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 b...
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Frontiers Media S.A.
2022-05-01
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| Series: | Frontiers in Endocrinology |
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| author | Mirella L. Meyer-Ficca Mirella L. Meyer-Ficca Alexie E. Zwerdling Corey A. Swanson Abby G. Tucker Sierra A. Lopez Sierra A. Lopez Miles K. Wandersee Miles K. Wandersee Gina M. Warner Gina M. Warner Katie L. Thompson Katie L. Thompson Claudia C.S. Chini Claudia C.S. Chini Haolin Chen Eduardo N. Chini Eduardo N. Chini Ralph G. Meyer Ralph G. Meyer |
| author_facet | Mirella L. Meyer-Ficca Mirella L. Meyer-Ficca Alexie E. Zwerdling Corey A. Swanson Abby G. Tucker Sierra A. Lopez Sierra A. Lopez Miles K. Wandersee Miles K. Wandersee Gina M. Warner Gina M. Warner Katie L. Thompson Katie L. Thompson Claudia C.S. Chini Claudia C.S. Chini Haolin Chen Eduardo N. Chini Eduardo N. Chini Ralph G. Meyer Ralph G. Meyer |
| author_sort | Mirella L. Meyer-Ficca |
| collection | DOAJ |
| 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. |
| first_indexed | 2024-12-10T05:03:11Z |
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| issn | 1664-2392 |
| language | English |
| last_indexed | 2024-12-10T05:03:11Z |
| publishDate | 2022-05-01 |
| publisher | Frontiers Media S.A. |
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| series | Frontiers in Endocrinology |
| spelling | doaj.art-b2ca36068f6c4b30b2c371a2d2a7a93c2022-12-22T02:01:20ZengFrontiers Media S.A.Frontiers in Endocrinology1664-23922022-05-011310.3389/fendo.2022.896356896356Low NAD+ Levels Are Associated With a Decline of Spermatogenesis in Transgenic ANDY and Aging MiceMirella L. Meyer-Ficca0Mirella L. Meyer-Ficca1Alexie E. Zwerdling2Corey A. Swanson3Abby G. Tucker4Sierra A. Lopez5Sierra A. Lopez6Miles K. Wandersee7Miles K. Wandersee8Gina M. Warner9Gina M. Warner10Katie L. Thompson11Katie L. Thompson12Claudia C.S. Chini13Claudia C.S. Chini14Haolin Chen15Eduardo N. Chini16Eduardo N. Chini17Ralph G. Meyer18Ralph G. Meyer19School of Veterinary Medicine, Utah State University, Logan, UT, United StatesDepartment of Animal, Dairy, and Veterinary Sciences, College of Agriculture and Applied Sciences, Utah State University, Logan, UT, United StatesDepartment of Animal, Dairy, and Veterinary Sciences, College of Agriculture and Applied Sciences, Utah State University, Logan, UT, United StatesSchool of Veterinary Medicine, Utah State University, Logan, UT, United StatesDepartment of Animal, Dairy, and Veterinary Sciences, College of Agriculture and Applied Sciences, Utah State University, Logan, UT, United StatesSchool of Veterinary Medicine, Utah State University, Logan, UT, United StatesDepartment of Animal, Dairy, and Veterinary Sciences, College of Agriculture and Applied Sciences, Utah State University, Logan, UT, United StatesSchool of Veterinary Medicine, Utah State University, Logan, UT, United StatesDepartment of Animal, Dairy, and Veterinary Sciences, College of Agriculture and Applied Sciences, Utah State University, Logan, UT, United StatesSignal Transduction and Molecular Nutrition Laboratory, Kogod Aging Center, Department of Anesthesiology and Perioperative Medicine, Mayo Clinic College of Medicine, Rochester, MN, United StatesDepartment of Anesthesiology and Perioperative Medicine Mayo Clinic, Jacksonville, FL, United StatesSignal Transduction and Molecular Nutrition Laboratory, Kogod Aging Center, Department of Anesthesiology and Perioperative Medicine, Mayo Clinic College of Medicine, Rochester, MN, United StatesDepartment of Anesthesiology and Perioperative Medicine Mayo Clinic, Jacksonville, FL, United StatesSignal Transduction and Molecular Nutrition Laboratory, Kogod Aging Center, Department of Anesthesiology and Perioperative Medicine, Mayo Clinic College of Medicine, Rochester, MN, United StatesDepartment of Anesthesiology and Perioperative Medicine Mayo Clinic, Jacksonville, FL, United StatesDepartment of Biochemistry and Molecular Biology, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, United StatesSignal Transduction and Molecular Nutrition Laboratory, Kogod Aging Center, Department of Anesthesiology and Perioperative Medicine, Mayo Clinic College of Medicine, Rochester, MN, United StatesDepartment of Anesthesiology and Perioperative Medicine Mayo Clinic, Jacksonville, FL, United StatesSchool of Veterinary Medicine, Utah State University, Logan, UT, United StatesDepartment of Animal, Dairy, and Veterinary Sciences, College of Agriculture and Applied Sciences, Utah State University, Logan, UT, United StatesAdvanced 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.https://www.frontiersin.org/articles/10.3389/fendo.2022.896356/fullvitamin B3niacinnicotinamidetestisagingretinoic acid |
| spellingShingle | Mirella L. Meyer-Ficca Mirella L. Meyer-Ficca Alexie E. Zwerdling Corey A. Swanson Abby G. Tucker Sierra A. Lopez Sierra A. Lopez Miles K. Wandersee Miles K. Wandersee Gina M. Warner Gina M. Warner Katie L. Thompson Katie L. Thompson Claudia C.S. Chini Claudia C.S. Chini Haolin Chen Eduardo N. Chini Eduardo N. Chini Ralph G. Meyer Ralph G. Meyer Low NAD+ Levels Are Associated With a Decline of Spermatogenesis in Transgenic ANDY and Aging Mice Frontiers in Endocrinology vitamin B3 niacin nicotinamide testis aging retinoic acid |
| 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 | vitamin B3 niacin nicotinamide testis aging retinoic acid |
| url | https://www.frontiersin.org/articles/10.3389/fendo.2022.896356/full |
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