{"doi":"10.3389/fendo.2022.896356","title":"Low NAD+ Levels Are Associated With a Decline of Spermatogenesis in Transgenic ANDY and Aging Mice","abstract":"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.","journal":"Frontiers in Endocrinology","year":2022,"id":257460,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":18,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9469,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2022-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":908491,"name":"Alexie E. Zwerdling","orcid":null,"position":1,"is_corresponding":false},{"id":908492,"name":"Corey A. Swanson","orcid":null,"position":2,"is_corresponding":false},{"id":908493,"name":"Abby G. Tucker","orcid":null,"position":3,"is_corresponding":false},{"id":908494,"name":"Sierra A. Lopez","orcid":null,"position":4,"is_corresponding":false},{"id":908495,"name":"Miles K. Wandersee","orcid":null,"position":5,"is_corresponding":false},{"id":639580,"name":"Gina M. Warner","orcid":null,"position":6,"is_corresponding":false},{"id":865284,"name":"Katie L. Thompson","orcid":null,"position":7,"is_corresponding":false},{"id":115405,"name":"Claudia C.S. Chini","orcid":null,"position":8,"is_corresponding":false},{"id":657418,"name":"Haolin Chen","orcid":"0000-0001-7021-7115","position":9,"is_corresponding":false},{"id":256584,"name":"Eduardo N. Chini","orcid":"0000-0003-1555-4834","position":10,"is_corresponding":false},{"id":907939,"name":"Ralph G. Meyer","orcid":"0000-0002-1518-4872","position":11,"is_corresponding":false},{"id":907938,"name":"Mirella L. Meyer‐Ficca","orcid":"0000-0002-9949-8157","position":0,"is_corresponding":true}],"reference_count":38,"raw_metadata":null,"created_at":"2026-07-19T00:25:34.440699Z","pmid":"35600581","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}