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Low NAD(+) Levels Are Associated With a Decline of Spermatogenesis in Transgenic ANDY and Aging Mice

Advanced paternal age has increasingly been recognized as a risk factor for male fertility and progeny health. While underlying causes are not well understood, aging is associated with a continuous decline of blood and tissue NAD(+) levels, as well as a decline of testicular functions. The important...

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Autores principales: Meyer-Ficca, Mirella L., Zwerdling, Alexie E., Swanson, Corey A., Tucker, Abby G., Lopez, Sierra A., Wandersee, Miles K., Warner, Gina M., Thompson, Katie L., Chini, Claudia C.S., Chen, Haolin, Chini, Eduardo N., Meyer, Ralph G.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2022
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Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9120959/
https://www.ncbi.nlm.nih.gov/pubmed/35600581
http://dx.doi.org/10.3389/fendo.2022.896356
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author Meyer-Ficca, Mirella L.
Zwerdling, Alexie E.
Swanson, Corey A.
Tucker, Abby G.
Lopez, Sierra A.
Wandersee, Miles K.
Warner, Gina M.
Thompson, Katie L.
Chini, Claudia C.S.
Chen, Haolin
Chini, Eduardo N.
Meyer, Ralph G.
author_facet Meyer-Ficca, Mirella L.
Zwerdling, Alexie E.
Swanson, Corey A.
Tucker, Abby G.
Lopez, Sierra A.
Wandersee, Miles K.
Warner, Gina M.
Thompson, Katie L.
Chini, Claudia C.S.
Chen, Haolin
Chini, Eduardo N.
Meyer, Ralph G.
author_sort Meyer-Ficca, Mirella L.
collection PubMed
description Advanced paternal age has increasingly been recognized as a risk factor for male fertility and progeny health. While underlying causes are not well understood, aging is associated with a continuous decline of blood and tissue NAD(+) levels, as well as a decline of testicular functions. The important basic question to what extent ageing-related NAD(+) decline is functionally linked to decreased male fertility has been difficult to address due to the pleiotropic effects of aging, and the lack of a suitable animal model in which NAD(+) levels can be lowered experimentally in chronologically young adult males. We therefore developed a transgenic mouse model of acquired niacin dependency (ANDY), in which NAD(+) levels can be experimentally lowered using a niacin-deficient, chemically defined diet. Using ANDY mice, this report demonstrates for the first time that decreasing body-wide NAD(+) levels in young adult mice, including in the testes, to levels that match or exceed the natural NAD(+) decline observed in old mice, results in the disruption of spermatogenesis with small testis sizes and reduced sperm counts. ANDY mice are dependent on dietary vitamin B3 (niacin) for NAD(+) synthesis, similar to humans. NAD(+)-deficiency the animals develop on a niacin-free diet is reversed by niacin supplementation. Providing niacin to NAD(+)-depleted ANDY mice fully rescued spermatogenesis and restored normal testis weight in the animals. The results suggest that NAD(+) is important for proper spermatogenesis and that its declining levels during aging are functionally linked to declining spermatogenesis and male fertility. Functions of NAD(+) in retinoic acid synthesis, which is an essential testicular signaling pathway regulating spermatogonial proliferation and differentiation, may offer a plausible mechanism for the hypospermatogenesis observed in NAD(+)-deficient mice.
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spelling pubmed-91209592022-05-21 Low NAD(+) Levels Are Associated With a Decline of Spermatogenesis in Transgenic ANDY and Aging Mice Meyer-Ficca, Mirella L. Zwerdling, Alexie E. Swanson, Corey A. Tucker, Abby G. Lopez, Sierra A. Wandersee, Miles K. Warner, Gina M. Thompson, Katie L. Chini, Claudia C.S. Chen, Haolin Chini, Eduardo N. Meyer, Ralph G. Front Endocrinol (Lausanne) Endocrinology Advanced paternal age has increasingly been recognized as a risk factor for male fertility and progeny health. While underlying causes are not well understood, aging is associated with a continuous decline of blood and tissue NAD(+) levels, as well as a decline of testicular functions. The important basic question to what extent ageing-related NAD(+) decline is functionally linked to decreased male fertility has been difficult to address due to the pleiotropic effects of aging, and the lack of a suitable animal model in which NAD(+) levels can be lowered experimentally in chronologically young adult males. We therefore developed a transgenic mouse model of acquired niacin dependency (ANDY), in which NAD(+) levels can be experimentally lowered using a niacin-deficient, chemically defined diet. Using ANDY mice, this report demonstrates for the first time that decreasing body-wide NAD(+) levels in young adult mice, including in the testes, to levels that match or exceed the natural NAD(+) decline observed in old mice, results in the disruption of spermatogenesis with small testis sizes and reduced sperm counts. ANDY mice are dependent on dietary vitamin B3 (niacin) for NAD(+) synthesis, similar to humans. NAD(+)-deficiency the animals develop on a niacin-free diet is reversed by niacin supplementation. Providing niacin to NAD(+)-depleted ANDY mice fully rescued spermatogenesis and restored normal testis weight in the animals. The results suggest that NAD(+) is important for proper spermatogenesis and that its declining levels during aging are functionally linked to declining spermatogenesis and male fertility. Functions of NAD(+) in retinoic acid synthesis, which is an essential testicular signaling pathway regulating spermatogonial proliferation and differentiation, may offer a plausible mechanism for the hypospermatogenesis observed in NAD(+)-deficient mice. Frontiers Media S.A. 2022-05-06 /pmc/articles/PMC9120959/ /pubmed/35600581 http://dx.doi.org/10.3389/fendo.2022.896356 Text en Copyright © 2022 Meyer-Ficca, Zwerdling, Swanson, Tucker, Lopez, Wandersee, Warner, Thompson, Chini, Chen, Chini and Meyer https://creativecommons.org/licenses/by/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
spellingShingle Endocrinology
Meyer-Ficca, Mirella L.
Zwerdling, Alexie E.
Swanson, Corey A.
Tucker, Abby G.
Lopez, Sierra A.
Wandersee, Miles K.
Warner, Gina M.
Thompson, Katie L.
Chini, Claudia C.S.
Chen, Haolin
Chini, Eduardo N.
Meyer, Ralph G.
Low NAD(+) Levels Are Associated With a Decline of Spermatogenesis in Transgenic ANDY and Aging Mice
title Low NAD(+) Levels Are Associated With a Decline of Spermatogenesis in Transgenic ANDY and Aging Mice
title_full Low NAD(+) Levels Are Associated With a Decline of Spermatogenesis in Transgenic ANDY and Aging Mice
title_fullStr Low NAD(+) Levels Are Associated With a Decline of Spermatogenesis in Transgenic ANDY and Aging Mice
title_full_unstemmed Low NAD(+) Levels Are Associated With a Decline of Spermatogenesis in Transgenic ANDY and Aging Mice
title_short Low NAD(+) Levels Are Associated With a Decline of Spermatogenesis in Transgenic ANDY and Aging Mice
title_sort low nad(+) levels are associated with a decline of spermatogenesis in transgenic andy and aging mice
topic Endocrinology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9120959/
https://www.ncbi.nlm.nih.gov/pubmed/35600581
http://dx.doi.org/10.3389/fendo.2022.896356
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