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1.  Short Leukocyte Telomere Length Predicts Risk of Diabetes in American Indians: the Strong Heart Family Study 
Diabetes  2013;63(1):354-362.
Telomeres play a central role in cellular aging, and shorter telomere length has been associated with age-related disorders including diabetes. However, a causal link between telomere shortening and diabetes risk has not been established. In a well-characterized longitudinal cohort of American Indians participating in the Strong Heart Family Study, we examined whether leukocyte telomere length (LTL) at baseline predicts incident diabetes independent of known diabetes risk factors. Among 2,328 participants free of diabetes at baseline, 292 subjects developed diabetes during an average 5.5 years of follow-up. Compared with subjects in the highest quartile (longest) of LTL, those in the lowest quartile (shortest) had an almost twofold increased risk of incident diabetes (hazard ratio [HR] 1.83 [95% CI 1.26–2.66]), whereas the risk for those in the second (HR 0.87 [95% CI 0.59–1.29]) and the third (HR 0.95 [95% CI 0.65–1.38]) quartiles was statistically nonsignificant. These findings suggest a nonlinear association between LTL and incident diabetes and indicate that LTL could serve as a predictive marker for diabetes development in American Indians, who suffer from disproportionately high rates of diabetes.
doi:10.2337/db13-0744
PMCID: PMC3868043  PMID: 23949319
2.  Soda and Cell Aging: Associations between Sugar-Sweetened Beverage Consumption and Leukocyte Telomere Length in Healthy Adults from the National Health and Nutrition Examination Surveys 
American journal of public health  2014;104(12):2425-2431.
Objectives
We tested whether leukocyte telomere length maintenance, which underlies healthy cellular aging, provides a link between sugar-sweetened beverage (SSB) consumption and risk of cardiometabolic disease. We examined cross-sectional associations between consumption of SSBs, diet soda and fruit juice and telomere length in a nationally representative sample of healthy adults.
Methods
The study population included 5,309 adults, aged 20 to 65 years, with no prior history of diabetes or cardiovascular disease, from the 1999–2002 National Health and Nutrition Examination Surveys. Leukocyte telomere length was assayed from DNA specimens. Diet was assessed using 24-hour dietary recalls. Associations were examined using multivariate linear regression for the outcome of log-transformed telomere length.
Results
After adjustment for sociodemographic and health-related characteristics, sugar-sweetened soda consumption was associated with shorter telomeres (β=−0.010, 95% CI −0.020, −0.001, P=0.04). Consumption of 100% fruit juice was marginally associated with longer telomeres (β= 0.016, 95% CI −0.000, 0.033). No significant associations were observed between consumption of diet sodas or non-carbonated sugar-sweetened beverages and telomere length.
Conclusions
Regular consumption of sugar-sweetened sodas may influence metabolic disease development through accelerated cell aging.
doi:10.2105/AJPH.2014.302151
PMCID: PMC4229419  PMID: 25322305
3.  Longer leukocyte telomere length in Costa Rica's Nicoyan Peninsula: A population-based study 
Experimental gerontology  2013;48(11):10.1016/j.exger.2013.08.005.
Studies in humans suggest that leukocyte telomere length may act as a marker of biological aging. We investigated whether individuals in the Nicoya region of Costa Rica, known for exceptional longevity, had longer telomere length than those in other parts of the country. After controlling for age, age squared, rurality, rainy season and gender, mean leukocyte telomere length in Nicoya was substantially longer (81 base pairs, p<0.05) than in other areas of Costa Rica, providing evidence of a biological pathway to which this notable longevity may be related. This relationship remains unchanged (79 base pairs, p<0.05) after statistically controlling for nineteen potential biological, dietary and social and demographic mediators. Thus the difference in mean leukocyte telomere length that characterizes this unique region does not appear to be explainable by traditional behavioral and biological risk factors. More detailed examination of mean leukocyte telomere length by age shows that the regional telomere length difference declines at older ages.
doi:10.1016/j.exger.2013.08.005
PMCID: PMC3819141  PMID: 23988653
telomere length; Costa Rica; aging; biomarkers; socioeconomic; longevity
4.  Stress and Telomere Biology: A Lifespan Perspective 
Psychoneuroendocrinology  2013;38(9):1835-1842.
In the past decade, the growing field of telomere science has opened exciting new avenues for understanding the cellular and molecular substrates of stress and stress-related aging processes ver the lifespan. Shorter telomere length is associated with advancing chronological age and also increased disease morbidity and mortality. Emerging studies suggest that stress accelerates the erosion of telomeres from very early in life and possibly even influences the initial (newborn) setting of telomere length. In this review, we highlight recent empirical evidence linking stress and mental illnesses at various times across the lifespan with telomere erosion. We first present findings in the developmental programming of telomere biology linking prenatal stress to newborn and adult telomere length. We then present findings linking exposure to childhood trauma and to certain mental disorders with telomere shortening. Last, we review studies that characterize the relationship between related health-risk behaviors with telomere shortening over the lifespan, and how this process may further buffer the negative effects of stress on telomeres. A better understanding of the mechanisms that govern and regulate telomere biology throughout the lifespan may inform our understanding of etiology and the long-term consequences of stress and mental illnesses on aging processes in diverse populations and settings.
doi:10.1016/j.psyneuen.2013.03.010
PMCID: PMC3735679  PMID: 23639252
Telomere length; telomerase; stress; lifespan; prenatal; fetal/developmental programming; childhood stress; mental health; depression; lifestyle
5.  Seasonal variation of peripheral blood leukocyte telomere length in Costa Rica: a population based observational study 
Objectives
Peripheral blood leukocyte telomere length is increasingly being used as a biomarker of aging, but its natural variation in human populations is not well understood. Several other biomarkers show seasonal variation, as do several determinants of leukocyte telomere length. We examined whether there was monthly variation in leukocyte telomere length in Costa Rica, a country with strong seasonal differences in precipitation and infection.
Methods
We examined a longitudinal population based cohort of 581 Costa Rican adults age 60 and above, from which blood samples were drawn between October 2006 and July 2008. Leukocyte telomere length was assayed from these samples using the quantitative PCR method. Multivariate regression models were used to examine correlations between month of blood draw and leukocyte telomere length.
Results
Telomere length from peripheral blood leukocytes varied by as much as 200 base pairs depending on month of blood draw, and this difference is not likely to be due to random variation. A moderate proportion of this association is statistically accounted for by month and region specific average rainfall. We found shorter telomere length associated with greater rainfall.
Conclusions
There are two possible explanations of our findings. First, there could be relatively rapid month-to-month changes in leukocyte telomere length. This conclusion would have implications for understanding the natural population dynamics of telomere length. Second, there could be seasonal differences in constituent cell populations. This conclusion would suggest that future studies of leukocyte telomere length use methods to account for the potential impact of constituent cell type.
doi:10.1002/ajhb.22529
PMCID: PMC4136920  PMID: 24615938
telomere length; seasonality; lymphocytes; infection; rainfall
6.  Socioeconomic status, health behavior, and leukocyte telomere length in the National Health and Nutrition Examination Survey, 1999–2002 
The purpose of this study was to examine the association between socioeconomic status (SES) and leukocyte telomere length (LTL) – a marker of cell aging that has been linked to stressful life circumstances – in a nationally representative, socioeconomically and ethnically diverse sample of US adults aged 20–84. Using data from the National Health and Nutrition Examination Survey (NHANES), 1999–2002, we found that respondents who completed less than a high school education had significantly shorter telomeres than those who graduated from college. Income was not associated with LTL. African-Americans had significantly longer telomeres than whites, but there were no significant racial/ethnic differences in the association between education and telomere length. Finally, we found that the association between education and LTL was partially mediated by smoking and body mass index but not by drinking or sedentary behavior.
doi:10.1016/j.socscimed.2013.02.023
PMCID: PMC3666871  PMID: 23540359
socioeconomic status; cell aging; telomere length; health behavior; United States
7.  Short leukocyte telomere length is associated with obesity in American Indians: The strong heart family study 
Aging (Albany NY)  2014;6(5):380-389.
Shorter leukocyte telomere length (LTL) has been associated with a wide range of age-related disorders including cardiovascular disease (CVD) and diabetes. Obesity is an important risk factor for CVD and diabetes. The association of LTL with obesity is not well understood. This study for the first time examines the association of LTL with obesity indices including body mass index, waist circumference, percent body fat, waist-to-hip ratio, and waist-to-height ratio in 3,256 American Indians (14-93 years old, 60% women) participating in the Strong Heart Family Study. Association of LTL with each adiposity index was examined using multivariate generalized linear mixed model, adjusting for chronological age, sex, study center, education, lifestyle (smoking, alcohol consumption, and total energy intake), high-sensitivity C-reactive protein, hypertension and diabetes. Results show that obese participants had significantly shorter LTL than non-obese individuals (age-adjusted P=0.0002). Multivariate analyses demonstrate that LTL was significantly and inversely associated with all of the studied obesity parameters. Our results may shed light on the potential role of biological aging in pathogenesis of obesity and its comorbidities.
PMCID: PMC4069265  PMID: 24861044
obesity; Leukocyte telomere length; American Indians; strong heart family study
8.  Short leukocyte telomere length predicts incidence and progression of carotid atherosclerosis in American Indians: The Strong Heart Family Study 
Aging (Albany NY)  2014;6(5):414-427.
Short leukocyte telomere length (LTL) has been associated with atherosclerosis in cross-sectional studies, but the prospective relationship between telomere shortening and risk of developing carotid atherosclerosis has not been well-established. This study examines whether LTL at baseline predicts incidence and progression of carotid atherosclerosis in American Indians in the Strong Heart Study. The analysis included 2,819 participants who were free of overt cardiovascular disease at baseline (2001-2003) and were followed through the end of 2006-2009 (average 5.5-yr follow-up). Discrete atherosclerotic plaque was defined as focal protrusion with an arterial wall thickness ≥50% the surrounding wall. Carotid progression was defined as having a higher plaque score at the end of study follow-up compared to baseline. Associations of LTL with incidence and progression of carotid plaque were examined using Cox proportional hazard regression, adjusting for standard coronary risk factors. Compared to participants in the highest LTL tertile, those in the lowest tertile had significantly elevated risk for both incident plaque (HR, 1.49; 95% CI, 1.09–2.03) and plaque progression (HR, 1.61; 95% CI, 1.26–2.07). Our results provide initial evidence for a potential prognostic utility of LTL in risk prediction for atherosclerosis.
PMCID: PMC4069268  PMID: 24902894
leukocyte telomere length; carotid atherosclerosis; risk prediction; American Indians; Strong Heart Study
9.  Cytomegalovirus is associated with reduced telomerase activity in the Whitehall II cohort 
Experimental gerontology  2013;48(4):385-390.
Telomere length and telomerase activity have received increased attention as markers of cellular aging, but the determinants of inter-individual variation in these markers are incompletely understood. Cytomegalovirus (CMV) infection may be particularly important for telomere and telomerase dynamics due to its dramatic impact on peripheral blood lymphocyte composition, i.e., increasing the number and proportions of highly differentiated T cells that are characterized by shorter telomere length (TL) and lowered telomerase activity (TA). However, the possible relationship between CMV infection and leukocyte TL and TA has not been well-examined in vivo. This study examined the associations of CMV seropositivity and CMV IgG antibodies with leukocyte (TL) and (TA) in a sample of 434 healthy individuals (ages 53–76) from the Whitehall II cohort. Positive CMV serostatus was significantly associated with lower TA among women, and higher CMV IgG antibody levels were associated with lower TA in the overall sample. However, neither CMV seropositivity nor CMV IgG antibody levels (reflecting subclinical reactivation) among the seropositive were significantly associated with TL. These associations were robust to adjustment for age, employment grade, BMI, and smoking status. The results demonstrate that CMV seropositivity and subclinical reactivation predict lower TA. Future longitudinal studies should test whether the association of CMV with lower TA contributes to accelerated telomere shortening over time.
doi:10.1016/j.exger.2013.01.016
PMCID: PMC3626117  PMID: 23403382
telomeres; telomerase; cytomegalovirus; infections; Whitehall II
10.  Metabolic profiles of biological aging in American Indians: The strong heart family study 
Aging (Albany NY)  2014;6(3):176-186.
Short telomere length, a marker of biological aging, has been associated with age-related metabolic disorders. Telomere attrition induces profound metabolic dysfunction in animal models, but no study has examined the metabolome of telomeric aging in human. Here we studied 423 apparently healthy American Indians participating in the Strong Family Heart Study. Leukocyte telomere length (LTL) was measured by qPCR. Metabolites in fasting plasma were detected by untargeted LC/MS. Associations of LTL with each metabolite and their combined effects were examined using generalized estimating equation adjusting for chronological age and other aging-related factors. Multiple testing was corrected using the q-value method (q<0.05). Of the 1,364 distinct m/z features detected, nineteen metabolites in the classes of glycerophosphoethanolamines, glycerophosphocholines, glycerolipids, bile acids, isoprenoids, fatty amides, or L-carnitine ester were significantly associated with LTL, independent of chronological age and other aging-related factors. Participants with longer (top tertile) and shorter (bottom tertile) LTL were clearly separated into distinct groups using a multi-marker score comprising of all these metabolites, suggesting that these newly detected metabolites could be novel metabolic markers of biological aging. This is the first study to interrogate the human metabolome of telomeric aging. Our results provide initial evidence for a metabolic control of LTL and may reveal previously undescribed new roles of various lipids in the aging process.
PMCID: PMC4012935  PMID: 24799415
metabolic profiles; metabolomics; telomeric age; telomere length; American Indians
11.  Omega-3 Fatty Acids, Oxidative Stress, and Leukocyte Telomere Length: A Randomized Controlled Trial 
Shorter telomeres have been associated with poor health behaviors, age-related diseases, and early mortality. Telomere length is regulated by the enzyme telomerase, and is linked to exposure to proinflammatory cytokines and oxidative stress. In our recent randomized controlled trial, omega-3 (n-3) polyunsaturated fatty acid (PUFA) supplementation lowered the concentration of serum proinflammatory cytokines. This study assessed whether n-3 PUFA supplementation also affected leukocyte telomere length, telomerase, and oxidative stress. In addition to testing for group differences, changes in the continuous n-6:n-3 PUFA ratio were assessed to account for individual differences in adherence, absorption, and metabolism. The double-blind 4-month trial included 106 healthy sedentary overweight middle-aged and older adults who received (1) 2.5 g/day n-3 PUFAs, (2) l.25 g/day n-3 PUFAs, or (3) placebo capsules that mirrored the proportions of fatty acids in the typical American diet. Supplementation significantly lowered oxidative stress as measured by F2-isoprostanes (p=0.02). The estimated geometric mean log-F2-isoprostanes values were 15% lower in the two supplemented groups compared to placebo. Although group differences for telomerase and telomere length were nonsignificant, changes in the n-6:n-3 PUFA plasma ratios helped clarify the intervention’s impact: telomere length increased with decreasing n-6:n-3 ratios, p=0.02. The data suggest that lower n-6:n-3 PUFA ratios can impact cell aging. The triad of inflammation, oxidative stress, and immune cell aging represents important pre-disease mechanisms that may be ameliorated through nutritional interventions. This translational research broadens our understanding of the potential impact of the n-6:n-3 PUFA balance. ClinicalTrials.gov identifier: NCT00385723
doi:10.1016/j.bbi.2012.09.004
PMCID: PMC3545053  PMID: 23010452
omega-3; omega-6; telomeres; inflammation; cell aging; nutritional neuroscience; oxidative stress; F2-isoprostanes; fish oil
12.  Maternal psychosocial stress during pregnancy is associated with newborn leukocyte telomere length 
Objective
In adults, one of the major determinants of leukocyte telomere length (LTL), a predictor of age-related diseases and mortality, is cumulative psychosocial stress exposure. More recently we reported that exposure to maternal psychosocial stress during intrauterine life is associated with LTL in young adulthood. The objective of the present study was to determine how early in life this effect of stress on LTL is apparent by quantifying the association of maternal psychosocial stress during pregnancy with newborn telomere length.
Study Design
In a prospective study of N = 27 mother-newborn dyads maternal pregnancy-specific stress was assessed in early gestation and cord blood peripheral blood mononuclear cells were subsequently collected and analyzed for LTL measurement.
Results
After accounting for the effects of potential determinants of newborn LTL (gestational age at birth, weight, sex, and exposure to antepartum obstetric complications), there was a significant, independent, linear effect of pregnancy-specific stress on newborn LTL that accounted for 25% of the variance in adjusted LTL (β = −0.099; P = .04).
Conclusion
Our finding provides the first preliminary evidence in human beings that maternal psychological stress during pregnancy may exert a “programming” effect on the developing telomere biology system that is already apparent at birth, as reflected by the setting of newborn LTL.
doi:10.1016/j.ajog.2012.11.033
PMCID: PMC3612534  PMID: 23200710
fetal/developmental programming of health and disease risk; maternal psychosocial stress; newborn telomere biology
14.  Chronic stress elevates telomerase activity in rats 
Biology Letters  2012;8(6):1063-1066.
The enzyme telomerase lengthens telomeres—protective structures containing repetitive DNA sequences at chromosome ends. Telomere shortening is associated with diseases of ageing in mammals. Chronic stress has been related to shorter immune-cell telomeres, but telomerase activity under stress may be low, permitting telomere loss, or high, partially attenuating it. We developed an experimental model to examine the impacts of extended unpredictable stress on telomerase activity in male rats. Telomerase activity was 54 per cent higher in stressed rats than in controls, and associated with stress-related physiological and behavioural outcomes. This significant increase suggests a potential mechanism for resilience to stress-related replicative senescence.
doi:10.1098/rsbl.2012.0747
PMCID: PMC3497144  PMID: 23054915
chronic stress; telomere; telomerase; ageing; resilience
15.  Multisystem resiliency moderates the major depression–Telomere length association: Findings from the Heart and Soul Study 
Brain, behavior, and immunity  2013;33:10.1016/j.bbi.2013.05.008.
Major depressive disorder (MDD) has been associated with reduced leukocyte telomere length (LTL). It is not known, however, whether psychosocial and behavioral protective factors moderate this association. In the current study, we examine whether multisystem resiliency – defined by healthy emotion regulation, strong social connections, and health behaviors (sleep and exercise) – predicts LTL and mitigates previously demonstrated associations between depression diagnosis and LTL. LTL was measured, using a quantitative PCR assay, in 954 patients with stable cardiovascular disease in the Heart and Soul Study. In a fully adjusted model, high multisystem resiliency predicted longer LTL (b = 80.00, SE = 27.17, p = .003), whereas each individual factor did not. Multisystem resiliency significantly moderated the MDD-LTL association (p = .02). Specifically, MDD was significantly related to LTL at 1 SD below the mean of multisystem resiliency (b = −142.86, SE = 56.46, p = .01), but not at 1 SD above the mean (b = 49.07, SE = 74.51, p = .51). This study suggests that MDD associations with biological outcomes should be examined within a psychosocial–behavioral context, because this context shapes the nature of the direct relationship. Further research should explore the cognitive, neural, and other physiological pathways through which multisystem resiliency may confer biological benefit.
doi:10.1016/j.bbi.2013.05.008
PMCID: PMC3855878  PMID: 23727245
Major depressive disorder; Telomeres; Cell aging; Resiliency; Social connections; Emotion regulation; Physical activity
16.  Association between kidney function and telomere length: the Heart and Soul Study 
American journal of nephrology  2012;36(5):405-411.
Background
Telomere attrition is a novel risk factor for cardiovascular disease. Studies of telomere length in relation to kidney function are limited. We explored the association of kidney function with telomere length and telomere shortening.
Methods
The Heart and Soul study is a longitudinal study of patients with stable coronary heart disease (CHD). Measures of baseline kidney function included: serum creatinine, creatinine-derived estimated glomerular filtration rate (eGFRCKD-EPI), 24-hour urine measured creatinine clearance, cystatin C, cystatin C-derived estimated glomerular filtration rate (eGFRcys) and urine albumin to creatinine ratio. Telomere length was measured from peripheral blood leukocytes at baseline (N=954) and 5 years later (N=608). Linear regression models were used to test the association of kidney function with i) baseline telomere length and ii) change in telomere length over 5 years.
Results
At baseline, mean eGFRCKD-EPI was 72.6 (± 21.5) ml/min/1.73 m2, eGFRcys was 71.0 (± 23.1) ml/min/1.73 m2 and ACR was 8.6 (±12.3) mg/gm. Only lower baseline eGFRCKD-EPI was associated with shorter baseline telomere length (9.1 [95% CI 1.2–16.9] fewer base pairs for every 5 ml/min/1.73 m2 lower eGFRCKD-EPI). Lower baseline eGFRCKD-EPI (and all other measures of kidney function) predicted more rapid telomere shortening (10.8 [95% CI 4.3–17.3] decrease in base pairs over 5 years for every 5 ml/min/1.73 m2 lower eGFRCKD-EPI). After adjustment for age, these associations were no longer statistically significant.
Conclusions
In patients with CHD, reduced kidney function is associated with i) shorter baseline telomere length and ii) more rapid telomere shortening over 5 years, however these associations are entirely explained by older age.
doi:10.1159/000343495
PMCID: PMC3552638  PMID: 23108000
kidney; CKD; telomere
17.  QTL mapping of leukocyte telomere length in American Indians: The Strong Heart Family Study 
Aging (Albany NY)  2013;5(9):704-716.
Telomeres play a central role in cellular senescence and are associated with a variety of age-related disorders such as dementia, Alzheimer's disease and atherosclerosis. Telomere length varies greatly among individuals of the same age, and is heritable. Here we performed a genome-wide linkage scan to identify quantitative trait loci (QTL) influencing leukocyte telomere length (LTL) measured by quantitative PCR in 3,665 American Indians (aged 14 – 93 years) from 94 large, multi-generational families. All participants were recruited by the Strong Heart Family Study (SHFS), a prospective study to identify genetic factors for cardiovascular disease and its risk factors in American Indians residing in Oklahoma, Arizona and Dakota. LTL heritability was estimated to be between 51% and 62%, suggesting a strong genetic predisposition to interindividual variation of LTL in this population. Significant QTLs were localized to chromosome 13 (Logarithm of odds score (LOD) = 3.9) at 13q12.11, to 18q22.2 (LOD = 3.2) and to 3p14.1 (LOD = 3.0) for Oklahoma. This is the first study to identify susceptibility loci influencing leukocyte telomere variation in American Indians, a minority group suffering from a disproportionately high rate of type 2 diabetes and other age-related disorders.
PMCID: PMC3808702  PMID: 24036517
leukocyte telomere length; genome-wide linkage scan; quantitative trait loci; American Indians
18.  Stress appraisals and cellular aging: A key role for anticipatory threat in the relationship between psychological stress and telomere length 
Brain, Behavior, and Immunity  2012;26(4):573-579.
Chronic psychological stressis a risk factor formultiple diseases of aging. Accelerated cellular aging as indexed by short telomere length has emerged as a potential common biological mechanism linking various forms of psychological stress and diseases of aging. Stress appraisals determine the degree and type of biological stress responses and altered stress appraisals may be a common psychological mechanism linking psychological stress and diseases of aging. However, no previous studies have examined the relationship between stress appraisals and telomere length. We exposed chronically stressed female caregivers and non-caregiving controls (N= 50; M age = 62.14±6.10) to a standardized acute laboratory stressor and measured their anticipatory and retrospective threat and challenge appraisals of the stressor. We hypothesized that threat and challenge appraisals would be associated with shorter and longer telomere length respectively, and that chronic care giving stress would influence telomere length through altered stress appraisals. Higher anticipatory threat appraisals were associated with shorter age-adjusted telomere length (β = −.32, p = .03), but challenge appraisals and retrospective threat appraisals showed no independent association with telomere length. Caregivers reported significantly higher anticipatory (β = −.36, p = .006)and retrospective (β = −.29, p = .03) threat appraisals than controls, but similar challenge appraisals. Although there was no significant main effect of caregiver status on telomere length, care giving had a significant indirect effect on telomere length through anticipatory threat appraisals. Exaggerated anticipatory threat appraisals may be a common and modifiable psychological mechanism of psychological stress effects on cellular aging.
doi:10.1016/j.bbi.2012.01.007
PMCID: PMC3322317  PMID: 22293459
cellular aging; challenge; chronic stress; stress appraisals; threat; telomere length
19.  Telomere Shortening in Formerly Abused and Never Abused Women 
Biological Research for Nursing  2011;14(2):115-123.
Recent studies suggest that chronic psychological stress may accelerate aging at the cellular level. Telomeres are protective components that stabilize the ends of chromosomes and modulate cellular aging. Women exposed to intimate partner violence (IPV) experience chronic stress and report worse health. The purpose of this exploratory study was to examine telomeric DNA length in women who have experienced chronic stress related to IPV. We hypothesized that IPV exposure would be associated with shorter telomere length. The investigation used a cross-sectional design to study telomere length in women with a history of IPV exposure and control women who reported no prior exposure to IPV. Advertisements and public notices were used to recruit a convenience sample of healthy women. Mean leukocyte telomere length was measured in DNA samples from peripheral blood mononuclear cells (PBMCs) by a quantitative polymerase chain reaction assay (qPCR). Telomere length was significantly shorter in the 61 formerly abused women compared to the 41 controls (t = 2.4, p = .02). Length of time in the abusive relationship and having children were associated with telomere length after controlling for age and body mass index (F(2,99) = 10.23, p < .001). Numerous studies suggest that women who experience IPV have poorer overall health. It is often presumed that the stress of IPV may be causing greater morbidity. Findings from this descriptive study suggest a link between IPV exposure, duration of IPV-related stress, and telomere length molecular mechanisms that regulate cellular aging.
doi:10.1177/1099800411398479
PMCID: PMC3207021  PMID: 21385798
intimate partner violence; telomere length; chronic stress
20.  Accelerated Cell Aging in Female APOE-ε4 Carriers: Implications for Hormone Therapy Use 
PLoS ONE  2013;8(2):e54713.
Apolipoprotein-ε4 (APOE-ε4) is a major genetic risk factor for cognitive decline, Alzheimer's disease (AD) and early mortality. An accelerated rate of biological aging could contribute to this increased risk. Here, we determined whether APOE-ε4 status impacts leukocyte telomere length (TL) and the rate of cellular senescence in healthy mid-life women and, further, whether hormone replacement therapy (HT) modifies this association. Post-menopausal women (N = 63, Mean age = 57.7), all HT users for at least one year, were enrolled in a randomized longitudinal study. Half of the participants (N = 32) remained on their HT regimen and half (N = 31) went off HT for approximately two years (Mean  = 1.93 years). Participants included 24 APOE-ε4 carriers and 39 non-carrier controls. Leukocyte TL was measured at baseline and the end of year 2 using quantitative polymerase chain reaction. Logistic regression analysis indicated that the odds of an APOE-ε4 carrier exhibiting telomere shortening (versus maintenance/growth) over the 2-year study were more than 6 (OR  = 6.26, 95% CI  = 1.02, 38.49) times higher than a non-carrier, adjusting for established risk factors and potential confounds. Despite the high-functioning, healthy mid-life status of study participants, APOE-ε4 carriers had marked telomere attrition during the 2-year study window, the equivalent of approximately one decade of additional aging compared to non-carriers. Further analyses revealed a modulatory effect of hormone therapy on the association between APOE status and telomere attrition. APOE-ε4 carriers who went off their HT regimen exhibited TL shortening, as predicted for the at-risk population. APOE-ε4 carriers who remained on HT, however, did not exhibit comparable signs of cell aging. The opposite pattern was found in non-carriers. The results suggest that hormone use might buffer against accelerated cell aging in mid-life women at risk for dementia. Importantly, for non-carrier women there was no evidence that HT conferred protective effects on telomere dynamics.
doi:10.1371/journal.pone.0054713
PMCID: PMC3572118  PMID: 23418430
21.  CHILDHOOD TRAUMA ASSOCIATED WITH SHORT LEUKOCYTE TELOMERE LENGTH IN POST-TRAUMATIC STRESS DISORDER 
Biological psychiatry  2011;70(5):465-471.
Background
Post-traumatic stress disorder (PTSD) is associated with increased risk for age-related diseases and early mortality. An accelerated rate of biological aging could contribute to this increased risk. To investigate, we assessed leukocyte telomere length (LTL), an emerging marker of biological age, in men and women with and without PTSD. We also examined childhood trauma, a risk factor for both PTSD and short LTL, as a potential contributor to short LTL in PTSD.
Methods
Participants included 43 adults with chronic PTSD (n=18 with multiple categories of childhood trauma) and 47 controls (none with multiple categories of childhood trauma) (M age = 30.55, SD = 7.44). Exclusion criteria included physical illness, medication use, obesity, alcohol or substance abuse, and pregnancy. Structured clinical interviews were conducted to assess PTSD and other psychiatric disorders and childhood trauma exposure. LTL was measured with quantitative polymerase chain reaction.
Results
As predicted, participants with PTSD had shorter age-adjusted LTL than controls. Exposure to childhood trauma was also associated with short LTL. In fact, childhood trauma appeared to account for the PTSD group difference in LTL; only participants with PTSD and exposure to multiple categories of childhood trauma had significantly shorter LTL than controls.
Conclusions
Childhood trauma is associated with short LTL in individuals with PTSD. Chronic exposure to the psychobiological sequelae of childhood trauma could increase risk for PTSD and short LTL. Thus, the lasting psychological impact of exposure to trauma in childhood may be accompanied by equally enduring changes at the molecular level.
doi:10.1016/j.biopsych.2011.01.035
PMCID: PMC3152637  PMID: 21489410
anxiety; biological aging; childhood trauma; post-traumatic stress disorder; telomere length
22.  Depression and leukocyte telomere length in patients with coronary heart disease: data from The Heart and Soul study 
Psychosomatic medicine  2011;73(7):541-547.
Objective
Shortened telomere length has been associated with mortality in patients with coronary heart disease (CHD) and is considered an emerging marker of biological age. Whether depression is associated with telomere length or trajectory has not been evaluated in patients with CHD.
Methods
In a prospective cohort study, we measured leukocyte telomere length in 952 participants with stable CHD at baseline and in 608 of these participants after 5 years of follow up. Presence of major depressive disorder (MDD) in the past month was assessed using the computerized Diagnostic Interview Schedule (CDIS-IV) at baseline. We used linear and logistic regression models to evaluate the association of depression with baseline and 5-year change in leukocyte telomere length.
Results
Of the 952 participants, 206 (22%) had major depression at baseline. After adjustment for age and sex, patients with current major depressive disorder had shorter baseline telomere length than those without depression (mean ± SE: 0.86±0.02 vs. 0.90±0.01, P= 0.02). This association was similar (but no longer statistically significant) after adjustment for body mass index, smoking, diabetes, left ventricular ejection fraction, statin use, antidepressant use, physical inactivity, and anxiety (0.85±0.02 vs. 0.89±0.01, P= 0.06). Depression was not predictive of 5-year change in telomere length after adjustment for the above covariates and baseline telomere length.
Conclusions
Depression is associated with reduced leukocyte telomere length in patients with coronary heart disease but does not predict 5-year change in telomere length. Future research is necessary to elucidate the potential mechanisms underlying the association between depression and telomere length.
doi:10.1097/PSY.0b013e31821b1f6e
PMCID: PMC3161173  PMID: 21597035
Depression; telomere length; stable CHD
23.  Autonomic and adrenocortical reactivity and buccal cell telomere length in kindergarten children 
Psychosomatic medicine  2011;73(7):533-540.
Objective
To examine associations between autonomic nervous system and adrenocortical reactivity to laboratory stressors and buccal cell telomere length (BTL) in children.
Methods
The study sample comprised 78 five- and six-year-old children from a longitudinal cohort study of kindergarten social hierarchies, biological responses to adversity, and child health. Buccal cell samples and reactivity measures were collected in the spring of the kindergarten year. BTL was measured by realtime PCR, as the telomere-to-single copy gene (T/S) ratio. Parents provided demographic information; parents and teachers reported children’s internalizing and externalizing behavior problems. Components of children’s autonomic (heart rate (HR), respiratory sinus arrhythmia (RSA), pre-ejection period (PEP)) and adrenocortical (salivary cortisol) responses were monitored during standardized laboratory challenges. We examined relations between reactivity, internalizing and externalizing behavior, and BTL, adjusted for age, race, and gender.
Results
Heart rate and cortisol reactivity were inversely related to BTL, PEP was positively related to BTL, and RSA was unrelated. Internalizing behaviors were also inversely related to BTL (standardized β=−0.33, p=0.004). Split at the median of reactivity parameters, children with high sympathetic activation (decreasing PEP) and high parasympathetic withdrawal (decreasing RSA) did not differ with regard to BTL. However, children with both this profile and high cortisol reactivity (N=12) had significantly shorter BTL (0.80 vs. 1.00, χ2=7.6, p=0.006), compared with other children.
Conclusions
Autonomic and adrenocortical reactivity in combination were associated with shorter buccal cell telomere length in children. These data suggest that psychophysiological processes may influence, and that BTL may be a useful marker of, early biological aging.
doi:10.1097/PSY.0b013e318229acfc
PMCID: PMC3212037  PMID: 21873585
autonomic reactivity; adrenocortical reactivity; buccal cell telomeres; internalizing; stress; children
24.  Changes in stress, eating, and metabolic factors are related to changes in telomerase activity in a randomized mindfulness intervention pilot study 
Psychoneuroendocrinology  2011;37(7):917-928.
Summary
Background
Psychological distress and metabolic dysregulation are associated with markers of accelerated cellular aging, including reduced telomerase activity and shortened telomere length. We examined whether participation in a mindfulness-based intervention, and, secondarily, improvements in psychological distress, eating behavior, and metabolic factors are associated with increases in telomerase activity in peripheral blood mononuclear cells (PBMCs).
Methods
We enrolled 47 overweight/obese women in a randomized waitlist-controlled pilot trial (n = 47) of a mindfulness-based intervention for stress eating and examined changes in telomerase activity from pre- to post-intervention. In secondary analyses, changes in telomerase activity across the sample were examined in relation to pre- to post-intervention changes in psychological distress, eating behavior, and metabolic factors (weight, serum cortisol, fasting glucose and insulin, and insulin resistance).
Results
Both groups increased in mean telomerase activity over 4 months in intent-to-treat and treatment efficacy analyses (p < 0.001). Nonsignificant trends showed that greater attendance was associated with increases in telomerase, and telomerase increases were 18% higher among ‘as treated’ participants compared to controls. Across groups, changes in chronic stress, anxiety, dietary restraint, dietary fat intake, cortisol, and glucose were negatively correlated with changes in telomerase activity. In exploratory analyses, decreases in dietary fat intake partially mediated the association between dietary restraint and telomerase activity with marginal significance.
Conclusions
While there was no clear effect of the intervention on telomerase activity, there was a striking pattern of correlations between improvements in psychological distress, eating behavior, and metabolic health and increases in telomerase activity. These findings suggest that telomerase activity may be in part regulated by levels of both psychological and metabolic stress.
doi:10.1016/j.psyneuen.2011.10.008
PMCID: PMC3384690  PMID: 22169588
Stress; Anxiety; Mindfulness; Dietary restraint; Telomerase; Cell aging; Cortisol
25.  Does cellular aging relate to patterns of allostasis? An examination of basal and stress reactive HPA axis activity and telomere length 
Physiology & behavior  2011;106(1):40-45.
Long-term exposure to stress and its physiological mediators, in particular cortisol, may lead to impaired telomere maintenance. In this study, we examine if greater cortisol responses to an acute stressor and/or dysregulated patterns of daily cortisol secretion are associated with shorter telomere length. Twenty-three post-menopausal women comprising caregivers for dementia partners (n=14) and age- and BMI-matched non-caregivers provided home sampling of cortisol–saliva samples at waking, 30 min after waking, and bedtime, and a 12-hour overnight urine collection. They were also exposed to an acute laboratory stressor throughout which they provided saliva samples. Peripheral blood mononuclear cells were isolated from a fasting blood sample and assayed for telomere length. As hypothesized, greater cortisol responses to the acute stressor were associated with shorter telomeres, as were higher overnight urinary free cortisol levels and flatter daytime cortisol slopes. While robust physiological responses to acute stress serve important functions, the long-term consequences of frequent high stress reactivity may include accelerated telomere shortening.
doi:10.1016/j.physbeh.2011.11.016
PMCID: PMC3361080  PMID: 22138440
Cortisol; Allostasis; Allostatic load; Telomere; Cellular aging; Stress; HPA axis

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