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Childhood Maltreatment and Telomere Shortening:

Preliminary Support for an Effect of Early Stress on


Cellular Aging
Audrey R. Tyrka, Lawrence H. Price, Hung-Teh Kao, Barbara Porton, Sarah A. Marsella, and
Linda L. Carpenter
Background: Psychological stress and trauma are risk factors for several medical and psychiatric illnesses. Recent studies have implicated
advanced cellular aging as a potential mechanism of this association. Telomeres, DNA repeats that cap the ends of chromosomes and
promote stability, shorten progressively with each cell division; their length is a marker of biological aging. Based on previous evidence
linking psychosocial stress to shorter telomere length, this study was designed to evaluate the effect of childhood adversity on telomere
length.

Methods: Thirty-one adults with no current or past major Axis I psychiatric disorder participated. Subjects reported on their history of
childhood maltreatment and telomere length was measured from DNA extracted from frozen whole blood using quantitative polymerase
chain reaction.

Results: Participants reporting a history of childhood maltreatment had significantly shorter telomeres than those who did not report a
history of maltreatment. This finding was not due to effects of age, sex, smoking, body mass index, or other demographic factors. Analysis of
subscales showed that both physical neglect and emotional neglect were significantly linked to telomere length.

Conclusions: These results extend previous reports linking shortened leukocyte telomere length and caregiver stress to more remote
stressful experiences in childhood and suggest that childhood maltreatment could influence cellular aging.

Key Words: Child abuse, stress, telomeres senescence, and exposure to stressors can hasten telomere
shortening and lead to premature cell senescence (for a review,
see [6]). Shortened leukocyte telomere length has been linked to

S
tressful life experiences have long been identified as risk
factors for psychiatric disorders and, more recently, for morbidity and mortality of age-related illnesses (7,8).
cardiovascular and immune diseases (1–3). Psychiatric dis- Several genes and proteins that regulate telomere length have
orders such as major depression and posttraumatic stress disor- been identified (6), and telomere shortening is also induced by
der are commonly comorbid with disorders of the cardiovascu- physiological stressors such as exposure to radiation and toxins
lar, metabolic, and immune systems (3,4). Recent research has (9), oxidative stress (10), and cigarette smoke (11,12). Of partic-
focused on identifying how stress might influence common ular relevance to psychiatric disorders are recent findings in
biological mechanisms for these disorders. humans of an association between psychological stress and
The biological response to stress involves the coordinated shortened leukocyte telomere length.
activity of several systems, including the hypothalamic-pituitary- Epel et al. (13) found that both perceived stress and chronicity
adrenal (HPA) axis, the sympathetic nervous system, and the of caregiving stress were linked to telomere shortening in
immune system. Acute activation of these systems serves to peripheral blood leukocytes of healthy adult women. These
mobilize energy resources and prepare the individual for coping indices of stress were also linked to higher levels of oxidative
with stressors. With chronic stress exposure, however, attempts stress and lower levels of telomerase, a reverse transcriptase that
at adaptation can result in pathological perturbation of endo- limits telomere shortening. Damjanovic et al. (14) recently found
crine, immune, and metabolic systems (3,5). Chronic or exces- shortened telomeres in caregivers of Alzheimer’s disease patients
sive activation of these stress-response systems may also result in who exhibited higher stress levels and higher average levels of
telomere shortening, a cellular marker of biological aging. Telo- depressive symptoms than a comparison group. Leukocyte telo-
meres are regions at the ends of linear chromosomes comprised mere shortening has also been documented in relation to pessi-
of DNA repeats that serve to “cap” the chromosomal termini, mism in a sample of healthy postmenopausal women (15) and in
promote stability, and prevent end-to-end fusion of chromo- patients with unipolar and bipolar mood disorders (16).
somes. In replicating somatic cells, telomeres shorten progres- Prior studies of the relationship of psychosocial stress to
sively with each cell division, ultimately leading to replicative telomere biology have not examined effects of adversity occur-
ring early in development. Neurobiological effects of stress may
be greatest in childhood, when the brain and other systems are
undergoing profound maturational changes. Rates of telomere
From the Mood Disorders Research Program (ART, LHP, SAM, LLC) and
shortening are fastest during infancy and early childhood (17,18),
Laboratory of Molecular Psychiatry (H-TK, BP), Butler Hospital; and De-
partment of Psychiatry and Human Behavior (ART, LHP, H-TK, BP, LLC),
and regulation of telomere length may be programmed in early
Alpert Medical School of Brown University, Providence, Rhode Island. development (19). In humans, childhood maltreatment is a
Address correspondence to Audrey R. Tyrka, M.D., Ph.D., Butler Hospital, 345 common form of early adversity and is a major risk factor for a
Blackstone Boulevard, Providence, RI 02906; E-mail: Audrey_Tyrka@ range of adverse outcomes, including major depression, anxiety
Brown.edu. disorders, and substance abuse (e.g., [20 –22]). The present study
Received Mar 6, 2009; revised Aug 11, 2009; accepted Aug 11, 2009. was designed to test the hypothesis that reports of childhood

0006-3223/10/$36.00 BIOL PSYCHIATRY 2010;67:531–534


doi:10.1016/j.biopsych.2009.08.014 © 2010 Society of Biological Psychiatry
532 BIOL PSYCHIATRY 2010;67:531–534 A.R. Tyrka et al.

maltreatment would be associated with leukocyte telomere telomere length using the method of Cawthon (32). The number
shortening in a sample of healthy adults. of telomere repeats was determined in conjunction with the
number of copies of the beta-hemoglobin gene, which served as
Methods and Materials a reference single-copy gene to account for genome copy
number in each sample. Thus, telomere length was expressed as
Subjects a ratio of telomere copy number over single gene copy number
Participants were 31 adults (22 women, 9 men), ages 18 to 64 (T/S), which was normalized to the T/S from a reference DNA
(mean, 26.9 ⫾ SD 10.1). Subjects were recruited via advertise- each time the assay was performed. Polymerase chain reactions
ments in the community for a larger study of stress reactivity and were performed in 96-well reaction plates; the quantification of
psychiatric symptoms. Included in this study were individuals telomere length and the single-copy gene were performed
with no current or past major Axis I psychiatric disorder who separately in triplicate. Each 96-well plate contained six serial
reported either no history of childhood maltreatment (n ⫽ 21) or dilutions of the same DNA standard spanning the estimated DNA
a history of moderate or severe childhood maltreatment (n ⫽ 10). concentrations of the samples to be assayed. All measurements
Participants completed a medical history, physical and neurolog- on the same plate were normalized to the DNA standards and a
ical examinations, blood chemistries, electrocardiogram (EKG), conversion factor applied to control for batch-to-batch variation.
and urine analysis/toxicology to rule out acute or unstable Following the method of Shen et al. (33), we standardized our
medical illness, endocrine disease, or ongoing treatment with values to the average of all the white blood cell T/S ratios. Data
drugs that might influence HPA axis function, including psycho- are reported as the average of the three triplicate measurements.
tropics, beta blockers, angiotensin-converting enzyme inhibitors, Intra-assay variability for the standard ranged from a standard
ketoconazole, metyrapone, and corticosteroids. Oral contracep- deviation of 2.5% to 15% of the control (a set of dilutions of the
tives were permitted. After complete description of the study to standard DNA). Interassay variability ranged from 1.7% to 7.3%
the subjects, written informed consent was obtained. This study (standard deviation) for actual samples quantitated in triplicate.
was approved by the Butler Hospital Institutional Review Board. Statistical Analysis. T tests and chi-square tests were used
to test for differences between the maltreatment and comparison
Measures groups on demographic factors and the measure of telomere
Demographic Characteristics. Height and weight were mea- length. The primary analysis assessed whether the maltreatment
sured in the laboratory by a research nurse and body mass index group and the no maltreatment group differed with respect to
(BMI) was calculated. Participants reported the highest education telomere length. In addition, exploratory analyses examined the
level they had attained. Socioeconomic adversity was assessed association of the individual maltreatment types with telomere
with the following true/false statement: “My family was generally length.
financially stable when I was growing up, and all of my basic
needs (food, shelter, and clothing) were met during my child-
Results
hood.”
The Structured Clinical Interview for DSM-IV. Current and Subject Characteristics and Analysis of Potential Confounds
lifetime history of Axis I psychiatric diagnoses were assessed Most participants reporting a history of moderate or severe
using the Structured Clinical Interview for DSM-IV Axis I Disor- maltreatment endorsed more than one form of maltreatment
ders (SCID-I), and participants with no lifetime major Axis I (minimal, moderate, or severe; n ⫽ 7, 70%). Eight subjects (80%)
disorder were included in this study (23). Current Axis II reported emotional abuse, eight (80%) reported emotional ne-
diagnoses were assessed using the Structured Clinical Interview glect, seven (70%) reported physical neglect, four (40%) reported
for DSM-IV Axis II Disorders (SCID-II) but did not form the basis physical abuse, and two (20%) reported sexual abuse. The
for inclusion or exclusion (24). One participant was missing individual maltreatment subscales of the CTQ were highly inter-
SCID-II data, one participant met the criteria for obsessive- correlated (rs ⬎.5), with the exception of the sexual abuse
compulsive personality disorder, and one met the criteria for subscale (only two participants reported sexual abuse). Mean
personality disorder not otherwise specified. Both of the latter scores on the subscales are shown for each group in Table 1.
participants reported a history of childhood maltreatment as Table 1 shows the demographic and abuse characteristics of
defined below. the maltreatment and no maltreatment groups. The maltreatment
Childhood Trauma Questionnaire. The 28-item version of group did not differ significantly from the comparison group with
the Childhood Trauma Questionnaire (CTQ) (25) was used to respect to age, sex, smoking status, BMI, hormonal contraception
assess childhood maltreatment. This measure has excellent psy- use in female subjects, race, education, socioeconomic adversity,
chometric properties (26), including high test-retest reliability or perceived stress on the PSS.
(27,28) as well as convergent validity (25,29,30). Participants
were selected if they reported either no childhood maltreatment
(no maltreatment group) or moderate to severe levels of child- Telomere Length in Relation to Childhood Maltreatment
hood maltreatment (maltreatment group) on any of five sub- A t test showed that the maltreatment group had significantly
scales (physical abuse, sexual abuse, emotional abuse, physical shorter telomeres than the group reporting no childhood mal-
neglect, emotional neglect). treatment [.70 ⫾ .24 vs. 1.02 ⫾ .52; t (29) ⫽ 2.4, p ⫽ .03; Figure
Perceived Stress Scale. The Perceived Stress Scale (PSS) 1]. Analysis of the CTQ subscales (excluding sexual abuse, which
(31), a 14-item questionnaire, was used to measure the degree to was endorsed by only two subjects) showed that shorter telo-
which life situations were perceived as stressful over the past meres were associated with both physical neglect [.59 ⫾ .15 vs.
month. .99 ⫾ .49; t (26.9) ⫽ 3.5, p ⫽ .002] and emotional neglect [.69 ⫾
Telomere Measurement. DNA was extracted from frozen .24 vs. .99 ⫾ .51; t (25.6) ⫽ 2.2, p ⫽ .04]. This association did not
whole blood using standard methods. The real-time quantitative reach statistical significance for physical abuse or emotional
polymerase chain reaction was used to obtain a measure of abuse (p ⫽ .057 and p ⫽ .054, respectively).

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A.R. Tyrka et al. BIOL PSYCHIATRY 2010;67:531–534 533

Table 1. Subject Characteristics these participants may have some factors that confer resil-
ience, given the absence of psychiatric disorder even in the
No Maltreatment Maltreatment
maltreatment group.
(n ⫽ 21) (n ⫽ 10)
This study is limited by the modest sample size and the
Age (Mean ⫾ SD Years) 27.6 ⫾ 10.8 25.5 ⫾ 8.5 cross-sectional nature of the study. In addition, the CTQ is a brief,
Sex, Women, n (%) 14 (67%) 8 (80%) retrospective self-report questionnaire that may be subject to
BMI, (Mean ⫾ SD) 25.4 ⫾ 4.6 26.2 ⫾ 6.3 recall and other biases. We did not find an association of
Smoker, n (%) 1 (4.8%) 2 (20%) telomere length with age in this sample, which is not surprising
Oral Contraceptive, n (% of Females) 6 (43%) 2 (25%) given that all but three subjects were younger than age 40. The
Race, n (%) rate of telomere sequence loss in human leukocytes varies with
Caucasian 16 (76.2%) 5 (50%) age, and little change in telomere length occurs in young adults
Black 1 (4.8%) 2 (20%) (34). Given the range of influences on telomere length, it is
Hispanic 0 1 (10%) possible that other variables, including genetic factors (35), could
Asian 2 (9.5%) 1 (10%) have influenced telomere length. However, the findings cannot
Other 2 (9.5%) 1 (10%) be explained by effects of age, sex, smoking status, BMI, level of
Highest Education Level, n (%) education, medical or psychiatric illness, or a measure of child-
High school 1 (4.8%) 1 (10%) hood socioeconomic adversity.
Partial college 7 (33.3%) 5 (50%) The pathway from psychological stress to telomere shorten-
College 8 (38.1%) 3 (30%) ing remains to be elucidated, but glucocorticoid-associated oxi-
Professional degree 5 (23.8%) 1 (10%)
dative stress damage is a likely mediator of this association
Childhood Socioeconomic
(36,37). Glucocorticoids are released from the adrenal gland in
Adversity, n (%)
response to stress and have been shown to increase neuronal
Experienced 2 (9.5%) 4 (40%)
Did not experience 19 (90.5%) 6 (60%)
oxidative stress damage (36 –39). Increased levels of oxidative
Perceived Stress Scale, (Mean ⫾ SD) 16.5 ⫾ 10.9 20.9 ⫾ 6.3 stress have been seen in subjects reporting psychological stress
CTQ Subscale Score, (Mean ⫾ SD) (13,40) and depressive symptoms (41), and oxidative stress
Physical abuse 5.2 ⫾ .5 7.8 ⫾ 2.6 reduces telomere length in vitro (42).
Sexual abuse 5.0 ⫾ .0 5.6 ⫾ 1.4 The present findings suggest that links of childhood mal-
Emotional abuse 5.4 ⫾ .9 12.6 ⫾ 3.3 treatment with psychopathology and associated medical prob-
Emotional neglect 6.1 ⫾ 1.3 14.7 ⫾ 4.1 lems could be due to effects of stress on cellular aging. Further
Physical neglect 5.0 ⫾ .0 9.4 ⫾ 3.0 work is needed to replicate these preliminary findings and
determine whether potential mediators of this effect, including
T tests and chi-squares were used to test for differences between the
maltreatment and no maltreatment groups on the demographic vari- glucocorticoid activity, oxidative stress, reduced telomerase
ables, hormonal contraception use among women, and the Perceived levels, and immune activation, may be responsible for telomere
Stress Scale. There were no significant differences between the groups shortening in response to psychological stress. Moreover, longi-
on these variables. Due to the small numbers of participants from differ- tudinal studies on the effects of psychosocial stress and trauma
ent racial groups, race was dichotomized as Caucasian versus non-Cau- on changes in telomere length over time are needed to more fully
casian. Education was dichotomized as completed college versus did not
characterize this relationship.
complete college.
BMI, body mass index; CTQ, Childhood Trauma Questionnaire (subscale
scores range from 5–25). 2.5

Discussion
These results extend previous reports linking shortened leu- 2
kocyte telomere length and caregiver stress to more remote
stressful experiences in childhood. In this study, reported mal-
treatment was moderate-severe in degree, and a variety of types
Telomere Length (T/S)

of abuse and neglect were represented. Analysis of subtypes of 1.5

maltreatment suggested that neglect may have the most robust


effect, but given the modest sample size, we cannot rule out
effects of other forms of abuse. Both emotional neglect and
physical neglect were linked to shorter telomeres; thus, it is 1

possible that in addition to the psychological effects of stress,


physical stressors such as inadequate nutrition or illness contrib-
uted to the findings.
In contrast with previous work, this study did not find an 0.5

effect of recent perceived stress on leukocyte telomere length; it


is of note that childhood maltreatment was not correlated with
recent perceived stress in this sample. This study included only
individuals with no current or past Axis I psychiatric disorder 0
0.5No Childhood
0.7 0.9 Maltreatment
1.1 1.3 1.5 Childhood
1.7 1.9 Maltreatment
2.1 2.3 2.5
because some psychiatric disorders have been linked to (N=21) (N=10)
telomere shortening. Shortened telomeres may represent a
risk factor for such disorders or other adverse health outcomes Figure 1. Telomere length in no childhood maltreatment and childhood
in this sample. By contrast, in addition to such a risk factor, maltreatment groups.

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534 BIOL PSYCHIATRY 2010;67:531–534 A.R. Tyrka et al.

This study was supported by National Institute of Mental lymphocyte subsets point to a high turnover of hematopoietic stem cells
Health Grants 1 K23 MH067947 (ART), R01 MH070898 (BP), and memory T cells in early childhood. J Exp Med 190:157–167.
and R01 MH068767-01 (LLC), and National Institute of Neuro- 18. Zeichner SL, Palumbo P, Feng Y, Xiao X, Gee D, Sleasman J, et al. (1999):
Rapid telomere shortening in children. Blood 93:2824 –2830.
logical Disorders and Stroke Grant R01 NS047209 (H-TK). 19. Cameron N, Demerath EW (2002): Critical periods in human growth and
In the past year, Drs. Tyrka, Price, and Carpenter have their relationship to diseases of aging. Am J Phys Anthropol 35:159 –184.
received grant/research support from the National Institutes of 20. Burns BJ, Phillips SD, Wagner HR, Barth RP, Kolko DJ, Campbell Y, Lands-
Health, the US Department of the Interior, the US Department of verk J (2004): Mental health need and access to mental health services
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21. Melchior M, Moffitt TE, Milne BJ, Poulton R, Caspi A (2007): Why do
education from Lundbeck and Takeda Pharmaceuticals. Dr. Price
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has received speakers bureau honoraria from Jazz Pharmaceuti- poor health when they reach adulthood? A life-course study. Am J
cals and has served as a consultant for Gerson Lehrman, Wiley, Epidemiol 166:966 –974.
and Springer. Dr. Carpenter has served as a consultant or on the 22. Springer KW, Sheridan J, Kuo D, Carnes M (2007): Long-term physical
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