Reproductive Ageing: Current insights and a potential role of NAD in the reproductive health of aging fathers and their children

in Reproduction
Authors:
Morgan B Feuz Department of Veterinary, Clinical and Life Sciences, College of Veterinary Medicine, Utah State University, Logan, Utah, USA

Search for other papers by Morgan B Feuz in
Current site
Google Scholar
PubMed
Close
,
D Colton Nelson Department of Veterinary, Clinical and Life Sciences, College of Veterinary Medicine, Utah State University, Logan, Utah, USA

Search for other papers by D Colton Nelson in
Current site
Google Scholar
PubMed
Close
,
Laura B Miller Department of Veterinary, Clinical and Life Sciences, College of Veterinary Medicine, Utah State University, Logan, Utah, USA

Search for other papers by Laura B Miller in
Current site
Google Scholar
PubMed
Close
,
Alexie E Zwerdling Department of Veterinary, Clinical and Life Sciences, College of Veterinary Medicine, Utah State University, Logan, Utah, USA

Search for other papers by Alexie E Zwerdling in
Current site
Google Scholar
PubMed
Close
,
Ralph G Meyer Department of Veterinary, Clinical and Life Sciences, College of Veterinary Medicine, Utah State University, Logan, Utah, USA

Search for other papers by Ralph G Meyer in
Current site
Google Scholar
PubMed
Close
, and
Mirella L Meyer-Ficca Department of Veterinary, Clinical and Life Sciences, College of Veterinary Medicine, Utah State University, Logan, Utah, USA

Search for other papers by Mirella L Meyer-Ficca in
Current site
Google Scholar
PubMed
Close
https://orcid.org/0000-0002-9949-8157

Correspondence should be addressed to M L Meyer-Ficca; Email: mirella.meyer@usu.edu

*(M B Feuz, D C Nelson, L B Miller and A E Zwerdling contributed equally to this work)

This paper forms part of a special issue on Reproductive Ageing. The guest editor for this special collection is Professor Karen Schindler, The State University of New Jersey, NJ, USA.

Restricted access
Rent on DeepDyve

Sign up for journal news

In brief

In light of the increasing age of first-time fathers, this article summarizes the current scientific knowledge base on reproductive aging in the male, including sperm quality and health impacts for the offspring. The emerging role of NAD decline in reproductive aging is highlighted.

Abstract

Over the past decades, the age of first-time fathers has been steadily increasing due to socio-economic pressures. While general mechanisms of aging are subject to intensive research, male reproductive aging has remained an understudied area, and the effects of increased age on the male reproductive system are still only poorly understood, despite new insights into the potential dire consequences of advanced paternal age for the health of their progeny. There is also growing evidence that reproductive aging is linked to overall health in men, but this review mainly focuses on pathophysiological consequences of old age in men, such as low sperm count and diminished sperm genetic integrity, with an emphasis on mechanisms underlying reproductive aging. The steady decline of NAD levels observed in aging men represents one of the emerging concepts in that regard. Because it offers some mechanistic rationale explaining the effects of old age on the male reproductive system, some of the NAD-dependent functions in male reproduction are briefly outlined in this review. The overview also provides many questions that remain open about the basic science of male reproductive aging.

 

  • Collapse
  • Expand
  • Aitken RJ 2022 Role of sperm DNA damage in creating de-novo mutations in human offspring: the ‘post-meiotic oocyte collusion’ hypothesis. Reproductive Biomedicine Online 45 109124. (https://doi.org/10.1016/j.rbmo.2022.03.012)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Aitken RJ 2023 Male reproductive ageing: a radical road to ruin. Human Reproduction 38 18611871. (https://doi.org/10.1093/humrep/dead157)

  • Aitken RJ & & Bakos HW 2021 Should we be measuring DNA damage in human spermatozoa? New light on an old question. Human Reproduction 36 11751185. (https://doi.org/10.1093/humrep/deab004)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Aitken RJ & & Lewis SEM 2023 DNA damage in testicular germ cells and spermatozoa. When and how is it induced? How should we measure it? What does it mean? Andrology 11 15451557. (https://doi.org/10.1111/andr.13375)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Albani E, Castellano S, Gurrieri B, Arruzzolo L, Negri L, Borroni EM & & Levi-Setti PE 2019 Male age: negative impact on sperm DNA fragmentation. Aging 11 27492761. (https://doi.org/10.18632/aging.101946)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Almeida S, Rato L, Sousa M, Alves MG & & Oliveira PF 2017 Fertility and sperm quality in the aging male. Current Pharmaceutical Design 23 44294437. (https://doi.org/10.2174/1381612823666170503150313)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Alves MBR, De Arruda RP, De Bem THC, Florez-Rodriguez SA, Sá Filho MFD, Belleannée C, Meirelles FV, Da Silveira JC, Perecin F & & Celeghini ECC 2019 Sperm-borne miR-216b modulates cell proliferation during early embryo development via K-RAS. Scientific Reports 9 10358. (https://doi.org/10.1038/s41598-019-46775-8)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Alves MBR, Celeghini ECC & & Belleannée C 2020 From sperm motility to sperm-borne microRNA signatures: new approaches to predict male fertility potential. Frontiers in Cell and Developmental Biology 8 791. (https://doi.org/10.3389/fcell.2020.00791)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Amir S, Vakonaki E, Tsiminikaki K, Tzatzarakis M, Michopoulou V, Flamourakis M, Kalliantasi K, Karzi V, Fragkiadaki P, Renieri E, et al.2020 Sperm telomere length: diagnostic and prognostic biomarker in male infertility (Review). World Academy of Sciences Journal 1 259263. (https://doi.org/10.3892/wasj.2020.31)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Amjad S, Nisar S, Bhat AA, Shah AR, Frenneaux MP, Fakhro K, Haris M, Reddy R, Patay Z, Baur J, et al.2021 Role of NAD+ in regulating cellular and metabolic signaling pathways. Molecular Metabolism 49 101195. (https://doi.org/10.1016/j.molmet.2021.101195)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Amorim JA, Coppotelli G, Rolo AP, Palmeira CM, Ross JM & & Sinclair DA 2022 Mitochondrial and metabolic dysfunction in ageing and age-related diseases. Nature Reviews Endocrinology 18 243258. (https://doi.org/10.1038/s41574-021-00626-7)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Andolz P, Bielsa MA & & Vila J 1999 Evolution of semen quality in North-Eastern Spain: a study in 22,759 infertile men over a 36 year period. Human Reproduction 14 731735. (https://doi.org/10.1093/humrep/14.3.731)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Anjum S, Krishna A, Sridaran R & & Tsutsui K 2012 Localization of gonadotropin-releasing hormone (GnRH), gonadotropin-inhibitory hormone (GnIH), kisspeptin and GnRH receptor and their possible roles in testicular activities from birth to senescence in mice. Journal of Experimental Zoology Part A 317 630644. (https://doi.org/10.1002/jez.1765)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Arnqvist G, Rönn J, Watson C, Goenaga J & & Immonen E 2022 Concerted evolution of metabolic rate, economics of mating, ecology, and pace of life across seed beetles. PNAS 119 e2205564119. (https://doi.org/10.1073/pnas.2205564119)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Arpanahi A, Brinkworth M, Iles D, Krawetz SA, Paradowska A, Platts AE, Saida M, Steger K, Tedder P & & Miller D 2009 Endonuclease-sensitive regions of human spermatozoal chromatin are highly enriched in promoter and CTCF binding sequences. Genome Research 19 13381349. (https://doi.org/10.1101/gr.094953.109)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Ashapkin V, Suvorov A, Pilsner JR, Krawetz SA & & Sergeyev O 2023 Age-associated epigenetic changes in mammalian sperm: implications for offspring health and development. Human Reproduction Update 29 2444. (https://doi.org/10.1093/humupd/dmac033)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Auger J, Kunstmann JM, Czyglik F & & Jouannet P 1995 Decline in semen quality among fertile men in Paris during the past 20 years. New England Journal of Medicine 332 281285. (https://doi.org/10.1056/NEJM199502023320501)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Bagatell CJ & & Bremner WJ 1996 Androgens in men – uses and abuses. New England Journal of Medicine 334 707714. (https://doi.org/10.1056/NEJM199603143341107)

  • Bartke A 2022 Somatotropic axis, pace of life and aging. Frontiers in Endocrinology 13 916139. (https://doi.org/10.3389/fendo.2022.916139)

  • Batra V, Norman E, Morgan HL & & Watkins AJ 2022 Parental programming of offspring health: the intricate interplay between diet, environment, reproduction and development. Biomolecules 12 1289. (https://doi.org/10.3390/biom12091289)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Beneke S & & Bürkle A 2007 Poly(ADP-ribosyl)ation in mammalian ageing. Nucleic Acids Research 35 74567465. (https://doi.org/10.1093/nar/gkm735)

  • Bernhardt L, Dittrich M, Prell A, Potabattula R, Drummer C, Behr R, Hahn T, Schorsch M, Müller T & & Haaf T 2023 Age-related methylation changes in the human sperm epigenome. Aging 15 12571278. (https://doi.org/10.18632/aging.204546)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Bhasin S, Brito JP, Cunningham GR, Hayes FJ, Hodis HN, Matsumoto AM, Snyder PJ, Swerdloff RS, Wu FC & & Yialamas MA 2018 Testosterone therapy in men with hypogonadism: an endocrine society clinical practice guideline. Journal of Clinical Endocrinology and Metabolism 103 17151744. (https://doi.org/10.1210/jc.2018-00229)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Bibi R, Jahan S, Kafeel Qureshi S, Razak S, Afsar T, Almajwal A, Kafeel Qureshi M, Hammadeh ME & & Amor H 2023 Analysis of sperm chromatin packaging and reproductive biomarker to evaluate the consequence of advanced male age. Frontiers in Endocrinology 14 1092603. (https://doi.org/10.3389/fendo.2023.1092603)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Bujan L, Mieusset R, Mondinat C, Mansat A & & Pontonnier F 1988 Sperm morphology in fertile men and its age related variation. Andrologia 20 121128. (https://doi.org/10.1111/j.1439-0272.1988.tb00672.x)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Caballero-Campo P, Lin W, Simbulan R, Liu X, Feuer S, Donjacour A & & Rinaudo PF 2018 Advanced paternal age affects sperm count and anogenital distance in mouse offspring. Reproductive Sciences 25 515522. (https://doi.org/10.1177/1933719118759441)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Cao M, Shao X, Chan P, Cheung W, Kwan T, Pastinen T & & Robaire B 2020 High-resolution analyses of human sperm dynamic methylome reveal thousands of novel age-related epigenetic alterations. Clinical Epigenetics 12 192. (https://doi.org/10.1186/s13148-020-00988-1)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Carone BR, Hung JH, Hainer SJ, Chou MT, Carone DM, Weng Z, Fazzio TG & & Rando OJ 2014 High-resolution mapping of chromatin packaging in mouse embryonic stem cells and sperm. Developmental Cell 30 1122. (https://doi.org/10.1016/j.devcel.2014.05.024)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Celik-Ozenci C & & Tasatargil A 2013 Role of poly(ADP-ribose) polymerases in male reproduction. Spermatogenesis 3 e24194. (https://doi.org/10.4161/spmg.24194)

  • Champroux A, Torres-Carreira J, Gharagozloo P, Drevet JR & & Kocer A 2016 Mammalian sperm nuclear organization: resiliencies and vulnerabilities. Basic and Clinical Andrology 26 17. (https://doi.org/10.1186/s12610-016-0044-5)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Chan PTK & & Robaire B 2022 Advanced paternal age and future generations. Frontiers in Endocrinology 13 897101. (https://doi.org/10.3389/fendo.2022.897101)

  • Chen GX, Li HY, Lin YH, Huang ZQ, Huang PY, Da LC, Shi H, Yang L, Feng YB & & Zheng BH 2022 The effect of age and abstinence time on semen quality: a retrospective study. Asian Journal of Andrology 24 7377. (https://doi.org/10.4103/aja202165)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Chini CCS, Peclat TR, Warner GM, Kashyap S, Espindola-Netto JM, de Oliveira GC, Gomez LS, Hogan KA, Tarragó MG, Puranik AS, et al.2020 CD38 ecto-enzyme in immune cells is induced during aging and regulates NAD+ and NMN levels. Nature Metabolism 2 12841304. (https://doi.org/10.1038/s42255-020-00298-z)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Chini CCS, Cordeiro HS, Tran NLK & & Chini EN 2024 nad metabolism: role in senescence regulation and aging. Aging Cell 23 e13920. (https://doi.org/10.1111/acel.13920)

  • Choubey M, Ranjan A, Bora PS, Baltazar F, Martin LJ & & Krishna A 2019 Role of adiponectin as a modulator of testicular function during aging in mice. Biochimica et Biophysica Acta 1865 413427. (https://doi.org/10.1016/j.bbadis.2018.11.019)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Chu C, Yu L, Henry-Berger J, Ru YF, Kocer A, Champroux A, Li ZT, He M, Xie SS, Ma WB, et al.2020 Knockout of glutathione peroxidase 5 down-regulates the piRNAs in the caput epididymidis of aged mice. Asian Journal of Andrology 22 590601. (https://doi.org/10.4103/aja.aja_3_20)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Chung JY, Chen H & & Zirkin B 2021 Sirt1 and Nrf2: regulation of Leydig cell oxidant/antioxidant intracellular environment and steroid formation†. Biology of Reproduction 105 13071316. (https://doi.org/10.1093/biolre/ioab150)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Condorelli RA, La Vignera S, Barbagallo F, Alamo A, Mongioì LM, Cannarella R, Aversa A & & Calogero AE 2020 Bio-functional sperm parameters: does age matter? Frontiers in Endocrinology 11 558374. (https://doi.org/10.3389/fendo.2020.558374)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Conine CC, Sun F, Song L, Rivera-Pérez JA & & Rando OJ 2018 Small RNAs gained during epididymal transit of sperm are essential for embryonic development in mice. Developmental Cell 46 470480.e3. (https://doi.org/10.1016/j.devcel.2018.06.024)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Coussens M, Maresh JG, Yanagimachi R, Maeda G & & Allsopp R 2008 Sirt1 deficiency attenuates spermatogenesis and germ cell function. PLoS One 3 e1571. (https://doi.org/10.1371/journal.pone.0001571)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Covarrubias AJ, Perrone R, Grozio A & & Verdin E 2021 NAD+ metabolism and its roles in cellular processes during ageing. Nature Reviews Molecular Cell Biology 22 119141. (https://doi.org/10.1038/s41580-020-00313-x)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Dahlen CR, Amat S, Caton JS, Crouse MS, Diniz WJDS & & Reynolds LP 2023 Paternal effects on fetal programming. Animal Reproduction 20 e20230076. (https://doi.org/10.1590/1984-3143-AR2023-0076)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Dantzer F, Mark M, Quenet D, Scherthan H, Huber A, Liebe B, Monaco L, Chicheportiche A, Sassone-Corsi P, de Murcia G, et al.2006 Poly(ADP-ribose) polymerase-2 contributes to the fidelity of male meiosis I and spermiogenesis. PNAS 103 1485414859. (https://doi.org/10.1073/pnas.0604252103)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Dong S, Chen C, Zhang J, Gao Y, Zeng X & & Zhang X 2022 Testicular aging, male fertility and beyond. Frontiers in Endocrinology 13 1012119. (https://doi.org/10.3389/fendo.2022.1012119)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Duan R, Fu Q, Sun Y & & Li Q 2022 Epigenetic clock: a promising biomarker and practical tool in aging. Ageing Research Reviews 81 101743. (https://doi.org/10.1016/j.arr.2022.101743)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Eisenberg ML 2022 Can a father be too old? Fertility and Sterility 118 9991000. (https://doi.org/10.1016/j.fertnstert.2022.09.021)

  • Eisenberg DTA & & Kuzawa CW 2018 The paternal age at conception effect on offspring telomere length: mechanistic, comparative and adaptive perspectives. Philosophical Transactions of the Royal Society B 373 20160442. (https://doi.org/10.1098/rstb.2016.0442)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Erkek S, Hisano M, Liang CY, Gill M, Murr R, Dieker J, Schübeler D, van der Vlag J, Stadler MB & & Peters AHFM 2013 Molecular determinants of nucleosome retention at CpG-rich sequences in mouse spermatozoa. Nature Structural and Molecular Biology 20 868875. (https://doi.org/10.1038/nsmb.2599)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Fang EF, Lautrup S, Hou Y, Demarest TG, Croteau DL, Mattson MP & & Bohr VA 2017 NAD+ in aging: molecular mechanisms and translational implications. Trends in Molecular Medicine 23 899916. (https://doi.org/10.1016/j.molmed.2017.08.001)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Fang W, Chen S, Jin X, Liu S, Cao X & & Liu B 2023 Metabolomics in aging research: aging markers from organs. Frontiers in Cell and Developmental Biology 11 1198794. (https://doi.org/10.3389/fcell.2023.1198794)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Fice HE & & Robaire B 2019 Telomere dynamics throughout spermatogenesis. Genes 10 525. (https://doi.org/10.3390/genes10070525)

  • Fice HE & & Robaire B 2023 Aging affects gene expression in spermatids of Brown Norway rats. Experimental Gerontology 173 112086. (https://doi.org/10.1016/j.exger.2023.112086)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Frungieri MB, Calandra RS, Bartke A & & Matzkin ME 2018 Ageing and inflammation in the male reproductive tract. Andrologia 50 e13034. (https://doi.org/10.1111/and.13034)

  • Frungieri MB, Calandra RS, Bartke A & & Matzkin ME 2021 Male and female gonadal ageing: its impact on health span and life span. Mechanisms of Ageing and Development 197 111519. (https://doi.org/10.1016/j.mad.2021.111519)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Garza S, Chen L, Galano M, Cheung G, Sottas C, Li L, Li Y, Zirkin BR & & Papadopoulos V 2022 Mitochondrial dynamics, Leydig cell function, and age-related testosterone deficiency. FASEB Journal 36 e22637. (https://doi.org/10.1096/fj.202201026R)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Gau CC, Lee HJ, Lu HY, Wu CY, Huang HY, Tsai HJ & & Yao TC 2022 Association of advanced paternal age with lung function at school age. Respiratory Research 23 259. (https://doi.org/10.1186/s12931-022-02178-4)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Golan R, Scovell JM & & Ramasamy R 2015 Age-related testosterone decline is due to waning of both testicular and hypothalamic-pituitary function. Aging Male 18 201204. (https://doi.org/10.3109/13685538.2015.1052392)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Gonzalez DC, Ory J, Blachman-Braun R, Nackeeran S, Best JC & & Ramasamy R 2022 Advanced paternal age and sperm DNA fragmentation: a systematic review. World Journal of Men’s Health 40 104. (https://doi.org/10.5534/wjmh.200195)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Goriely A, McGrath JJ, Hultman CM, Wilkie AOM & & Malaspina D 2013 “Selfish spermatogonial selection”: a novel mechanism for the association between advanced paternal age and neurodevelopmental disorders. American Journal of Psychiatry 170 599608. (https://doi.org/10.1176/appi.ajp.2013.12101352)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Grover MM & & Jenkins TG 2020 Transgenerational epigenetics. Urologic Clinics of North America 47 219225. (https://doi.org/10.1016/j.ucl.2019.12.010)

  • Gunes S, Hekim GNT, Arslan MA & & Asci R 2016 Effects of aging on the male reproductive system. Journal of Assisted Reproduction and Genetics 33 441454. (https://doi.org/10.1007/s10815-016-0663-y)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Hammoud SS, Nix DA, Zhang H, Purwar J, Carrell DT & & Cairns BR 2009 Distinctive chromatin in human sperm packages genes for embryo development. Nature 460 473478. (https://doi.org/10.1038/nature08162)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Han G, Hong SH, Lee SJ, Hong SP & & Cho C 2021 Transcriptome analysis of testicular aging in mice. Cells 10 2895. (https://doi.org/10.3390/cells10112895)

  • Han D, Yao J, Chen W, Zhuang J, Bian J, Ouyang B, Sun X, Deng C, Xie Y & & Yang Q 2023 Altered transcriptomic and metabolomic profiles of testicular interstitial fluid during aging in mice. Theriogenology 200 8695. (https://doi.org/10.1016/j.theriogenology.2023.02.004)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Hogan KA, Chini CCS & & Chini EN 2019 The multi-faceted ecto-enzyme CD38: roles in immunomodulation, cancer, aging, and metabolic diseases. Frontiers in Immunology 10 1187. (https://doi.org/10.3389/fimmu.2019.01187)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Horta F, Catt S, Ramachandran P, Vollenhoven B & & Temple-Smith P 2020 Female ageing affects the DNA repair capacity of oocytes in IVF using a controlled model of sperm DNA damage in mice. Human Reproduction 35 529544. (https://doi.org/10.1093/humrep/dez308)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Horvath S & & Raj K 2018 DNA methylation-based biomarkers and the epigenetic clock theory of ageing. Nature Reviews Genetics 19 371384. (https://doi.org/10.1038/s41576-018-0004-3)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Houtkooper RH, Pirinen E & & Auwerx J 2012 Sirtuins as regulators of metabolism and healthspan. Nature Reviews Molecular Cell Biology 13 225238. (https://doi.org/10.1038/nrm3293)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Huang Y, Li X, Sun X, Yao J, Gao F, Wang Z, Hu J, Wang Z, Ouyang B, Tu X, et al.2022a Anatomical transcriptome atlas of the male mouse reproductive system during aging. Frontiers in Cell and Developmental Biology 9 782824. (https://doi.org/10.3389/fcell.2021.782824)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Huang D, Zuo Y, Zhang C, Sun G, Jing Y, Lei J, Ma S, Sun S, Lu H, Zhang X, et al.2022b A single-nucleus transcriptomic atlas of primate testicular aging reveals exhaustion of the spermatogonial stem cell reservoir and loss of Sertoli cell homeostasis. Protein and Cell 14 888907. (https://doi.org/10.1093/procel/pwac057)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Ide H 2023 The impact of testosterone in men’s health. Endocrine Journal 70 655662. (https://doi.org/10.1507/endocrj.EJ22-0604)

  • Ihara M, Meyer-Ficca ML, Leu NA, Rao S, Li F, Gregory BD, Zalenskaya IA, Schultz RM & & Meyer RG 2014 Paternal poly (ADP-ribose) metabolism modulates retention of inheritable sperm histones and early embryonic gene expression. PLoS Genetics 10 e1004317. (https://doi.org/10.1371/journal.pgen.1004317)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Janecka M, Mill J, Basson MA, Goriely A, Spiers H, Reichenberg A, Schalkwyk L & & Fernandes C 2017 Advanced paternal age effects in neurodevelopmental disorders – review of potential underlying mechanisms. Translational Psychiatry 7 e1019. (https://doi.org/10.1038/tp.2016.294)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Jarak I, Almeida S, Carvalho RA, Sousa M, Barros A, Alves MG & & Oliveira PF 2018 Senescence and declining reproductive potential: insight into molecular mechanisms through testicular metabolomics. Biochimica et Biophysica Acta 1864 33883396. (https://doi.org/10.1016/j.bbadis.2018.07.028)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Jenkins TG & & Carrell DT 2011 The paternal epigenome and embryogenesis: poising mechanisms for development. Asian Journal of Andrology 13 7680. (https://doi.org/10.1038/aja.2010.61)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Jenkins TG, Aston KI, Pflueger C, Cairns BR & & Carrell DT 2014 Age-associated sperm DNA methylation alterations: possible implications in offspring disease susceptibility. PLoS Genetics 10 e1004458. (https://doi.org/10.1371/journal.pgen.1004458)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Jiang H, Zhu WJ, Li J, Chen QJ, Liang WB & & Gu YQ 2014 Quantitative histological analysis and ultrastructure of the aging human testis. International Urology and Nephrology 46 879885. (https://doi.org/10.1007/s11255-013-0610-0)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Johnson S & & Imai SI 2018 NAD + biosynthesis, aging, and disease. F1000Research 7 132. (https://doi.org/10.12688/f1000research.12120.1)

  • Joshi M & & Rajender S 2020 Long non-coding RNAs (lncRNAs) in spermatogenesis and male infertility. Reproductive Biology and Endocrinology 18 103. (https://doi.org/10.1186/s12958-020-00660-6)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Kanatsu-Shinohara M, Yamamoto T, Toh H, Kazuki Y, Kazuki K, Imoto J, Ikeo K, Oshima M, Shirahige K, Iwama A, et al.2019 Aging of spermatogonial stem cells by Jnk-mediated glycolysis activation. PNAS 116 1640416409. (https://doi.org/10.1073/pnas.1904980116)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Kaufman JM, Lapauw B, Mahmoud A, T’Sjoen G & & Huhtaniemi IT 2019 Aging and the male reproductive system. Endocrine Reviews 40 906972. (https://doi.org/10.1210/er.2018-00178)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Kaur G, Thompson LA & & Dufour JM 2014 Sertoli cells--immunological sentinels of spermatogenesis. Seminars in Cell and Developmental Biology 30 3644. (https://doi.org/10.1016/j.semcdb.2014.02.011)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Khandwala YS, Zhang CA, Lu Y & & Eisenberg ML 2017 The age of fathers in the USA is rising: an analysis of 168 867 480 births from 1972 to 2015. Human Reproduction 32 21102116. (https://doi.org/10.1093/humrep/dex267)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Khandwala YS, Baker VL, Shaw GM, Stevenson DK, Lu Y & & Eisenberg ML 2018 Association of paternal age with perinatal outcomes between 2007 and 2016 in the United States: population based cohort study. BMJ 363 k4372. (https://doi.org/10.1136/bmj.k4372)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Khokhlova EV, Fesenko ZS, Sopova JV & & Leonova EI 2020 Features of DNA repair in the early stages of mammalian embryonic development. Genes 11 1138. (https://doi.org/10.3390/genes11101138)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Kimmins S, Anderson RA, Barratt CLR, Behre HM, Catford SR, De Jonge CJ, Delbes G, Eisenberg ML, Garrido N, Houston BJ, et al.2023 Frequency, morbidity and equity – the case for increased research on male fertility. Nature Reviews Urology 21 102124. (https://doi.org/10.1038/s41585-023-00820-4)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Kleshchev M, Osadchuk L & & Osadchuk A 2023 Age-related changes in sperm morphology and analysis of multiple sperm defects. Frontiers in Bioscience 15 12. (https://doi.org/10.31083/j.fbs1503012)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Kumar N, Singh AK & & Choudhari AR 2017 Impact of age on semen parameters in male partners of infertile couples in a rural tertiary care center of central India: a cross-sectional study. International Journal of Reproductive Biomedicine 15 497502. (https://doi.org/10.29252/ijrm.15.8.497)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Lankenau S, Burkle A & & Lankenau DH 1999 Detection of poly(ADP-ribose) synthesis in Drosophila testes upon gamma-irradiation. Chromosoma 108 4451. (https://doi.org/10.1007/s004120050350)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Larson-Cook KL, Brannian JD, Hansen KA, Kasperson KM, Aamold ET & & Evenson DP 2003 Relationship between the outcomes of assisted reproductive techniques and sperm DNA fragmentation as measured by the sperm chromatin structure assay. Fertility and Sterility 80 895902. (https://doi.org/10.1016/s0015-0282(0301116-6)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Lautrup S, Hou Y, Fang EF & & Bohr VA 2024 Roles of NAD+ in health and aging. Cold Spring Harbor Perspectives in Medicine 14 a041193. (https://doi.org/10.1101/cshperspect.a041193)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Leduc F, Maquennehan V, Nkoma GB & & Boissonneault G 2008 DNA damage response during chromatin remodeling in elongating spermatids of mice. Biology of Reproduction 78 324332. (https://doi.org/10.1095/biolreprod.107.064162)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Levy S, Serre V, Hermo L & & Robaire B 1999 The effects of aging on the seminiferous epithelium and the blood-testis barrier of the Brown Norway rat. Journal of Andrology 20 356365. (https://doi.org/10.1002/j.1939-4640.1999.tb02529.x)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Li X, Yao J, Hu J, Deng C, Xie Y & & Wang Z 2021 iTRAQ-based proteomics of testicular interstitial fluid during aging in mice. Theriogenology 175 4453. (https://doi.org/10.1016/j.theriogenology.2021.08.034)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Liao J, Suen HC, Luk ACS, Yang L, Lee AWT, Qi H & & Lee TL 2021 Transcriptomic and epigenomic profiling of young and aged spermatogonial stem cells reveals molecular targets regulating differentiation. PLoS Genetics 17 e1009369. (https://doi.org/10.1371/journal.pgen.1009369)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Lismer A & & Kimmins S 2023 Emerging evidence that the mammalian sperm epigenome serves as a template for embryo development. Nature Communications 14 2142. (https://doi.org/10.1038/s41467-023-37820-2)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • López-Otín C, Blasco MA, Partridge L, Serrano M & & Kroemer G 2023 Hallmarks of aging: an expanding universe. Cell 186 243278. (https://doi.org/10.1016/j.cell.2022.11.001)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Lord T & & Aitken RJ 2015 Fertilization stimulates 8-hydroxy-2′-deoxyguanosine repair and antioxidant activity to prevent mutagenesis in the embryo. Developmental Biology 406 113. (https://doi.org/10.1016/j.ydbio.2015.07.024)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Lowe X, Eskenazi B, Nelson DO, Kidd S, Alme A & & Wyrobek AJ 2001 Frequency of XY sperm increases with age in fathers of boys with Klinefelter syndrome. American Journal of Human Genetics 69 10461054. (https://doi.org/10.1086/323763)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Ma Y, Zhou Y, Zhu YC, Wang SQ, Ping P & & Chen XF 2018 Lipophagy contributes to testosterone biosynthesis in male rat Leydig cells. Endocrinology 159 11191129. (https://doi.org/10.1210/en.2017-03020)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Ma Q, You X, Zhu K, Zhao X, Yuan D, Wang T, Dun Y, Wu J, Ren D, Zhang C, et al.2022 Changes in the tight junctions of the testis during aging: role of the p38 MAPK/MMP9 pathway and autophagy in Sertoli cells. Experimental Gerontology 161 111729. (https://doi.org/10.1016/j.exger.2022.111729)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Madeo F, Tavernarakis N & & Kroemer G 2010 Can autophagy promote longevity? Nature Cell Biology 12 842846. (https://doi.org/10.1038/ncb0910-842)

  • Mahfouz R, Sharma R, Sharma D, Sabanegh E & & Agarwal A 2009 Diagnostic value of the total antioxidant capacity (TAC) in human seminal plasma. Fertility and Sterility 91 805811. (https://doi.org/10.1016/j.fertnstert.2008.01.022)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Malavasi F, Deaglio S, Funaro A, Ferrero E, Horenstein AL, Ortolan E, Vaisitti T & & Aydin S 2008 Evolution and function of the ADP ribosyl cyclase/CD38 gene family in physiology and pathology. Physiological Reviews 88 841886. (https://doi.org/10.1152/physrev.00035.2007)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Martin RH 2008 Meiotic errors in human oogenesis and spermatogenesis. Reproductive Biomedicine Online 16 523531. (https://doi.org/10.1016/s1472-6483(1060459-2)

  • Martin RH & & Rademaker AW 1987 The effect of age on the frequency of sperm chromosomal abnormalities in normal men. American Journal of Human Genetics 41 484492.

  • Martins Da Silva S & & Anderson RA 2022 Reproductive axis ageing and fertility in men. Reviews in Endocrine and Metabolic Disorders 23 11091121. (https://doi.org/10.1007/s11154-022-09759-0)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Massudi H, Grant R, Braidy N, Guest J, Farnsworth B & & Guillemin GJ 2012 Age-associated changes in oxidative stress and NAD+ metabolism in human tissue. PLoS One 7 e42357. (https://doi.org/10.1371/journal.pone.0042357)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Mateo-Otero Y, Llavanera M, Recuero S, Delgado-Bermúdez A, Barranco I, Ribas-Maynou J & & Yeste M 2022 Sperm DNA damage compromises embryo development, but not oocyte fertilisation in pigs. Biological Research 55 15. (https://doi.org/10.1186/s40659-022-00386-2)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Matoba H, Fujii C, Maruyama K, Kawakubo M, Momose M, Sano K, Imamura H, Kurihara H & & Nakayama J 2024 Sirt3 regulates proliferation and progesterone production in Leydig cells via suppression of reactive oxygen species. Endocrinology 165 bqae017. (https://doi.org/10.1210/endocr/bqae017)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Matzkin ME, Calandra RS, Rossi SP, Bartke A & & Frungieri MB 2021 Hallmarks of testicular aging: the challenge of anti-inflammatory and antioxidant therapies using natural and/or pharmacological compounds to improve the physiopathological status of the aged male gonad. Cells 10 3114. (https://doi.org/10.3390/cells10113114)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Meyer RG & & Meyer-Ficca ML 2021 Metabolism in male reproductive aging. Advances in Geriatric Medicine and Research 3 e210005. (https://doi.org/10.20900/agmr20210005)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Meyer RG, Ketchum CC & & Meyer-Ficca ML 2017 Heritable sperm chromatin epigenetics: a break to remember. Biology of Reproduction 97 784797. (https://doi.org/10.1093/biolre/iox137)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Meyer-Ficca ML, Ihara M, Lonchar JD, Meistrich ML, Austin CA, Min W, Wang ZQ & & Meyer RG 2011a Poly(ADP-ribose) metabolism is essential for proper nucleoprotein exchange during mouse spermiogenesis. Biology of Reproduction 84 218228. (https://doi.org/10.1095/biolreprod.110.087361)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Meyer-Ficca ML, Lonchar JD, Ihara M, Meistrich ML, Austin CA & & Meyer RG 2011b Poly(ADP-ribose) polymerases PARP1 and PARP2 modulate topoisomerase II beta (TOP2B) function during chromatin condensation in mouse spermiogenesis. Biology of Reproduction 84 900909. (https://doi.org/10.1095/biolreprod.110.090035)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Meyer-Ficca ML, Lonchar JD, Ihara M, Bader JJ & & Meyer RG 2013 Alteration of poly(ADP-ribose) metabolism affects murine sperm nuclear architecture by impairing pericentric heterochromatin condensation. Chromosoma 122 319335. (https://doi.org/10.1007/s00412-013-0416-y)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Meyer-Ficca ML, Ihara M, Bader JJ, Leu NA, Beneke S & & Meyer RG 2015 Spermatid head elongation with normal nuclear shaping requires ADP-ribosyltransferase PARP11 (ARTD11) in mice. Biology of Reproduction 92 80. (https://doi.org/10.1095/biolreprod.114.123661)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Meyer-Ficca ML, Zwerdling AE, Swanson CA, Tucker AG, Lopez SA, Wandersee MK, Warner GM, Thompson KL, Chini CCS, Chen H, et al.2022 Low NAD+ levels are associated with a decline of spermatogenesis in transgenic ANDY and aging mice. Frontiers in Endocrinology 13 896356. (https://doi.org/10.3389/fendo.2022.896356)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Miller D, Brinkworth M & & Iles D 2010 Paternal DNA packaging in spermatozoa: more than the sum of its parts? DNA, histones, protamines and epigenetics. Reproduction 139 287301. (https://doi.org/10.1530/REP-09-0281)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Moritz L & & Hammoud SS 2022 The art of packaging the sperm genome: molecular and structural basis of the histone-to-protamine exchange. Frontiers in Endocrinology 13 895502. (https://doi.org/10.3389/fendo.2022.895502)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Mueller A, Hermo L & & Robaire B 1998 The effects of aging on the expression of glutathione S-transferases in the testis and epididymis of the Brown Norway rat. Journal of Andrology 19 450465. (https://doi.org/10.1002/j.1939-4640.1998.tb02039.x)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Mularoni V, Esposito V, Di Persio S, Vicini E, Spadetta G, Berloco P, Fanelli F, Mezzullo M, Pagotto U, Pelusi C, et al.2020 Age-related changes in human Leydig cell status. Human Reproduction 35 26632676. (https://doi.org/10.1093/humrep/deaa271)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Musson R, Gąsior Ł, Bisogno S & & Ptak GE 2022 DNA damage in preimplantation embryos and gametes: specification, clinical relevance and repair strategies. Human Reproduction Update 28 376399. (https://doi.org/10.1093/humupd/dmab046)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Navas LE & & Carnero A 2021 NAD+ metabolism, stemness, the immune response, and cancer. Signal Transduction and Targeted Therapy 6 2. (https://doi.org/10.1038/s41392-020-00354-w)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Nguyen-Powanda P & & Robaire B 2020 Oxidative stress and reproductive function in the aging male. Biology 9 282. (https://doi.org/10.3390/biology9090282)

  • Nie X, Munyoki SK, Sukhwani M, Schmid N, Missel A, Emery BR, DonorConnect, Stukenborg J-B, Mayerhofer A, Orwig KE, et al.2022 Single-cell analysis of human testis aging and correlation with elevated body mass index. Developmental Cell 57 1160–1176.e5. (https://doi.org/10.1016/j.devcel.2022.04.004)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • O’Donnell L 2014 Mechanisms of spermiogenesis and spermiation and how they are disturbed. Spermatogenesis 4 e979623. (https://doi.org/10.4161/21565562.2014.979623)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Oliveira JBA, Petersen CG, Mauri AL, Vagnini LD, Baruffi RLR & & Franco JG 2014 The effects of age on sperm quality: an evaluation of 1,500 semen samples. JBRA Assisted Reproduction 18 3441. (https://doi.org/10.5935/1518-0557.20140002)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Ozawa M, Mori H, Endo T, Ishikawa-Yamauchi Y, Motooka D, Emori C & & Ikawa M 2023 Age-related decline in spermatogenic activity accompanied with endothelial cell senescence in male mice. iScience 26 108456. (https://doi.org/10.1016/j.isci.2023.108456)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Pahune PP 2013 The total antioxidant power of semen and its correlation with the fertility potential of human male subjects. Journal of Clinical and Diagnostic Research 7 991995. (https://doi.org/10.7860/JCDR/2013/4974.3040)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Paniagua R, Nistal M, Sáez FJ & & Fraile B 1991 Ultrastructure of the aging human testis. Journal of Electron Microscopy Technique 19 241260. (https://doi.org/10.1002/jemt.1060190209)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Paul C & & Robaire B 2013 Impaired function of the blood-testis barrier during aging is preceded by a decline in cell adhesion proteins and GTPases. PLoS One 8 e84354. (https://doi.org/10.1371/journal.pone.0084354)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Pilsner JR, Saddiki H, Whitcomb BW, Suvorov A, Buck Louis GM, Mumford SL, Schisterman EF, Oluwayiose OA & & Balzer LB 2022 Sperm epigenetic clock associates with pregnancy outcomes in the general population. Human Reproduction 37 15811593. (https://doi.org/10.1093/humrep/deac084)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Pohl E, Höffken V, Schlatt S, Kliesch S, Gromoll J & & Wistuba J 2019 Ageing in men with normal spermatogenesis alters spermatogonial dynamics and nuclear morphology in Sertoli cells. Andrology 7 827839. (https://doi.org/10.1111/andr.12665)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Quesada P, Atorino L, Cardone A, Ciarcia G & & Farina B 1996 Poly(ADPribosyl)ation system in rat germinal cells at different stages of differentiation. Experimental Cell Research 226 183190. (https://doi.org/10.1006/excr.1996.0217)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Raee P, Tan SC, Najafi S, Zandsalimi F, Low TY, Aghamiri S, Fazeli E, Aghapour M, Mofarahe ZS, Heidari MH, et al.2023 Autophagy, a critical element in the aging male reproductive disorders and prostate cancer: a therapeutic point of view. Reproductive Biology and Endocrinology 21 88. (https://doi.org/10.1186/s12958-023-01134-1)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Rato L, Alves MG, Silva BM, Sousa M & & Oliveira PF 2016 Sirtuins: novel players in male reproductive health. Current Medicinal Chemistry 23 10841099. (https://doi.org/10.2174/0929867323666160229114248)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Roh E & & Kim MS 2020 Hypothalamic NAD+-sirtuin axis: function and regulation. Biomolecules 10 396. (https://doi.org/10.3390/biom10030396)

  • Ryu BY, Orwig KE, Oatley JM, Avarbock MR & & Brinster RL 2006 Effects of aging and niche microenvironment on spermatogonial stem cell self-renewal. Stem Cells 24 15051511. (https://doi.org/10.1634/stemcells.2005-0580)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Sakkas D & & Alvarez JG 2010 Sperm DNA fragmentation: mechanisms of origin, impact on reproductive outcome, and analysis. Fertility and Sterility 93 10271036. (https://doi.org/10.1016/j.fertnstert.2009.10.046)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Samans B, Yang Y, Krebs S, Sarode GV, Blum H, Reichenbach M, Wolf E, Steger K, Dansranjavin T & & Schagdarsurengin U 2014 Uniformity of nucleosome preservation pattern in Mammalian sperm and its connection to repetitive DNA elements. Developmental Cell 30 2335. (https://doi.org/10.1016/j.devcel.2014.05.023)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Sampino S, Juszczak GR, Zacchini F, Swiergiel AH, Modlinski JA, Loi P & & Ptak GE 2014 Grand-paternal age and the development of autism-like symptoms in mice progeny. Translational Psychiatry 4 e386e386. (https://doi.org/10.1038/tp.2014.27)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Santiago J, Silva JV, Alves MG, Oliveira PF & & Fardilha M 2019 Testicular aging: an overview of ultrastructural, cellular, and molecular alterations. Journals of Gerontology Series A 74 860871. (https://doi.org/10.1093/gerona/gly082)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Schmid TE, Eskenazi B, Baumgartner A, Marchetti F, Young S, Weldon R, Anderson D & & Wyrobek AJ 2007 The effects of male age on sperm DNA damage in healthy non-smokers. Human Reproduction 22 180187. (https://doi.org/10.1093/humrep/del338)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Seidman SN, Araujo AB, Roose SP, Devanand DP, Xie S, Cooper TB & & McKinlay JB 2002 Low testosterone levels in elderly men with dysthymic disorder. American Journal of Psychiatry 159 456459. (https://doi.org/10.1176/appi.ajp.159.3.456)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Serre V & & Robaire B 1998 Paternal age affects fertility and progeny outcome in the Brown Norway rat. Fertility and Sterility 70 625631. (https://doi.org/10.1016/s0015-0282(9800259-3)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Setti AS, Braga DPDAF, Provenza RR, Iaconelli A & & Borges E 2021 Oocyte ability to repair sperm DNA fragmentation: the impact of maternal age on intracytoplasmic sperm injection outcomes. Fertility and Sterility 116 123129. (https://doi.org/10.1016/j.fertnstert.2020.10.045)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Sharma R, Agarwal A, Rohra VK, Assidi M, Abu-Elmagd M & & Turki RF 2015 Effects of increased paternal age on sperm quality, reproductive outcome and associated epigenetic risks to offspring. Reproductive Biology and Endocrinology 13 35. (https://doi.org/10.1186/s12958-015-0028-x)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Sharma U, Sun F, Conine CC, Reichholf B, Kukreja S, Herzog VA, Ameres SL & & Rando OJ 2018 Small RNAs are trafficked from the epididymis to developing mammalian sperm. Developmental Cell 46 481494.e6. (https://doi.org/10.1016/j.devcel.2018.06.023)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Siddeek B, Mauduit C, Simeoni U & & Benahmed M 2018 Sperm epigenome as a marker of environmental exposure and lifestyle, at the origin of diseases inheritance. Mutation Research 778 3844. (https://doi.org/10.1016/j.mrrev.2018.09.001)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Simon L, Emery B & & Carrell DT Sperm DNA fragmentation: consequences for reproduction. In Genetic Damage in Human Spermatozoa, pp. 87105. Eds. Baldi E, & Muratori M. Cham: Springer International Publishing, 2019. (https://doi.org/10.1007/978-3-030-21664-1_6)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Singh NP, Muller CH & & Berger RE 2003 Effects of age on DNA double-strand breaks and apoptosis in human sperm. Fertility and Sterility 80 14201430. (https://doi.org/10.1016/j.fertnstert.2003.04.002)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Sloter ED, Marchetti F, Eskenazi B, Weldon RH, Nath J, Cabreros D & & Wyrobek AJ 2007 Frequency of human sperm carrying structural aberrations of chromosome 1 increases with advancing age. Fertility and Sterility 87 10771086. (https://doi.org/10.1016/j.fertnstert.2006.08.112)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Smith A & & Haaf T 1998 DNA nicks and increased sensitivity of DNA to fluorescence in situ end labeling during functional spermiogenesis. BioTechniques 25 496502. (https://doi.org/10.2144/98253rr05)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Sokanovic SJ, Capo I, Medar MM, Andric SA & & Kostic TS 2018 Long-term inhibition of PDE5 ameliorates aging-induced changes in rat testis. Experimental Gerontology 108 139148. (https://doi.org/10.1016/j.exger.2018.04.007)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Stock AJ & & Liu Y 2021 NAD-linked metabolism and intervention in short telomere syndromes and murine models of telomere dysfunction. Frontiers in Aging 2 785171. (https://doi.org/10.3389/fragi.2021.785171)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Strømland Ø, Diab J, Ferrario E, Sverkeli LJ & & Ziegler M 2021 The balance between NAD+ biosynthesis and consumption in ageing. Mechanisms of Ageing and Development 199 111569. (https://doi.org/10.1016/j.mad.2021.111569)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Suvorov A, Pilsner JR, Naumov V, Shtratnikova V, Zheludkevich A, Gerasimov E, Logacheva M & & Sergeyev O 2020 Aging induces profound changes in sncRNA in rat sperm and these changes are modified by perinatal exposure to environmental flame retardant. International Journal of Molecular Sciences 21 8252. (https://doi.org/10.3390/ijms21218252)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Syed V & & Hecht