NAD+ repletion rescues female fertility during reproductive aging

Michael J. Bertoldo, Dave R. Listijono, Wing Hong Jonathan Ho, Angelique H. Riepsamen, Dale M. Goss, Dulama Richani, Xing L. Jin, Saabah Mahbub, Jared M. Campbell, Abbas Habibalahi, Wei Guo Nicholas Loh, Neil A. Youngson, Jayanthi Maniam, Ashley S. A. Wong, Kaisa Selesniemi, Sonia Bustamante, Catherine Li, Yiqing Zhao, Maria B. Marinova, Lynn Jee KimLaurin Lau, Rachael M. Wu, A. Stefanie Mikolaizak, Toshiyuki Araki, David G. Le Couteur, Nigel Turner, Margaret J. Morris, Kirsty A. Walters, Ewa Goldys, Christopher O'Neill, Robert B. Gilchrist, David A. Sinclair*, Hayden A. Homer, Lindsay E. Wu

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

32 Citations (Scopus)

Abstract

Reproductive aging in female mammals is an irreversible process associated with declining oocyte quality, which is the rate-limiting factor to fertility. Here, we show that this loss of oocyte quality with age accompanies declining levels of the prominent metabolic cofactor nicotinamide adenine dinucleotide (NAD +). Treatment with the NAD + metabolic precursor nicotinamide mononucleotide (NMN) rejuvenates oocyte quality in aged animals, leading to restoration in fertility, and this can be recapitulated by transgenic overexpression of the NAD +-dependent deacylase SIRT2, though deletion of this enzyme does not impair oocyte quality. These benefits of NMN extend to the developing embryo, where supplementation reverses the adverse effect of maternal age on developmental milestones. These findings suggest that late-life restoration of NAD + levels represents an opportunity to rescue female reproductive function in mammals.

Original languageEnglish
Pages (from-to)1670-1681
Number of pages19
JournalCell Reports
Volume30
Issue number6
DOIs
Publication statusPublished - 11 Feb 2020
Externally publishedYes

Keywords

  • aging
  • embryo development
  • female fertility
  • in vitro fertilization
  • infertility
  • nicotinamide adenine dinucleotide (NAD+)
  • nicotinamide mononucleotide (NMN)
  • oocyte
  • reproductive aging
  • SIRT2

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