Stress-related telomere length in children: A systematic review
Introduction
Exposure to repeated or prolonged stress is associated with telomere shortening and the development of age-related diseases (Quinlan et al., 2014), such as diabetes mellitus (Salpea et al., 2010), cardiopathology (Haycock et al., 2014, Willeit et al., 2010), dementia (Honig et al., 2012), and osteoarthritis (Kuszel et al., 2015). Accelerated aging and senescence have also become major concerns in psychiatry (Blaze et al., 2015), with shorter telomeres found in individuals with bipolar disorder (Lima et al., 2015), schizophrenia (Kao et al., 2008), major depression (Cai et al., 2015, Verhoeven et al., 2014), and post-traumatic stress disorder (Lohr et al., 2015).
Telomeres are DNA-protein complexes that cap the ends of eukaryotic chromosomes (Lindqvist et al., 2015) binding to G-rich DNA clusters, forming loops and acting as protective structures at chromosome termini (Koliada et al., 2015). A word derived from Greek — telos (end) and meros (part) (Boukamp and Mirancea, 2007, McClintock, 1939) — telomeres are essential for cell stability, preventing chromosomes from degenerating and from fusing with one another (Houben et al., 2008). In humans, telomeres are composed of the repeating hexanucleotide sequence TTAGGG and require a minimal length to maintain stability (Blackburn, 1990).
In somatic cells, telomere shortening occurs after each chromosome replication. This incomplete replication of telomeric ends (Xu and Goldkorn, 2016) is termed the “End Replication Problem”. Other damage-causing mechanisms that contribute to telomere shortening include nuclease action, chemical damage (such as oxidative stress), DNA replication stress, epigenetic regulation, and genetic factors (Blackburn et al., 2015). Once telomeres reach a critical length, cellular defense mechanisms activate tumor suppressor genes, resulting in cells entering a state of arrest (senescence) or apoptosis (death) (Zakian, 2012). These biological responses are triggered to protect DNA coding regions from degradation, and to prevent DNA-damaged cells from proliferating (Zakian, 2012).
As chronic or excessive activation of the stress response may result in telomere shortening, it is important to understand the impact of psychological stress on cell aging (Grippo and Johnson, 2009). One of the first studies to examine stress and telomere length was conducted by Epel et al. (2004), who found that higher levels of perceived stress in healthy women positively correlated with shorter telomere length (Epel et al., 2004).
Some studies have proposed that individuals exposed to child maltreatment or abuse would show accelerated shortening of telomeres in peripheral cells (Price et al., 2013, Shalev, 2012). Also, some studies suggest that stress and glucocorticoid exposure hasten telomere shortening and ageing (Haussmann et al., 2012). O'Donovan et al. (2011) and Tyrka et al. (2010) found telomere shortening in adults exposed to early-life adversity compared with healthy adults who were not (O'Donovan et al., 2011, Tyrka et al., 2010). In contrast, Glass et al. (2010) and Kuffer et al. (2016) did not find any difference in telomere length when comparing similar groups (Glass et al., 2010, Kuffer et al., 2016).
Childhood adversity is a consistent risk factor for many psychiatric disorders (Benjet et al., 2010) and neurobiological alterations (Heim et al., 2010). The aim of our study was to examine the association between telomere length in children/adolescents and stressful events caused by early-life adversities, such as abuse, maltreatment, family disruption, institutionalization, and low socioeconomic status. We aimed to search the literature from the perspective of childhood telomere length to investigate whether telomere shortening is related to early-life stress as opposed to address the relationship between retroactive report of childhood adversities and telomere length in adults.
Published studies correlating exposure to adverse events during childhood and telomere length in adults are retrospective. This self-assessment is biased due to memory bias and confounding factors like age. Evaluation of telomere length in adults, many years after exposure, may make it difficult to separate out the effects of other subsequent factors, such as smoking and alcohol/drug abuse, other difficulties, and trauma during life. Our review aimed to reveal whether telomere shortening is observed in children during, or shortly after, exposure to stress. This strategy addresses the limitations of retrospective reports of childhood adversity and telomere length in adults (Naess and Kirkengen, 2015, Price et al., 2013, Quinlan et al., 2014, Shalev et al., 2013).
We have identified, assessed, and summarized the literature to: (a) evaluate the cross-sectional association between stress and telomere length; (b) investigate longitudinal associations between stress and telomere length; and (c) investigate case-control studies to determine whether telomere length in case groups is more greatly affected. To our knowledge, there is no existing published review compiling the findings of studies in which telomere length was measured only in children.
Section snippets
Systematic review
Articles included in the present systematic review were retrieved from PubMed (www.ncbi.nlm.nih.gov/pubmed), the Cochrane Library (www.cochranelibrary.com), the American Psychological Association – PsycINFO database (www.apa.org), and Lilacs (lilacs.bvsalud.org/) with a publication date prior to 30 July 2016. The MeSH terms used were “telomere” AND “children stress,” “childhood stress,” “child psychiatry,” “child sex abuse,” “child abuse,” “maltreatment”, “early adversity”, “children
Literature search
Eligible studies were identified through a systematic search in PubMed, Cochrane, PsycINFO, and Lilacs using specific MeSH terms. The search process is shown in Fig. 1. Each article title was initially assessed, followed by the abstract, and all duplicates removed. We found 109 articles following this initial search that were further evaluated by their abstracts. Sixty-seven studies were excluded using the following exclusion criteria: animal studies (N = 3), studies that did not perform
Discussion
All studies included in this review showed a significant relationship between early-life adversity and childhood telomere length, however no causal relationship can be claimed. It is important to highlight that life adversity is a broad concept that includes a range of different negative experiences, such as family and community poverty, exposure to household violence, family disruption, social deprivation, institutionalization, and maternal depression. These adversities may be intertwined, as
Conflict of interest
None.
Acknowledgment
This work was supported by a research grant from the Fundação de Amparo à Pesquisa do Estado de São Paulo (Vidi grant: FAPESP 2014/12559-5 and FAPESP 2014/07280-1).
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These authors contributed equally to this work.