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

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 journal › Article › peer-review

205 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 language	English
Pages (from-to)	1670-1681
Number of pages	19
Journal	Cell Reports
Volume	30
Issue number	6
DOIs	https://doi.org/10.1016/j.celrep.2020.01.058
Publication status	Published - 11 Feb 2020
Externally published	Yes

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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Bertoldo, M. J., Listijono, D. R., Ho, W. H. J., Riepsamen, A. H., Goss, D. M., Richani, D., Jin, X. L., Mahbub, S., Campbell, J. M., Habibalahi, A., Loh, W. G. N., Youngson, N. A., Maniam, J., Wong, A. S. A., Selesniemi, K., Bustamante, S., Li, C., Zhao, Y., Marinova, M. B., ... Wu, L. E. (2020). NAD⁺ repletion rescues female fertility during reproductive aging. Cell Reports, 30(6), 1670-1681. https://doi.org/10.1016/j.celrep.2020.01.058

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title = "NAD+ repletion rescues female fertility during reproductive aging",

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

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

year = "2020",

month = feb,

day = "11",

doi = "10.1016/j.celrep.2020.01.058",

language = "English",

volume = "30",

pages = "1670--1681",

journal = "Cell Reports",

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Bertoldo, MJ, Listijono, DR, Ho, WHJ, Riepsamen, AH, Goss, DM, Richani, D, Jin, XL, Mahbub, S, Campbell, JM, Habibalahi, A, Loh, WGN, Youngson, NA, Maniam, J, Wong, ASA, Selesniemi, K, Bustamante, S, Li, C, Zhao, Y, Marinova, MB, Kim, LJ, Lau, L, Wu, RM, Mikolaizak, AS, Araki, T, Le Couteur, DG, Turner, N, Morris, MJ, Walters, KA, Goldys, E, O'Neill, C, Gilchrist, RB, Sinclair, DA, Homer, HA & Wu, LE 2020, 'NAD⁺ repletion rescues female fertility during reproductive aging', Cell Reports, vol. 30, no. 6, pp. 1670-1681. https://doi.org/10.1016/j.celrep.2020.01.058

TY - JOUR

T1 - NAD+ repletion rescues female fertility during reproductive aging

AU - Bertoldo, Michael J.

AU - Listijono, Dave R.

AU - Ho, Wing Hong Jonathan

AU - Riepsamen, Angelique H.

AU - Goss, Dale M.

AU - Richani, Dulama

AU - Jin, Xing L.

AU - Mahbub, Saabah

AU - Campbell, Jared M.

AU - Habibalahi, Abbas

AU - Loh, Wei Guo Nicholas

AU - Youngson, Neil A.

AU - Maniam, Jayanthi

AU - Wong, Ashley S. A.

AU - Selesniemi, Kaisa

AU - Bustamante, Sonia

AU - Li, Catherine

AU - Zhao, Yiqing

AU - Marinova, Maria B.

AU - Kim, Lynn Jee

AU - Lau, Laurin

AU - Wu, Rachael M.

AU - Mikolaizak, A. Stefanie

AU - Araki, Toshiyuki

AU - Le Couteur, David G.

AU - Turner, Nigel

AU - Morris, Margaret J.

AU - Walters, Kirsty A.

AU - Goldys, Ewa

AU - O'Neill, Christopher

AU - Gilchrist, Robert B.

AU - Sinclair, David A.

AU - Homer, Hayden A.

AU - Wu, Lindsay E.

PY - 2020/2/11

Y1 - 2020/2/11

N2 - 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.

AB - 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.

KW - aging

KW - embryo development

KW - female fertility

KW - in vitro fertilization

KW - infertility

KW - nicotinamide adenine dinucleotide (NAD+)

KW - nicotinamide mononucleotide (NMN)

KW - oocyte

KW - reproductive aging

KW - SIRT2

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U2 - 10.1016/j.celrep.2020.01.058

DO - 10.1016/j.celrep.2020.01.058

M3 - Article

C2 - 32049001

AN - SCOPUS:85079339561

SN - 2211-1247

VL - 30

SP - 1670

EP - 1681

JO - Cell Reports

JF - Cell Reports

IS - 6

ER -

NAD⁺ repletion rescues female fertility during reproductive aging

Abstract

Keywords

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