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Article| Volume 44, ISSUE 6, P1090-1100, June 2022

Effects of age and oligoasthenozoospermia on telomeres of sperm and blood cells

Published:October 24, 2021DOI:https://doi.org/10.1016/j.rbmo.2021.10.010

      Highlights

      • Sperm telomeres were shorter in older OAZ men than in older NZ men.
      • Younger OAZ men had a higher number of short telomeres in spermatozoa and a tendency towards lower TERC accumulation.
      • Mean telomere length in PBMC was shorter in younger OAZ patients, who also showed a higher percentage of short telomeres.
      • Positive correlations between STL and sperm count and motility were found in younger NZ men.
      • Spermatozoa from younger NZ accumulated lower TRF1 mRNA levels.

      Abstract

      Research question

      How do age and normo- or oligoasthenozoospermia affect telomere length dynamics in spermatozoa and blood?

      Design

      Sperm and blood samples were collected from a cohort of 37 men aged 25 and under and 40 men aged 40 and over, with either normozoospermia (NZ) or oligoasthenozoospermia (OAZ). Telomere length was evaluated using quantitative fluorescence in-situ hybridization. Telomerase mRNA (TERC and TERT) and shelterin (TRF1) gene expression were analysed using quantitative real-time polymerase chain reaction. TRF1 protein immunoreactivity was also evaluated using immunofluorescence.

      Results

      Mean sperm telomere length (STL) increased with age in the NZ group; older NZ men accumulated the longest telomeres (P < 0.001). In peripheral blood mononuclear cells (PBMC), mean telomere length decreased with age in NZ groups, although not reaching statistical significance. Interestingly, the younger OAZ group had the shortest mean telomere length (versus young NZ, P = 0.0081; versus old NZ, P = 0.0116; versus old OAZ, P = 0.0009) and accumulated the highest percentage of short telomeres compared with the other groups (overall P = 0.0017). Analysis of TERC and TERT mRNA expression in spermatozoa and PBMC did not show significant differences among groups. Statistically significant positive correlations were found between STL and seminal parameters in younger NZ men (P = 0.009 for sperm count and P = 0.007 for total progressive motility). Protein immunoreactivity of TRF1 in blood was not significantly different in all groups analysed.

      Conclusions

      The OAZ group did not show the increase of STL with age that is seen in NZ individuals, suggesting that telomere length elongation mechanisms fail in OAZ patients. In PBMC, younger OAZ individuals showed significantly shorter mean telomere length, suggesting that this parameter could be a good biomarker of OAZ in younger OAZ patients. Telomerase gene and TRF1 mRNA expression and TRF1 protein immunoreactivity did not differ significantly between groups, and so these factors cannot be used as OAZ biomarkers.

      Keywords

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      References

        • Allsopp R.C.
        • Vaziri H.
        • Patterson C.
        • Goldstein S.
        • Younglai E.V.
        • Futcher A.B.
        • Greider C.W.
        • Harley C.B.
        Telomere length predicts replicative capacity of human fibroblasts.
        Proc. Natl. Acad. Sci U S A. 1992; 89: 10114-10118
        • Amirchaghmaghi E.
        • Rezaei A.
        • Moini A.
        • Roghaei M.A.
        • Hafezi M.
        • Aflatoonian R.
        Gene expression analysis of VEGF and its receptors and assessment of its serum level in unexplained recurrent spontaneous abortion.
        Cell J. 2015; 16: 538-545
        • Amirzadegan M.
        • Sadeghi N.
        • Tavalaee M.
        • Nasr-Esfahani M.H.
        Analysis of leukocyte and sperm telomere length in oligozoospermic men.
        Andrologia. 2021; 53: e14204
        • Antunes D.M.
        • Kalmbach K.H.
        • Wang F.
        • Dracxler R.C.
        • Seth-Smith M.L.
        • Kramer Y.
        • Buldo-Licciardi J.
        • Kohlrausch F.B.
        • Keefe D.L.
        A single-cell assay for telomere DNA content shows increasing telomere length heterogeneity, as well as increasing mean telomere length in human spermatozoa with advancing age.
        J. Assist. Reprod. Genet. 2015; 32: 1685-1690
        • Aston K.I.
        • Hunt S.C.
        • Susser E.
        • Kimura M.
        • Factor-Litvak P.
        • Carrell D.
        • Aviv A.
        Divergence of sperm and leukocyte age-dependent telomere dynamics: implications for male-driven evolution of telomere length in humans.
        Mol. Hum. Reprod. 2012; 18: 517-522
        • Baird D.M.
        • Britt-Compton B.
        • Rowson J.
        • Amso N.N.
        • Gregory L.
        • Kipling D.
        Telomere instability in the male germline.
        Hum. Mol. Genet. 2006; 15: 45-51
        • Balmori C.
        • Varela E.
        Should we consider telomere length and telomerase activity in male factor infertility?.
        Curr. Opin. Obstet. Gynecol. 2018; 30: 197-202
        • Berneau S.C.
        • Shackleton J.
        • Nevin C.
        • Altakroni B.
        • Papadopoulos G.
        • Horne G.
        • Brison D.R.
        • Murgatroyd C.
        • Povey A.C.
        • Carroll M.
        Associations of sperm telomere length with semen parameters, clinical outcomes and lifestyle factors in human normozoospermic samples.
        Andrology. 2020; 8: 583-593
        • Bianchi A.
        • Smith S.
        • Chong L.
        • Elias P.
        • de Lange T.
        TRF1 is a dimer and bends telomeric DNA.
        EMBO J. 1997; 16: 1785-1794
        • Biron-Shental T.
        • Wiser A.
        • Hershko-Klement A.
        • Markovitch O.
        • Amiel A.
        • Berkovitch A.
        Sub-fertile sperm cells exemplify telomere dysfunction.
        J. Assist. Reprod. Genet. 2018; 35: 143-148
        • Blackburn E.H.
        Structure and function of telomeres.
        Nature. 1991; 350: 569-573
        • Blackburn E.H.
        • Epel E.S.
        • Lin J.
        Human telomere biology: a contributory and interactive factor in aging, disease risks, and protection.
        Science. 2015; 350: 1193-1198
        • Canela A.
        • Vera E.
        • Klatt P.
        • Blasco M.A.
        High-throughput telomere length quantification by FISH and its application to human population studies.
        Proc. Natl. Acad. Sci. U S A. 2007; 104: 5300-5305
        • Cariati F.
        • Jaroudi S.
        • Alfarawati S.
        • Raberi A.
        • Alviggi C.
        • Pivonello R.
        • Wells D.
        Investigation of sperm telomere length as a potential marker of paternal genome integrity and semen quality.
        Reprod. Biomed. Online. 2016; 33: 404-411
        • Chua A.C.
        • Abdul Karim A.K.
        • Tan A.C.C.
        • Abu M.A.
        • Ahmad M.F.
        The outcome of intra-cytoplasmic sperm injection (ICSI): do the sperm concentration and motility matter?.
        Horm. Mol. Biol. Clin. Investig. 2021; 42: 367-372
        • Colasante A.
        • Minasi M.G.
        • Scarselli F.
        • Casciani V.
        • Zazzaro V.
        • Ruberti A.
        • Greco P.
        • Varricchio M.T.
        • Greco E.
        The aging male: relationship between male age, sperm quality and sperm DNA damage in an unselected population of 3124 men attending the fertility centre for the first time.
        Arch. Ital. Urol. Androl. 2019; 90: 254-259
        • Cooke H.J.
        • Smith B.A.
        Variability at the telomeres of the human X/Y pseudoautosomal region.
        Cold Spring Harb. Symp. Quant. Biol. 1986; 51: 213-219
        • Crow J.F.
        The origins, patterns and implications of human spontaneous mutation.
        Nat. Rev. Genet. 2000; 1: 40-47
        • Darmishonnejad Z.
        • Tavalaee M.
        • Izadi T.
        • Tanhaei S.
        • Nasr-Esfahani M.H.
        Evaluation of sperm telomere length in infertile men with failed/low fertilization after intracytoplasmic sperm injection.
        Reprod. Biomed. Online. 2019; 38: 579-587
        • Darmishonnejad Z.
        • Zarei-Kheirabadi F.
        • Tavalaee M.
        • Zarei-Kheirabadi M.
        • Zohrabi D.
        • Nasr-Esfahani M.H.
        Relationship between sperm telomere length and sperm quality in infertile men.
        Andrologia. 2020; 52: e13546
        • de Lange T.
        Shelterin: the protein complex that shapes and safeguards human telomeres.
        Genes Dev. 2005; 19: 2100-2110
        • de Lange T.
        Shelterin-mediated telomere protection.
        Annu. Rev. Genet. 2018; 52: 223-247
        • Derevyanko A.
        • Whittemore K.
        • Schneider R.P.
        • Jimenez V.
        • Bosch F.
        • Blasco M.A.
        Gene therapy with the TRF1 telomere gene rescues decreased TRF1 levels with aging and prolongs mouse health span.
        Aging Cell. 2017; 16: 1353-1368
        • Eisenhauer K.M.
        • Gerstein R.M.
        • Chiu C.P.
        • Conti M.
        • Hsueh A.J.
        Telomerase activity in female and male rat germ cells undergoing meiosis and in early embryos.
        Biol. Reprod. 1997; 56: 1120-1125
        • Fainberg J.
        • Kashanian J.A.
        Recent advances in understanding and managing male infertility.
        F1000 Res. 2019; 8: 670
        • Ferlin A.
        • Rampazzo E.
        • Rocca M.S.
        • Keppel S.
        • Frigo A.C.
        • De Rossi A.
        • Foresta C.
        In young men sperm telomere length is related to sperm number and parental age.
        Hum. Reprod. 2013; 28: 3370-3376
        • Flores I.
        • Canela A.
        • Vera E.
        • Tejera A.
        • Cotsarelis G.
        • Blasco M.A.
        The longest telomeres: a general signature of adult stem cell compartments.
        Genes Dev. 2008; 22: 654-667
        • Gonzalez D.C.
        • Ory J.
        • Blachman-Braun R.
        • Nackeeran S.
        • Best J.C.
        • Ramasamy R.
        Advanced paternal age and sperm DNA fragmentation: a systematic review.
        World J. Mens Health. 2022; 40: 104-115
        • Greider C.W.
        • Blackburn E.H.
        Identification of a specific telomere terminal transferase activity in Tetrahymena extracts.
        Cell. 1985; 43: 405-413
        • Greider C.W.
        • Blackburn E.H.
        The telomere terminal transferase of Tetrahymena is a ribonucleoprotein enzyme with two kinds of primer specificity.
        Cell. 1987; 51: 887-898
        • Hao L.Y.
        • Armanios M.
        • Strong M.A.
        • Karim B.
        • Feldser D.M.
        • Huso D.
        • Greider C.W.
        Short telomeres, even in the presence of telomerase, limit tissue renewal capacity.
        Cell. 2005; 123: 1121-1131
        • Ioannou D.
        • Millan N.M.
        • Jordan E.
        • Tempest H.G.
        A new model of sperm nuclear architecture following assessment of the organization of centromeres and telomeres in three-dimensions.
        Sci. Rep. 2017; 7: 41585
        • Johnson S.L.
        • Dunleavy J.
        • Gemmell N.J.
        • Nakagawa S.
        Consistent age-dependent declines in human semen quality: a systematic review and meta-analysis.
        Ageing Res. Rev. 2015; 19: 22-33
        • Jungwirth A.
        • Giwercman A.
        • Tournaye H.
        • Diemer T.
        • Kopa Z.
        • Dohle G.
        • Krausz C.
        European Association of Urology Working Group on Male Infertility. European Association of Urology guidelines on Male Infertility: the 2012 update.
        Eur. Urol. 2012; 62: 324-332
        • Kalmbach K.
        • Robinson Jr., L.G.
        • Wang F.
        • Liu L.
        • Keefe D.
        Telomere length reprogramming in embryos and stem cells.
        Biomed. Res. Int. 2014; 2014925121
        • Karlseder J.
        • Kachatrian L.
        • Takai H.
        • Mercer K.
        • Hingorani S.
        • Jacks T.
        • de Lange T.
        Targeted deletion reveals an essential function for the telomere length regulator TRF1.
        Mol. Cell Biol. 2003; 23: 6533-6541
        • Kimura M.
        • Cherkas L.F.
        • Kato B.S.
        • Demissie S.
        • Hjelmborg J.B.
        • Brimacombe M.
        • Cupples A.
        • Hunkin J.L.
        • Gardner J.P.
        • Lu X.
        • Cao X.
        • Sastrasinh M.
        • Province M.A.
        • Hunt S.C.
        • Christensen K.
        • Levy D.
        • Spector T.D.
        • Aviv A.
        Offspring's leukocyte telomere length, paternal age, and telomere elongation in sperm.
        PLoS Genet. 2008; 4: e37
        • Lafuente R.
        • Bosch-Rue E.
        • Ribas-Maynou J.
        • Alvarez J.
        • Brassesco C.
        • Amengual M.J.
        • Benet J.
        • Garcia-Peiro A.
        • Brassesco M.
        Sperm telomere length in motile sperm selection techniques: a qFISH approach.
        Andrologia. 2018 Mar; 50
        • Laurentino S.
        • Cremers J.F.
        • Horsthemke B.
        • Tuttelmann F.
        • Czeloth K.
        • Zitzmann M.
        • Pohl E.
        • Rahmann S.
        • Schroder C.
        • Berres S.
        • Redmann K.
        • Krallmann C.
        • Schlatt S.
        • Kliesch S.
        • Gromoll J.
        A germ cell-specific ageing pattern in otherwise healthy men.
        Aging Cell. 2020; 19: e13242
        • Lee Y.W.
        • Arora R.
        • Wischnewski H.
        • Azzalin C.M.
        TRF1 participates in chromosome end protection by averting TRF2-dependent telomeric R loops.
        Nat. Struct. Mol. Biol. 2018; 25: 147-153
        • Liu L.
        • Bailey S.M.
        • Okuka M.
        • Munoz P.
        • Li C.
        • Zhou L.
        • Wu C.
        • Czerwiec E.
        • Sandler L.
        • Seyfang A.
        • Blasco M.A.
        • Keefe D.L.
        Telomere lengthening early in development.
        Nat. Cell Biol. 2007; 9: 1436-1441
        • Lopez-Otin C.
        • Blasco M.A.
        • Partridge L.
        • Serrano M.
        • Kroemer G.
        The hallmarks of aging.
        Cell. 2013; 153: 1194-1217
        • Lymbery R.A.
        • Evans J.P.
        • Kennington W.J.
        Post-ejaculation thermal stress causes changes to the RNA profile of sperm in an external fertilizer.
        Proc. Biol. Sci. 2020; 28720202147
        • M'Kacher R.
        • Colicchio B.
        • Marquet V.
        • Borie C.
        • Najar W.
        • Hempel W.M.
        • Heidingsfelder L.
        • Oudrhiri N.
        • al Jawhari M.
        • Wilhelm-Murer N.
        • Miguet M.
        • Dieterlen A.
        • Deschenes G.
        • Tabet A.C.
        • Junker S.
        • Grynberg M.
        • Fenech M.
        • Bennaceur-Griscelli A.
        • Voisin P.
        • Carde P.
        • Jeandidier E.
        • Yardin C.
        Telomere aberrations, including telomere loss, doublets, and extreme shortening, are increased in patients with infertility.
        Fertil. Steril. 2021; 115: 164-173
        • Martinez P.
        • Blasco M.A.
        Telomere-driven diseases and telomere-targeting therapies.
        J. Cell Biol. 2017; 216: 875-887
        • Martinez P.
        • Thanasoula M.
        • Munoz P.
        • Liao C.
        • Tejera A.
        • McNees C.
        • Flores J.M.
        • Fernandez-Capetillo O.
        • Tarsounas M.
        • Blasco M.A.
        Increased telomere fragility and fusions resulting from TRF1 deficiency lead to degenerative pathologies and increased cancer in mice.
        Genes Dev. 2009; 23: 2060-2075
        • Palm W.
        • de Lange T.
        How shelterin protects mammalian telomeres.
        Annu. Rev. Genet. 2008; 42: 301-334
        • Reig-Viader R.
        • Capilla L.
        • Vila-Cejudo M.
        • Garcia F.
        • Anguita B.
        • Garcia-Caldes M.
        • Ruiz-Herrera A.
        Telomere homeostasis is compromised in spermatocytes from patients with idiopathic infertility.
        Fertil. Steril. 2014; 102 (e721): 728-738
        • Reig-Viader R.
        • Vila-Cejudo M.
        • Vitelli V.
        • Busca R.
        • Sabate M.
        • Giulotto E.
        • Caldes M.G.
        • Ruiz-Herrera A.
        Telomeric repeat-containing RNA (TERRA) and telomerase are components of telomeres during mammalian gametogenesis.
        Biol. Reprod. 2014; 90: 103
        • Rocca M.S.
        • Dusi L.
        • Di Nisio A.
        • Alviggi E.
        • Iussig B.
        • Bertelle S.
        • De Toni L.
        • Garolla A.
        • Foresta C.
        • Ferlin A.
        TERRA: a novel biomarker of embryo quality and ART outcome.
        Genes (Basel). 2021; 12: 475
        • Rocca M.S.
        • Speltra E.
        • Menegazzo M.
        • Garolla A.
        • Foresta C.
        • Ferlin A.
        Sperm telomere length as a parameter of sperm quality in normozoospermic men.
        Hum. Reprod. 2016; 31: 1158-1163
        • Schaetzlein S.
        • Lucas-Hahn A.
        • Lemme E.
        • Kues W.A.
        • Dorsch M.
        • Manns M.P.
        • Niemann H.
        • Rudolph K.L.
        Telomere length is reset during early mammalian embryogenesis.
        Proc. Natl. Acad. Sci. U S A. 2004; 101: 8034-8038
        • Schrader M.
        • Muller M.
        • Heicappell R.
        • Krause H.
        • Schulze W.
        • Miller K.
        Telomerase activity and expression of telomerase subunits in the testicular tissue of infertile patients.
        Fertil. Steril. 2000; 73: 706-711
        • Schratz K.E.
        • Armanios M.
        Cancer and myeloid clonal evolution in the short telomere syndromes.
        Curr. Opin. Genet. Dev. 2020; 60: 112-118
        • Sfeir A.
        • Kosiyatrakul S.T.
        • Hockemeyer D.
        • MacRae S.L.
        • Karlseder J.
        • Schildkraut C.L.
        • de Lange T.
        Mammalian telomeres resemble fragile sites and require TRF1 for efficient replication.
        Cell. 2009; 138: 90-103
        • Singh D.
        • Paduch D.A.
        • Schlegel P.N.
        • Orwig K.E.
        • Mielnik A.
        • Bolyakov A.
        • Wright W.W.
        The production of glial cell line-derived neurotrophic factor by human Sertoli cells is substantially reduced in Sertoli cell-only testes.
        Hum. Reprod. 2017; 32: 1108-1117
        • Sun L.
        • Nakajima S.
        • Teng Y.
        • Chen H.
        • Yang L.
        • Chen X.
        • Gao B.
        • Levine A.S.
        • Lan L.
        WRN is recruited to damaged telomeres via its RQC domain and tankyrase1-mediated poly-ADP-ribosylation of TRF1.
        Nucleic Acids Res. 2017; 45: 3844-3859
        • Tahamtan S.
        • Tavalaee M.
        • Izadi T.
        • Barikrow N.
        • Zakeri Z.
        • Lockshin R.A.
        • Abbasi H.
        • Nasr-Esfahani M.H.
        Reduced sperm telomere length in individuals with varicocele is associated with reduced genomic integrity.
        Sci. Rep. 2019; 9: 4336
        • Thilagavathi J.
        • Kumar M.
        • Mishra S.S.
        • Venkatesh S.
        • Kumar R.
        • Dada R.
        Analysis of sperm telomere length in men with idiopathic infertility.
        Arch. Gynecol. Obstet. 2013; 287: 803-807
        • Thilagavathi J.
        • Mishra S.S.
        • Kumar M.
        • Vemprala K.
        • Deka D.
        • Dhadwal V.
        • Dada R.
        Analysis of telomere length in couples experiencing idiopathic recurrent pregnancy loss.
        J. Assist. Reprod. Genet. 2013; 30: 793-798
        • van Steensel B.
        • de Lange T.
        Control of telomere length by the human telomeric protein TRF1.
        Nature. 1997; 385: 740-743
        • Varela E.
        • Munoz-Lorente M.A.
        • Tejera A.M.
        • Ortega S.
        • Blasco M.A.
        Generation of mice with longer and better preserved telomeres in the absence of genetic manipulations.
        Nat. Commun. 2016; 7: 11739
        • Varela E.
        • Schneider R.P.
        • Ortega S.
        • Blasco M.A.
        Different telomere-length dynamics at the inner cell mass versus established embryonic stem (ES) cells.
        Proc. Natl. Acad. Sci. U S A. 2011; 108: 15207-15212
        • Vera E.
        • Bernardes de Jesus B.
        • Foronda M.
        • Flores J.M.
        • Blasco M.A.
        The rate of increase of short telomeres predicts longevity in mammals.
        Cell Rep. 2012; 2: 732-737
        • Wallace H.A.
        • Rana V.
        • Nguyen H.Q.
        • Bosco G.
        Condensin II subunit NCAPH2 associates with shelterin protein TRF1 and is required for telomere stability.
        J. Cell Physiol. 2019; 234: 20755-20768
        • Wang L.
        • Tu Z.
        • Liu C.
        • Liu H.
        • Kaldis P.
        • Chen Z.
        • Li W.
        Dual roles of TRF1 in tethering telomeres to the nuclear envelope and protecting them from fusion during meiosis.
        Cell Death Differ. 2018; 25: 1174-1188
        • Weikert S.
        • Christoph F.
        • Schulze W.
        • Krause H.
        • Kempkensteffen C.
        • Schostak M.
        • Miller K.
        • Schrader M.
        Testicular expression of survivin and human telomerase reverse transcriptase (hTERT) associated with spermatogenic function in infertile patients.
        Asian J. Androl. 2006; 8: 95-100
        • Weise J.M.
        • Gunes C.
        Differential regulation of human and mouse telomerase reverse transcriptase (TERT) promoter activity during testis development.
        Mol. Reprod. Dev. 2009; 76: 309-317
        • Wilkerson R.G.
        • Adler J.D.
        • Shah N.G.
        • Brown R.
        Silent hypoxia: a harbinger of clinical deterioration in patients with COVID-19.
        Am. J. Emerg. Med. 2020; 38 (e2245–2243 e2246): 2243
        • World Health Organization
        WHO Laboratory Manual for the Examination and Processing of Human Semen.
        5th edn. World Health Organization, Geneva2010
        • Wright W.E.
        • Piatyszek M.A.
        • Rainey W.E.
        • Byrd W.
        • Shay J.W.
        Telomerase activity in human germline and embryonic tissues and cells.
        Dev. Genet. 1996; 18: 173-179
        • Xu J.
        • Yang X.
        Telomerase activity in bovine embryos during early development.
        Biol. Reprod. 2000; 63: 1124-1128
        • Xu J.
        • Yang X.
        Telomerase activity in early bovine embryos derived from parthenogenetic activation and nuclear transfer.
        Biol. Reprod. 2001; 64: 770-774
        • Zimmermann M.
        • Kibe T.
        • Kabir S.
        • de Lange T.
        TRF1 negotiates TTAGGG repeat-associated replication problems by recruiting the BLM helicase and the TPP1/POT1 repressor of ATR signaling.
        Genes Dev. 2014; 28: 2477-2491

      Biography

      Carlos Balmori is Chief of the Urology and Andrology Department at IVI-RMA Madrid. In 2019, he started his PhD in telomere research at the Rey Juan Carlos University and IVI-RMA Madrid. His research interests focus on biomarkers of male fertility for diagnosis and treatment, as well as semen quality improvement techniques.
      Key message
      Telomere maintenance was altered in oligoasthenozoospermic (OAZ) men, leading to an impairment of sperm telomere length elongation with age. Younger OAZ patients had shorter telomeres in blood. This opens up the possibility of using peripheral blood mononuclear cell telomere length as a biomarker of OAZ.