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

doi:10.1016/j.celrep.2020.01.058

NAD⁺ Repletion Rescues Female Fertility during Reproductive Aging

Cell Rep. 2020 Feb 11;30(6):1670-1681.e7. doi: 10.1016/j.celrep.2020.01.058.

Authors

Michael J Bertoldo¹, Dave R Listijono¹, Wing-Hong Jonathan Ho¹, Angelique H Riepsamen², Dale M Goss³, Dulama Richani², Xing L Jin⁴, Saabah Mahbub⁵, Jared M Campbell⁵, Abbas Habibalahi⁵, Wei-Guo Nicholas Loh², Neil A Youngson³, Jayanthi Maniam³, Ashley S A Wong³, Kaisa Selesniemi⁶, Sonia Bustamante⁷, Catherine Li³, Yiqing Zhao², Maria B Marinova², Lynn-Jee Kim³, Laurin Lau², Rachael M Wu⁸, A Stefanie Mikolaizak⁹, Toshiyuki Araki¹⁰, David G Le Couteur¹¹, Nigel Turner³, Margaret J Morris³, Kirsty A Walters², Ewa Goldys⁵, Christopher O'Neill⁴, Robert B Gilchrist², David A Sinclair¹², Hayden A Homer¹³, Lindsay E Wu¹⁴

Affiliations

¹ School of Medical Sciences, UNSW Sydney, Sydney, NSW, Australia; School of Women's and Children's Health, UNSW Sydney, Sydney, NSW, Australia.
² School of Women's and Children's Health, UNSW Sydney, Sydney, NSW, Australia.
³ School of Medical Sciences, UNSW Sydney, Sydney, NSW, Australia.
⁴ Human Reproduction Unit, Kolling Institute, Sydney Medical School, University of Sydney, St Leonards, NSW, Australia.
⁵ ARC Centre of Excellence in Nanoscale Biophotonics, UNSW Sydney, NSW, Australia.
⁶ Paul F. Glenn Laboratories for the Biological Mechanisms of Aging, Harvard Medical School, Boston MA, USA; Jumpstart Fertility Pty Ltd., Sydney, NSW, Australia.
⁷ Bioanalytical Mass Spectrometry Facility, Mark Wainwright Analytical Centre, UNSW Sydney, Sydney, NSW, Australia.
⁸ Graduate Entry Medical School, University of Limerick, Limerick, Republic of Ireland.
⁹ Neuroscience Research Australia, Randwick, NSW, Australia.
¹⁰ Department of Peripheral Nervous System Research, National Institute of Neuroscience, National Center of Neurology and Psychiatry, Tokyo, Japan.
¹¹ ANZAC Medical Research Institute, University of Sydney, Concord, NSW, Australia.
¹² 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. Electronic address: david_sinclair@hms.harvard.edu.
¹³ 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. Electronic address: h.homer@uq.edu.au.
¹⁴ School of Medical Sciences, UNSW Sydney, Sydney, NSW, Australia. Electronic address: lindsay.wu@unsw.edu.au.

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.

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

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Aging
Animals
Female
Fertility / genetics*
Mice
Mice, Transgenic
NAD / metabolism*

Substances

NAD

Abstract

Publication types

MeSH terms

Substances

Grants and funding