Stress, Telomeres, and Psychopathology: Toward a Deeper Understanding of a Triad of Early Aging

Abstract

Telomeres play an important part in aging and show relationships to lifetime adversity, particularly childhood adversity. Meta-analyses demonstrate reliable associations between psychopathology (primarily depression) and shorter telomere length, but the nature of this relationship has not been fully understood. Here, we review and evaluate the evidence for impaired telomere biology as a consequence of psychopathology or as a contributing factor, and the important mediating roles of chronic psychological stress and impaired allostasis. There is evidence for a triadic relationship among stress, telomere shortening, and psychiatric disorders that is positively reinforcing and unfolds across the life course and, possibly, across generations. We review the role of genetics and biobehavioral responses that may contribute to shorter telomere length, as well as the neurobiological impact of impaired levels of telomerase. These complex interrelationships are important to elucidate because they have implications for mental and physical comorbidity and, potentially, for the prevention and treatment of depression.

Keywords: allostasis; depression; early life adversity; psychopathology; stress; telomerase; telomeres.

Figure 1

The triad of stress exposure, depression, and telomere biology. This triad illustrates the strength of predictive or causal relationships shown in the literature, represented by arrow thickness. The most consistent and well-established relationships, from both longitudinal studies and experimental animal studies, show that greater exposure to major life stressors, especially early in life, leads to a greater rate of telomere attrition (as well as likelihood of major depression). This is presumably exaggerated if one has genetic loading for greater vulnerability to stress. In turn, major depression is consistently related to shorter telomeres, although fewer studies find that depression leads to a greater rate of shortening over time. While aspects of having major depression can clearly lead to telomere shortening, it is likely that the greater telomere shortness in depression is at least in part the result of cumulative exposure to chronic stress and, consequently, impaired allostasis (stress causing both attrition and depression). People with greater reactivity tend to have faster telomere attrition, but no studies have tested whether telomere shortness predicts greater stress reactivity. There is also the possibility of reverse causation, as one study found that a genotype for low telomerase levels predicts depression. Last, chronic stress, depression, and telomere shortness have all been associated with indices of impaired allostasis.

Figure 2

A model of life span relations among stress exposure, telomeres, and psychiatric disorders. Stress has effects throughout life. It has imprinting effects during pregnancy, leading to shorter telomere length (TL) in cord blood. In addition to genetic transmission, parents also transmit directly to their offspring their own acquired TL in the germ line. After birth, TL is further shortened by early adversity, which can have lifelong effects, possibly by impacting stem cell reserves. Early signs of dysregulated mood and high-risk temperaments in childhood are already related to shorter TL at that time. These early exposures put children at risk for psychopathology emerging in adolescence. Hippocampal volume appears to be associated with telomerase activity or TL. Recurrent mood disorders can further impact TL, likely through stress-related pathways. This can be a lifelong, iterative, positive-feedback loop in which greater stress vulnerability and mood disorders impact TL. These interrelations, leading to a vicious cycle, can help explain the greater comorbidity with physical disease later in life.

Figure 3

A model of Research Domain Criteria (RDoC) pathways linking psychopathology with telomere attrition. A move by mental health researchers to adopt the RDoC framework, which focuses on transdiagnostic processes present across psychiatric disorders, provides a new way to think about how psychopathology confers a biological influence on accelerated cellular aging, which in turn results in elevated rates of chronic disease. Some of the RDoC domains have been examined with respect to telomere attrition, and this is reflected in the figure. Additional research is needed to test many of the proposed constructs within each domain to determine which of these common pathways may account for the telomere attrition observed across multiple psychiatric illnesses.