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Telomeres and Early-Life Stress: An Overview

  • Lawrence H. Price
    Affiliations
    Mood Disorders Research Program and Laboratory for Clinical and Translational Neuroscience, Butler Hospital, Providence, Rhode Island

    Department of Psychiatry and Human Behavior, Alpert Medical School of Brown University, Providence, Rhode Island
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  • Hung-Teh Kao
    Affiliations
    Laboratory of Molecular Psychiatry, Butler Hospital, Providence, Rhode Island

    Department of Psychiatry and Human Behavior, Alpert Medical School of Brown University, Providence, Rhode Island
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  • Darcy E. Burgers
    Affiliations
    Mood Disorders Research Program and Laboratory for Clinical and Translational Neuroscience, Butler Hospital, Providence, Rhode Island
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  • Linda L. Carpenter
    Affiliations
    Mood Disorders Research Program and Laboratory for Clinical and Translational Neuroscience, Butler Hospital, Providence, Rhode Island

    Department of Psychiatry and Human Behavior, Alpert Medical School of Brown University, Providence, Rhode Island
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  • Audrey R. Tyrka
    Correspondence
    Address Correspondence to Audrey R. Tyrka, M.D., Ph.D., Butler Hospital, Mood Disorders Research Program and Laboratory for Clinical and Translational Neuroscience, 345 Blackstone Blvd, Providence, RI 02906
    Affiliations
    Mood Disorders Research Program and Laboratory for Clinical and Translational Neuroscience, Butler Hospital, Providence, Rhode Island

    Department of Psychiatry and Human Behavior, Alpert Medical School of Brown University, Providence, Rhode Island
    Search for articles by this author
      The long-term sequelae of adverse early-life experiences have long been a focus in psychiatry, with a historic neurobiological emphasis on physiological systems that are demonstrably stress-responsive, such as the hypothalamic-pituitary-adrenal axis and neuroimmune function. However, there has been increasing recognition in the general medical literature that such sequelae might encompass more pervasive alterations in health status and physiology. Recent findings in telomere biology have suggested a new avenue for exploring the adverse health effects of childhood maltreatment. Telomere length in proliferative tissues declines with cell replication and the effect can be accelerated by such factors as inflammation, oxidative stress, radiation, and toxins. Reduced telomere length, as a proxy for cellular aging, has been associated with numerous chronic somatic diseases that are generally considered to be diseases of aging, such as diabetes, cancer, and heart disease. More recently, shorter telomeres have been demonstrated in several psychiatric conditions, particularly depression. Sustained psychosocial stress of a variety of types in adulthood appears to be associated with shorter telomeres. Now, emerging work suggests a robust, and perhaps dose-dependent, relationship with early-life stress. These findings present new opportunities to reconceptualize the complex relationships between experience, physical and psychiatric disease, and aging.

      Key Words

      That early-life experiences have enduring sequelae has been a central tenet of psychiatry for over a century. Initial formulations of this idea emphasized clinical implications, particularly in classical psychoanalytic theory, and it is now well documented that childhood adversity increases risk for major depression (MDD), bipolar disorder, anxiety disorders, substance disorders, schizophrenia, eating disorders, personality disorders, and suicidality (
      • Heim C.
      • Newport D.J.
      • Mletzko T.
      • Miller A.H.
      • Nemeroff C.B.
      The link between childhood trauma and depression: Insights from HPA axis studies in humans.
      ). Risk appears to be dose-dependent, and these disorders may have a more virulent course in individuals with a history of childhood maltreatment (
      • Heim C.
      • Newport D.J.
      • Mletzko T.
      • Miller A.H.
      • Nemeroff C.B.
      The link between childhood trauma and depression: Insights from HPA axis studies in humans.
      ).
      More recently, an etiological role for early-life stress has been documented for several prevalent somatic conditions, including irritable bowel syndrome (
      • Barreau F.
      • Ferrier L.
      • Fioramonti J.
      • Bueno L.
      New insights in the etiology and pathophysiology of irritable bowel syndrome: Contribution of neonatal stress models.
      ), fibromyalgia (
      • Schweinhardt P.
      • Sauro K.M.
      • Bushnell M.C.
      Fibromyalgia: A disorder of the brain?.
      ), chronic fatigue syndrome (
      • Heim C.
      • Nater U.M.
      • Maloney E.
      • Boneva R.
      • Jones J.F.
      • Reeves W.C.
      Childhood trauma and risk for chronic fatigue syndrome: Association with neuroendocrine dysfunction.
      ), obesity (
      • Charmandari E.
      • Kino T.
      • Souvatzoglou E.
      • Chrousos G.P.
      Pediatric stress: Hormonal mediators and human development.
      ), migraine (
      • Tietjen G.E.
      • Peterlin B.L.
      Childhood abuse and migraine: Epidemiology, sex differences, and potential mechanisms.
      ), and chronic pain (
      • Jones G.T.
      • Power C.
      • Macfarlane G.J.
      Adverse events in childhood and chronic widespread pain in adult life: Results from the 1958 British Birth Cohort Study.
      ). These disorders have in common an unclear, perhaps multifactorial, etiology and pathophysiology. However, some investigators suggest that early environmental factors can also impact the risk for conditions generally thought to have a relatively clear pathogenesis, such as cardiovascular disease and type 2 diabetes (
      • Gluckman P.D.
      • Hanson M.A.
      Living with the past: Evolution, development, and patterns of disease.
      ). Indeed, individuals with a history of early-life stress show increased risk for premature death, with one recent study reporting that adults with six or more adverse childhood experiences died nearly 20 years earlier than those without adverse childhood experiences (
      • Brown D.W.
      • Anda R.F.
      • Tiemeier H.
      • Felitti V.J.
      • Edwards V.J.
      • Croft J.B.
      • Giles W.H.
      Adverse childhood experiences and the risk of premature mortality.
      ).
      Efforts to elucidate how early-life stress is transduced into physiological dysfunction and clinical impairment have focused on the hypothalamic-pituitary-adrenal axis (
      • Heim C.
      • Newport D.J.
      • Mletzko T.
      • Miller A.H.
      • Nemeroff C.B.
      The link between childhood trauma and depression: Insights from HPA axis studies in humans.
      ), not surprisingly, given the historic centrality of that system in understanding the stress response. Other research has provided evidence for the role of neuroimmunological mechanisms in linking early-life stress and disease (
      • Graham J.E.
      • Christian L.M.
      • Kiecolt-Glaser J.K.
      Stress, age, and immune function: Toward a lifespan approach.
      ). Now, rapidly emerging clinical findings suggest that telomere biology might offer a new avenue for exploring the adverse health effects of childhood maltreatment. This review will examine those findings; contextualize them in light of current understanding of the relationship between telomeres, illness, and stress; and highlight key methodological issues requiring consideration as the field moves forward.

      Telomeres: Basic Concepts

      Telomeres (from the Greek telos [end] and meros [part]) are DNA protein complexes at the ends of chromosomes, composed of tandem TTAGGG repeats ranging from a few to 15 kilobases in length. Their critical role in maintaining chromosomal stability was first described in the 1930s by McClintock (
      • McClintock B.
      The behavior in successive nuclear divisions of a chromosome broken at meiosis.
      ) and Muller (
      • Muller H.J.
      The re-making of chromosomes.
      ). It is now established that telomeres shorten with each cell division (
      • Blackburn E.H.
      Telomeres and telomerase: Their mechanisms of action and the effects of altering their functions.
      ) and that maintenance of telomere function depends on both a minimal length of TTAGGG repeats and telomere-binding proteins (
      • Blackburn E.H.
      Telomeres: Structure and synthesis.
      ). Telomere length can be maintained by the enzyme telomerase, a ribonucleoprotein reverse transcriptase mainly expressed in stem cells, germ cells, and regenerating tissues. However, there is insufficient telomerase in somatic cells to indefinitely maintain telomere length, and most tissues have very low telomerase levels. Consequently, telomeres shorten with age in most somatic tissues, and telomere length can serve as a kind of biological counter, ticking off the passage of time with each cell division (
      • Aubert G.
      • Lansdorp P.M.
      Telomeres and aging.
      ). Telomere shortening is also influenced by recombination, epigenetic regulation, and genetic factors, as well as oxidative stress, and the ability of telomerase to counteract these influences is limited.

      Measurement of Telomere Length

      For years, the gold standard for measuring telomere length has been the Southern blot. There are significant limitations to this method: it is time consuming and labor intensive, significant amounts of genomic DNA are required, deducing telomere length from a Southern blot smear is problematic, and there are potential issues of reproducibility. Cawthon (
      • Cawthon R.M.
      Telomere measurement by quantitative PCR.
      ) developed an easier method utilizing quantitative polymerase chain reaction (PCR), which mimics DNA replication. The method developed by Cawthon (
      • Cawthon R.M.
      Telomere measurement by quantitative PCR.
      ) entails separate PCRs to measure telomeres (T), which are normalized to a single copy gene (S), yielding a T/S ratio as a measure of telomere length. Quantitative PCR demonstrates good correlation with results from Southern blot analyses and is now widely used. However, this method has greater measurement error than the Southern blot and can show substantial variability across laboratories (
      • Aviv A.
      • Hunt S.C.
      • Lin J.
      • Cao X.
      • Kimura M.
      • Blackburn E.
      Impartial comparative analysis of measurement of leukocyte telomere length/DNA content by Southern blots and qPCR.
      ), necessitating careful quality controls and multiple sampling to assure reliability.
      There are also methods employing hybridization coupled with cytometry (
      • Lauzon W.
      • Sanchez Dardon J.
      • Cameron D.W.
      • Badley A.D.
      Flow cytometric measurement of telomere length.
      ,
      • Slijepcevic P.
      Telomere length measurement by Q-FISH.
      ), designed to measure the shortest telomeres and telomeres from specific chromosomes. Once the shortest telomeres are depleted, cells either die or become senescent, so the length of the shortest telomeres is a better indicator of cellular aging than average telomere length. A more detailed discussion of telomere measurement is available in Aubert et al. (
      • Aubert G.
      • Hills M.
      • Lansdorp P.M.
      Telomere length measurement-caveats and a critical assessment of the available technologies and tools.
      ). Most psychiatric studies examining telomere length have used either Southern blot analyses or the Cawthon (
      • Cawthon R.M.
      Telomere measurement by quantitative PCR.
      ) quantitative PCR method. Since individual laboratories internally calibrate their measurements of telomere length, it can be difficult to compare measurements across groups.

      Cross-Sectional Versus Longitudinal Approaches in Studies of Telomere Length

      A major drawback to using telomere length as a clinical measure is the high variability between individuals, which is present at birth (
      • Takubo K.
      • Izumiyama-Shimomura N.
      • Honma N.
      • Sawabe M.
      • Arai T.
      • Kato M.
      • et al.
      Telomere lengths are characteristic in each human individual.
      ,
      • Aviv A.
      • Valdes A.M.
      • Spector T.D.
      Human telomere biology: Pitfalls of moving from the laboratory to epidemiology.
      ). Moreover, although telomere length is equal between the sexes at birth, shortening with age occurs more rapidly in male than female individuals, and rates may also differ between ethnic groups (
      • Geronimus A.T.
      • Hicken M.T.
      • Pearson J.A.
      • Seashols S.J.
      • Brown K.L.
      • Cruz T.D.
      Do US Black women experience stress-related accelerated biological aging?: A novel theory and first population-based test of Black-White differences in telomere length.
      ). These factors limit the power of cross-sectional studies, which utilize measurements at a single time point. Such studies require large sample sizes because of the marked variability of telomere length, as well as careful control subjects for age and sex. Aviv et al. (
      • Aviv A.
      • Valdes A.M.
      • Spector T.D.
      Human telomere biology: Pitfalls of moving from the laboratory to epidemiology.
      ) estimates that longitudinal studies, measuring actual telomere erosion rates within individuals over time, would require five times fewer subjects than cross-sectional studies. Longitudinal studies also better support an assertion of causality by the independent variable of interest, which is severely constrained in cross-sectional designs.
      Despite these considerations, very few longitudinal telomere studies have been conducted, and their dearth is particularly evident in work involving psychiatric or stress-related conditions. An alternative approach would be to standardize telomere length in an easily accessible proliferative tissue, representing the effects of exposure to the variable of interest against telomere length in a postmitotic source, since telomere lengths in such tissues change little from birth. However, obtaining samples from postmitotic tissues (i.e., nerves, skeletal muscle, bone) presents practical obstacles. Indeed, even peripheral blood can be difficult to obtain in a longitudinal context.

      Telomeres and Somatic Disease

      Because of their prominence in aging (
      • Oeseburg H.
      • de Boer R.A.
      • van Gilst W.H.
      • van der Harst P.
      Telomere biology in healthy aging and disease.
      ), telomeres have been intensively investigated in medical conditions associated with aging. Most clinical studies have utilized telomeres derived from leukocytes, since peripheral blood is more easily obtained than most other tissues. The major determinants of aging, including cell replication, inflammation, and oxidative stress, are all demonstrable in leukocyte telomeres (
      • Aubert G.
      • Lansdorp P.M.
      Telomeres and aging.
      ,
      • Oeseburg H.
      • de Boer R.A.
      • van Gilst W.H.
      • van der Harst P.
      Telomere biology in healthy aging and disease.
      ,
      • von Zglinicki T.
      • Martin-Ruiz C.
      Telomeres as biomarkers for ageing and age-related diseases.
      ). A potential pitfall to this approach is that telomere length may differ among different leukocyte subsets, so that factors favoring predominance of one subset over another can introduce bias (
      • Aviv A.
      • Valdes A.M.
      • Spector T.D.
      Human telomere biology: Pitfalls of moving from the laboratory to epidemiology.
      ). If such a factor is of major interest (e.g., human immunodeficiency virus), telomere length might be more appropriately ascertained in a specific subset. Similarly, since telomere length reflects the leukocyte's replicative history, any condition that increases leukocyte turnover can introduce bias. Controlling for factors that alter leukocyte turnover or subsets (e.g., acute or chronic inflammatory conditions) can help minimize bias. An alternative approach is to use buccal mucosa cells obtained by oral swab, which is less invasive than venipuncture and therefore ideal for studies with children (
      • Kroenke C.H.
      • Epel E.
      • Adler N.
      • Bush N.R.
      • Obradovic J.
      • Lin J.
      • et al.
      Autonomic and adrenocortical reactivity and buccal cell telomere length in kindergarten children.
      ,
      • Needham B.L.
      • Fernandez J.R.
      • Lin J.
      • Epel E.S.
      • Blackburn E.H.
      Socioeconomic status and cell aging in children.
      ,
      • Shalev I.
      • Moffitt T.E.
      • Sugden K.
      • Williams B.
      • Houts R.M.
      • Danese A.
      • et al.
      Exposure to violence during childhood is associated with telomere erosion from 5 to 10 years of age: A longitudinal study [published online ahead of print April 24].
      ), although at present there is less experience with this tissue source.
      A key finding from clinical studies is that alteration of leukocyte telomere dynamics reflects organ dysfunction elsewhere in the body (
      • von Zglinicki T.
      • Martin-Ruiz C.
      Telomeres as biomarkers for ageing and age-related diseases.
      ). A prime example is cardiovascular disease, in which reduced telomere length is observed not only in leukocytes but also in myocardial and arterial wall tissue (
      • Chang E.
      • Harley C.B.
      Telomere length and replicative aging in human vascular tissues.
      ,
      • Oh H.
      • Wang S.C.
      • Prahash A.
      • Sano M.
      • Moravec C.S.
      • Taffet G.E.
      • et al.
      Telomere attrition and Chk2 activation in human heart failure.
      ). Findings in other medical conditions, including cancers (
      • Blasco M.A.
      Telomeres and human disease: Ageing, cancer and beyond.
      ,
      • Holt S.E.
      • Shay J.W.
      Role of telomerase in cellular proliferation and cancer.
      ), stroke (
      • Martin-Ruiz C.
      • Dickinson H.O.
      • Keys B.
      • Rowan E.
      • Kenny R.A.
      • Von Zglinicki T.
      Telomere length predicts poststroke mortality, dementia, and cognitive decline.
      ,
      • von Zglinicki T.
      • Pilger R.
      • Sitte N.
      Accumulation of single-strand breaks is the major cause of telomere shortening in human fibroblasts.
      ), diabetes (
      • Halvorsen T.L.
      • Beattie G.M.
      • Lopez A.D.
      • Hayek A.
      • Levine F.
      Accelerated telomere shortening and senescence in human pancreatic islet cells stimulated to divide in vitro.
      ,
      • Jeanclos E.
      • Krolewski A.
      • Skurnick J.
      • Kimura M.
      • Aviv H.
      • Warram J.H.
      • Aviv A.
      Shortened telomere length in white blood cells of patients with IDDM.
      ,
      • Sampson M.J.
      • Winterbone M.S.
      • Hughes J.C.
      • Dozio N.
      • Hughes D.A.
      Monocyte telomere shortening and oxidative DNA damage in type 2 diabetes.
      ), and autoimmune diseases (
      • Andrews N.P.
      • Fujii H.
      • Goronzy J.J.
      • Weyand C.M.
      Telomeres and immunological diseases of aging.
      ), support the notion that reduced telomere length in leukocytes correlates with shorter telomeres in the target tissue.
      A possible explanation for this observation could be that common underlying mechanisms for these diseases also manifest themselves in leukocytes. For example, oxidative stress, which is caused by age-related mitochondrial dysfunction, is involved in diabetes, cardiovascular disease, and cancer and affects tissues in general. Telomerase could also be involved, perhaps as a mediating agent. Indeed, some evidence implicates telomerase in the cell survival-promoting actions of brain-derived neurotrophic factor in early postmitotic hippocampal neurons (
      • Fu W.
      • Lu C.
      • Mattson M.P.
      Telomerase mediates the cell survival-promoting actions of brain-derived neurotrophic factor and secreted amyloid precursor protein in developing hippocampal neurons.
      ), which could be relevant to the association of telomere length with stress and depression, as discussed below.
      While telomere length in these conditions could be merely a disease marker (i.e., an indicator of ongoing disease), other evidence implicates telomere length as a risk marker (i.e., a predictor of the likelihood of disease despite current clinical health). For example, in a study of healthy older adults, Cawthon et al. (
      • Cawthon R.M.
      • Smith K.R.
      • O'Brien E.
      • Sivatchenko A.
      • Kerber R.A.
      Association between telomere length in blood and mortality in people aged 60 years or older.
      ) found telomere length highly predictive of eventual mortality, even though cause of death was variable. Other studies implicate telomere length as a risk marker for cancer (
      • Wu X.
      • Amos C.I.
      • Zhu Y.
      • Zhao H.
      • Grossman B.H.
      • Shay J.W.
      • et al.
      Telomere dysfunction: A potential cancer predisposition factor.
      ,
      • Ma H.
      • Zhou Z.
      • Wei S.
      • Liu Z.
      • Pooley K.A.
      • Dunning A.M.
      • et al.
      Shortened telomere length is associated with increased risk of cancer: A meta-analysis.
      ) and hypertension (
      • Yang Z.
      • Huang X.
      • Jiang H.
      • Zhang Y.
      • Liu H.
      • Qin C.
      • et al.
      Short telomeres and prognosis of hypertension in a chinese population.
      ). Reports of reduced telomere length in association with smoking (
      • Morla M.
      • Busquets X.
      • Pons J.
      • Sauleda J.
      • MacNee W.
      • Agusti A.G.
      Telomere shortening in smokers with and without COPD.
      ), obesity (
      • Valdes A.M.
      • Andrew T.
      • Gardner J.P.
      • Kimura M.
      • Oelsner E.
      • Cherkas L.F.
      • et al.
      Obesity, cigarette smoking, and telomere length in women.
      ), and alcohol abuse (
      • Pavanello S.
      • Hoxha M.
      • Dioni L.
      • Bertazzi P.A.
      • Snenghi R.
      • Nalesso A.
      • et al.
      Shortened telomeres in individuals with abuse in alcohol consumption.
      ) are consistent with these conditions as risk factors for increased mortality.
      Telomere dysfunction can play a causal role in disease. Telomerase deficiency has been causally linked with the genetic disorder dyskeratosis congenita, familial idiopathic pulmonary fibrosis, and familial bone marrow failure syndromes (
      • Aubert G.
      • Lansdorp P.M.
      Telomeres and aging.
      ). Progeroid syndromes, characterized by clinical manifestations of accelerated aging and molecular evidence of defective DNA repair, may also reflect causal involvement of telomeres (
      • Aubert G.
      • Lansdorp P.M.
      Telomeres and aging.
      ). A preliminary report suggests an increased rate of neuropsychiatric disorders in dyskeratosis congenita (
      • Rackley S.
      • Pao M.
      • Seratti G.F.
      • Giri N.
      • Rasimas J.J.
      • Alter B.P.
      • Savage S.A.
      Neuropsychiatric conditions among patients with dyskeratosis congenita: A link with telomere biology?.
      ). At this point, it would be premature to exclude an etiologic contribution of telomere dysfunction in other conditions.

      Telomeres and Psychiatric Conditions

      Independent of stress, most of the findings implicating telomeres in psychiatry have involved mood disorders (Table 1). In an initial epidemiological study (n = 433), Lung et al. (
      • Lung F.W.
      • Fan P.L.
      • Chen N.C.
      • Shu B.C.
      Telomeric length varies with age and polymorphisms of the MAOA gene promoter in peripheral blood cells obtained from a community in Taiwan.
      ) reported an association of reduced telomere length with the high-activity allele of the monoamine oxidase A promoter polymorphism, which has been linked to aggression and impulsivity; this association was later found mediated by MDD (
      • Lung F.W.
      • Chen N.C.
      • Shu B.C.
      Genetic pathway of major depressive disorder in shortening telomeric length.
      ). Simon et al. (
      • Simon N.M.
      • Smoller J.W.
      • McNamara K.L.
      • Maser R.S.
      • Zalta A.K.
      • Pollack M.H.
      • et al.
      Telomere shortening and mood disorders: Preliminary support for a chronic stress model of accelerated aging.
      ) demonstrated shorter telomeres in patients with MDD (n = 15) or bipolar disorder (type I or II not stated) (n = 29) compared with healthy control subjects (n = 44) (
      • Simon N.M.
      • Smoller J.W.
      • McNamara K.L.
      • Maser R.S.
      • Zalta A.K.
      • Pollack M.H.
      • et al.
      Telomere shortening and mood disorders: Preliminary support for a chronic stress model of accelerated aging.
      ). This was replicated by Hartmann et al. (
      • Hartmann N.
      • Boehner M.
      • Groenen F.
      • Kalb R.
      Telomere length of patients with major depression is shortened but independent from therapy and severity of the disease.
      ), who found no effect of illness duration or severity or nature or intensity of treatment in a study comparing MDD patients (n = 54) with control subjects (n = 20). Elvsåshagen et al. (
      • Elvsashagen T.
      • Vera E.
      • Boen E.
      • Bratlie J.
      • Andreassen O.A.
      • Josefsen D.
      • et al.
      The load of short telomeres is increased and associated with lifetime number of depressive episodes in bipolar II disorder.
      ), describing reduced telomere length in bipolar II patients (n = 28) compared with control subjects (n = 28), detected an association with lifetime number of depressive episodes but not illness duration. Wikgren et al. (
      • Wikgren M.
      • Maripuu M.
      • Karlsson T.
      • Nordfjall K.
      • Bergdahl J.
      • Hultdin J.
      • et al.
      Short telomeres in depression and the general population are associated with a hypocortisolemic state.
      ), reporting shorter telomeres in MDD patients (n = 91) versus control subjects (n = 451), also noted an association with hypocortisolism in both groups. Wolkowitz et al. (
      • Wolkowitz O.M.
      • Mellon S.H.
      • Epel E.S.
      • Lin J.
      • Dhabhar F.S.
      • Su Y.
      • et al.
      Leukocyte telomere length in major depression: Correlations with chronicity, inflammation and oxidative stress–preliminary findings.
      ) found no difference in telomere length between drug-free MDD (n = 18) and control (n = 17) subjects but inverse correlations with lifetime depression exposure and measures of oxidative stress and inflammation. This group also reported increased telomerase activity in drug-free MDD patients versus control subjects, with superior antidepressant responses in patients showing the greatest further increases (
      • Wolkowitz O.M.
      • Mellon S.H.
      • Epel E.S.
      • Lin J.
      • Reus V.I.
      • Rosser R.
      • et al.
      Resting leukocyte telomerase activity is elevated in major depression and predicts treatment response.
      ). In an epidemiological study of 952 patients with coronary heart disease, Hoen et al. (
      • Hoen P.W.
      • de Jonge P.
      • Na B.Y.
      • Farzaneh-Far R.
      • Epel E.
      • Lin J.
      • et al.
      Depression and leukocyte telomere length in patients with coronary heart disease: Data from the heart and soul study.
      ) found MDD associated with shorter telomeres. While these studies all utilized leukocytes, no differences from control subjects were found in telomere length in occipital cortex of patients with MDD (n = 24) (
      • Teyssier J.R.
      • Ragot S.
      • Chauvet-Gelinier J.C.
      • Trojak B.
      • Bonin B.
      Expression of oxidative stress-response genes is not activated in the prefrontal cortex of patients with depressive disorder.
      ) or in cerebellar gray matter of patients with MDD (n = 15), bipolar disorder (n = 46), or schizophrenia (n = 46) (
      • Zhang D.
      • Cheng L.
      • Craig D.W.
      • Redman M.
      • Liu C.
      Cerebellar telomere length and psychiatric disorders.
      ).
      Table 1Telomeres and Psychiatric Conditions
      DiagnosisReferencesTotal nFindings
      MDD
      • Lung F.W.
      • Chen N.C.
      • Shu B.C.
      Genetic pathway of major depressive disorder in shortening telomeric length.
      ,
      • Simon N.M.
      • Smoller J.W.
      • McNamara K.L.
      • Maser R.S.
      • Zalta A.K.
      • Pollack M.H.
      • et al.
      Telomere shortening and mood disorders: Preliminary support for a chronic stress model of accelerated aging.
      ,
      • Hartmann N.
      • Boehner M.
      • Groenen F.
      • Kalb R.
      Telomere length of patients with major depression is shortened but independent from therapy and severity of the disease.
      ,
      • Wikgren M.
      • Maripuu M.
      • Karlsson T.
      • Nordfjall K.
      • Bergdahl J.
      • Hultdin J.
      • et al.
      Short telomeres in depression and the general population are associated with a hypocortisolemic state.
      ,
      • Wolkowitz O.M.
      • Mellon S.H.
      • Epel E.S.
      • Lin J.
      • Dhabhar F.S.
      • Su Y.
      • et al.
      Leukocyte telomere length in major depression: Correlations with chronicity, inflammation and oxidative stress–preliminary findings.
      ,
      • Wolkowitz O.M.
      • Mellon S.H.
      • Epel E.S.
      • Lin J.
      • Reus V.I.
      • Rosser R.
      • et al.
      Resting leukocyte telomerase activity is elevated in major depression and predicts treatment response.
      ,
      • Hoen P.W.
      • de Jonge P.
      • Na B.Y.
      • Farzaneh-Far R.
      • Epel E.
      • Lin J.
      • et al.
      Depression and leukocyte telomere length in patients with coronary heart disease: Data from the heart and soul study.
      ,
      • Teyssier J.R.
      • Ragot S.
      • Chauvet-Gelinier J.C.
      • Trojak B.
      • Bonin B.
      Expression of oxidative stress-response genes is not activated in the prefrontal cortex of patients with depressive disorder.
      ,
      • Zhang D.
      • Cheng L.
      • Craig D.W.
      • Redman M.
      • Liu C.
      Cerebellar telomere length and psychiatric disorders.
      MDD = 700 (including 204 with stable CHD)

      HC = 1765 (including 746 with stable CHD)
      Shorter telomeres associated with MDD: 5 studies

      No difference in telomere length: 3 studies

      Increased telomerase activity with MDD: 1 study
      BIP
      • Simon N.M.
      • Smoller J.W.
      • McNamara K.L.
      • Maser R.S.
      • Zalta A.K.
      • Pollack M.H.
      • et al.
      Telomere shortening and mood disorders: Preliminary support for a chronic stress model of accelerated aging.
      ,
      • Elvsashagen T.
      • Vera E.
      • Boen E.
      • Bratlie J.
      • Andreassen O.A.
      • Josefsen D.
      • et al.
      The load of short telomeres is increased and associated with lifetime number of depressive episodes in bipolar II disorder.
      ,
      • Zhang D.
      • Cheng L.
      • Craig D.W.
      • Redman M.
      • Liu C.
      Cerebellar telomere length and psychiatric disorders.
      BIP = 103

      HC = 118
      Shorter telomeres associated with BIP: 2 studies

      No difference in telomere length: 1 study
      SCZ
      • Zhang D.
      • Cheng L.
      • Craig D.W.
      • Redman M.
      • Liu C.
      Cerebellar telomere length and psychiatric disorders.
      ,
      • Kao H.T.
      • Cawthon R.M.
      • Delisi L.E.
      • Bertisch H.C.
      • Ji F.
      • Gordon D.
      • et al.
      Rapid telomere erosion in schizophrenia.
      ,
      • Yu W.Y.
      • Chang H.W.
      • Lin C.H.
      • Cho C.L.
      Short telomeres in patients with chronic schizophrenia who show a poor response to treatment.
      SCZ = 145

      HC = 187
      Shorter telomeres associated with SCZ: 2 studies
      Only in treatment-resistant patients in one study.


      No difference in telomere length: 1 study
      BIP, bipolar disorder (I and II); CHD, coronary heart disease; HC, healthy control subjects; MDD, major depressive disorder; SCZ, schizophrenia.
      a Only in treatment-resistant patients in one study.
      Shorter leukocyte telomeres have been reported in schizophrenia (
      • Kao H.T.
      • Cawthon R.M.
      • Delisi L.E.
      • Bertisch H.C.
      • Ji F.
      • Gordon D.
      • et al.
      Rapid telomere erosion in schizophrenia.
      ), treatment-resistant schizophrenia (
      • Yu W.Y.
      • Chang H.W.
      • Lin C.H.
      • Cho C.L.
      Short telomeres in patients with chronic schizophrenia who show a poor response to treatment.
      ), obstructive sleep apnea (
      • Barcelo A.
      • Pierola J.
      • Lopez-Escribano H.
      • de la Pena M.
      • Soriano J.B.
      • Alonso-Fernandez A.
      • et al.
      Telomere shortening in sleep apnea syndrome.
      ), migraine (
      • Ren H.
      • Collins V.
      • Fernandez F.
      • Quinlan S.
      • Griffiths L.
      • Choo K.H.
      Shorter telomere length in peripheral blood cells associated with migraine in women.
      ), mild cognitive impairment (
      • Grodstein F.
      • van Oijen M.
      • Irizarry M.C.
      • Rosas H.D.
      • Hyman B.T.
      • Growdon J.H.
      • De Vivo I.
      Shorter telomeres may mark early risk of dementia: Preliminary analysis of 62 participants from the nurses' health study.
      ), and Alzheimer disease (
      • Hochstrasser T.
      • Marksteiner J.
      • Humpel C.
      Telomere length is age-dependent and reduced in monocytes of Alzheimer patients.
      ) (one study failed to replicate the latter two findings [
      • Zekry D.
      • Herrmann F.R.
      • Irminger-Finger I.
      • Graf C.
      • Genet C.
      • Vitale A.M.
      • et al.
      Telomere length and ApoE polymorphism in mild cognitive impairment, degenerative and vascular dementia.
      ]). Reduced telomere length correlated with decreased mental health in chronic heart failure (
      • Huzen J.
      • van der Harst P.
      • de Boer R.A.
      • Lesman-Leegte I.
      • Voors A.A.
      • van Gilst W.H.
      • et al.
      Telomere length and psychological well-being in patients with chronic heart failure.
      ) (but not in community-dwelling elderly men [
      • Rius-Ottenheim N.
      • Houben J.M.
      • Kromhout D.
      • Kafatos A.
      • van der Mast R.C.
      • Zitman F.G.
      • et al.
      Telomere length and mental well-being in elderly men from the Netherlands and Greece.
      ]), poorer cognition in community-dwelling elders (
      • Yaffe K.
      • Lindquist K.
      • Kluse M.
      • Cawthon R.
      • Harris T.
      • Hsueh W.C.
      • et al.
      Telomere length and cognitive function in community-dwelling elders: Findings from the Health ABC Study.
      ) and healthy women (
      • Valdes A.M.
      • Deary I.J.
      • Gardner J.
      • Kimura M.
      • Lu X.
      • Spector T.D.
      • et al.
      Leukocyte telomere length is associated with cognitive performance in healthy women.
      ), unspecified poor sleep quality in healthy women (
      • Prather A.A.
      • Puterman E.
      • Lin J.
      • O'Donovan A.
      • Krauss J.
      • Tomiyama A.J.
      • et al.
      Shorter leukocyte telomere length in midlife women with poor sleep quality [published ahead of print October 20].
      ), and pessimism in postmenopausal women (
      • O'Donovan A.
      • Lin J.
      • Dhabhar F.S.
      • Wolkowitz O.
      • Tillie J.M.
      • Blackburn E.
      • Epel E.
      Pessimism correlates with leukocyte telomere shortness and elevated interleukin-6 in post-menopausal women.
      ). It remains to be clarified whether the shorter telomeres observed in these heterogeneous conditions reflect a specific or nonspecific preexisting marker of illness vulnerability, a specific or nonspecific marker of ongoing disease, or an entirely nonspecific sequela of the psychosocial stress or lifestyle factors (e.g., smoking, obesity) with which these conditions are associated.

      Telomeres and Psychosocial Stress

      It is established that biophysical stress and stressors (e.g., radiation, toxins) (
      • Blasco M.A.
      Telomeres and human disease: Ageing, cancer and beyond.
      ,
      • Holt S.E.
      • Shay J.W.
      Role of telomerase in cellular proliferation and cancer.
      ) can impact telomere dynamics. However, Epel et al. (
      • Epel E.S.
      • Blackburn E.H.
      • Lin J.
      • Dhabhar F.S.
      • Adler N.E.
      • Morrow J.D.
      • Cawthon R.M.
      Accelerated telomere shortening in response to life stress.
      ), in a study of mothers caring for either a chronically ill (n = 39) or healthy (n = 19) child, were the first to demonstrate shorter telomeres (and reduced telomerase activity) in association with psychosocial stress (Table 2). In a follow-up study of 62 women, these investigators found that reduced telomere length correlated with increased nocturnal urinary cortisol and catecholamines, while low telomerase activity correlated with increased nocturnal urinary epinephrine and greater decreases in heart rate variability during the Trier Social Stress Test (TSST) (
      • Epel E.S.
      • Lin J.
      • Wilhelm F.H.
      • Wolkowitz O.M.
      • Cawthon R.
      • Adler N.E.
      • et al.
      Cell aging in relation to stress arousal and cardiovascular disease risk factors.
      ). Subsequent studies have examined telomere length and telomerase activity in various stress-related contexts. Damjanovic et al. (
      • Damjanovic A.K.
      • Yang Y.
      • Glaser R.
      • Kiecolt-Glaser J.K.
      • Nguyen H.
      • Laskowski B.
      • et al.
      Accelerated telomere erosion is associated with a declining immune function of caregivers of Alzheimer's disease patients.
      ) reported shorter telomeres and increased telomerase activity in caregivers of Alzheimer's disease patients (n = 41) compared with control subjects (n = 41). Kiefer et al. (
      • Kiefer A.
      • Lin J.
      • Blackburn E.
      • Epel E.
      Dietary restraint and telomere length in pre- and postmenopausal women.
      ), in a study of 56 women, observed reduced telomere length with greater dietary restraint, defined as chronic preoccupation with weight and attempts at restricting food intake leading to chronic psychological stress. In an epidemiological study of 647 sisters of women with breast cancer, Parks et al. (
      • Parks C.G.
      • Miller D.B.
      • McCanlies E.C.
      • Cawthon R.M.
      • Andrew M.E.
      • DeRoo L.A.
      • Sandler D.P.
      Telomere length, current perceived stress, and urinary stress hormones in women.
      ) found that reduced telomere length correlated with perceived stress, especially in women who were >55 years old, had a recent major loss, or had higher morning urinary epinephrine levels. Humphreys et al. (
      • Humphreys J.
      • Epel E.S.
      • Cooper B.A.
      • Lin J.
      • Blackburn E.H.
      • Lee K.A.
      Telomere shortening in formerly abused and never abused women.
      ) detected shorter telomeres in women with a history of intimate partner violence (n = 61) compared with control subjects (n = 41). In a study of female caregivers of dementia partners (n = 14) and control subjects (n = 9), Tomiyama et al. (
      • Tomiyama A.J.
      • O'Donovan A.
      • Lin J.
      • Puterman E.
      • Lazaro A.
      • Chan J.
      • et al.
      Does cellular aging relate to patterns of allostasis?: An examination of basal and stress reactive HPA axis activity and telomere length.
      ) found that shorter telomeres were associated with greater salivary cortisol responses to the TSST and higher overnight urinary free cortisol. In one expanded sample from this study (n = 22 caregivers, n = 22 control subjects), telomerase activity was lower at baseline in caregivers but rose similarly in both groups during the TSST (
      • Epel E.S.
      • Lin J.
      • Dhabhar F.S.
      • Wolkowitz O.M.
      • Puterman E.
      • Karan L.
      • Blackburn E.H.
      Dynamics of telomerase activity in response to acute psychological stress.
      ); in another expanded sample (n = 27 caregivers, n = 23 control subjects), reduced telomere length correlated with higher anticipatory threat appraisal, which correlated, in turn, with caregiver status, even though telomere length did not differ between the two groups (
      • O'Donovan A.
      • Tomiyama A.J.
      • Lin J.
      • Puterman E.
      • Adler N.E.
      • Kemeny M.
      • et al.
      Stress appraisals and cellular aging: A key role for anticipatory threat in the relationship between psychological stress and telomere length.
      ). Kroenke et al. (
      • Kroenke C.H.
      • Epel E.
      • Adler N.
      • Bush N.R.
      • Obradovic J.
      • Lin J.
      • et al.
      Autonomic and adrenocortical reactivity and buccal cell telomere length in kindergarten children.
      ) found that buccal telomere length was inversely correlated with heart rate and cortisol reactivity in 78 children during mildly stressful laboratory challenge tasks. Malan et al. (
      • Malan S.
      • Hemmings S.
      • Kidd M.
      • Martin L.
      • Seedat S.
      Investigation of telomere length and psychological stress in rape victims.
      ) observed shorter telomeres in women who developed posttraumatic stress disorder (PTSD) following rape (n = 9) compared with those who did not (n = 53). In a study of patients with (n = 18) and without (n = 18) chronic osteoarthritis pain, Sibille et al. (
      • Sibille K.T.
      • Langaee T.
      • Burkley B.
      • Gong Y.
      • Glover T.L.
      • King C.
      • et al.
      Chronic pain, perceived stress, and cellular aging: An exploratory study.
      ) found reduced telomere length in those with chronic pain and high stress versus those with no pain and low stress. Reasoning that hostility correlates with heightened stress reactivity, Brydon et al. (
      • Brydon L.
      • Lin J.
      • Butcher L.
      • Hamer M.
      • Erusalimsky J.D.
      • Blackburn E.H.
      • Steptoe A.
      Hostility and cellular aging in men from the Whitehall II cohort.
      ) found hostility inversely correlated with telomere length and positively correlated with telomerase activity, in men but not women, in an epidemiological sample of 434 adults. Supporting these observational findings in humans, Kotrschal et al. (
      • Kotrschal A.
      • Ilmonen P.
      • Penn D.J.
      Stress impacts telomere dynamics.
      ) showed that a 6-month exposure to reproductive stress in female mice and crowding stress in male mice induced telomere shortening compared with unstressed control mice.
      Table 2Telomeres and Psychosocial Stress
      Type of StressReferencesTotal nFindings
      Caregiver Stress
      • Epel E.S.
      • Blackburn E.H.
      • Lin J.
      • Dhabhar F.S.
      • Adler N.E.
      • Morrow J.D.
      • Cawthon R.M.
      Accelerated telomere shortening in response to life stress.
      ,
      • Damjanovic A.K.
      • Yang Y.
      • Glaser R.
      • Kiecolt-Glaser J.K.
      • Nguyen H.
      • Laskowski B.
      • et al.
      Accelerated telomere erosion is associated with a declining immune function of caregivers of Alzheimer's disease patients.
      ,
      • Tomiyama A.J.
      • O'Donovan A.
      • Lin J.
      • Puterman E.
      • Lazaro A.
      • Chan J.
      • et al.
      Does cellular aging relate to patterns of allostasis?: An examination of basal and stress reactive HPA axis activity and telomere length.
      ,
      • Epel E.S.
      • Lin J.
      • Dhabhar F.S.
      • Wolkowitz O.M.
      • Puterman E.
      • Karan L.
      • Blackburn E.H.
      Dynamics of telomerase activity in response to acute psychological stress.
      ,
      • O'Donovan A.
      • Tomiyama A.J.
      • Lin J.
      • Puterman E.
      • Adler N.E.
      • Kemeny M.
      • et al.
      Stress appraisals and cellular aging: A key role for anticipatory threat in the relationship between psychological stress and telomere length.
      Stressed = 126
      ns estimated due to overlapping samples.


      Control subjects = 64
      ns estimated due to overlapping samples.
      Shorter telomeres associated with perceived stress: 1 study

      Shorter telomeres associated with caregiver status: 1 study

      Telomere length not associated with caregiver status: 1 study

      Reduced telomerase activity associated with perceived stress: 1 study

      Reduced telomerase activity associated with caregiver status: 1 study

      Increased telomerase activity associated with caregiver status: 1 study

      Shorter telomeres associated with greater salivary cortisol response to TSST: 1 study

      Shorter telomeres associated with higher anticipatory threat appraisal to the TSST: 1 study
      TSST
      • Epel E.S.
      • Lin J.
      • Wilhelm F.H.
      • Wolkowitz O.M.
      • Cawthon R.
      • Adler N.E.
      • et al.
      Cell aging in relation to stress arousal and cardiovascular disease risk factors.
      Stressed = 62Shorter telomeres and reduced telomerase activity associated with increased nocturnal urinary cortisol and catecholamines: 1 study
      Laboratory Challenge Tasks
      • Kroenke C.H.
      • Epel E.
      • Adler N.
      • Bush N.R.
      • Obradovic J.
      • Lin J.
      • et al.
      Autonomic and adrenocortical reactivity and buccal cell telomere length in kindergarten children.
      78 (children)Shorter telomeres associated with increased heart rate and cortisol reactivity
      Dietary Restraint (Preoccupation with Weight, Restricted Food Intake)
      • Kiefer A.
      • Lin J.
      • Blackburn E.
      • Epel E.
      Dietary restraint and telomere length in pre- and postmenopausal women.
      Stressed = 56Shorter telomeres associated with greater dietary restraint: 1 study
      Perceived Stress (PSS)
      • Parks C.G.
      • Miller D.B.
      • McCanlies E.C.
      • Cawthon R.M.
      • Andrew M.E.
      • DeRoo L.A.
      • Sandler D.P.
      Telomere length, current perceived stress, and urinary stress hormones in women.
      647Shorter telomeres associated with perceived stress: 1 study
      Interpersonal Violence
      • Humphreys J.
      • Epel E.S.
      • Cooper B.A.
      • Lin J.
      • Blackburn E.H.
      • Lee K.A.
      Telomere shortening in formerly abused and never abused women.
      Stressed = 61

      Control subjects = 41
      Shorter telomeres associated with interpersonal violence: 1 study
      Rape
      • Malan S.
      • Hemmings S.
      • Kidd M.
      • Martin L.
      • Seedat S.
      Investigation of telomere length and psychological stress in rape victims.
      Stressed = 64 (9 with PTSD)Shorter telomeres associated with PTSD following rape: 1 study
      Chronic Pain
      • Sibille K.T.
      • Langaee T.
      • Burkley B.
      • Gong Y.
      • Glover T.L.
      • King C.
      • et al.
      Chronic pain, perceived stress, and cellular aging: An exploratory study.
      Stressed = 18

      Control subjects = 18
      Shorter telomeres associated with chronic pain + high stress: 1 study
      Hostility
      • Brydon L.
      • Lin J.
      • Butcher L.
      • Hamer M.
      • Erusalimsky J.D.
      • Blackburn E.H.
      • Steptoe A.
      Hostility and cellular aging in men from the Whitehall II cohort.
      434Shorter telomeres and increased telomerase activity associated with hostility in men: 1 study
      SES
      • Needham B.L.
      • Fernandez J.R.
      • Lin J.
      • Epel E.S.
      • Blackburn E.H.
      Socioeconomic status and cell aging in children.
      ,
      • Cherkas L.F.
      • Aviv A.
      • Valdes A.M.
      • Hunkin J.L.
      • Gardner J.P.
      • Surdulescu G.L.
      • et al.
      The effects of social status on biological aging as measured by white-blood-cell telomere length.
      1622Shorter telomeres associated with lower SES: 2 studies
      Minority Ethnicity
      • Geronimus A.T.
      • Hicken M.T.
      • Pearson J.A.
      • Seashols S.J.
      • Brown K.L.
      • Cruz T.D.
      Do US Black women experience stress-related accelerated biological aging?: A novel theory and first population-based test of Black-White differences in telomere length.
      African American = 117

      Caucasian =115
      Shorter telomeres associated with African American ethnicity (trend): 1 study
      Educational Attainment
      • Steptoe A.
      • Hamer M.
      • Butcher L.
      • Lin J.
      • Brydon L.
      • Kivimaki M.
      • et al.
      Educational attainment but not measures of current socioeconomic circumstances are associated with leukocyte telomere length in healthy older men and women.
      ,
      • Surtees P.G.
      • Wainwright N.W.
      • Pooley K.A.
      • Luben R.N.
      • Khaw K.T.
      • Easton D.F.
      • Dunning A.M.
      Educational attainment and mean leukocyte telomere length in women in the European Prospective Investigation into Cancer (EPIC)-Norfolk population study.
      5046Shorter telomeres associated with lower educational attainment: 2 studies
      Employment/Work Schedule
      • Parks C.G.
      • DeRoo L.A.
      • Miller D.B.
      • McCanlies E.C.
      • Cawthon R.M.
      • Sandler D.P.
      Employment and work schedule are related to telomere length in women.
      608Shorter telomeres associated with current and long-term full-time work schedule: 1 study
      PSS, Perceived Stress Scale; PTSD, posttraumatic stress disorder; SES, socioeconomic status; TSST, Trier Social Stress Test.
      a ns estimated due to overlapping samples.
      Reduced telomere length has been correlated with several sociodemographic variables thought to represent proxies for sustained psychosocial stress, including lower socioeconomic status (
      • Needham B.L.
      • Fernandez J.R.
      • Lin J.
      • Epel E.S.
      • Blackburn E.H.
      Socioeconomic status and cell aging in children.
      ,
      • Cherkas L.F.
      • Aviv A.
      • Valdes A.M.
      • Hunkin J.L.
      • Gardner J.P.
      • Surdulescu G.L.
      • et al.
      The effects of social status on biological aging as measured by white-blood-cell telomere length.
      ), African American ethnicity (
      • Geronimus A.T.
      • Hicken M.T.
      • Pearson J.A.
      • Seashols S.J.
      • Brown K.L.
      • Cruz T.D.
      Do US Black women experience stress-related accelerated biological aging?: A novel theory and first population-based test of Black-White differences in telomere length.
      ), lower educational attainment (
      • Steptoe A.
      • Hamer M.
      • Butcher L.
      • Lin J.
      • Brydon L.
      • Kivimaki M.
      • et al.
      Educational attainment but not measures of current socioeconomic circumstances are associated with leukocyte telomere length in healthy older men and women.
      ,
      • Surtees P.G.
      • Wainwright N.W.
      • Pooley K.A.
      • Luben R.N.
      • Khaw K.T.
      • Easton D.F.
      • Dunning A.M.
      Educational attainment and mean leukocyte telomere length in women in the European Prospective Investigation into Cancer (EPIC)-Norfolk population study.
      ), and current and long-term full-time work schedule (
      • Parks C.G.
      • DeRoo L.A.
      • Miller D.B.
      • McCanlies E.C.
      • Cawthon R.M.
      • Sandler D.P.
      Employment and work schedule are related to telomere length in women.
      ).

      Telomeres and Early-Life Stress

      Tyrka et al. (
      • Tyrka A.R.
      • Price L.H.
      • Kao H.T.
      • Porton B.
      • Marsella S.A.
      • Carpenter L.L.
      Childhood maltreatment and telomere shortening: Preliminary support for an effect of early stress on cellular aging.
      ) offered the first evidence linking early-life stress with reduced telomere length, in a study of physically and psychiatrically healthy adults with (n = 10) or without (n = 21) a reported history of childhood maltreatment (Table 3). Eight other studies have since appeared examining this issue, a remarkable number given the short time interval. In response to Tyrka et al. (
      • Tyrka A.R.
      • Price L.H.
      • Kao H.T.
      • Porton B.
      • Marsella S.A.
      • Carpenter L.L.
      Childhood maltreatment and telomere shortening: Preliminary support for an effect of early stress on cellular aging.
      ), Glass et al. (
      • Glass D.
      • Parts L.
      • Knowles D.
      • Aviv A.
      • Spector T.D.
      No correlation between childhood maltreatment and telomere length.
      ) presented data on adults from the Twins United Kingdom cohort in which they detected no difference in telomere length between individuals who endorsed childhood sexual (n = 34) or physical abuse (n = 20) compared with those who did not (n = 516 and n = 520, respectively). However, Kananen et al. (
      • Kananen L.
      • Surakka I.
      • Pirkola S.
      • Suvisaari J.
      • Lonnqvist J.
      • Peltonen L.
      • et al.
      Childhood adversities are associated with shorter telomere length at adult age both in individuals with an anxiety disorder and controls.
      ) confirmed an association of shorter telomere length with increasing number of reported childhood adverse life events in n = 974 adults in the Finnish Health 2000 project, even absent a relationship with current psychological distress or DSM-IV anxiety disorder diagnosis. Kiecolt-Glaser et al. (
      • Kiecolt-Glaser J.K.
      • Gouin J.P.
      • Weng N.P.
      • Malarkey W.B.
      • Beversdorf D.Q.
      • Glaser R.
      Childhood adversity heightens the impact of later-life caregiving stress on telomere length and inflammation.
      ) reported that shorter telomeres were associated with multiple childhood adversities in a study comprising dementia family caregivers (n = 58) and control subjects (n = 74). Surtees et al. (
      • Surtees P.G.
      • Wainwright N.W.
      • Pooley K.A.
      • Luben R.N.
      • Khaw K.T.
      • Easton D.F.
      • Dunning A.M.
      Life stress, emotional health, and mean telomere length in the European Prospective Investigation into Cancer (EPIC)-Norfolk population study.
      ), studying 4441 women in the United Kingdom European Prospective Investigation into Cancer-Norfolk database, found that shorter telomeres correlated with increased reported childhood adverse experiences, although not with current social adversity or emotional health. Consistent with Malan et al. (
      • Malan S.
      • Hemmings S.
      • Kidd M.
      • Martin L.
      • Seedat S.
      Investigation of telomere length and psychological stress in rape victims.
      ), O'Donovan et al. (
      • O'Donovan A.
      • Epel E.
      • Lin J.
      • Wolkowitz O.
      • Cohen B.
      • Maguen S.
      • et al.
      Childhood trauma associated with short leukocyte telomere length in posttraumatic stress disorder.
      ) observed reduced telomere length in adults with chronic PTSD (n = 43) versus healthy control subjects (n = 47); however, this was accounted for by those PTSD subjects reporting multiple categories of childhood trauma (n = 18). In the first study to show effects of early adversity on telomere length in children, Drury et al. (
      • Drury S.S.
      • Theall K.
      • Gleason M.M.
      • Smyke A.T.
      • De Vivo I.
      • Wong J.Y.
      • et al.
      Telomere length and early severe social deprivation: Linking early adversity and cellular aging.
      ) found that greater time spent in institutional care correlated with reduced buccal cell telomere length in 100 children aged 6 to 10 years in the prospective Bucharest Early Intervention Project. Extending the period of vulnerability, Entringer et al. (
      • Entringer S.
      • Epel E.S.
      • Kumsta R.
      • Lin J.
      • Hellhammer D.H.
      • Blackburn E.H.
      • et al.
      Stress exposure in intrauterine life is associated with shorter telomere length in young adulthood.
      ) demonstrated that maternal experience of severe psychosocial stress during pregnancy was associated with shorter telomeres in young adult offspring (n = 45) versus control subjects (n = 49). In the only prospective longitudinal study thus far, involving 236 children tested at age 5 and again at age 10 years, Shalev et al. (
      • Shalev I.
      • Moffitt T.E.
      • Sugden K.
      • Williams B.
      • Houts R.M.
      • Danese A.
      • et al.
      Exposure to violence during childhood is associated with telomere erosion from 5 to 10 years of age: A longitudinal study [published online ahead of print April 24].
      ) found greater buccal cell telomere shortening in children exposed to >2 forms of violence (n = 39) compared with those unexposed (n = 128) or less exposed (n = 69). Taken together, these studies support a relationship between early-life stress and reduced telomere length and strongly suggest that this effect is dose-dependent.
      Table 3Studies Examining the Relationship Between Telomere Length and Early-Life Stress
      AuthorSex DistributionPresence of ELS in SampleAge at Telomere Measurement (X̄ ± SD or Range, Years)Type of ELS and Assessment MethodSample Composition and Assessment of PsychopathologyControlled CovariatesTelomere Measurement MethodFindings
      Tyrka et al. (2010) (
      • Tyrka A.R.
      • Price L.H.
      • Kao H.T.
      • Porton B.
      • Marsella S.A.
      • Carpenter L.L.
      Childhood maltreatment and telomere shortening: Preliminary support for an effect of early stress on cellular aging.
      )
      9 M, 22 F10/3126.9 ± 10.1Emotional/physical/sexual abuse, emotional/physical neglect; CTQ subscalesNo current or past major Axis I disorder; SCIDAge, sex, oral contraceptives, smoking, BMI, race, education, SES, perceived stressqPCR; leukocytesShorter telomeres associated with ELS.
      Glass et al. (2010) (
      • Glass D.
      • Parts L.
      • Knowles D.
      • Aviv A.
      • Spector T.D.
      No correlation between childhood maltreatment and telomere length.
      )
      Not specified20/540 (physical abuse); 34/550 (sexual abuse)Not specifiedPhysical/sexual abuse; individual survey questionsEpidemiological sample; psychopathology not specifiedAge, sex, BMI, smokingSouthern blot; leukocytesTelomere length no different between subjects with and without ELS.
      Kananen et al. (2010) (
      • Kananen L.
      • Surakka I.
      • Pirkola S.
      • Suvisaari J.
      • Lonnqvist J.
      • Peltonen L.
      • et al.
      Childhood adversities are associated with shorter telomere length at adult age both in individuals with an anxiety disorder and controls.
      )
      617 F (202 Anx), 357 M (119 Anx)1.94 adverse events (Anx); .97 adverse events (control subjects)49.7 ± 12.8 (Anx); 49.8 ± 12.6 (control subjects)Adverse childhood social environment (financial difficulties, parental unemployment, parental physical/mental illness, familial conflict, bullying, personal illness); sum of individual survey questionsAnxiety disorder (full or subthreshold) versus control subjects; assessed MDD/dysthymia, alcohol use disorder; M-CIDIComorbid disorders, psychiatric medication, BMI, blood pressure, blood chemistries (homocysteine, triglycerides, HDL, LDL, glucose, insulin), diabetes, lifestyle factors (smoking, sleep, exercise)qPCR; leukocytesShorter telomeres associated with ELS (greater number of childhood adverse events). Telomere length no different between anxiety and control groups.
      Kiecolt-Glaser et al. (2011) (
      • Kiecolt-Glaser J.K.
      • Gouin J.P.
      • Weng N.P.
      • Malarkey W.B.
      • Beversdorf D.Q.
      • Glaser R.
      Childhood adversity heightens the impact of later-life caregiving stress on telomere length and inflammation.
      )
      37 M, 95 F42/132 (abuse); 74/132 (adverse event)70.10 ± 9.41 (caregivers); 69.37 ± 10.73 (control subjects)Emotional/physical/sexual abuse, childhood adversity (parental death, parental marital conflict, familial mental illness, familial alcohol problems, lack of close relationship with adult); CTQ; sum of individual survey questionsCaregivers versus control subjects; assessed depressive symptoms; CES-DAge, sex, BMI, exercise, sleep, alcohol use, caregiving statusSouthern blot; leukocytesShorter telomeres associated with ELS (≥2 childhood adversities; abuse without other adversities not associated with telomere length). Shorter telomeres associated with increased plasma IL-6.
      Surtees et al. (2011) (
      • Surtees P.G.
      • Wainwright N.W.
      • Pooley K.A.
      • Luben R.N.
      • Khaw K.T.
      • Easton D.F.
      • Dunning A.M.
      Life stress, emotional health, and mean telomere length in the European Prospective Investigation into Cancer (EPIC)-Norfolk population study.
      )
      0 M, 4441 F2234/444162 (median)Childhood social adversity (separation from mother for >1 year, extended hospital stays, parental unemployment, traumatic events, removal from home, divorce, parental substance use, physical abuse); HLEQEpidemiological sample; assessed MDD, GAD; HLEQ, SF-36Age, physical health score, self-reported health, social class, obesity, smoking, preexisting diseaseqPCR; leukocytesShorter telomeres associated with ELS (greater number of childhood adverse events).
      O'Donovan et al. (2011) (
      • O'Donovan A.
      • Epel E.
      • Lin J.
      • Wolkowitz O.
      • Cohen B.
      • Maguen S.
      • et al.
      Childhood trauma associated with short leukocyte telomere length in posttraumatic stress disorder.
      )
      43 M (22 PTSD), 45 F (20 PTSD)50 trauma reports (PTSD); 6 trauma reports (control subjects)30.40 ± 6.63 (PTSD); 30.68 ± 8.19 (control subjects)Physical neglect, physical abuse, family violence, forced sexual touch, forced sexual intercourse; sum of individual interview items on Life Stressor Checklist interviewPTSD versus control subjects; assessed alcohol/substance abuse/dependence, MDD; CAPS, SCIDAge, sex, BMI, smoking, educationqPCR; leukocytesShorter telomeres associated with ELS (greater number of ELS types); shorter telomeres in PTSD versus control subjects (accounted for by effect of ELS).
      Drury et al. (2011) (
      • Drury S.S.
      • Theall K.
      • Gleason M.M.
      • Smyke A.T.
      • De Vivo I.
      • Wong J.Y.
      • et al.
      Telomere length and early severe social deprivation: Linking early adversity and cellular aging.
      )
      67 M, 69 F136/1366–10Time spent in institutionalized carePsychopathology not specifiedInstitutionalized versus foster care, ethnicity, age at telomere collection, low birth weightqPCR; buccal cellsShorter telomeres associated with ELS (greater time in institutionalized care).
      Entringer et al. (2011) (
      • Entringer S.
      • Epel E.S.
      • Kumsta R.
      • Lin J.
      • Hellhammer D.H.
      • Blackburn E.H.
      • et al.
      Stress exposure in intrauterine life is associated with shorter telomere length in young adulthood.
      )
      21 M, 73 F45/9425 ± .8 (prenatal stress); 24 ± .6 (controls)Exposure to prenatal stress during mother's pregnancy (defined as experience of negative life events, such as death/illness in family, loss of residence, etc.); interviewAssessed depressive symptoms; CES-DAge, BMI, birth weight percentile, early-life and concurrent life stressqPCR; leukocytesShorter telomeres associated with ELS (prenatal stress); effect greater in females than males.
      Shalev et al. (2012) (
      • Shalev I.
      • Moffitt T.E.
      • Sugden K.
      • Williams B.
      • Houts R.M.
      • Danese A.
      • et al.
      Exposure to violence during childhood is associated with telomere erosion from 5 to 10 years of age: A longitudinal study [published online ahead of print April 24].
      )
      120 M, 116 F108/236Baseline: 5; Follow-up: 10Exposure to domestic violence between mother and her partner, frequent bullying victimization, physical maltreatment by an adult; CTS, interviewSubset of epidemiological sample; psychopathology not specifiedAge, sex, BMI, SESqPCR; buccal cellsTelomere shortening from age 5 to age 10 associated with exposure to ≥2 forms of violence.
      Anx, anxiety disorder (full or subthreshold); BMI, body mass index; CAPS, Clinician-Administered PTSD Scale; CES-D, Center for Epidemiologic Studies Depression Scale; CTQ, Childhood Trauma Questionnaire; CTS, Conflict Tactics Scale; ELS, early-life stress; F, female; GAD, generalized anxiety disorder; HDL, high-density lipoproteins; HLEQ, Health and Life Experiences Questionnaire; IL-6, interleukin-6; LDL, low-density lipoproteins; M, male; M-CIDI, Munich-Composite International Diagnostic Interview; MDD, major depressive disorder; PTSD, posttraumatic stress disorder; qPCR, quantitative polymerase chain reaction; SCID, Structured Clinical Interview for DSM-IV; SES, socioeconomic status; SF-36, Short Form Health Survey.

      Telomeres and Early-Life Stress: Mechanisms

      In their review of the neurobiological interrelationship between stress, depression, and aging, Wolkowitz et al. (
      • Wolkowitz O.M.
      • Epel E.S.
      • Reus V.I.
      • Mellon S.H.
      Depression gets old fast: Do stress and depression accelerate cell aging?.
      ) observe that many of the biochemical derangements in depression, and in chronic stress, result in cellular effects indistinguishable from aging. Indeed, they propose that the high comorbidity of depression with diseases of aging, such as cardiovascular disease, cerebrovascular disease, and metabolic syndrome, suggests that stress-engendered depression is itself such a disease. In this conceptualization, telomere shortening would be an expected concomitant, and/or consequence, of the hypothalamic-pituitary-adrenal axis dysregulation, enhanced glutamatergic excitotoxicity, increased oxidative stress, impaired neurotrophin function, and immune dysregulation reported in chronic stress and depression. Supporting this is evidence that cortisol can reduce telomerase activity (
      • Tomiyama A.J.
      • O'Donovan A.
      • Lin J.
      • Puterman E.
      • Lazaro A.
      • Chan J.
      • et al.
      Does cellular aging relate to patterns of allostasis?: An examination of basal and stress reactive HPA axis activity and telomere length.
      ,
      • Choi J.
      • Fauce S.R.
      • Effros R.B.
      Reduced telomerase activity in human T lymphocytes exposed to cortisol.
      ).
      However, while examination of the biochemistry of aging and telomere dynamics (
      • Aubert G.
      • Lansdorp P.M.
      Telomeres and aging.
      ,
      • Oeseburg H.
      • de Boer R.A.
      • van Gilst W.H.
      • van der Harst P.
      Telomere biology in healthy aging and disease.
      ,
      • von Zglinicki T.
      • Martin-Ruiz C.
      Telomeres as biomarkers for ageing and age-related diseases.
      ,
      • Blasco M.A.
      Telomeres and human disease: Ageing, cancer and beyond.
      ,
      • Holt S.E.
      • Shay J.W.
      Role of telomerase in cellular proliferation and cancer.
      ) is beyond the present scope, there has yet to be direct demonstration of these mechanisms in affected human subjects or relevant animal models. Similarly, even as attention has turned to the role of epigenetics as a major transductive mechanism for adult sequelae of early-life stress (
      • Low F.M.
      • Gluckman P.D.
      • Hanson M.A.
      Developmental plasticity and epigenetic mechanisms underpinning metabolic and cardiovascular diseases.
      ,
      • Tyrka A.R.
      • Price L.H.
      • Marsit C.
      • Walters O.C.
      • Carpenter L.L.
      Childhood adversity and epigenetic modulation of the leukocyte glucocorticoid receptor: Preliminary findings in healthy adults.
      ), there are still no direct studies of telomere dynamics in this regard. Finally, as noted above, problematic lifestyle factors (e.g., smoking, obesity, alcohol abuse) are frequent sequelae of early-life stress. While most studies of telomere length and early-life stress controlled for such influences, it remains possible that these or other factors could account for the association between reduced telomere length and early-life stress.

      Telomeres and Early-Life Stress: Methodological Issues

      Nearly all of the clinical and epidemiological studies examining health implications of telomere length have been cross-sectional in design with respect to telomere assessment, limiting the ability to draw causal inferences about telomere shortening; the same is true for all but one (
      • Shalev I.
      • Moffitt T.E.
      • Sugden K.
      • Williams B.
      • Houts R.M.
      • Danese A.
      • et al.
      Exposure to violence during childhood is associated with telomere erosion from 5 to 10 years of age: A longitudinal study [published online ahead of print April 24].
      ) of the nine studies addressing the effects of early-life stress. Analogously, assessment of early-life stress can be either prospective or retrospective; all but two (
      • Shalev I.
      • Moffitt T.E.
      • Sugden K.
      • Williams B.
      • Houts R.M.
      • Danese A.
      • et al.
      Exposure to violence during childhood is associated with telomere erosion from 5 to 10 years of age: A longitudinal study [published online ahead of print April 24].
      ,
      • Drury S.S.
      • Theall K.
      • Gleason M.M.
      • Smyke A.T.
      • De Vivo I.
      • Wong J.Y.
      • et al.
      Telomere length and early severe social deprivation: Linking early adversity and cellular aging.
      ) of the studies in this area have been retrospective.
      The limitations of cross-sectional versus longitudinal measurement of telomere length have been discussed. How early-life stress is retrospectively ascertained and assessed is highly variable across studies, but more systematic and comprehensive approaches seem more likely to compensate for the bias toward false negatives (
      • Hardt J.
      • Rutter M.
      Validity of adult retrospective reports of adverse childhood experiences: Review of the evidence.
      ). Several studies have found an effect of the number of discrete childhood adversities, suggesting that early stressors may have additive effects on telomere length. Ideally, assessment tools should have demonstrable validity and reliability; short of that, ascertainment methods requiring the least amount of judgment or interpretation by the subject are preferable. Such considerations may explain why Glass et al. (
      • Glass D.
      • Parts L.
      • Knowles D.
      • Aviv A.
      • Spector T.D.
      No correlation between childhood maltreatment and telomere length.
      ) failed to replicate an association between early-life stress and reduced telomere length. Timing and type of early-life stress and the impact of mitigating psychosocial or genetic factors (resilience factors) (
      • Nugent N.R.
      • Tyrka A.R.
      • Carpenter L.L.
      • Price L.H.
      Gene-environment interactions: Early life stress and risk for depressive and anxiety disorders.
      ) could also affect findings.

      Effects of Therapeutic Stress Reduction on Telomeres

      Epel et al. (
      • Epel E.
      • Daubenmier J.
      • Moskowitz J.T.
      • Folkman S.
      • Blackburn E.
      Can meditation slow rate of cellular aging? Cognitive stress, mindfulness, and telomeres.
      ) have proposed that therapeutic interventions designed to mitigate adverse effects of psychosocial stress (e.g., threat appraisal, rumination, negative affect, stress arousal) might promote telomere maintenance. Supporting this, vigorous exercise attenuated the correlation between perceived stress and reduced telomere length in a sample of 63 healthy women (
      • Puterman E.
      • Lin J.
      • Blackburn E.
      • O'Donovan A.
      • Adler N.
      • Epel E.
      The power of exercise: Buffering the effect of chronic stress on telomere length.
      ). In a prospective study, Jacobs et al. (
      • Jacobs T.L.
      • Epel E.S.
      • Lin J.
      • Blackburn E.H.
      • Wolkowitz O.M.
      • Bridwell D.A.
      • et al.
      Intensive meditation training, immune cell telomerase activity, and psychological mediators.
      ) showed that a 3-month intensive meditation retreat increased telomerase activity in participants (n = 30) compared with control subjects (n = 30), an effect mediated by increased perceived control and decreased neuroticism. Daubenmier et al. (
      • Daubenmier J.
      • Lin J.
      • Blackburn E.
      • Hecht F.M.
      • Kristeller J.
      • Maninger N.
      • et al.
      Changes in stress, eating, and metabolic factors are related to changes in telomerase activity in a randomized mindfulness intervention pilot study.
      ) found that telomerase activity increased both in overweight women receiving a 4-month mindfulness-based intervention for stress eating (n = 47) and in wait-list control subjects (n = 47), with increases correlated with decreased chronic stress, anxiety, dietary restraint, dietary fat intake, cortisol, and glucose. Lin et al. (
      • Lin J.
      • Epel E.
      • Blackburn E.
      Telomeres and lifestyle factors: Roles in cellular aging.
      ) have summarized other recent work examining effects of lifestyle interventions on telomere length and general health status.

      Summary and Implications

      In the 4 years since Aubert and Landsorp (
      • Aubert G.
      • Lansdorp P.M.
      Telomeres and aging.
      ) published their review, telomere research has exploded: they identified over 5000 articles on this topic indexed in PubMed, whereas a current search yields nearly 14,000 articles. Most studies addressing the relationship between telomere length, psychosocial stress, and psychiatric illness have been published during this brief period. At present, evidence is strongest in supporting an association of reduced telomere length with psychosocial stress and depression. Given the relationship between stress and depression, this is not surprising; it remains to be established exactly when, how, and why shorter telomeres are observed in these conditions.
      The more recent demonstration that reduced telomere length is associated with early-life stress poses challenges and opportunities. Should the adverse health outcomes in adults after early adversity be conceptualized as accelerated aging, following Wolkowitz et al. (
      • Wolkowitz O.M.
      • Epel E.S.
      • Reus V.I.
      • Mellon S.H.
      Depression gets old fast: Do stress and depression accelerate cell aging?.
      )? Or can these findings be better accommodated by the dysregulated homeostasis/allostatic load model (
      • McEwen B.S.
      • Stellar E.
      Stress and the individual Mechanisms leading to disease.
      ) that currently predominates? Alternatively, perhaps reduced telomere length is not even caused by early-life stress but is rather a preexisting (risk) or acquired (disease) marker for those individuals who subsequently characterize their early-life experiences as stressful. Nor has the possibility been excluded of a spurious association between early-life stress and reduced telomere length, accounted for by other adverse health and behavioral sequelae of childhood adversity.
      The role of telomerase in understanding these findings must also be considered. Since telomerase maintains telomere length, it might be expected that decreased telomerase activity would result in telomere shortening, perhaps suggesting a more proximal effect of chronic stress on this enzyme rather than on the telomere itself. However, the studies reviewed above suggest inconsistent relationships between telomere length and telomerase activity, and some authorities suggest that telomerase activity might compensatorily increase in the face of stress and/or telomere shortening. These conceptual challenges, in conjunction with the greater technical difficulty associated with the telomerase assay, limit the current utility of telomerase activity for informing our understanding of stress and telomere length.
      The early findings reviewed above raise hopes that telomere length might serve as a deep biomarker of early-life stress in terms of damage done, future vulnerability, and efficacy of therapeutic interventions. But a final caveat must acknowledge that, as in most rapidly emerging areas, publication bias in favor of positive findings could be a significant factor in overstating the robustness of this association. Much of the published literature is based on studies originally designed for other purposes, with telomere findings deriving from secondary analyses using banked blood specimens. Prospective research in this area over the next several years will clarify whether telomere assessment will merely constitute a new outcome measure or serve as the basis for a new paradigm.
      The authors thank Yuliya Kuras for bibliographic assistance.
      Drs. Price, Carpenter, and Tyrka report having received research funding from the National Institutes of Health, NeoSync, Neuronetics, Medtronic, and Cyberonics. Dr. Price also received research funding from Health Resources and Services Administration, served on advisory panels for Abbott and AstraZeneca, and served as a paid consultant to Gerson Lehrman, Wiley, Springer, Qatar National Research Fund, Alberta Heritage Foundation for Medical Research, Abbott, and AstraZeneca. Dr. Carpenter discloses consulting fees from Abbott, Cyberonics, Novartis, Wyeth, AstraZenica and Neuronetics; serving on the speakers' bureau for Neuronetics; and receiving honoraria for continuing medical education from AstraZenica. Dr. Tyrka received honoraria for continuing medical education from Lundbeck and Takeda. Dr. Kao and Ms. Burgers report no biomedical financial interests or potential conflicts of interest.

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