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Oxidative Stress Induces Telomere Dysfunction and Shortening in Human Oocytes of Advanced Age Donors

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Oxidative Stress Induces Telomere Dysfunction and Shortening in Human Oocytes of Advanced Age Donors cells Commentary Oxidative Stress Induces Telomere Dysfunction and Shortening in Human Oocytes of Advanced Age Donors Paweł Kordowitzki Institute of Animal 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 humans the pool of oocytes starts to decline already before the birth of a female individual, and from menarche to menopause the oocyte is exposed to different environmental stimuli. Since more and more women of the 21st century in developed countries wish to postpone the first pregnancy to their thirties, higher rates of miscarriage 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 reactive oxygen species and not upon replicative senescence, similar to how it is common in dividing cells. Keywords: oxidative stress; ROS; telomeres; chromosome 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 biology in oocyte aging and women’s fertility 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 telomerase in ovarian cell types Accepted: 22 July 2021 and oocytes is a common property of women’s sub-and infertility 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 chromosome instability 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 genomes into linear chromosomes, 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 protein complexes (shelterin) 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 proteins 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 ovulation (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 oogenesis 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 al.telomere [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 meiosis level (Figure of ROS.1) after Further, reaching functional puberty 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 science and reproductive medicine, 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
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