cells

Commentary Induces Telomere Dysfunction and Shortening in of Advanced Age Donors

Paweł Kordowitzki

Institute of Reproduction and Food Research of Polish Academy of Sciences, Tuwima Street 10, 10-243 Olsztyn, Poland; [email protected]

Abstract: Research from the past decades provided strong evidence that in the pool of oocytes starts to decline already before the of a female individual, and from to the is exposed to different environmental stimuli. Since more and more women of the 21st century in developed countries wish to postpone the first to their thirties, higher rates of and chromosomal non-disjunction might occur. In oocytes of advanced maternal age, meaning above 35 years of age, characteristics such as chromosomal instabilities/abnormalities, spindle defects, decreased mitochondrial function and telomere shortening become more prevalent than in younger counterparts. Telomere attrition belongs to the so-called “hallmarks of aging” which are also relevant for the female germ-line cells. In oocytes, telomeres shorten with advancing maternal age due to the effects of and not upon replicative , similar to how it is common in dividing cells.

Keywords: oxidative stress; ROS; telomeres; instability; oocytes; aging  

Citation: Kordowitzki, P. Oxidative Stress Induces Telomere Dysfunction 1. Introduction and Shortening in Human Oocytes of Advanced Age Donors. Cells 2021, 10, Telomere attrition and dysfunction are recognized as a hallmark of aging [1] since 1866. https://doi.org/10.3390/ they are well-established phenomena contributing to organismal aging and telomere cells10081866 homeostasis is a contributor to other processes of aging, too. However, the implication of telomere in oocyte aging and women’s is barely starting to be unveiled. Due Academic Editors: Ioannis Trougakos to changing demographics in the last years, meaning the shift of women’s age having their and Vassilis Gorgoulis first baby, the correlation between the accumulation of short telomeres, reactive oxygen species (ROS) and ovarian senescence has emerged [2,3]. Therefore, researchers provided evidence Received: 5 July 2021 that telomere dysfunction and the decreasing activity of the in ovarian types Accepted: 22 July 2021 and oocytes is a common property of women’s sub-and with regards to advanced Published: 23 July 2021 maternal age [4]. Therefore, in this commentary piece, the most recent knowledge about the correlation between ROS, telomere dysfunction and in oocytes Publisher’s Note: MDPI stays neutral of women will be provided since age-related fertility decline could represent an interesting with regard to jurisdictional claims in model to study fundamental phenomena contributing to organismal aging in humans. published maps and institutional affil- iations. 2. Telomeres and the Aging Oocyte Telomeres attracted researchers’ attention since they are crucial for chromosomal stability, meaning for the organization of mammalian into linear , and age-related telomere shortening can serve as a biological clock of a cell or organism [5]. Copyright: © 2021 by the author. The regulation of telomere length in mammals requires the defined interplay between Licensee MDPI, Basel, Switzerland. telomeric complexes () and the ribonucleoprotein telomerase which is This article is an open access article responsible for telomere elongation by adding consecutive 50-TTAGGG-30 repeats [6]. More distributed under the terms and precisely, there is a wide range of tasks for which telomeric are responsible, among conditions of the Creative Commons others they modify the telomere’s architecture, and orchestrate the process during which Attribution (CC BY) license (https:// the newly generated telomeric single-stranded DNA tail is changed into double-stranded creativecommons.org/licenses/by/ DNA [7]. Consequentially, it appears obvious that a reduced function of telomeres in 4.0/).

Cells 2021, 10, 1866. https://doi.org/10.3390/cells10081866 https://www.mdpi.com/journal/cells Cells 2021, 10, 1866 2 of 6

Cells 2021, 10, x FOR PEER REVIEW 2 of 6 oocytes, meaning the dysfunctional telomere maintenance upon the exposure to ROS leads to telomere shortening. Recent studies postulate that there is a dynamic nature of the telomere architecture and new insights described telomerase-related interactions [7]. Due to which the newly generated telomeric single-stranded DNA tail is changed into double- the factstranded that a girlDNA is [7]. born Consequentially with a defined, it appears pool of obvious ovarian that follicles a reduced which function gradually of telo- diminishes throughoutmeres inlife, oocytes, oocytes meaning experience the dysfunctional chronic telomere exposure maintenance to ROS upon (Figure the exposure1). Moreover, to the longerROS an leads oocyte to telomere is arrested shortening. in prophase Recent studies I, “waiting”postulate that to there be is selected a dynamic for nature (in nowadaysof the demographictelomere architecture situation and new even insights more thandescribed three telomerase decades),-related the longer interactions is the exposure time of[7]. ROS Due towardsto the fact oocytes.that a girl is Following born with a the defined telomere pool of theory ovarian of follicles reproductive which gradu- aging [8,9] the ally diminishes throughout life, oocytes experience chronic exposure to ROS (Figure 1). age-relatedMoreover, oocyte the longer dysfunction an oocyte in is womenarrested in is prophase caused byI, “waiting” the progressive to be selected telomere for ov- shortening sinceulation telomeres (in nowadays in oocytes demographic begin to situation shorten even already more duringthan three decades), the in thelonger fetal is phase [9]. Moreover,the exposure as recently time of reviewedROS towards by oocytes. van der Following Reest the et telomere al. [3], with theory advancing of reproductive maternal age an accumulationaging [8,9] the age of mitochondrial-related oocyte dysfunction DNA mutations in women is occurs caused leadingby the progressive to respiratory te- chain deficiencylomereand shortening increased since leveltelomeres of ROS. in oocytes Further, begin functionalto shorten already telomeres during are oogenesis required for the in the fetal phase [9]. Moreover, as recently reviewed by van der Reest et al. [3], with ad- metaphasevancing chromosome maternal age an alignment accumulation and of integrity mitochondrial of meiotic DNA mutations spindles occurs [10]. Theleading physiological segregationto respiratory of chromosomes chain deficiency during and increased level (Figure of ROS.1) after Further, reaching functional telomeres is related the chiasmataare required formed for during the metaphase fetal life. chromosome Importantly alignment though, and chiasmata integrity of delivermeiotic spindles counterattraction alongside[10]. The spindle-pulling physiological segregation forces to of enablechromosomes kinetochores during meiosis to secure (Figure connections 1) after reach- to spindle fibersing [11 puberty]. Due is to related Telomere the chiasmata function formed is essential during fetal for life. meiosis Importantly The lengththough, chias- of telomeres in mata deliver counterattraction alongside spindle-pulling forces to enable kinetochores to metaphasesecure connections II oocytes to (during spindle fibers which [11]. the Due metaphase-plate to Telomere function of is chromosomes essential for meiosis is established and theThe first length polar of telomeres body is in extruded) metaphase can II oocytes be estimated (during which via the the labeling metaphase of- telomericplate of repeats with achromosomes probe using is theestablished Q-FISH and method the first(Figure polar body2). is In extruded) human newborns,can be estimated the via telomere the length is aroundlabeling 10–15 of telomeric kb [12 repeats]. Therefore, with a probe there using is the a gross Q-FISH need method for (Figure a better 2). In understanding human in sciencenewborns, and reproductive the telomere length medicine, is around how 10– to15 kb prevent [12]. Therefore, oocyte there aging is a by gross minimizing need for ROS or a better understanding in and , how to prevent oocyte aging upon the supplementation with antioxidants. by minimizing ROS or upon the supplementation with antioxidants.

.

Figure 1. Scheme showing the single phases of meiosis I and II. Every girl (as most of the mammalian species) is born with a defined set of primordial follicles containing the oocytes, however, already at the onset of puberty this ovarian pool has diminished substantially. The oocytes are arrested in prophase I, and from menarche to menopause some of the oocytes are selected for further development when resumption of meiosis occurs. Thereby, the “waiting time” of an oocyte to be fertilized after reaching metaphase II could last many years, nowadays even up to 35 years or more, depending on women’s wish to become pregnant. In consequence, the chance and number of telomeric DNA damage and telomere dysfunction increase with advancing maternal age of the oocyte. Cells 2021, 10, x FOR PEER REVIEW 3 of 6

Figure 1. Scheme showing the single phases of meiosis I and II. Every girl (as most of the mammalian species) is born with a defined set of primordial follicles containing the oocytes, however, already at the onset of puberty this ovarian pool has diminished substantially. The oocytes are arrested in prophase I, and from menarche to menopause some of the oocytes are selected for further development when resumption of meiosis occurs. Thereby, the “waiting time” of an oocyte to be Cells 2021fertilized, 10, 1866 after reaching metaphase II could last many years, nowadays even up to 35 years or more, depending on 3 of 6 women’s wish to become pregnant. In consequence, the chance and number of telomeric DNA damage and telomere dysfunction increase with advancing maternal age of the oocyte.

Figure 2.2. Microscopic visualization of the metaphase II oocyteoocyte andand chromosomes.chromosomes. (A):): This panel shows an exemplaryexemplary bright-fieldbright-field microscopicmicroscopic picturepicture ofof aa bovinebovine oocyteoocyte inin metaphase II with the visible extruded polar body. The white square showsshows the approximate approximate localization localization of of the the chromosomes. chromosomes. (B) (:B This): This panel panel shows shows the thestained stained chromosomes chromosomes (blue) (blue) and telo- and telomeresmeres (red) (red) using using the theQ-FISH Q-FISH method. method.

3. Oxidative Stress Impact on Telomeres inin OocytesOocytes Interestingly, although it has has been been generally generally accepted accepted that that several several environmental environmental causes are are responsible responsible for for telomere telomere dysfunction dysfunction and and shortening, shortening, oxidativ oxidativee stress stress (OS) (OS) ap- pearsappears to be to bethe the most most cited cited mechanistic mechanistic reason reason for the for thebefore before-mentioned-mentioned phenomenon. phenomenon. Mi- tochondrialMitochondrial dysfunction dysfunction accounts accounts for for one one possible possible explanation explanation for for the the generation generation of ROS due to a lack of the the antioxidant antioxidant defense mechanism in the oocyte [1 [133].]. More More precisely, precisely, ROS are generated as a by-productby-product of severalseveral reactionsreactions inin whichwhich enzymesenzymes contribute,contribute, similarsimilar to, for for instance instance,, the the NADPH NADPH oxidase oxidase enzymes [14,15]. [14,15 ].Noteworthy, Noteworthy, the the neutralization neutralization of ROSof ROS is important is important not not only only in the in theoocyte oocyte since since an imbalanc an imbalancee provoked provoked by excess by excess ROS ROSpro- productionduction will will damage damage cellular cellular DNA, DNA, lipids lipids and andproteins proteins [3,14]. [3 ,To14]. protect To protect or prevent or prevent pro- protectiontection against against excess excess ROS ROS enzymes enzymes such such as as the the superoxide superoxide dismutase dismutase play play a a crucial crucial role •−•- by converting OO22 toto H H2O2O2 2[3].[3]. Interestingly, Interestingly, popula populationtion studies studies provided provided evidence thatthat OS is correlated with shorter average telomere lengths in white blood cells [16]. [16]. However, However, what about the the oxidative oxidative stress stress (OS) (OS) impact impact on on women’s women’s oocytes? oocytes? Starting Starting from from the dis- the coverydiscovery of telomeres of telomeres until until today, today, different different pathways pathways have have been been suggested suggested to elucidate to elucidate how OShow provokes OS provokes telomeric telomeric DNA DNAdamage damage and shortening. and shortening. One explanation One explanation is that OS is thatinduces OS cellinduces death cell and/or death senescence, and/or senescence, and in consequence, and in consequence, in the surrounding in the surrounding vital cells vital acceler- cells atedaccelerated cell divisions cell divisions take place take as place a com aspensatory a compensatory mechanism mechanism that leads that to leads telomere to telomere short- ening.shortening. However, However, this process this process does doesnot reflect not reflect the characteristic the characteristic of telomere of telomere shortening shortening and dysfunctionand dysfunction in oocytes, in oocytes, since since after afterbirth birthoocytes oocytes are non are-dividing non-dividing cells cells[17,18], [17 and,18], after and birthafter birththe telomerase the telomerase activity activity is largely is largely repressed repressed in somatic in somatic tissues tissues [19].[ 19Noteworthy,]. Noteworthy, the the telomere length differs across somatic tissues in relation to replicative activity and the quantity of cell divisions is limited upon the “Hayflick limit” at which telomeres become so short leading to [19]. According to another very commonly discussed explanation, ROS triggers (locally at telomeres) single-strand breaks (SSB) [20] or even provokes the collapse of the replication fork and telomere loss in somatic cells [13]. According to Barnes et al., it appears to be possible that oxidative lesions impact the of TERRA at telomeres or the shelterin binding [13]. Research provided Cells 2021, 10, x FOR PEER REVIEW 4 of 6

telomere length differs across somatic tissues in relation to replicative activity and the quantity of cell divisions is limited upon the “” at which telomeres become so short leading to cellular senescence [19]. According to another very commonly dis- cussed explanation, ROS triggers (locally at telomeres) single-strand breaks (SSB) [20] or Cells 2021, 10, 1866 even provokes the collapse of the replication fork and telomere loss in somatic cells [14 of3]. 6 According to Barnes et al., it appears to be possible that oxidative lesions impact the tran- scription of TERRA at telomeres or the shelterin binding [13]. Research provided evidence thatevidence ROS thatcan provoke ROS can different provoke differenttypes of typestelomeric of telomeric DNA damage DNA damage[20,21], [however,20,21], however, due to thedue high to the high guanine content contentof the tandem of the tandemre-peated re-peated hexamers hexamers (TTAGGG), (TTAGGG), which is which suscep- is tiblesusceptible for oxidation, for oxidation, very often very 8- oftenoxoguanine 8-oxoguanine (8-oxoG) (8-oxoG) is produced is produced (Figure (Figure 3) [22,23].3)[ More-22,23]. over,Moreover, those thosetelomeric telomeric hexamers hexamers are susceptible are susceptible sites for sites iron for bindi ironng binding too, and too, iron and-medi- iron- atedmediated biochemical biochemical reactions reactions have havebeen beensuggested suggested to produce to produce hydroxyl hydroxyl radicals radicals which which lead tolead the to cleavage the cleavage at 5′of atGGG 50of [24]. GGG In [addition24]. In addition to the formation to the formation of 8-oxoG, of research 8-oxoG, provided research evidenceprovided that evidence ROS is that able ROS to react is able with to reactfree nucleotid with freee pools in quiescent pools in cells, quiescent and inter- cells, estingly,and interestingly, so called oxidized so called deoxynucleoside oxidized deoxynucleoside triphosphates triphosphates (dNTP) seem (dNTP) to be seemcrucial to for be cellcrucial viability for cell and viability chromosome and chromosome stability [25]. stabilityHowever, [25 it ].remains However, not fully it remains understood not fully yet, howunderstood oxidized yet, dNTPs how influence oxidized dNTPstelomere influence maintenance telomere and maintenanceintegrity due andto the integrity pleiotropic due effectto the of pleiotropic ROS, and effecthow efficiently of ROS, and oxidative how efficiently telomeric oxidativeDNA damage telomeric is repaired DNA [26]. damage Re- centlyis repaired it has [been26]. Recentlyreported that it has a chronic been reported appearance that of a chronic8-oxoG at appearance telomeres ofinduces 8-oxoG telo- at meretelomeres shortening induces [26], telomere although shortening it was shown [26], although by Abey itet was al., shownthat the by Abey et peroxire- al., that doxin1the enzyme is highly peroxiredoxin1 abundant at is highlytelomeres abundant during atS telomeresphase and during is able S to phase protect and telomeres is able to fromprotect oxidative telomeres damage from oxidative[27]. damage [27].

. Figure 3. Scheme showing the origin and consequences of oxidative telomeric DNA base damage. Upon ROS the in situ Figure 3. Scheme showing the origin and consequences of oxidative telomeric DNA base damage. Upon ROS the in situ oxidation of a guanine DNA base takes place leading to the generation of 8-oxoguanine (place of oxidation depicted as oxidation of a guanine DNA base takes place leading to the generation of 8-oxoguanine (place of oxidation depicted as red dot). red dot). 4. Impact of Telomere- and Telomerase-Related Diseases on Oocytes 4. Impact of Telomere- and Telomerase-Related Diseases on Oocytes So far, only few telomere-related diseases have been discovered and have been linked to mutationsSo far, only of few some telomere specific-related , diseases such as have in DKC1, been discovered in TERC and and TERT,have been in NOP10 linked toand mutations NHP2 and of some in the specific TINF2 genes, [such28]. as In in addition DKC1, toin TERC aplastic and anemia TERT, and in NOP10 idiopathic and NHP2lung fibrosis, and in the dyskeratosis TINF2 gene congenita [28]. In addition is commonly to aplastic named anemia as a humanand idiopathic telomeropathy lung fi- brosis,which isdyskeratosis a disease based congenita on mutations is commonly in the named telomerase as a human [29]. Intelomeropathy patients with which the latter is a diseasementioned based disease on mutations decreased in blood the telomerase levels of the [29]. Anti-Müllerian In patients with Hormone the latter was mentioned observed diseasewhat reflects decreased a diminished blood levels ovarian of the reserve Anti- [Müllerian30]. The same Hormone was shown was observed in another what case reflects report aabout diminished a woman ovarian suffering reserv frome dyskeratosis[30]. The same congenita, was shown and additionally,in another case this report patient about poorly a womanresponded suffering to the ovarian from dyskeratosis stimulation, andcongenita, telomeres and were additionally, severely shortened this patient in oocytes poorly and re- spondedgenerated to embryos the ovarian [29]. stimulation, Importantly and though, telomeres this shows were severely that critical shortened short telomeres in oocytes upon and generateda disease negatively embryos [29]. affect Importantly women’s fertility though, regardless this shows of that maternal critical . short telomeres In consequence, upon it appears to be plausible, that other individual factors such as obesity, malnutrition and environmental factors (e.g., smoking) which potentially could influence telomeres or lead to malfunction/mutations of telomerase, could be reflected by a diminished oocyte quality and developmental competence, too.

5. Conclusions and Final Remarks In this Commentary, the current understanding of the impact of oxidative stress on telomere dysfunction and shortening in oocytes of advanced maternal age has been Cells 2021, 10, 1866 5 of 6

presented. Herein, potential explanations were provided on how elevated ROS alter telomere length homeostasis and biology, and there is no doubt that in human oocytes oxidative telomeric DNA damage appears to be the most relevant cause. However, some questions still remain unelucidated, and future studies on oocytes could aim to reveal if changes in telomere length and function upon ROS are induced directly or indirectly. This novel knowledge would be valuable for developing new therapeutic or prophylactic strategies that protect telomeres from oxidative stress or at least minimize the effects of ROS on telomeres in oocytes of advanced maternal age.

Author Contributions: P.K.: Conceptualization, writing, review and editing, visualization. The author has read and agreed to the published version of the manuscript. Funding: P.K. received internal funding of the Institute of Animal Reproduction and Food Research of Polish Academy (3/FBW/2020). Acknowledgments: Figures were created with BioRender.com (accessed on 1 July 2021). Figure1 was adapted from “Meiosis-Oocyte”, by BioRender.com (2021), retrieved from https://app.biorender. com/biorender-templates (accessed on 1 July 2021). Conflicts of Interest: The author declares no conflict of interest.

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