Cellular aging is an emerging area of scientific interest, as efforts are underway to identify markers that might reflect biologic senescence better than chronologic age. The most widely studied measures of cellular aging include components of deoxynucleic acid (DNA) repair capacity, epigenetics, and telomeres. Given the growing amount of literature on maternal and/or neonatal telomeres in pregnancy, telomere length as a marker of cellular aging is the focus of this review.
WHAT ARE TELOMERES?
Telomeres are tandem DNA repeats that cap the ends of linear chromosomes with thousands of repeats of the noncoding 6-nucleotide sequence TTAGG. Their purpose is thought to be to protect the coding region of chromosomes from degradation from the natural shortening that occurs with cell division due to the ‘end replication problem’ [1▪]. Because of this, telomeres within diving cells shorten over time until they reach a critical length that can either trigger apoptosis or arrest of division, after which the cell enters a state of senescence [2▪▪,3]. For this reason, telomere length has been described as a ‘mitotic clock’ that reflects where a given cell is in its overall lifespan. Naturally, this idea has extrapolated into the idea of an overall ‘biologic clock’ for the organism in question; in fact, older chronologic age in humans has been the measure most strongly correlated with shorter telomere length. This baseline age-related telomere shortening has been estimated to be between 25 and 50 basepairs per year in nonpregnant adults . To this end, in their review discussing telomeres as a biomarker, Notterman and Schneper [1▪] refer to the metric of telomere shortening as ‘telomere time’.
The primary nuance of telomere biology rests on the fact that telomere length varies by cell type [5▪]. As discussed in a review by Vaiserman and Krasnienkov [2▪▪], leukocyte telomere length is among the most widely studied in human research; this may be due to the ease with which to obtain leukocytes from blood samples. Furthermore, leukocyte telomere length has been postulated to mirror telomeres among the whole hematopoietic stem cell population [6▪▪]. That being said, telomeres can be measured in a variety of other tissue types including the placenta (both amnion and chorion) [7▪]. Even within leukocytes, or within any single cell type, there can be variability in telomere length. For example, Kresovich et al.[8▪] demonstrated that telomeres are longer in blood samples with higher proportions of CD8+ T-cells or B-cells than other types. Their study concluded that leukocyte subtype can account for a high amount of inter-individual variability in telomere length, which can be further exacerbated by other factors that might affect leukocyte composition.
Despite this inherent variability in telomere length, chronic oxidative stress appears to accelerate telomere shortening across many different tissue and cell types. For example, Fouquerel et al.[9▪] demonstrated in vitro that chronic targeted 8-oxoguanine damage to telomeres promotes shortening that ultimately contributes to genomic instability for the cell. Ultimately, whether telomere shortening is truly the cause of a ‘biologic clock’ or, rather, the cumulative effect of chronic biochemical stressors on a cell over time remains to be elucidated.
Implications of short telomeres
Short telomeres have been associated with an increased risk of early death  as well as subsequent development of cardiovascular disease , diabetes mellitus type II, and cancer, among other adverse health outcomes [12,13]. This compliments the findings above that the most consistent factor linked to telomere length is chronologic age – the older the person, the shorter all of their telomeres are. Therefore, adults who are age-matched who have earlier-onset telomere shortening have been described as entering a biologic aging-related ‘disease’ state earlier than their counterparts with longer telomeres . In light of this evidence, short telomeres are widely considered to be a marker of cellular aging.
What shortens telomeres?
Given the proposed association between oxidative stress and telomere shortening, it is not surprising that both medical and psychological stressors have been shown to accelerate telomere shortening beyond the average annual baseline rate [15,16]. Poor mental health has repeatedly been shown to affect telomere length; for example, in their prospective cohort of adolescents, Humphreys et al.[17▪] found that depressive symptoms at baseline predicted higher rates of telomere erosion and greater increases in mitochondrial DNA copy number. They concluded that depressive symptoms preceded changes in cellular aging.
Although biologic, physical, and psychosocial stressors can accelerate telomere shortening, shortening can also be slowed or even reversed with lifestyle changes or psychological ‘resilience’. For example, Arsenis et al. discuss the available literature on how physical activity might slow telomere shortening in their recent systematic review. In this review, the authors suggest biologic plausibility through decreases in inflammatory markers, leukocyte replication, and oxidative stress as well as increases in activity of telomerase – the enzyme present in some cells that facilitates telomere replication and lengthening.
TELOMERES DURING PREGNANCY
Although telomere biology has been extensively studied in nonpregnant adults, data regarding about what happens to telomeres during pregnancy are limited. Distinct data on telomere changes in pregnancy is needed, since leukocyte telomere length is the predominant measurement in the literature and there is a natural leukocytosis that occurs in pregnancy. As rates of high-risk pregnancies increase, the idea of biologic rather than chronologic age – and its association with pregnancy outcomes in both mother and child – is becoming increasingly relevant. Here, we will present what is known about telomere dynamics in pregnancy and how telomeres might play a role in parturition, adverse pregnancy outcomes, and fetal programming.
Maternal telomere length
Most studies that are available on telomeres in pregnancy focus on fetal or neonatal telomeres rather than maternal telomeres. One recent study focusing on maternal telomeres was conducted by Nsereko et al.[19▪] They prospectively studied maternal leukocyte telomere length among 297 healthy pregnant people in Rwanda during the first trimester of pregnancy. In their study, the mean ± SD of maternal leukocyte telomere length (which is commonly reported as a telomere to single-copy gene T/S ratio if analyzed via quantitative polymerase chain reaction [PCR]) was 1.17 ± 0.23 in the first trimester. The T/S ratios were normally distributed, and maternal age had a significant negative association with leukocyte telomere length consistent with results from nonpregnant literature. Furthermore, they found significant associations between maternal telomere length and micronutrient status (specifically ferritin levels), but not infectious disease status (specifically genitourinary disease status such as vaginal or cervical infection with Trichomonas vaginalis, Candida albicans, or Chlamydia trachomatis). They did not identify differences in telomere length when comparing nulliparas versus multiparas or when trying to correlate with pro-inflammatory markers such as C-Reactive Protein. Taking this idea further, Cheng et al.[20▪] reviewed the role of maternal nutrition in transgenerational healthy aging by describing available literature on placental telomere length. In this review, the author discusses differences in the impact of nutrition on placental versus neonatal (cord blood) telomeres, and postulates that cord blood telomere length may be unique in that cord blood cells are at early hematopoiesis and have an abundance of cells that express telomerase, which lengthens telomeres. This would result in cord blood cells being more well suited to maintain their telomere length, in comparison to other maternal or placental cells.
Telomeres in the chorion and amnion
Although data on maternal leukocyte telomere length in pregnancy is limited, some researchers have examined telomere biology in the placenta and amnion. Polettini et al.[21▪] published a literature review outlining evidence to data on the role of fetal membrane telomeres in stimulating parturition. In this review, they describe the contribution of factors such as inflammation, DNA methylation, and telomerase activity, to telomere biology in the fetal chorion and amnion. There is evidence that cellular senescence in the fetal membranes may be related to term delivery mechanisms, and mouse models have shown that the quantity of short telomeres in fetal membrane and placental tissues increases significantly prior to the onset of parturition [22▪▪]. Further investigation of this ‘telomere gestational clock’ is ongoing.
Recently, researchers have also investigated the association between maternal nutritional status and placental tissue telomere length [23▪]. They found that greater maternal body-mass index, body fat percentage, and vitamin B-12 status were associated with shorter placental relative telomere length whereas greater vitamin D levels were associated with longer placental telomere length. However, these findings were not replicated in analysis of cord blood.
The association between physical, biochemical, and emotional stress and short telomeres may also translate across the maternal–fetal unit in pregnancy, as studies have shown that maternal psychosocial stress correlates with shorter telomeres in neonates at birth . This is in line with the fetal origin of adult disease hypothesis, which is that health-related events such as environmental toxin exposure or inflammation during pregnancy can affect the fetus in the future across their lifespan. In their recent review on this topic , Entringer et al. refer to this phenomenon – that stress-related environments at the maternal-placental interface may affect the initial setting of fetal telomeres – as the ‘fetal programming of telomere biology hypothesis’. This notion goes beyond the traditional idea that fetal programming is largely related to predetermined genetic control. When considering fetal programming of telomeres specifically, they discuss that – while telomere length is heritable, with greater maternal than paternal influence – there is growing data that the cellular environment can heavily influence the fetal telomere starting point. There is particular interest on the role of inflammation and environmental exposures in this cellular environment. This review also highlights the importance of considering telomerase activity when studying telomere biology, as many studies focus solely on isolated telomere length yet the dynamics of the system are closely tied to regulation of telomerase.
Neonatal telomere length and maternal stress
Following suit with studies linking stress with short telomeres in adults, there have been studies suggesting an association between greater maternal stress in pregnancy and short neonatal telomeres . Recently, Verner et al.[6▪▪] examined correlations between maternal stress in pregnancy and newborn cord blood telomere length in a sample of 656 mother-infant dyads from the Prediction and Prevention of Preeclampsia and Intrauterine Growth Restriction cohort in Finland who were enrolled between 2006 and 2010. In this study, three measures of psychosocial stress were used as exposures: the Positive and Negative Affect Schedule (PNAS), the State-Trait Anxiety Inventory (STAI), and positive mood reactivity to pregnancy events from the Pregnancy Experience Scale. Participants responded to these psychological measures serially during their pregnancies. Newborn leukocyte telomere length was measured from cord blood using quantitative PCR. Consistent with prior studies [24,26▪], newborn leukocyte telomere length was found to be significantly inversely associated with maternal stress during pregnancy (greater maternal stress, shorter newborn telomeres). In contrast, maternal ‘positivity’ and resilience during pregnancy were significantly positively associated with newborn telomeres (greater positivity and resilience, longer newborn telomeres). These results highlight important areas of future research, namely on ways to optimize these facets of maternal mental health which might affect fetal programming and, ultimately, the child's lifespan.
Taking this one step further, Carroll et al. found higher maternal perceived stress during the latter part of pregnancy was associated with shorter child buccal cell telomere length even after adjusting for age of the child and concurrent maternal stress levels [26▪]. This association was not identified between maternal stress levels during the preconception or postpartum period, highlighting again the importance of the maternal–fetal compartment in pregnancy on fetal telomere programming.
Shorter neonatal telomere length has also been linked to higher levels of air pollution during pregnancy [27▪]. In their study, Scholten et al. examined telomere length in maternal leukocytes, placenta, and cord blood in 296 maternal-infant dyads and correlated these with environmental exposures using advanced air pollution modeling systems. They identified significant inverse associations between exposure to pollutants such as PM2.5 in later trimesters of pregnancy and neonatal telomere length from cord blood. Interestingly, they did not identify associations between air pollution exposure and telomere length in either the full-thickness placental samples or maternal leukocytes.
Telomere differences in offspring beyond the neonatal period
Several recent studies have looked at telomere length in children and adolescents to evaluate the impact of events that occurred during pregnancy on telomeres during the child's lifespan. In one such study by Parkinson et al.[28▪], telomere length was measured among 156 healthy adults and compared between 69 who were born before 33wks and 87 who were born at term. Men born preterm had a higher proportion of short telomeres which the researchers defined as telomeres of 1.3–4.2 kilo base pairs in length though the absolute differences were small; no significant difference was seen in women who were born preterm. In another study by McAninch et al.[29▪], short telomeres in children at age 10 were significantly associated with maternal metabolic syndrome during pregnancy. Although there is great variability in the available literature on this topic with regard to exposures in pregnancy and age of child at telomere ascertainment, there do appear to be underlying trends that warrant further investigation of how telomere length fits into the larger biochemical mileu that encompasses the fetal programming system.
In conclusion, telomere biology as it relates to cellular aging is an innovative area of future research in pregnancy. Telomeres in the maternal, placental, and fetal compartments may each play their own roles in fetal programming and gestational physiology, and there is much to be learned from studying these domains. That being said, variability in telomere assays and nuance of factors that can influence telomere length must be considered when interpreting telomere data.
Furthermore, this review highlights the lack of available data on the natural history of maternal telomere dynamics. Instead, much of the recent literature on telomeres in pregnancy focuses on the fetal programming aspect; this is probably because of the implications current events might have for future generations. Given the importance of the maternal environment to the fetal compartment, we advocate for future research characterizing cellular aging in mothers and correlating this with measures of both physical and psychosocial stress. In doing so, we may work toward a better understanding of factors influencing the maternal–fetal environment in pregnancy that may have far reaching intergenerational impacts.
Financial support and sponsorship
D.M.P.'s time is partially supported by the Women's Reproductive Health Research National Institutes of Health K-12 program at Stanford University.
K.B.'s research is partially supported by SeraCare Life Sciences, Inc which was not involved in the production of this manuscript.
Conflicts of interest
There are no conflicts of interest.
REFERENCES AND RECOMMENDED READING
Papers of particular interest, published within the annual period of review, have been highlighted as:
▪ of special interest
▪▪ of outstanding interest
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