Chronic Psychological Stress
Information about studies assessing associations between chronic stress and TL are summarized in Table 3. Seminal findings that linked TL with chronic psychological stress were first reported by Epel et al. (2004). In this study, LTL was evaluated in PBMCs along with telomerase activity and an index of oxidative stress in 58 mothers who were caring for either a healthy or a chronically ill child. There was no difference in LTL between the two groups; however, on comparison of extreme high and low levels of psychological stress, the high-stress group had significantly shorter telomeres, lower telomerase activity, and higher oxidative stress. Although the findings were based on cross-sectional analysis and the sample size was small, the length of caregiving was significantly associated with shorter LTL, suggesting that chronic stress was important in this relationship.
Similar findings were reported by Damjanovic et al. (2007), who compared depressive symptoms, PBMC composition, cytokine production, LTL, and telomerase activity between caregivers of individuals with Alzheimer’s disease and a group of age- and gender-matched controls. Depressive symptoms were significantly higher in caregivers along with higher production of immune-regulatory cytokines, and caregivers had significantly shorter LTL in PBMCs than controls did; however, basal telomerase activity in PBMCs and T cells was significantly higher in caregivers. A weakness of this study was that perceived stress, as well as the caregiver’s health status and level of caregiving, was not assessed.
To examine whether personality traits influence the relationship between psychological stress and LTL, O’Donovan et al. (2009) measured dispositional traits in 36 healthy postmenopausal women who were caregivers and noncaregivers. Pessimism was independently associated with shorter LTL and higher levels of interleukin-6 (IL-6); however, optimism was not associated with either measure. The association between pessimism and LTL remained significant when controlling for age, caregiver status, optimism, perceived stress, neuroticism, body mass index (BMI), exercise, and sleep but not for IL-6. As with the previous studies, the cross-sectional design and small sample size were major limitations.
Using a larger sample, Parks et al. (2009) evaluated LTL, current perceived stress, and urinary stress hormones in women enrolled in the National Institute of Environmental Health Sciences Sister Study, a cohort of women aged 35–74 years who had a sister with breast cancer. Women with higher perceived stress had somewhat shorter LTL, but it did not decrease monotonically with higher stress levels. Significantly shorter LTL was found in women 55 years or older, with recent major losses and above average urinary catecholamines. Finally, Humphreys et al. (2012) reported significantly shorter LTL in women with chronically elevated psychological stress related to interpartner violence and found that length of time in the abusive relationship and having children were associated with shortened telomeres.
Collectively, these studies suggest that there is a link between chronically high levels of perceived stress and shortened LTL in a subset of participants. Nonetheless, several aspects of the design and methodologies of these studies warrant caution in generalizing the findings, particularly because most of the studies included only women, and the psychological stress endured in most of the studies was related to the caregiving role. Most importantly, the cross-sectional nature of these studies provides only a glimpse of TL; therefore, it cannot be inferred that accelerated LTL shortening continues over time. Even with the large sample size in the study of Parks et al. (2009), the relationship between psychological stress and telomere shortening was modest, yet the small elevation in perceived stress in the subgroups with shorter LTL was comparable with associations with obesity, smoking, or diagnosis of cardiovascular disease (CVD; Table 3).
Acute Psychological Stress
Three studies addressing the association between acute stress and TL are summarized in Table 4. Following their study from 2004, Epel et al. (2006) assessed the relationship between acute psychological stress, TL, and telomerase activity in leukocytes of 62 healthy women. Low telomerase activity was associated with exaggerated autonomic reactivity to acute mental stress and elevated nocturnal epinephrine, as well as major risk factors for CVD, including smoking, poor lipid profile, high systolic blood pressure, high fasting glucose, and greater abdominal adiposity. Shorter LTL was related to elevated catecholamines and cortisol. These findings, along with those of a study by Bekaert et al. (2007), suggest an association between markers of hypothalamic–pituitary–adrenocortical (HPA) axis dysregulation, inflammation, and oxidative stress with decreased telomerase activity and shortened telomeres. Epel et al. (2010) also found that elderly highly stressed caregivers had lower levels of basal telomerase activity compared with low-stress controls, but during a stress task, telomerase activity increased by approximately 18% in both groups along with an increase in cortisol. This study suggests that increased telomere shortening associated with chronically high perceived stress (in caregivers) is related to decreased basal telomerase activity and not an altered response to acute stress.
Two studies to date have assessed the relationship between stress during pregnancy and the offspring’s LTL (Table 5). In the first study, Entringer et al. (2011) assessed the association between maternal stress during pregnancy and LTL of adult offspring and found that prenatal stress exposure was a significant predictor of subsequent adult offspring LTL. Although maternal stress was evaluated retrospectively, the authors controlled for age, sex, BMI, birth weight percentile, postnatal early-life adversity, chronic stress, and depressive symptoms. The second study assessed maternal pregnancy-specific psychological stress and newborn LTL in a prospective study of 27 mother–newborn dyads (Entringer et al., 2013). The authors reported a significant, independent, linear effect of pregnancy-specific stress on newborn LTL that accounted for 25% of the variance in adjusted LTL after accounting for gestational age at birth, weight, sex, and exposure to antepartum obstetric complications. While the results are intriguing, other potential determinants of newborn LTL, particularly the mother’s CVD risk factors and paternal age at birth, were not included in the analyses (Broer et al., 2013).
The notion that other forms of psychological or physical stress during critical time points of growth and development could lead to stress-induced changes in LTL in later life was also assessed by several investigators (Table 6). The association between childhood maltreatment and shortened telomeres was studied by Tyrka et al. (2010) in 31 adults who reported either no childhood maltreatment or moderate to severe levels of childhood maltreatment on any of the five subscales of the Childhood Trauma Questionnaire. Participants reporting a history of physical or emotional neglect had significantly shorter telomeres than did those who did not. However, the association did not reach statistical significance for physical or emotional abuse. Glass, Parts, Knowles, Aviv, and Spector (2010) reported no association between being a victim of physical, emotional, or sexual abuse and LTL in participants of the twins UK cohort. However, the assessment of abuse entailed only whether it had occurred (yes/no) and not duration or extent.
Shorter TL was found to be associated with a greater number of childhood adverse life events among adults with and without anxiety disorder, and the number of childhood adversities was found to have a significant age- and sex-adjusted effect on LTL in adulthood (Kananen et al., 2010). The most significant childhood adversity was chronic or serious illness during childhood. No significant difference in LTL was evident overall between those with and without anxiety disorder; among older individuals, however, LTL was shorter among those with anxiety disorder. In a study by Surtees et al. (2011), social adversity, including traumatic circumstances experienced before age 17 years and lifetime occurrence of a set of stressful adverse life events, was associated with shorter LTL in 4,441 women. Similarly, multiple childhood adversities measured with the Childhood Trauma Questionnaire and a six-item tool were related to both increased IL-6 and shorter telomeres compared with the absence of adversity in a community sample of 132 healthy older adults (Kiecolt-Glaser et al., 2011). In the first prospective longitudinal study with repeated telomere measurements in children, Shalev et al. (2013) reported that exposure to two or more kinds of violence (maternal domestic violence, frequent bullying victimization, and physical maltreatment by an adult) was associated with significantly more telomere erosion between the ages of 5 and 10 years.
Overall, these studies provide some evidence of an association between childhood maltreatment and shortened telomeres, with both the type(s) of maltreatment or stress exposures and intensity of the exposures showing an association with TL. Similar to the studies on maternal stress, other influences on TL, such as paternal age at birth, as well as diet, exercise, and other health behaviors may have played a role in LTL shortening (Broer et al., 2013). Two challenges for this area of research entail identifying the most appropriate measures to assess childhood maltreatment and understanding the biological mechanisms that lead to shortened telomeres. Clearly, more longitudinal studies are needed to assess the long-term consequences of childhood maltreatment on LTL, as well as other outcomes of physical, emotional, and mental health. In addition, there has been a lack of research on aspects of resiliency that may play a protective role in mitigating the association between childhood maltreatment and LTL, which would help to inform the development of appropriate interventions.
Mental health is an integral component of successful aging. Several studies have assessed the relationship between a diagnosed mental health problem, mainly major depressive disorder (MDD), and LTL (Table 7). The first study to examine this association focused on mood disorders and LTL (Simon et al., 2006). Although there were no differences when comparing the three types of mood disorders individually (MDD and bipolar disorder with and without comorbid anxiety), when combined as a group, LTL was significantly shorter in those with mood disorders compared with the control group. In two other cross-sectional studies, LTL was compared between outpatients diagnosed with MDD (Lung, Chen, & Shu, 2007) and hospitalized patients receiving various treatment for MDD (Hartmann, Boehner, Groenen, & Kalb, 2010) and controls. Although these three studies reported an association between mood disorders/MDD and shorter telomeres, they were limited by a lack of ethnic/racial diversity, or data on paternal age at birth, and evaluation of stress levels.
In patients with coronary artery disease, the relationship between shorter LTL and MDD became insignificant when controlling for age, gender, BMI, smoking status, physical inactivity, antidepressant use, anxiety, left ventricular ejection fraction, and statin use (Hoen et al., 2011). At 5 years after their baseline measures, MDD did not predict shorter TL; however, the study did not report whether MDD or the extent of CVD was reevaluated over that period of time. Malan, Hemmings, Kidd, Martin, and Seedat (2011) tested their hypothesis that shorter LTL would predict MDD or posttraumatic stress disorder (PTSD) in 64 women who were survivors of rape. They found a weak association between LTL and the development of PTSD and none with MDD at 3 months postbaseline measures (Malan et al., 2011). Still, this may have been too short of a time span to detect changes in TL (Epel et al., 2010).
Wolkowitz et al. (2011) reported a significant difference in LTL compared with a healthy control group only among individuals with MDD who experienced depression the longest. In a subsequent study (Wolkowitz et al., 2012), telomerase activity was higher in individuals with MDD compared with controls and was associated with higher levels of depression and stress. Although the sample sizes were small in both studies, the results suggest that the duration of MDD is an important factor and support a connection between telomerase activity and severity of MDD and perceived stress. A study by Wikgren et al. (2012) found that participants with MDD, who had low postdexamethasone suppression test cortisol levels, had shorter LTL, suggesting that the difference in LTL between MDD and control participants was due to hypocortisolemia. This finding is consistent with other studies that have described alterations in HPA axis dysfunction as one of the etiologies underlying MDD.
Thus, from the research that assessed the relationship between MDD and LTL, it appears that the duration and, possibly, severity of MDD are associated with some degree of increased LTL shortening compared with not having MDD. Similar to the other psychosocial factors reviewed, more longitudinal research on the mechanisms of MDD that may be responsible for increased telomere shortening is needed. In addition, there has been a lack of research on aspects of resiliency that may play a protective role in mitigating the association between depression and LTL. Recently, a study by Puterman et al. (2013) examined these aspects using a model of multisystem resiliency defined by health emotional regulation, strong social connections, and health behaviors in sleep and exercise. In this study of 954 participants with stable CVD, high multisystem resiliency predicted longer LTL, whereas each individual factor did not. Multisystem resiliency significantly moderated the MDD–LTL association, suggesting that biological outcomes should be examined within a psychosocial–behavioral context and supporting the notion that even small differences in resiliency and positive health behaviors can have a significant influence on TL.
Socioeconomic Status and Educational Attainment
Findings about associations between TL and socioeconomic status (SES)/educational attainment are summarized in Table 8. In 2006, Cherkas et al. reported an association between lower SES and shorter LTL in a cross-sectional study with 1,552 female twins. However, Adams et al. (2007) found no evidence of an association between any measure of SES and LTL in a homogeneous birth cohort at age 50 years. In addition, Batty et al. (2009) reported that unemployed men had significantly shorter telomeres than did those who were employed, but there was no association between LTL and educational attainment or residence within “area-based deprivation.” In contrast, Woo, Suen, Leung, Tang, and Ebrahim (2009) reported that a higher self-rated community standing was associated with shorter TL in men only.
A study involving participants of the Whitehall II epidemiological cohort (Steptoe et al., 2011) and another involving the UK European Prospective Investigation Into Cancer–Norfolk Study participants (Surtees et al., 2012) found that lower educational attainment was associated with shorter LTL. Both studies controlled for age, gender, blood pressure, glycated hemoglobin, high-density lipoprotein, cholesterol, smoking, BMI, and physical activity. Needham, Fernandez, Lin, Epel, and Blackburn (2012) found that parental education was positively associated with child LTL when controlling for sex, age, race/ethnicity, and family income. Using data from the National Health and Nutrition Examination Survey, 1999–2002, they also reported significantly shorter LTL in respondents who completed less than a high school degree compared with those who graduated from college (Needham et al., 2013).
Carroll, Diez-Roux, Adler, and Seeman (2013) reported a significant difference in LTL between homeowners and renters in Hispanic and White participants but not African Americans. There were no significant associations between educational attainment or family income and LTL, but there was an inverse association between the father’s educational level and LTL. In another study, Carroll, Diez-Roux, Fitzpatrick, and Seeman (2013) reported that low social support was significantly associated with shorter LTL in adults aged 65 years or older but not younger participants. In a different cohort of older adults, Adler et al. (2013) reported that those with only a high school education had significantly shorter LTL than did those with post-high school education, and a significant interaction of race and education revealed more beneficial effects of post-high school education for Blacks than for Whites.
Collectively, these studies suggest that there is a small but significant association between some aspects of SES, particularly educational attainment and social support with LTL. There is also some evidence of a relationship between parental educational attainment and LTL of their offspring. However, the connection between educational attainment and the behavioral and/or biological mechanisms that promote telomere maintenance remains to be elucidated.
Only two studies were identified that assessed the relationship between LTL and the environment, specifically, the amount of green space and neighborhood risk (Table 9). The association between LTL and living in an area of Hong Kong with more green spaces (near the river with more parks and markets) compared with residing in an older part of the city was assessed by Woo, Tang, Suen, Leung, and Wong (2009). They reported that shorter LTL was associated with living in the older regions of the city after adjusting for age, smoking, SES, and physical activity level. Theall, Brett, Shirtcliff, Dunn, and Drury (2013) evaluated the association between salivary TL (sTL) in children and neighborhood-level social environmental risk from data collected at the level of the child, family/household, and neighborhood. They found that children living in neighborhoods characterized by high disorder had lower sTL values than did children not living in a high disordered environment. The findings from these two studies, although limited, suggest that some characteristics of the environment may be related to shortened telomeres. Whether this association is due to perception, behavior (more or less opportunities to exercise), the effects of an unmeasured third variable on both environment and TL, or more direct mechanisms (pollutants) remains an area of investigation that requires greater attention.
Oxidative stress and inflammation are two mechanisms that are known to cause accelerated telomere shortening. It follows that lifestyle behaviors that increase levels of oxidative stress and/or inflammation will also result in shortened telomeres. Smoking, which directly increases oxidative stress, is associated with a loss of 5 base pairs of telomeric sequence each year (Valdes et al., 2005). Clinically, these findings support that smoking one pack of cigarettes per day for 40 years could lead to telomeric attrition rates that would be equivalent to a loss of 7.4 years of life. Obesity is also a condition associated with increased oxidative stress and inflammation and is also associated with other CVD risk factors (arteriosclerosis, diabetes, hypertension, hyperlipidemia) that have been linked with accelerated telomere loss (Brouilette et al., 2008; Demissie et al., 2006; Ma, Zhu, Hu, Yu, & Yang, 2013). In contrast, lifestyle behaviors that decrease oxidative stress and inflammation will help to preserve TL (Cassidy et al., 2010). The health benefits of adequate physical activity and sleep are well established. Studies that assessed the relationship between these factors and LTL are reviewed (Tables 10 and 11 for physical activity and sleep, respectively).
Ludlow et al. (2008) evaluated the association between TL, telomerase activity, and level of physical activity using the Yale Physical Activity Survey in men and women aged 50–70 years. Their findings suggest that moderate levels of physical activity may protect PBMC TL compared with low or high exercise energy expenditure levels. Similarly, Cherkas et al. (2008) studied the association between physical activity during leisure time and LTL in 2,401 healthy twin volunteers. The LTLs of the most active participants were significantly longer compared with those of age- and sex-matched nonexercisers. Moderate exercise in midlife moderates the association between increased stress and shorter telomeres (Puterman et al., 2010) and is associated with longer telomeres in old age (Savela et al., 2013). Moderate to vigorous levels of physical activity or endurance exercise is associated with longer TL in most studies (Denham et al., 2013; Du et al., 2012; LaRocca, Seals, & Pierce, 2010), with one small study showing no difference when compared with nonexercisers (Mathur et al., 2013; Table 10).
Sleep Quality and Duration
Liang et al. (2011) reported a significant association between sleep duration and LTL in women under the age of 50 years, but not for those over 50 years, who were enrolled in the Nurses’ Health Study. Those with sleep duration of 6 hours or less had an equivalent to 9-year telomere attrition after adjustment for age, BMI, and cigarette smoking compared with women who had 9 hours or more of sleep per night. Although sleep duration and onset latency were unrelated to LTL in a community-dwelling sample of healthy women, poor sleep quality was associated with shorter LTL and predicted shorter LTL in participants who had chronic poor sleep quality (Prather et al., 2011). In contrast, a study among older adults found that shorter sleep duration was associated with significantly shorter telomeres in men only, independent of demographic, physical, and psychological covariates (Jackowska et al., 2012). On average, telomeres were 6% shorter in men sleeping 5 hours or less compared with those sleeping more than 7 hours per night (Table 11).
In addition to individual factors that are known to affect LTL, including age, sex, race/ethnicity, paternal age at birth, and genetic mutations of telomerase and telomere maintenance genes, this integrative review identified several additional psychosocial, environmental, and behavioral factors that should be considered when integrating LTL into biobehavioral research studies. The integrative review found evidence to support an association between shorter LTL and chronically high levels of perceived stress, the number of childhood adversities, duration of MDD, low educational attainment, low levels of physical activity, and short sleep duration. It should be noted that there were conflicting results identified for each of these factors. Explanations for the reason that conflicting conclusions have been observed by scientists regarding a purported association between psychosocial, environmental, and behavioral factors and LTL include, but are not limited to, heritable variation in LTL, study participant sampling, and methodological differences between investigations. Despite these limitations, the studies reviewed provide adequate justification for measuring perceived stress, childhood adversities, duration of MDD, educational attainment, physical activity, and sleep duration.
Consistent with the holistic lens of nursing, the integrative review found evidence to support the need for a multidimensional assessment of factors related to TL, which, in turn, has implications for biobehavioral research. Conceptual frameworks that incorporate the various factors related to LTL and plausible mechanisms underlying the changes are needed to guide future studies (Figure 3). A deeper understanding of the relationships between aspects of resiliency, coping, adaptation, behavioral change, and LTL would provide insight on the development of interventions to protect LTL. Carefully designed longitudinal studies are also needed to evaluate multidimensional nursing interventions and LTL, as well as potential underlying mechanisms.
As the science of telomere biology continues to expand, nurses need to be aware of the complexities in using LTL as a biomarker of health and disease risk. In addition to CVD and cancer, shorter TL has been associated with over 30 different metabolic and inflammatory diseases, and, at present, it remains unclear whether these relationships are bidirectional (Kong, Lee, & Wang, 2013). It was recently reported that a shorter mean LTL equivalent to one standard deviation in age-dependent length was associated with a 21% higher risk of CVD (Codd et al., 2013). Further research is needed to determine whether shorter telomeres play an etiological role in CVD or simply reflect an increased state of oxidative stress.
Alternatively, telomere shortening may directly contribute to alterations in the activity of genes that are adjacent to the proximal end of the telomere, allowing for changes in their expression that could lead to disease. These purported alterations in gene expression could be due to a more open chromatin conformation that occurs with shortening of the telomeric heterochromatic region with aging, also referred to as a telomere position effect (Mondoux & Zakian, 2005; Zakian, 2012). Indeed, this scenario has been observed in humans by experimental manipulation of TLs (Baur, Zou, Shay, & Wright, 2001), as well as in spontaneously occurring conditions, such as facioscapulohumeral muscular dystrophy, in which a deletion of telomeric sequences on chromosome 4 results in the expression of genes that are normally silenced (van Deutekom et al., 1996). A contrasting explanation for the observed relationship between TL and aging/disease risk is that this association may be simply correlative in nature, with TL serving as a “chronicle” (i.e., the “canary in the coal mine”) to document the occurrence of biologically relevant changes that could lead to an increased health risk (Effros, 2009).
There is now a robust body of research that has identified an association between LTL and various psychosocial, environmental, and biological factors. Although the evidence of a direct effect on TL is still lacking, the results of the integrative review suggest that perceived stress, childhood adversities, MDD, educational attainment, physical activity, and sleep duration should also be measured. A formidable challenge for this area of research will be to elucidate the exact mechanism(s) that underlie the associations with TL.
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Keywords:© 2014 Wolters Kluwer Health | Lippincott Williams & Wilkins.
aging; biobehavior; nursing research; oxidative stress; psychological stress; telomere