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Telomeres are considered to be an internal biological clock, and their progressive shortening has been associated with the risk of age-related diseases and reproductive alterations. Over recent years, an increasing number of studies have focused on the association between telomere length and fertility, identifying sperm telomere length (STL) as a novel biomarker of male fertility. Although typically considered to be repeated DNA sequences, telomeres have recently been shown to also include a long non-coding RNA (lncRNA) known as TERRA (telomeric repeat-containing RNAs). Interestingly, males with idiopathic infertility show reduced testicular TERRA expression, suggesting a link between TERRA and male fertility. The aim of this study was to investigate the role of seminal TERRA expression in embryo quality. To this end, STL and TERRA expression were quantified by Real Time qPCR in the semen of 35 men who underwent assisted reproductive technologies (ART) and 30 fertile men. We found that TERRA expression in semen and STL was reduced in patients that underwent ART (both p &lt, 0.001). Interestingly, TERRA and STL expressions were positively correlated (p = 0.010), and TERRA expression was positively associated with embryo quality (p &lt, 0.001). These preliminary findings suggest a role for TERRA in the maintenance of sperm telomere integrity during gametogenesis, and for the first time, TERRA expression was found as a predictive factor for embryo quality in the setting of assisted reproduction.

Study question Could sperm telomere length (STL) represent a novel parameter and biomarker of sperm quality? Summary answer STL is associated with standard semen quality parameters and, more importantly, it is significantly associated with levels of DNA fragmentation and sperm protamination. What is known already Telomeres are fundamental for genome integrity. Recent studies have demonstrated that STL increases with age and men with oligozoospermia have shorter sperm telomeres than normozoospermic men. Study design, size, duration Cohort study conducted from September 2014 to June 2015 on 100 subjects with normal standard semen parameters. Participants/materials, setting, methods STL was measured indirectly by quantitative polymerase chain reaction using telomere/single-copy gene ratio, sperm DNA fragmentation by terminal deoxynucleotidyltransferase-mediated dUTP nick-end labeling assay and protamination by aniline blue staining. Data were analyzed for determining the relationships between STL, standard semen parameters and DNA fragmentation and protamination. Main results and the role of chance Among standard semen parameters, STL was positively associated with progressive motility (P = 0.004) and vitality (P = 0.007). STL was significantly and negatively associated with sperm DNA fragmentation (P = 0.001) and significantly and positively associated with protamination (P = 0.002). The role of chance was limited and the findings have biological relevance and a pathophysiological explanation. Limitations, reasons for caution For the present study, we deliberately selected only men with normozoospermia to better analyze whether STL might represent a biomarker of sperm quality beyond traditional sperm parameters. Additional studies in proven fertile men with normal sperm parameters are needed. Wider implications of the findings The measurement of STL is a simple and rapid method that offers further information about the quality of sperm. The results of this study demonstrate that STL could be considered as an additional sperm parameter and opens new perspectives in the evaluation of the infertile male. Additional studies will clarify the significance of this parameter also as a prognostic biomarker in assisted reproduction. Study funding/competing interests No external funding was either sought or obtained for this study. There are no conflicts of interest to be declared.

Telomere length (TL) dynamics in vivo are defined by TL and its age-dependent change, brought about by cell replication. Leukocyte TL (LTL), which reflects TL in hematopoietic stem cells (HSCs), becomes shorter with age. In contrast, sperm TL, which reflects TL in the male germ cells, becomes longer with age. Moreover, offspring of older fathers display longer LTL. Thus far, no study has examined LTL and sperm TL relations with age in the same individuals, nor considered their implications for the paternal age at conception (PAC) effect on offspring LTL. We report that in 135 men (mean age: 34.4 years; range: 18 -68 years) on average, LTL became shorter by 19 bp/year (r ¼ 20.3; P ¼ 0.0004), while sperm TL became longer by 57 bp/year (r ¼ 0.32; P ¼ 0.0002). Based on previously reported replication rates of HSCs and male germ cells, we estimate that HSCs lose 26 bp per replication. However, male germ cells gain only 2.48 bp per rep- lication. As TL is inherited in an allele-specific manner, the magnitude of the PAC effect on the offspring's LTL should be approximately half of age-dependent sperm-TL elongation. When we compared the PAC effect data from previous studies with sperm-TL data from this study, the result was consistent with this prediction. As older paternal age is largely a feature of contemporary humans, we suggest that there may be progressive elongation of TL in future generations. In this sense, germ cell TL dynamics could be driving the evolution of TL in modern humans and perhaps telomere-related diseases in the general population.