Cell Reports (Feb 2020)
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 Kim,
- Laurin 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
Affiliations
- Michael J. Bertoldo
- School of Medical Sciences, UNSW Sydney, Sydney, NSW, Australia; School of Women’s and Children’s Health, UNSW Sydney, Sydney, NSW, Australia
- Dave R. Listijono
- School of Medical Sciences, UNSW Sydney, Sydney, NSW, Australia; School of Women’s and Children’s Health, UNSW Sydney, Sydney, NSW, Australia
- Wing-Hong Jonathan Ho
- School of Medical Sciences, UNSW Sydney, Sydney, NSW, Australia; School of Women’s and Children’s Health, UNSW Sydney, Sydney, NSW, Australia
- Angelique H. Riepsamen
- School of Women’s and Children’s Health, UNSW Sydney, Sydney, NSW, Australia
- Dale M. Goss
- School of Medical Sciences, UNSW Sydney, Sydney, NSW, Australia
- Dulama Richani
- School of Women’s and Children’s Health, UNSW Sydney, Sydney, NSW, Australia
- Xing L. Jin
- Human Reproduction Unit, Kolling Institute, Sydney Medical School, University of Sydney, St Leonards, NSW, Australia
- Saabah Mahbub
- ARC Centre of Excellence in Nanoscale Biophotonics, UNSW Sydney, NSW, Australia
- Jared M. Campbell
- ARC Centre of Excellence in Nanoscale Biophotonics, UNSW Sydney, NSW, Australia
- Abbas Habibalahi
- ARC Centre of Excellence in Nanoscale Biophotonics, UNSW Sydney, NSW, Australia
- Wei-Guo Nicholas Loh
- School of Women’s and Children’s Health, UNSW Sydney, Sydney, NSW, Australia
- Neil A. Youngson
- School of Medical Sciences, UNSW Sydney, Sydney, NSW, Australia
- Jayanthi Maniam
- School of Medical Sciences, UNSW Sydney, Sydney, NSW, Australia
- Ashley S.A. Wong
- School of Medical Sciences, UNSW Sydney, Sydney, NSW, Australia
- Kaisa Selesniemi
- Paul F. Glenn Laboratories for the Biological Mechanisms of Aging, Harvard Medical School, Boston MA, USA; Jumpstart Fertility Pty Ltd., Sydney, NSW, Australia
- Sonia Bustamante
- Bioanalytical Mass Spectrometry Facility, Mark Wainwright Analytical Centre, UNSW Sydney, Sydney, NSW, Australia
- Catherine Li
- School of Medical Sciences, UNSW Sydney, Sydney, NSW, Australia
- Yiqing Zhao
- School of Women’s and Children’s Health, UNSW Sydney, Sydney, NSW, Australia
- Maria B. Marinova
- School of Women’s and Children’s Health, UNSW Sydney, Sydney, NSW, Australia
- Lynn-Jee Kim
- School of Medical Sciences, UNSW Sydney, Sydney, NSW, Australia
- Laurin Lau
- School of Women’s and Children’s Health, UNSW Sydney, Sydney, NSW, Australia
- Rachael M. Wu
- Graduate Entry Medical School, University of Limerick, Limerick, Republic of Ireland
- A. Stefanie Mikolaizak
- Neuroscience Research Australia, Randwick, NSW, Australia
- Toshiyuki Araki
- Department of Peripheral Nervous System Research, National Institute of Neuroscience, National Center of Neurology and Psychiatry, Tokyo, Japan
- David G. Le Couteur
- ANZAC Medical Research Institute, University of Sydney, Concord, NSW, Australia
- Nigel Turner
- School of Medical Sciences, UNSW Sydney, Sydney, NSW, Australia
- Margaret J. Morris
- School of Medical Sciences, UNSW Sydney, Sydney, NSW, Australia
- Kirsty A. Walters
- School of Women’s and Children’s Health, UNSW Sydney, Sydney, NSW, Australia
- Ewa Goldys
- ARC Centre of Excellence in Nanoscale Biophotonics, UNSW Sydney, NSW, Australia
- Christopher O’Neill
- Human Reproduction Unit, Kolling Institute, Sydney Medical School, University of Sydney, St Leonards, NSW, Australia
- Robert B. Gilchrist
- School of Women’s and Children’s Health, UNSW Sydney, Sydney, NSW, Australia
- David A. Sinclair
- School of Medical Sciences, UNSW Sydney, Sydney, NSW, Australia; Paul F. Glenn Laboratories for the Biological Mechanisms of Aging, Harvard Medical School, Boston MA, USA; Corresponding author
- Hayden A. Homer
- School of Women’s and Children’s Health, UNSW Sydney, Sydney, NSW, Australia; Christopher Chen Oocyte Biology Laboratory, University of Queensland Centre for Clinical Research, Royal Brisbane & Women’s Hospital, Herston, QLD, Australia; Corresponding author
- Lindsay E. Wu
- School of Medical Sciences, UNSW Sydney, Sydney, NSW, Australia; Corresponding author
- Journal volume & issue
-
Vol. 30,
no. 6
pp. 1670 – 1681.e7
Abstract
Summary: 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. : Declining oocyte quality is considered an irreversible feature of aging and is rate limiting for human fertility. Bertoldo et al. show that reversing an age-dependent decline in NAD(P)H restores oocyte quality, embryo development, and functional fertility in aged mice. These findings may be relevant to reproductive medicine. Keywords: oocyte, nicotinamide adenine dinucleotide (NAD+), nicotinamide mononucleotide (NMN), SIRT2, female fertility, infertility, reproductive aging, aging, embryo development, in vitro fertilization
