Increasing ovarian NAD+ levels improve mitochondrial functions and reverse ovarian aging

• Published in: Free radical biology & medicine 2020-08, Vol.156, p.1-10
• Main Authors: Yang, Qingling, Cong, Luping, Wang, Yujiao, Luo, Xiaoyan, Li, Hui, Wang, Huan, Zhu, Jing, Dai, Shanjun, Jin, Haixia, Yao, Guidong, Shi, Senlin, Hsueh, Aaron J., Sun, Yingpu
• Format: Article
• Language: English
• Subjects: Infertility; Mitochondria; NAD; Ovary aging
• ISSN: 0891-5849; 1873-4596
• DOI: 10.1016/j.freeradbiomed.2020.05.003

Loss of follicles together with decreased oocyte quality and quantity contribute to age-associated ovarian senescence and infertility. Although underlying mechanisms for ovarian senescence are still unknown, mitochondrial dysfunctions have been reported. Here, we showed age-dependent decreases in ovarian Nicotinamide Adenine Dinucleotide (NAD+) levels in mice whereas supplementing aging mice with nicotinamide riboside (NR), an NAD+ precursor, increased ovarian NAD+ content. We found that increases in ovarian NAD+ levels in aging mice led to increased number of ovarian follicles and ovulatory potential as well as increased live birth rate. NR supplementation also reduced levels of reactive oxygen species and decreased spindle anomalies in aging oocytes, together with increased mitochondrial membrane potential (ΔΨm) and decreased mitochondrial clustering. In addition, NR supplementation improved ovarian mitochondrial energy metabolism. Our data suggested that supplementation with NAD+ precursors in vivo and in vitro could be potential therapeutic approaches for treating age-related ovarian infertility. Ovarian NAD+ levels decrease with age, accompanied by decreased mitochondrial functions, resulting in decreased ovary reserve and reduced oocyte quantity and quality. After NR supplementation to elevate ovarian NAD+ levels and to restore age-related impairment of mitochondria functions, ovarian senescence was attenuated as characterized by improved oocyte quantity and quality as well as increased live birth rate. [Display omitted] •Ovarian NAD+ levels decrease with aging whereas supplementing nicotinamide riboside increased ovarian NAD+ levels in mice.•NR supplementation increased ovulatory potential, oocyte quantity and quality, and increased live birth rate in aging mice.•NR supplementation improved ovarian mitochondrial functions.