Abstract
In brief
Oxidative stress is recognized as an underlying driving factor of both telomere dysfunction and human subfertility/infertility. This review briefly reassesses telomere integrity as a fertility biomarker before proposing a novel, mechanistic rationale for the role of oxidative stress in the seemingly paradoxical lengthening of sperm telomeres with aging.
Abstract
The maintenance of redox balance in the male reproductive tract is critical to sperm health and function. Physiological levels of reactive oxygen species (ROS) promote sperm capacitation, while excess ROS exposure, or depleted antioxidant defenses, yields a state of oxidative stress which disrupts their fertilizing capacity and DNA structural integrity. The guanine moiety is the most readily oxidized of the four DNA bases and gets converted to the mutagenic lesion 8-hydroxy-deoxyguanosine (8-OHdG). Numerous studies have also confirmed oxidative stress as a driving factor behind accelerated telomere shortening and dysfunction. Although a clear consensus has not been reached, clinical studies also appear to associate telomere integrity with fertility outcomes in the assisted reproductive technology setting. Intriguingly, while sperm cellular and molecular characteristics make them more susceptible to oxidative insult than any other cell type, they are also the only cell type in which telomere lengthening accompanies aging. This article focuses on the oxidative stress response pathways to propose a mechanism for the explanation of this apparent paradox.
Introduction
The number of couples considering assisted reproductive technology (ART) worldwide continues to increase. In the United States alone, its use has more than doubled over the last decade and now accounts for approximately 2.2% of all infants born (CDC 2021). More than 25% of infertile couples are classified as idiopathic, thus the search for improved diagnostic biomarkers of male and female infertility has intensified over the last decade. Couples who present for ART are generally assessed for ovarian function and endocrinological serum evaluations in the woman and a ‘semen analysis’ for the male partner. Although these tests can be descriptive of fertility potential, they ultimately fail to effectively predict pregnancy or live birth outcomes. Over the past decade, a number of other ‘advanced’ and/or ‘extended’ examinations have been explored for further insight into a couple’s reproductive health status. Clinically, it is now suggested by international networks such as European Society of Human Reproduction and Embryology and American Society for Reproductive Medicine that it may be of interest to assess the integrity of the sperm nucleus including its level of condensation, fragmentation, and oxidation (Minhas et al. 2021, Baldi et al. 2022, Drevet et al. 2022, Llavanera et al. 2022, Loloi et al. 2022), although to date there is no consensus as to the tests that accurately assess these parameters. In the search for a relevant and accurate marker, of sperm/oocyte ability to fertilize and contribute to optimal embryo development, telomere length has been put forward but the significance of telomere integrity in mature germ cells remains unclear.
Telomeres have long been classically characterized by the string of non-coding TTAGGG nucleotide sequences that repeat thousands of times past the last coding genetic material to extend the chromosomal length (Moyzis et al. 1988). This free telomeric end strand is protectively capped by the scaffolding shelterin complex of proteins to avoid misidentification and targeting by cellular DNA repair machinery (Diotti & Loayza 2011). However, the mitotic process can only be facilitated by the excision/replacement of the shelterin complex, which results in a small loss of nucleotides with each subsequent round of DNA replication (McClintock 1941, Moyzis et al. 1988, Diotti & Loayza 2011). While a specialized reverse transcriptase called telomerase functions to restore lost telomeric DNA (Greider & Blackburn 1985), it is only actively expressed in germ cells and some stem cells. As telomerase activity is insufficient and/or completely lacking in most human somatic cells, they experience an unavoidable telomeric shortening with age (Harley et al. 1990, Bodnar et al. 1998). Once telomeres reach a critically short length and lose the protective shelterin ‘end-cap’ structure, the chromosome is exposed to degradation, and the cell is destined to become senescent (D’Adda di Fagagna et al. 2003).
The TTAGGG repeats are capable of forming the G-quadruplex (GQ), a pertinent noncanonical tetrahelical secondary nucleic acid structure that arises when two or more guanine quartets self-stack into a planar array via Hoogsteen hydrogen bonding (Bochman et al. 2012). The GQ impedes telomerase loading and extension, so it must first be dissociated to enable telomerase to act (Zahler et al. 1991, Biffi et al. 2013, Hwang et al. 2014). Recent genome mapping revealed overrepresentation of GQ structures in other key regions of the genome such as gene promoters and 5’ and 3’ UTRs (Hansel-Hertsch et al. 2016) and confirmed its importance in overall telomere integrity and regulation of gene expression (Fleming & Burrows 2017, 2021).
Telomere length and telomerase activity have been recognized as critical factors in general cellular health and numerous age-related diseases and premature aging syndromes (Blasco 2005). Concerning reproductive issues, over the past 15 years, clinical investigations of relative telomere length and its associations with male and female fertility have become more prevalent (Table 1). Going through the evolving literature, it is apparent that oxidative stress, one of the most common underlying mechanisms for male subfertility/infertility, is also thought to impact telomere integrity. With that perspective in mind, this review reconsiders the current literature through that lens in an attempt to better understand current clinical fertility-related observations and propose a mechanistic explanation for the apparent paradox associated with sperm telomere length, male age, and oxidative stress.
Studies (n = 33 in Females; n = 31 in males) reporting clinical investigations of relative telomere length and its associations with male and female fertility.
| Reference/gender studied | Association with infertility factor | Telomere length | Grading direction |
|---|---|---|---|
| Female | |||
| Hapangama et al. (2008) | Yes | Longer | 1 |
| Butts et al. (2009) | Yes | Shorter | −1 |
| Hanna et al. (2009) | Yes | Longer | 1 |
| Kuhn et al. (2011) | Yes | Shorter | −1 |
| Hapangama et al. (2010) | Yes | Longer | 1 |
| Treff et al. (2011) | Yes | Shorter | −1 |
| Kuhn et al. (2011) | Yes | Longer | 1 |
| Turner & Hartshorne (2013) | Yes | Shorter | −1 |
| Cheng et al. (2013) | Yes | Shorter | −1 |
| Thilagavathi et al. (2013a) | Yes | Shorter | −1 |
| Valentijn et al. (2013) | Yes | Longer | 1 |
| Li et al. (2014) | Yes | Shorter | −1 |
| Yu et al. (2014) | Yes | Shorter | −1 |
| Dracxler et al. (2014) | Yes | Longer | 1 |
| Czamanski-Cohen et al. (2015) | Yes | Shorter | −1 |
| Pedroso et al. (2015) | No | N/A | 0 |
| Valentijn et al. (2015) | Yes | Longer | 1 |
| Miranda-Furtado et al. (2016) | No | N/A | 0 |
| Li et al. (2017) | Yes | Shorter | −1 |
| Xu et al. (2017) | Yes | Shorter | −1 |
| Kalyan et al. (2017) | No | N/A | 0 |
| Wei et al. (2017) | Yes | Longer | 1 |
| Wang et al. (2017) | Yes | Longer | 1 |
| Sofiyeva et al. (2017) | Yes | Longer | 1 |
| Pollack et al. (2018) | Yes | Shorter | −1 |
| Weeg et al. (2020) | No | NS | 0 |
| Pedroso et al. (2020) | No | NS | 0 |
| Huang et al. (2020) | No | NS | 0 |
| M’kacher et al. (2021) | Yes | Shorter | −1 |
| Purdue-Smithe et al. (2021) | No | NS | 0 |
| Lekva et al. (2021) | No | NS | 0 |
| Piani et al. (2022) | No | NS | 0 |
| Michaeli et al. (2022) | Yes | Longer | 1 |
| Male | |||
| Moskovtsev et al. (2010) | Yes | N/A | 0 |
| Ferlin et al. (2013) | Yes | Shorter | −1 |
| Thilagavathi et al. (2013b) | Yes | Shorter | −1 |
| Thilagavathi et al. (2013a) | Yes | Shorter | −1 |
| Turner & Hartshorne (2013) | No | N/A | 0 |
| Reig-Viader et al. (2014) | Yes | Shorter | −1 |
| Yang et al. (2015a) | Yes | Shorter | −1 |
| Liu et al. (2015) | Yes | Shorter | −1 |
| Yang et al. (2015b) | Yes | Shorter | −1 |
| Antunes et al. (2015) | Yes | Longer | 1 |
| Rocca et al. (2016) | Yes | Shorter | −1 |
| Cariati et al. (2016) | Yes | Shorter | −1 |
| Mishra et al. (2016) | Yes | Shorter | −1 |
| Lafuente et al. (2018) | Yes | Shorter | −1 |
| Vecoli et al. (2017) | Yes | Longer | 1 |
| Biron-Shental et al. (2018) | Yes | Shorter | −1 |
| Heidary et al. (2018) | Yes | Shorter | −1 |
| Tahamtan et al. (2019) | Yes | Shorter | −1 |
| Darmishonnejad et al. (2019) | Yes | Shorter | −1 |
| Santana et al. (2019) | No | NS | 0 |
| Darmishonnejad et al. (2020) | Yes | Shorter | −1 |
| Berneau et al. (2020) | Yes | Shorter | −1 |
| Laurentino et al. (2020) | Yes | Longer | 1 |
| Amirzadegan et al. (2021) | Yes | Shorter | −1 |
| Rocca et al. (2021) | Yes | Shorter | −1 |
| Zhou et al. (2021) | Yes | Shorter | −1 |
| M’kacher et al. (2021) | Yes | Shorter | −1 |
| Gentiluomo et al. (2021) | No | NS | 0 |
| Berby et al. (2021) | No | NS | 0 |
| Lara-Cerrillo et al. (2022) | No | NS | 0 |
Telomere integrity and fertility outcomes
A recent review revealed clear associations between relative telomere length/integrity and male/female fertility factors (Vasilopoulos et al. 2019). In this review, we have identified any additional clinical investigations since the Vasilopoulos paper and characterized them in the same manner as previously reported (Darmishonnejad et al. 2019, 2020, Santana et al. 2019, Tahamtan et al. 2019, Berneau et al. 2020, Huang et al. 2020, Laurentino et al. 2020, Pedroso et al. 2020, Weeg et al. 2020, Amirzadegan et al. 2021, Berby et al. 2021, Gentiluomo et al. 2021, Lekva et al. 2021, M’kacher et al. 2021, Purdue-Smithe et al. 2021, Rocca et al. 2021, Lara-Cerrillo et al. 2022, Michaeli et al. 2022, Piani et al. 2022). A visualization of the associations of relative telomere length with known male/female fertility factors from all aforementioned clinical investigations can be found in Fig. 1.
Association of telomere length with infertility factors. Analysis of clinical studies investigating relative sperm, oocyte, leucocyte or granulosa cell telomere length and their respective association with known male (31 studies) or female infertility factors (33 studies). The graph was generated by assigning a grade of 0 (non-significant), −1 (statistically significant shorter), or +1 (statistically significant longer) to each study in the review. A detailed summary of the trials included can be found in Supplementary Table 1. Figure 1 was generated using GraphPad Prism version 9.3.1 for macOS, GraphPad Software, www.graphpad.com.
Citation: Reproduction 164, 6; 10.1530/REP-22-0189
Association of telomere length with infertility factors. Analysis of clinical studies investigating relative sperm, oocyte, leucocyte or granulosa cell telomere length and their respective association with known male (31 studies) or female infertility factors (33 studies). The graph was generated by assigning a grade of 0 (non-significant), −1 (statistically significant shorter), or +1 (statistically significant longer) to each study in the review. A detailed summary of the trials included can be found in Supplementary Table 1. Figure 1 was generated using GraphPad Prism version 9.3.1 for macOS, GraphPad Software, www.graphpad.com.
Citation: Reproduction 164, 6; 10.1530/REP-22-0189
Association of telomere length with infertility factors. Analysis of clinical studies investigating relative sperm, oocyte, leucocyte or granulosa cell telomere length and their respective association with known male (31 studies) or female infertility factors (33 studies). The graph was generated by assigning a grade of 0 (non-significant), −1 (statistically significant shorter), or +1 (statistically significant longer) to each study in the review. A detailed summary of the trials included can be found in Supplementary Table 1. Figure 1 was generated using GraphPad Prism version 9.3.1 for macOS, GraphPad Software, www.graphpad.com.
Citation: Reproduction 164, 6; 10.1530/REP-22-0189
Although there appears to be a clear and consistent trend associating shorter sperm telomeres with male infertility factors, the interpretation of the female factor relationship is less clear. This ambiguity can likely be largely attributed to the fact that often alternate cell types, such as leukocytes for example, are monitored as proxy indicators for oocyte telomere integrity despite a documented lack of correlation (Lara-Molina et al. 2020). Nevertheless, a recent retrospective analysis further confirmed that among several telomeric dysfunction biomarkers, the proportions of cells with extreme telomere shortening, as well as the extent of telomere loss, appear to be the best identifiable indicators of an increased risk of infertility in both men and women (M’kacher et al. 2021).
The impact of oxidative stress on telomere integrity
Although low physiological levels of reactive oxygen species (ROS) are required for normal cellular signaling and homeostasis (Sies & Jones 2020), an imbalance between ROS and the cellular small molecule/enzymatic antioxidant defenses can serve as the general characterization and definition of oxidative stress. Among many other genetic and environmental factors, oxidative stress is now recognized as the most common underlying mechanism to accelerate telomere shortening and dysfunction (Barnes et al. 2019). This can develop in numerous ways including, but not limited to, oxidation of the free nucleotide pool (Ito et al. 2005, Fouquerel et al. 2016), replication fork arrest (Coluzzi et al. 2019), disruption of the proteins regulating telomere length, for example, telomeric repeat binding factor 1 and 2 (TERF1 and TERF2) binding (Smogorzewska et al. 2000, Opresko et al. 2005), and/or the base modification of guanine to 8-OHdG due to its low redox potential (Kino et al. 2017), briefly depicted in Fig. 2 (adapted from De Rosa et al. 2021). The telomeric TTAGGG repeats are particularly susceptible to oxidation (Oikawa et al. 2001) and this observation has been confirmed by numerous in vitro and in vivo studies (as reviewed in Barnes et al. 2019).
Common oxidative stress insults and repair mechanisms to telomeric DNA. A brief summary of the most common guanine oxidation events and repair processing mechanisms in telomeric DNA (adapted from Lee et al. 2017, 2020, De Rosa et al. 2021). Whether occurring in the canonical double helix, or the GQ structure, 8-OHdG must be resolved by the base excision repair (BER) pathway. This starts with recognition and excision by OGG1, yielding an AP site, which must be cleaved by APE1, and processed by downstream BER to restore the original G:C bp. Only complete processing can facilitate reformation of the GQ structure. In the free nucleotide pool, MTH1 prevents misincorporation of 8-OHdGTP during replication through hydrolysis to 8-OHdGMP.
Citation: Reproduction 164, 6; 10.1530/REP-22-0189
Common oxidative stress insults and repair mechanisms to telomeric DNA. A brief summary of the most common guanine oxidation events and repair processing mechanisms in telomeric DNA (adapted from Lee et al. 2017, 2020, De Rosa et al. 2021). Whether occurring in the canonical double helix, or the GQ structure, 8-OHdG must be resolved by the base excision repair (BER) pathway. This starts with recognition and excision by OGG1, yielding an AP site, which must be cleaved by APE1, and processed by downstream BER to restore the original G:C bp. Only complete processing can facilitate reformation of the GQ structure. In the free nucleotide pool, MTH1 prevents misincorporation of 8-OHdGTP during replication through hydrolysis to 8-OHdGMP.
Citation: Reproduction 164, 6; 10.1530/REP-22-0189
Common oxidative stress insults and repair mechanisms to telomeric DNA. A brief summary of the most common guanine oxidation events and repair processing mechanisms in telomeric DNA (adapted from Lee et al. 2017, 2020, De Rosa et al. 2021). Whether occurring in the canonical double helix, or the GQ structure, 8-OHdG must be resolved by the base excision repair (BER) pathway. This starts with recognition and excision by OGG1, yielding an AP site, which must be cleaved by APE1, and processed by downstream BER to restore the original G:C bp. Only complete processing can facilitate reformation of the GQ structure. In the free nucleotide pool, MTH1 prevents misincorporation of 8-OHdGTP during replication through hydrolysis to 8-OHdGMP.
Citation: Reproduction 164, 6; 10.1530/REP-22-0189
There are several known enzymatic pathways in place to counter such oxidative insults. PRDX1 (peroxiredoxin 1, a ROS-scavenger) is highly enriched at telomeres during replication and reduces hydrogen peroxide to water and protects against oxidative attack (Abey et al. 2016). In addition, MTH1 (also known as 2-hydroxy-dATP diphosphatase or Nudix hydrolase 1 (NUDT1) or else, 7,8-dihydro-8-oxoguanine triphosphatase) converts oxidized dNTP pools to monophosphates to prevent their incorporation into DNA (Carter et al. 2015) as depicted in Fig. 2 (adapted from De Rosa et al. 2021). Perhaps most important is the general base excision repair (BER) pathway, as the impact of 8-OHdG formation and its removal on the destabilization of GQs may provide some insight to the counter-intuitive observation that sperm telomere length increases with age (Kimura et al. 2008, Laurentino et al. 2020). Once 8-OHdG is formed at a GQ, the 8-oxoG DNA glycosylase (OGG1) initiates repair via identification and removal of the oxidized base, which generates an apurinic site that impacts the thermal stability and destabilizes the GQ structure (Esposito et al. 2010, Minetti et al. 2018). The GQ cannot be reformed until the apurinic site has been fully repaired by AP endonuclease 1 (APEX1) (Wilson & Bohr 2007, Li & Wilson 2014) as depicted in Fig. 2 (adapted from De Rosa et al. 2021). Recent studies confirm that loss of APE1 activity and/or APE1-AP site coordination abrogates GQ formation (Madlener et al. 2013, Roychoudhury et al. 2020, Pramanik et al. 2022).
The dual nature of oxidative stress on telomere integrity
Interestingly, recent studies have shown that 8-OHdG-mediated destabilization of the GQ enhances telomerase activity and lengthening (Fouquerel et al. 2016). These findings offered some explanation for the observations that unrepaired 8-OHdG lesions in OGG1-deficient mice and yeast promotes telomere lengthening in vivo or cell cultures at 3% oxygen, whereas culturing cells at 20% oxygen promotes telomere shortening and aberrations (Lu & Liu 2010, Wang et al. 2010). A human clinical trial that evaluated sperm telomere length and its correlation to oxidative stress (classified as normal, mild, or severe) by seminal ROS measurement and 8-Isoprostane levels in infertile and healthy men concluded that infertile men have shorter telomeres than controls and that severe oxidative stress was negatively associated with sperm telomere length (Mishra et al. 2016). However, they also surprisingly reported that mild oxidative stress conditions actually resulted in telomere lengthening (Mishra et al. 2016). Recent work utilizing telomere-specific 8OHdG formation in normal and OGG1-deficient cells further supports the hormesis-like model in which low levels of telomeric 8-OHdG may be beneficial for telomere lengthening, whereas higher accumulated levels are detrimental (Fouquerel et al. 2019).
Sperm oxidative stress and telomere integrity
The human sperm cell is particularly vulnerable to oxidative stress for a number of reasons, including, but not limited to, a limited cytoplasmic space in which to house small molecule and/or enzymatic antioxidants, the abnormally high content of polyunsaturated fatty acids in the plasma membrane, as well as a truncated BER (Drevet et al. 2022). While sperm have OGG1 and the capacity to excise 8-OHdG residues, they do not contain APE1 (Smith et al. 2013), the next enzyme responsible for DNA incision and preparation for the new replacement base. This means they ultimately carry their abasic sites, as well as unresolved 8OHdG residues, through fertilization to the oocyte for final processing (Aitken et al. 2016).
As discussed elsewhere, aging is associated with oxidative stress in the male germ line. The spermatozoon’s unique susceptibility to oxidative stress would further imply that their telomeres would be at a greater risk of dysfunction and shorten at an even faster rate than other somatic cell types during aging. However, numerous studies have confirmed the opposite to be true, and sperm telomeres undergo age-dependent elongation (Aston et al. 2012). This seems to challenge both the oxidative stress and telomere ‘hallmarks of aging’ and is also in contrast with its gametic counterpart, the oocyte, that similar to somatic cells, experiences telomere shortening despite having active (albeit decreasing with age) telomerase activity as spermatozoa do (Kordowitzki 2021). This was previously explained as a simple evolutionary advantage, by further upregulating telomerase in the male germ line, the length of the sperm telomeres would increase with each replicative cycle and represent a paternally inherited trait that could have a multiplicative effect on human telomere length in a few successive generations (Aston et al. 2012). Until now however, an exact mechanism for this phenomenon had yet to be proposed.
Summary
In line with Opresko et al.’s recent work, we would suggest that a hormesis-like model of oxidative stress is at the heart of telomere modulation in human spermatozoa. According to this model, the unique combination of having both telomerase expression and lack of APE1 activity to process the 8OHdG lesion fully and effectively during spermatogenesis defines the telomeric response to oxidative stress. Thus, while other cell types are able to restore telomeric GQ structures and re-inhibit telomerase activity post 8OHdG processing, human spermatozoa cannot as they accumulate non-resolved abasic sites due to their truncated BER response. As such, the mild increase in ‘normal background’ physiological levels of ROS production with male age would confer a beneficial and stimulating environment to sustain telomerase activity and promote telomere lengthening. However, this characteristic is a double edged-sword, and as soon as the sperm’s antioxidant capacities are overcome and oxidative stress increases in severity, or becomes chronic, telomere dysfunction and shortening would be expected and is clearly evidenced by the male factor fertility associations presented earlier. A visualization of this proposed mechanism is provided in Fig. 3. However, the timing of the oxidative insult should be considered as well. If occurring in a premeiotic germ cell, then an adaptive response is possible leading to an upregulation of telomerase and an increase in telomere length in the germline. This may occur during aging in response to the systemic oxidative stress associated with this process. However, if the oxidative attack is on post-meiotic germ cells, or even mature spermatozoa, then the absence of both effective DNA repair and telomerase activity can only result in telomere shortening. So, it may not just be the intensity of the oxidative stress that defines the telomere response but also the timing.
Potential mechanism for sperm telomere elongation with aging. Following a hormesis-like model, oxidative stress at low physiological levels destabilizes the GQ structure, which normally blocks telomerase, and thereby facilitates telomere maintenance, replication, and lengthening. As sperm cells do not contain APE1, the GQ structure cannot be reformed, and telomerase activity could theoretically continue unchecked. In other cell types, telomerase activity would be limited to the time during which APE1 has not yet completed repair and reformation of the GQ structure. It is of critical note that although a low intensity of oxidative stress may be beneficial, too high would be detrimental for telomere stability, even in the sperm cell, as oxidized free dNTPs, 8-OHdG and its repair intermediates would inhibit telomerase functionality and impair replication.
Citation: Reproduction 164, 6; 10.1530/REP-22-0189
Potential mechanism for sperm telomere elongation with aging. Following a hormesis-like model, oxidative stress at low physiological levels destabilizes the GQ structure, which normally blocks telomerase, and thereby facilitates telomere maintenance, replication, and lengthening. As sperm cells do not contain APE1, the GQ structure cannot be reformed, and telomerase activity could theoretically continue unchecked. In other cell types, telomerase activity would be limited to the time during which APE1 has not yet completed repair and reformation of the GQ structure. It is of critical note that although a low intensity of oxidative stress may be beneficial, too high would be detrimental for telomere stability, even in the sperm cell, as oxidized free dNTPs, 8-OHdG and its repair intermediates would inhibit telomerase functionality and impair replication.
Citation: Reproduction 164, 6; 10.1530/REP-22-0189
Potential mechanism for sperm telomere elongation with aging. Following a hormesis-like model, oxidative stress at low physiological levels destabilizes the GQ structure, which normally blocks telomerase, and thereby facilitates telomere maintenance, replication, and lengthening. As sperm cells do not contain APE1, the GQ structure cannot be reformed, and telomerase activity could theoretically continue unchecked. In other cell types, telomerase activity would be limited to the time during which APE1 has not yet completed repair and reformation of the GQ structure. It is of critical note that although a low intensity of oxidative stress may be beneficial, too high would be detrimental for telomere stability, even in the sperm cell, as oxidized free dNTPs, 8-OHdG and its repair intermediates would inhibit telomerase functionality and impair replication.
Citation: Reproduction 164, 6; 10.1530/REP-22-0189
Conclusions/future perspectives
In conclusion, we would therefore also suggest that if oxidative stress is at the heart of telomere dysfunction, then it must be properly diagnosed and measured ahead of any telomere evaluation in the ART setting, or it will continue to be a silent confounder of any associations between telomere integrity and clinical fertility outcomes. Furthermore, although the scope of this review is focused to the telomere, the implications of the proposed mechanism extend far beyond that to any GQ sequence and offer novel, added insight to oxidative stress-induced epigenetic regulation/dysfunction of the paternal genome. Ultimately and by extension, accurate and robust diagnosis of sperm oxidative stress followed by regular chronic use of the appropriately dosed antioxidant therapy could potentially provide men the opportunity to delay fatherhood and pass on longer telomeres to their children with a reduced risk of passing on de novo mutations that would normally also accompany advancing paternal age at the time of conception.
Declaration of interest
All authors have an association with CellOxess LLC (Ewing, NJ, USA), a biotechnology engaged in the development and commercialization of diagnostics and antioxidant formulations for clinical use.
Funding
This work did not receive any specific grant from any funding agency in the public, commercial or not-for-profit sector.
Author contribution statement
A M wrote the first draft of the paper. R J A, P G and J R D critically reviewed the manuscript. All authors approved the final draft.
Acknowledgements
The authors would like to apologize to those investigators whose pertinent work was not cited in the interest of providing a concise perspective on the most recent overlapping advancements in the fields of oxidative stress, telomere integrity, and infertility. The authors would like to thank Laura Moazamian for creating the drawings used in Figs 2 and 3.
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