Telomeres and epigenetics: potential relevance to chronic pain.

Reciprocal interactions between stress and pain are well documented. Physical and psychosocial stressors, including childhood adversity, predict onset and exacerbation of clinical pain [17]. Conversely, chronic pain is a persistent endogenous stressor that can contribute to a cascade of psychosocial stressors including decreased activity level, reduced social support, and unemployment [5]. Despite growing appreciation for the importance of interactions between stress and pain, the mechanisms whereby the environment influences pain-related biological processes remain unclear. Further, the biological consequences of exposure to pain as a chronic stressor have received limited empirical attention. Converging work in telomere and epigenetics research indicates that adverse environmental experiences have a biological interface. The long-term effect of chronic stress appears to accelerate telomere shortening [13]. Epigenetic responses to the environment bridge stressful experiences with biological outcomes emphasizing the potential for epigenetic processes to influence individual pain experiences. Epigenome changes, occurring separate from and yet orchestrating the expression of the genome across the lifespan, may shape vulnerability and resilience factors implicated in chronic pain conditions [21]. Fig. 1 provides a heuristic model that conceptualizes the interactions between environmental influences and genome functioning. The model illustrates how stress and pain might influence molecular processes central to genome function. Specifically, events arising from both external and internal environments can (1) contribute to accelerated cellular aging, resulting in alterations in telomere length and/or (2) propel epigenetic modifications that ultimately modulate genomic regulation of peripheral and central pain processes. Advances in telomere and epigenetic research hold substantial promise for revealing how adverse environmental experiences are transduced to the genome to influence pain processing. In an effort to highlight the potential application of the molecular consequences of environmental stress to pain research, we discuss below evidence supporting the relevance of telomeres and epigenetic processes to chronic pain. Fig. 1 A heuristic model for conceptualizing the interactions between environmental influences and genome functioning. External factors are “outside” the individual, exogenous in nature, and represented by the outer light gray circle. Internal ... 2. Telomeres Pain elicits a stress response activating the autonomic, immune, and neuroendocrine systems [5]. While prior research has primarily addressed the biological profile of the acute stress response associated with clinical and experimental pain, the molecular consequences of chronic pain are not well understood. Identifying biological markers predicting the onset of chronic pain and reflecting the long-term impact of persistent pain would offer significant research and clinical utility. One such potential measure, leukocyte telomere length (TL), a marker of cellular aging, may benefit pain research given its association with the intensity and persistence of stress [10,38]. Telomeres are complexes comprising DNA and protein that cap and protect the ends of eukaryotic chromosomes, providing stability for replication and preventing fusions [4]. Telomeres are characterized by repetitive, single-strand DNA sequences that decrease in length with each cell division. As telomeres shorten to a critical length, cells typically become senescent; however, during this period, the risk of maladaptive cellular changes also increases [4,13]. Importantly, some cells are buffered by telomerase, a complex enzyme comprised of telomerase RNA, a reverse transcriptase, and accessory proteins. Telomerase adds telomeric DNA sequence repeats to the ends of chromosomes, providing protection, repair, and even potential lengthening of telomeres [4]. Although TL can be measured in various cells, a significant proportion of research has focused on peripheral blood mononuclear cells, leukocyte TL. Factors influencing mitosis in this cell population include oxidative stress, stress hormones, and inflammation [11–13,38]. In general, leukocyte TL shortens with chronological age, but the correlations are modest (r = −0.23 to −0.40) [10,28]. Some limitations identified in telomere research include differing measurement techniques, poor standardization across measures, and variability in TL across cell types within an individual [2]. Although conflicting findings exist, shorter leukocyte TL has been associated with age-related diseases, chronic mental and physical health conditions, and mortality [3,13,38], whereas longer TL has been associated with years of healthy life [27]. Growing evidence also indicates that TL is negatively associated with persistent psychosocial stress [13]; examples include caregiving stress [7,10] and a history of childhood adversity [18]. Importantly, in a group of adults providing extended care (average of 5 years) for a family member with Alzheimer's disease, TL was not only shorter compared to control subjects, impaired immune functioning was also demonstrated [7]. The effects of stress on TL may be modulated by external and internal factors (Fig. 1). For example, evidence demonstrates that shorter TL is related to high levels of trait pessimism in women [29], while moderate exercise is associated with longer TL [20]. Telomerase, which can buffer leukocyte telomere shortening, is theorized to be a dynamic measure with demonstrated responsiveness to acute stressors [11], and has been indicated as an outcome measure in short-term clinical interventions [39]. Consistent with the concept of allostatic overload, chronic pain may be the result of, or contribute to, dysregulated stress response systems [23]. Inversely correlated with the duration of stress [10,38], TL appears to function as a barometer of the organism's cumulative response to long-term endogenous and exogenous stressors. As such, TL may serve as a measure of system burden, the consequence of chronic pain and associated stressors on an individual system. Recent findings indicate that older adults reporting chronic pain and high stress had significantly shorter leukocyte TL than individuals reporting no chronic pain and low stress [33]. Further research is needed to determine if telomere measures are markers of pain-related system burden, sensitive to individual variability in the onset and persistence of pain-related conditions.