38 KO and WT mice indicate a strong phenotypic difference in young mouse ovaries and fertility, however, this phenotypic change was not maintained during reproductive aging. In addition, we have found that the lack of CD38 impacts the timeline of the initial ovarian reserve establishment. We find that the genetic ablation of CD38 may be beneficial in young reproductive life, but is not protective in female fertility during aging.

Comments

Data and findings exhibited in this academic thesis have been submitted to Cell Reports as a Research Article and are currently under review and is available as a pre-print on BioRxiv (Perrone et al. 2023), doi: https://doi.org/10.1101/2023.05.08.539779, https://www.biorxiv.org/content/10.1101/2023.05.08.539779v1

Loss of CD38 enhances young female ovarian function through its effects on NAD+ metabolism. Rosalba Perrone ^1,$, Prasanna Vadhana Ashok Kumaar ^1,$, Lauren Haky ^1,2,$, Cosmo Hahn ¹, Rebeccah Riley ¹, Julia Balough ¹, Giuliana Zaza ¹, Bikem Soygur ¹, Kaitlyn Hung ¹, Leandro Prado ¹, Herbert G. Kasler ¹, Ritesh Tiwari ¹, Hiroyuki Matsui ¹, Genesis Vega Hormazabal ¹, Francesca Elizabeth Duncan ^1,3,* and Eric Verdin ^1,*

¹ Buck Institute For Research on Aging, Novato, CA, USA

² The Dominican University of California, San Rafael, CA, USA

³ Department of Obstetrics and Gynecology, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA.

^$ R. Perrone, P. V. Ashok Kumaar and L. Haky equally contributed to this work

*Correspondence: f-duncan@northwestern.edu , everdin@buckinstitute.org