Publications by authors named "Elizabeth H Blackburn"

118 Publications

Telomere length and socioeconomic status at neighborhood and individual levels among 80,000 adults in the Genetic Epidemiology Research on Adult Health and Aging cohort.

Environ Epidemiol 2019 Jun 1;3(3):e049. Epub 2019 May 1.

Division of Research, Oakland, Kaiser Permanente Northern California, Oakland, California.

Background: Telomere length (TL) may serve as a biologic marker of aging. We examined neighborhood and individual-level socioeconomic status (SES) in relation to TL.

Methods: The study included 84,996 non-Hispanic white subjects from the Genetic Epidemiology Research on Adult Health and Aging (GERA) cohort, part of the Research Program on Genes, Environment and Health. Relative TL (T/S) was log transformed to improve normality and standardized to have mean 0 and variance 1. Neighborhood SES was measured using the Neighborhood Deprivation Index (NDI), and individual SES was measured by self-reported education level. We fit linear regression models of TL on age, sex, smoking, body mass index, comorbidities, NDI, and education level. We tested for differences in the associations by sex and nonlinearity in the association of NDI with TL.

Results: Each SD increase in NDI was associated with a decrease of 0.0192 in standardized TL, 95% confidence interval (CI) = -0.0306, -0.0078. There was no evidence of nonlinearity in the association of NDI with TL. We further found that less than high school education was associated with a decrease of 0.1371 in standardized TL, 95% CI = -0.1919, -0.0823 as compared to a college education. There were no differences in the associations by sex.

Conclusions: We found evidence that both lower neighborhood SES and lower individual-level SES are associated with shorter TL among non-Hispanic whites. Our findings suggest that socioeconomic factors may influence aging by contributing to shorter TL.
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http://dx.doi.org/10.1097/EE9.0000000000000049DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7939422PMC
June 2019

Maternal pro-inflammatory state during pregnancy and newborn leukocyte telomere length: A prospective investigation.

Brain Behav Immun 2019 08 8;80:419-426. Epub 2019 Apr 8.

Charité - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health (BIH), Institute of Psychological Medicine, Charitéplatz 1, 10117 Berlin, Germany; Department of Pediatrics, University of California, Irvine, CA 92617, USA; Development, Health and Disease Research Program, University of California, Irvine, CA 92617, USA. Electronic address:

Introduction: Telomere biology plays a fundamental role in maintaining the integrity of the genome and cell, and shortened telomeres have been linked to several age-related diseases. The initial (newborn) telomere length (TL) represents a critically important feature of the telomere biology system. Exposure to a variety of adverse prenatal conditions such as maternal stress, suboptimal diet, obesity, and obstetric complications, is associated with shorter offspring TL at birth and in adult life. Many, if not all, of these exposures are believed to have an inflammatory component. In this context, stress-related immunological processes during pregnancy may constitute a potential additional biological pathway because they can affect telomere length and telomerase activity via transcriptions factors such as cyclic adenosine monophosphate-dependent transcription factor (ATF7) and nuclear factor-kappa B (NF-κB). Thus, in the present study we examined the hypothesis that maternal pro-inflammatory state across pregnancy, operationalized as the balance between tumor necrosis factor (TNF)-α, a major pro-inflammatory cytokine, and interleukin-10 (IL-10), the major anti-inflammatory cytokine, is associated with newborn leukocyte telomere length (LTL) at birth.

Methods And Materials: Participants were healthy women (N = 112) recruited in early pregnancy. Concentrations of TNF- α and IL-10 were quantified in early, mid and late pregnancy from maternal blood samples. Telomere length was assessed in newborn blood samples soon after birth.

Results: After adjusting for maternal age, maternal pre-pregnancy BMI, birth weight percentile, and infant sex, a higher mean TNF-α/IL-10 ratio across pregnancy was significantly associated with shorter newborn TL (β = -.205, p = .030). Newborn TL was, on average, 10% shorter in offspring of women in the upper compared to lower quartile of the TNF-α/IL-10 ratio during pregnancy.

Discussion: These findings provide new evidence in humans for a potential "programming" mechanism linking maternal systemic pro-inflammatory processes during pregnancy with the initial (newborn) setting of her offspring's telomere system.
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http://dx.doi.org/10.1016/j.bbi.2019.04.021DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7954441PMC
August 2019

Local enrichment of HP1alpha at telomeres alters their structure and regulation of telomere protection.

Nat Commun 2018 09 4;9(1):3583. Epub 2018 Sep 4.

Department of Biochemistry and Biophysics, University of California, San Francisco, San Francisco, CA, 94143, USA.

Enhanced telomere maintenance is evident in malignant cancers. While telomeres are thought to be inherently heterochromatic, detailed mechanisms of how epigenetic modifications impact telomere protection and structures are largely unknown in human cancers. Here we develop a molecular tethering approach to experimentally enrich heterochromatin protein HP1α specifically at telomeres. This results in increased deposition of H3K9me3 at cancer cell telomeres. Telomere extension by telomerase is attenuated, and damage-induced foci at telomeres are reduced, indicating augmentation of telomere stability. Super-resolution STORM imaging shows an unexpected increase in irregularity of telomeric structure. Telomere-tethered chromo shadow domain (CSD) mutant I165A of HP1α abrogates both the inhibition of telomere extension and the irregularity of telomeric structure, suggesting the involvement of at least one HP1α-ligand in mediating these effects. This work presents an approach to specifically manipulate the epigenetic status locally at telomeres to uncover insights into molecular mechanisms underlying telomere structural dynamics.
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http://dx.doi.org/10.1038/s41467-018-05840-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6123478PMC
September 2018

Telomere attrition is associated with declines in medial temporal lobe volume and white matter microstructure in functionally independent older adults.

Neurobiol Aging 2018 09 8;69:68-75. Epub 2018 May 8.

Department of Neurology, Memory and Aging Center, University of California at San Francisco, San Francisco, CA, USA.

Although leukocyte telomere length (TL) shortens over the lifespan and is associated with diseases of aging, little is known about the relationships between TL, memory, and brain structure. Sixty-nine functionally normal older adults (mean age = 71.7) were assessed at 2 time points (mean interval = 2.9 years). Linear mixed models assessed relationships between TL and hippocampal volume, fractional anisotropy, and mean diffusivity (MD) of the fornix and verbal and visual episodic memory. Unstandardized coefficients are reported in the following, and p values are not corrected for multiple comparisons. A negative baseline trend was observed between TL and fornix MD (b = -0.01, p = 0.06), but no other cross-sectional associations were significant (ps > 0.16). Greater TL shortening at follow-up was associated with greater hippocampal volume loss (b = 27.09, p < 0.001), even after controlling for global volume loss (b = 10.83, p = 0.002). Greater telomere attrition was also associated with larger increases in fornix MD (b = -0.01, p = 0.012) and decreases in fornix fractional anisotropy (b = 0.004, p = 0.002). TL was not associated with changes in episodic memory (ps > 0.23). These relationships may reflect neurobiological influences that affect both TL and brain structure, as well as the effect of TL on brain aging via mechanisms such as cellular senescence and inflammation.
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http://dx.doi.org/10.1016/j.neurobiolaging.2018.04.021DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6430612PMC
September 2018

Telomere length is inversely correlated with urinary stress hormone levels in healthy controls but not in un-medicated depressed individuals-preliminary findings.

J Psychosom Res 2017 08 15;99:177-180. Epub 2017 Jun 15.

Dept. of Psychiatry, University of California, San Francisco, School of Medicine (UCSF), San Francisco, CA, USA. Electronic address:

Objective: Leukocyte telomere length (LTL) is a biomarker of cellular aging affected by chronic stress. The relationship of LTL to the stress hormones, cortisol and catecholamines, is unclear, as are possible differences between healthy controls (HC) and individuals with Major Depressive Disorder (MDD). This small pilot study is the first to examine the relationship between cortisol, catecholamines and LTL specifically in un-medicated MDD in comparison with HC.

Methods: Participants included 16 un-medicated MDD subjects and 15 HC for assay of LTL, 12-hour overnight urinary free cortisol and catecholamine levels.

Results: LTL, cortisol and catecholamine levels did not significantly differ between groups. In HC, a hierarchical regression analysis indicated that higher levels of cortisol were correlated with shorter LTL (p=0.003) above and beyond age and sex. Higher catecholamine levels were nearly-significant with shorter LTL (p=0.055). Neither hormone was correlated with shorter LTL in MDD (p's>0.28). To assess a possible cumulative effect of stress hormone activation, a summary score was calculated for each subject based on the number of stress hormone levels above the median for that group (HC or MDD). A significant inverse graded relationship was observed between LTL and the number of activated systems in HC (p=0.001), but not in MDD (p=0.96).

Conclusion: This pilot study provides preliminary evidence that stress hormone levels, especially cortisol, are inversely related to LTL in HC, but not in un-medicated MDD. Clarification of these relationships in larger samples could aid in understanding differential mechanisms underlying stress-related cellular aging in healthy and depressed populations.
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http://dx.doi.org/10.1016/j.jpsychores.2017.06.009DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5551436PMC
August 2017

Socioeconomic Status, Financial Strain, and Leukocyte Telomere Length in a Sample of African American Midlife Men.

J Racial Ethn Health Disparities 2018 06 20;5(3):459-467. Epub 2017 Jun 20.

Department of Human Development & Family Studies, College of Human Sciences, Auburn University, Auburn, AL, USA.

Background: African American men in the USA experience poorer aging-related health outcomes compared to their White counterparts, partially due to socioeconomic disparities along racial lines. Greater exposure to socioeconomic strains among African American men may adversely impact health and aging at the cellular level, as indexed by shorter leukocyte telomere length (LTL). This study examined associations between socioeconomic factors and LTL among African American men in midlife, a life course stage when heterogeneity in both health and socioeconomic status are particularly pronounced.

Methods: Using multinomial logistic regression, we examined associations between multiple measures of SES and tertiles of LTL in a sample of 92 African American men between 30 to 50 years of age.

Results: Reports of greater financial strain were associated with higher odds of short versus medium LTL (odds ratio (OR)=2.21, p = 0.03). Higher income was associated with lower odds of short versus medium telomeres (OR=0.97, p = 0.04). Exploratory analyses revealed a significant interaction between educational attainment and employment status (χ  = 4.07, p = 0.04), with greater education associated with lower odds of short versus long telomeres only among those not employed (OR=0.10, p = 0.040).

Conclusion: Cellular aging associated with multiple dimensions of socioeconomic adversity may contribute to poor aging-related health outcomes among African American men. Subjective appraisal of financial difficulty may impact LTL independently of objective dimensions of SES. Self-appraised success in fulfilling traditionally masculine gender roles, including being an economic provider, may be a particularly salient aspect of identity for African American men and have implications for cellular aging in this population.
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http://dx.doi.org/10.1007/s40615-017-0388-3DOI Listing
June 2018

The Longitudinal Relationship Between Cortisol Responses to Mental Stress and Leukocyte Telomere Attrition.

J Clin Endocrinol Metab 2017 03;102(3):962-969

Cardiff School of Health Sciences, Cardiff Metropolitan University, Cardiff CF5 2YB, Wales, United Kingdom.

Context: Chronic psychological stress has been associated with shorter telomeres, but the underlying mechanisms are poorly understood. One possibility is that the neuroendocrine responses to stress exposure are involved.

Objective: To test the hypothesis that greater cortisol responsivity to acute stressors predicts more rapid telomere attrition.

Design: We measured salivary cortisol responses to 2 challenging behavioral tasks. Leukocyte telomere length was measured at the time of mental stress testing and 3 years later.

Participants: We studied 411 initially healthy men and women aged 54 to 76 years.

Main Outcome Measure: Leukocyte telomere length.

Results: Cortisol responses to this protocol were small; we divided participants into cortisol responders (n = 156) and nonresponders (n = 255) using a criterion (≥20% increase in cortisol concentration) previously shown to predict increases in cardiovascular disease risk. There was no significant association between cortisol responsivity and baseline telomere length, although cortisol responders tended to have somewhat shorter telomeres (β = -0.061; standard error, 0.049). But cortisol responders had shorter telomeres and more rapid telomere attrition than nonresponders on follow-up, after controlling statistically for age, sex, socioeconomic status, smoking, time of day of stress , and baseline telomere length (β = -0.10; standard error, 0.046; P = 0.029). The association was maintained after additional control for cardiovascular risk factors (β = -0.11; P = 0.031). The difference between cortisol responders and nonresponders was equivalent to approximately 2 years in aging.

Conclusions: These findings suggest that cortisol responsivity may mediate, in part, the relationship between psychological stress and cellular aging.
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http://dx.doi.org/10.1210/jc.2016-3035DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5460695PMC
March 2017

Leukocyte Telomere Length in Relation to 17 Biomarkers of Cardiovascular Disease Risk: A Cross-Sectional Study of US Adults.

PLoS Med 2016 Nov 29;13(11):e1002188. Epub 2016 Nov 29.

Department of Psychiatry, University of California San Francisco, San Francisco, California, United States of America.

Background: Leukocyte telomere length (LTL) is a putative biological marker of immune system age, and there are demonstrated associations between LTL and cardiovascular disease. This may be due in part to the relationship of LTL with other biomarkers associated with cardiovascular disease risk. However, the strength of associations between LTL and adiposity, metabolic, proinflammatory, and cardiovascular biomarkers has not been systematically evaluated in a United States nationally representative population.

Methods And Findings: We examined associations between LTL and 17 cardiovascular biomarkers, including lipoproteins, blood sugar, circulatory pressure, proinflammatory markers, kidney function, and adiposity measures, in adults ages 20 to 84 from the cross-sectional US nationally representative 1999-2002 National Health and Nutrition Examination Survey (NHANES) (n = 7,252), statistically adjusting for immune cell type distributions. We also examine whether these associations differed systematically by age, race/ethnicity, gender, education, and income. We found that a one unit difference in the following biomarkers were associated with kilobase pair differences in LTL: BMI -0.00478 (95% CI -0.00749--0.00206), waist circumference -0.00211 (95% CI -0.00325--0.000969), percentage of body fat -0.00516 (95% CI -0.00761--0.0027), high density lipoprotein (HDL) cholesterol 0.00179 (95% CI 0.000571-0.00301), triglycerides -0.000285 (95% CI -0.000555--0.0000158), pulse rate -0.00194 (95% CI -0.00317--0.000705), C-reactive protein -0.0363 (95% CI 0.0601--0.0124), cystatin C -0.0391 (95% CI -0.0772--0.00107). When using clinical cut-points we additionally found associations between LTL and insulin resistance -0.0412 (95% CI -0.0685--0.0139), systolic blood pressure 0.0455 (95% CI 0.00137-0.0897), and diastolic blood pressure -0.0674 (95% CI -0.126--0.00889). These associations were 10%-15% greater without controlling for leukocyte cell types. There were very few differences in the associations by age, race/ethnicity, gender, education, or income. Our findings are relevant to the relationships between these cardiovascular biomarkers in the general population but not to cardiovascular disease as a clinical outcome.

Conclusions: LTL is most strongly associated with adiposity, but is also associated with biomarkers across several physiological systems. LTL may thus be a predictor of cardiovascular disease through its association with multiple risk factors that are physiologically correlated with risk for development of cardiovascular disease. Our results are consistent with LTL being a biomarker of cardiovascular aging through established physiological mechanisms.
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http://dx.doi.org/10.1371/journal.pmed.1002188DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5127504PMC
November 2016

Change in Leukocyte Telomere Length Predicts Mortality in Patients with Stable Coronary Heart Disease from the Heart and Soul Study.

PLoS One 2016 26;11(10):e0160748. Epub 2016 Oct 26.

Department of Medicine, University of California San Francisco, San Francisco, CA, 94143, United States of America.

Background: Short telomere length independently predicts mortality in patients with coronary heart disease. Whether 5-year change in telomere length predicts subsequent mortality in patients with coronary heart disease has not been evaluated.

Methods: In a prospective cohort study of 608 individuals with stable coronary artery disease, we measured leukocyte telomere length at baseline and after five years of follow-up. We divided the sample into tertiles of telomere change: shortened, maintained or lengthened. We used Cox survival models to evaluate 5-year change in telomere length as a predictor of mortality.

Results: During an average of 4.2 years follow-up, there were 149 deaths. Change in telomere length was inversely predictive of all-cause mortality. Using the continuous variable of telomere length change, each standard deviation (325 base pair) greater increase in telomere length was associated with a 24% reduction in mortality (HR 0.76, 95% CI 0.61-0.94; p = 0.01), adjusted for age, sex, waist to hip ratio, exercise capacity, LV ejection fraction, serum creatinine, and year 5 telomere length. Mortality occurred in 39% (79/203) of patients who experienced telomere shortening, 22% (45/203) of patients whose telomere length was maintained, and 12% (25/202) of patients who experienced telomere lengthening (p<0.001). As compared with patients whose telomere length was maintained, those who experienced telomere lengthening were 56% less likely to die (HR 0.44, 95% CI, 0.23-0.87).

Conclusions: In patients with coronary heart disease, an increase in leukocyte telomere length over 5 years is associated with decreased mortality.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0160748PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5081189PMC
June 2017

Leukocyte telomere length predicts SSRI response in major depressive disorder: A preliminary report.

Mol Neuropsychiatry 2016 Jul 22;2(2):88-96. Epub 2016 Jun 22.

Department of Psychiatry, University of California San Francisco (UCSF) School of Medicine, San Francisco, CA, USA.

Short leukocyte telomere length (LTL) may be associated with several psychiatric disorders, including major depressive disorder (MDD). Short LTL has previously been associated with poor response to psychiatric medications in bipolar disorder and schizophrenia, but no studies have prospectively assessed the relationship of LTL to SSRI response in MDD. We assessed pre-treatment LTL, depression severity (using the Hamilton Depression Rating Scale [HDRS]), and self-reported positive and negative affect in 27 healthy, unmedicated adults with MDD. Subjects then underwent open-label treatment with a selective serotonin reuptake inhibitor (SSRI) antidepressant for eight weeks, after which clinical ratings were repeated. Analyses were corrected for age, sex and BMI. "Non-responders" to treatment (HDRS improvement <50%) had significantly shorter pre-treatment LTL, compared to "Responders" (p=0.037). Further, shorter pre-treatment LTL was associated with less improvement in negative affect (p<0.010) but not with changes in positive affect (p=0.356). This preliminary study is the first to assess the relationship between LTL and SSRI response in MDD and among the first to prospectively assess its relationship to treatment outcome in any psychiatric illness. Our data suggest that short LTL may serve as a vulnerability index of poorer response to SSRI treatment, but this needs examination in larger samples.
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http://dx.doi.org/10.1159/000446500DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4943759PMC
July 2016

Early Loss of Telomerase Action in Yeast Creates a Dependence on the DNA Damage Response Adaptor Proteins.

Mol Cell Biol 2016 07 29;36(14):1908-19. Epub 2016 Jun 29.

Department of Biochemistry and Biophysics, University of California, San Francisco, California, USA

Telomeres cap the ends of chromosomes, protecting them from degradation and inappropriate DNA repair processes that can lead to genomic instability. A short telomere elicits increased telomerase action on itself that replenishes telomere length, thereby stabilizing the telomere. In the prolonged absence of telomerase activity in dividing cells, telomeres eventually become critically short, inducing a permanent cell cycle arrest (senescence). We recently showed that even early after telomerase inactivation (ETI), yeast cells have accelerated mother cell aging and mildly perturbed cell cycles. Here, we show that the complete disruption of DNA damage response (DDR) adaptor proteins in ETI cells causes severe growth defects. This synthetic-lethality phenotype was as pronounced as that caused by extensive DNA damage in wild-type cells but showed genetic dependencies distinct from such damage and was completely alleviated by SML1 deletion, which increases deoxynucleoside triphosphate (dNTP) pools. Our results indicated that these deleterious effects in ETI cells cannot be accounted for solely by the slow erosion of telomeres due to incomplete replication that leads to senescence. We propose that normally occurring telomeric DNA replication stress is resolved by telomerase activity and the DDR in two parallel pathways and that deletion of Sml1 prevents this stress.
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http://dx.doi.org/10.1128/MCB.00943-15DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4936065PMC
July 2016

Systematic and Cell Type-Specific Telomere Length Changes in Subsets of Lymphocytes.

J Immunol Res 2016 10;2016:5371050. Epub 2016 Feb 10.

Department of Biochemistry and Biophysics, University of California San Francisco, San Francisco, CA 94143, USA.

Telomeres, the protective DNA-protein complexes at the ends of linear chromosomes, are important for genome stability. Leukocyte or peripheral blood mononuclear cell (PBMC) telomere length is a potential biomarker for human aging that integrates genetic, environmental, and lifestyle factors and is associated with mortality and risks for major diseases. However, only a limited number of studies have examined longitudinal changes of telomere length and few have reported data on sorted circulating immune cells. We examined the average telomere length (TL) in CD4+, CD8+CD28+, and CD8+CD28- T cells, B cells, and PBMCs, cross-sectionally and longitudinally, in a cohort of premenopausal women. We report that TL changes over 18 months were correlated among these three T cell types within the same participant. Additionally, PBMC TL change was also correlated with those of all three T cell types, and B cells. The rate of shortening for B cells was significantly greater than for the three T cell types. CD8+CD28- cells, despite having the shortest TL, showed significantly more rapid attrition when compared to CD8+CD28+ T cells. These results suggest systematically coordinated, yet cell type-specific responses to factors and pathways contribute to telomere length regulation.
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http://dx.doi.org/10.1155/2016/5371050DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4764743PMC
November 2016

Human telomere biology: A contributory and interactive factor in aging, disease risks, and protection.

Science 2015 Dec;350(6265):1193-8

Department of Biochemistry and Biophysics, University of California, San Francisco, CA 94143, USA.

Telomeres are the protective end-complexes at the termini of eukaryotic chromosomes. Telomere attrition can lead to potentially maladaptive cellular changes, block cell division, and interfere with tissue replenishment. Recent advances in the understanding of human disease processes have clarified the roles of telomere biology, especially in diseases of human aging and in some aging-related processes. Greater overall telomere attrition predicts mortality and aging-related diseases in inherited telomere syndrome patients, and also in general human cohorts. However, genetically caused variations in telomere maintenance either raise or lower risks and progression of cancers, in a highly cancer type-specific fashion. Telomere maintenance is determined by genetic factors and is also cumulatively shaped by nongenetic influences throughout human life; both can interact. These and other recent findings highlight both causal and potentiating roles for telomere attrition in human diseases.
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http://dx.doi.org/10.1126/science.aab3389DOI Listing
December 2015

Association of dimensional psychological health measures with telomere length in male war veterans.

J Affect Disord 2016 Jan 28;190:537-542. Epub 2015 Oct 28.

Department of Psychiatry, University of California San Francisco, San Francisco, CA, USA. Electronic address:

Background: Several psychiatric disorders may be characterized by peripheral telomere shortening. However, it is unclear whether telomere shortening is associated with these psychiatric disorders per se or, rather, with underlying dimensional parameters that are often, but not necessarily, associated with them. We explored the association between dimensional psychopathological measures and telomere length (TL) in granulocytes among veterans independent of psychiatric diagnosis.

Methods: Seventy-six combat-exposed male veterans (41 psychiatrically healthy, 18 with Posttraumatic Stress Disorder [PTSD] and 17 with concomitant PTSD and Major Depressive Disorder [MDD]) had TL assayed. Assessments included Clinician-Administered PTSD Scale (CAPS), Beck Depression Inventory-II (BDI-II), Early Trauma Inventory (ETI), Symptom Checklist-90-R Global Severity Index (SCL-90-GSI), Perceived Stress Scale (PSS) and Positive and Negative Affect Schedule (PANAS). Correlations were corrected for age, BMI, antidepressants and ethnicity.

Results: Across subjects, TL was negatively correlated with early trauma (p<0.001), global psychopathological severity (p=0.044) and perceived stress (p=0.019), positively correlated with positive affect (p=0.026), not significantly correlated with symptom severity of PTSD, depression or negative affect. Across these dimensions, early trauma and positive affect were associated with TL after excluding subjects with somatic illnesses.

Limitations: The study was cross-sectional with a moderate sample size and only male combat-exposed subjects.

Conclusions: These preliminary findings suggest that early trauma, severity of perceived stress and general psychopathological symptoms are more closely associated with shorter TL than is the severity of core diagnostic symptoms of PTSD or MDD, whereas positive affect is associated with longer TL. Larger-scale studies should assess TL associated with specific psychiatric dimensions, apart from only categorical psychiatric diagnoses, to develop more specific biologically-relevant endophenotypes.
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http://dx.doi.org/10.1016/j.jad.2015.10.037DOI Listing
January 2016

Discrimination, mental health, and leukocyte telomere length among African American men.

Psychoneuroendocrinology 2016 Jan 5;63:10-6. Epub 2015 Sep 5.

Department of Health Services Administration, University of Maryland at College Park, School of Public Health, 2234 School of Public Health, College Park, MD 20742, USA.

African American men in the US experience disparities across multiple health outcomes. A common mechanism underlying premature declines in health may be accelerated biological aging, as reflected by leukocyte telomere length (LTL). Racial discrimination, a qualitatively unique source of social stress reported by African American men, in tandem with poor mental health, may negatively impact LTL in this population. The current study examined cross-sectional associations between LTL, self-reported racial discrimination, and symptoms of depression and anxiety among 92 African American men 30-50 years of age. LTL was measured in kilobase pairs using quantitative polymerase chain reaction assay. Controlling for sociodemographic factors, greater anxiety symptoms were associated with shorter LTL (b=-0.029, standard error [SE]=0.014; p<0.05). There were no main effects of racial discrimination or depressive symptoms on LTL, but we found evidence for a significant interaction between the two (b=0.011, SE=0.005; p<0.05). Racial discrimination was associated with shorter LTL among those with lower levels of depressive symptoms. Findings from this study highlight the role of social stressors and individual-level psychological factors for physiologic deterioration among African American men. Consistent with research on other populations, greater anxiety may reflect elevated stress associated with shorter LTL. Racial discrimination may represent an additional source of social stress among African American men that has detrimental consequences for cellular aging among those with lower levels of depression.
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http://dx.doi.org/10.1016/j.psyneuen.2015.09.001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5407686PMC
January 2016

Mitochondrial DNA copy number is reduced in male combat veterans with PTSD.

Prog Neuropsychopharmacol Biol Psychiatry 2016 Jan 26;64:10-7. Epub 2015 Jun 26.

Department of OB/GYN and Reproductive Science, University of California San Francisco, San Francisco, CA, USA.

Introduction: Mitochondrial abnormalities may be involved in PTSD, although few studies have examined this. Mitochondrial DNA copy number (mtDNAcn) in blood cells is an emerging systemic index of mitochondrial biogenesis and function. The present study assessed mtDNAcn in male combat-exposed veterans with PTSD compared to those without PTSD as well as its correlation with clinical scales.

Methods: mtDNAcn was assessed with a TaqMan multiplex assay in granulocytes of 43 male combat veterans with (n=43) or without (n=44) PTSD. Twenty of the PTSD subjects had co-morbid major depressive disorder (MDD). The Clinician Administered PTSD Scale (CAPS), the Positive and Negative Affect Schedule (PANAS), the Early Trauma Inventory (ETI) and the Beck Depression Inventory II (BDI-II) were used for the clinical assessments. All analyses were corrected for age and BMI.

Results: mtDNAcn was significantly lower in subjects with PTSD (p<0.05). Within the PTSD group, those with moderate PTSD symptom severity had relatively higher mtDNAcn than those with mild or severe symptoms (p<0.01). Within the PTSD group, mtDNAcn was positively correlated with PANAS positive subscale ratings (p<0.01) but was not significantly correlated with PANAS negative subscale, ETI or BDI-II ratings.

Discussion: This study provides the first evidence of: (i) a significant decrease of mtDNAcn in combat PTSD, (ii) a possible "inverted-U" shaped relationship between PTSD symptom severity and mtDNAcn within PTSD subjects, and (iii) a direct correlation of mtDNAcn with positive affectivity within PTSD subjects. Altered mtDNAcn in PTSD may reflect impaired energy metabolism, which might represent a novel aspect of its pathophysiology.
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http://dx.doi.org/10.1016/j.pnpbp.2015.06.012DOI Listing
January 2016

Automated Assay of Telomere Length Measurement and Informatics for 100,000 Subjects in the Genetic Epidemiology Research on Adult Health and Aging (GERA) Cohort.

Genetics 2015 Aug 19;200(4):1061-72. Epub 2015 Jun 19.

Department of Biochemistry and Biophysics, University of California, San Francisco, California 94158-2517

The Kaiser Permanente Research Program on Genes, Environment, and Health (RPGEH) Genetic Epidemiology Research on Adult Health and Aging (GERA) cohort includes DNA specimens extracted from saliva samples of 110,266 individuals. Because of its relationship to aging, telomere length measurement was considered an important biomarker to develop on these subjects. To assay relative telomere length (TL) on this large cohort over a short time period, we created a novel high throughput robotic system for TL analysis and informatics. Samples were run in triplicate, along with control samples, in a randomized design. As part of quality control, we determined the within-sample variability and employed thresholds for the elimination of outlying measurements. Of 106,902 samples assayed, 105,539 (98.7%) passed all quality control (QC) measures. As expected, TL in general showed a decline with age and a sex difference. While telomeres showed a negative correlation with age up to 75 years, in those older than 75 years, age positively correlated with longer telomeres, indicative of an association of longer telomeres with more years of survival in those older than 75. Furthermore, while females in general had longer telomeres than males, this difference was significant only for those older than age 50. An additional novel finding was that the variance of TL between individuals increased with age. This study establishes reliable assay and analysis methodologies for measurement of TL in large, population-based human studies. The GERA cohort represents the largest currently available such resource, linked to comprehensive electronic health and genotype data for analysis.
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http://dx.doi.org/10.1534/genetics.115.178624DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4574243PMC
August 2015

Maternal Folate Concentration in Early Pregnancy and Newborn Telomere Length.

Ann Nutr Metab 2015 9;66(4):202-8. Epub 2015 Jun 9.

Department of Pediatrics, University of California, Irvine, Calif.; USA.

Background/aims: Telomere biology plays a fundamental role in genomic integrity and cell physiology. The newborn setting of telomere length (TL) likely has important implications for telomere dynamics over the lifespan; however, its determinants are poorly understood. Folate is essential for DNA integrity. The maternal compartment is the only source of folate for the developing fetus. We, therefore, tested the hypothesis that variation in maternal folate during pregnancy is associated with newborn TL.

Methods: A prospective, longitudinal study was conducted in 119 mother-newborn dyads. Eligible mothers were enrolled at 9.5 (SD ±2.1) weeks gestation and followed through birth. Concentrations of maternal serum folate were measured in the first trimester of pregnancy. Newborn telomere length was measured in cord blood mononuclear cells (CBMC).

Results: After accounting for the effects of other established determinants of newborn TL, each 10 ng/ml increase in maternal total folate was associated with a 5.8% increase in median TL (p = 0.03). The median TL in newborns of mother in the lowest quartile of total folate levels was approximately 10% shorter than that of newborns of mothers in the highest folate quartile.

Conclusions: Our findings suggest that fetal TL exhibits developmental plasticity, and provide evidence that maternal nutrition may exert a 'programming' effect on this system.
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http://dx.doi.org/10.1159/000381925DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5457533PMC
November 2016

Leukocyte telomere length and mortality in the National Health and Nutrition Examination Survey, 1999-2002.

Epidemiology 2015 Jul;26(4):528-35

From the aDepartment of Epidemiology and Center for Social Epidemiology and Population Health, University of Michigan, Ann Arbor, MI; bDivision of General Medical Disciplines, Stanford University, Stanford, CA; cDepartment of Psychiatry, dDivision of General Internal Medicine, and eDepartment of Biochemistry and Biophysics, University of California, San Francisco, CA.

Background: This study examined the association between leukocyte telomere length--a marker of cell aging--and mortality in a nationally representative sample of US adults ages 50-84 years. We also examined moderating effects of age, sex, race/ethnicity, and education.

Methods: Data were from the National Health and Nutrition Examination Survey, 1999-2002 (n = 3,091). Cox proportional hazards regression was used to estimate the risk of all-cause and cause- specific mortality adjusting for sociodemographic characteristics, smoking, body mass index, and chronic conditions.

Results: Eight hundred and seventy deaths occurred over an average of 9.5 years of follow-up. In the full sample, a decrease of 1 kilobase pair in telomere length at baseline was marginally associated with a 10% increased hazard of all-cause mortality (hazard ratio [HR]: 1.1, 95% confidence interval [CI]: 0.9, 1.4) and a 30% increased hazard of death due to diseases other than cardiovascular disease or cancer (HR: 1.3, 95% CI: 0.9, 1.9). Among African-American but not white or Mexican-American respondents, a decrease of 1 kilobase pair in telomere length at baseline was associated with a two-fold increased hazard of cardiovascular mortality (HR: 2.0, 95% CI: 1.3, 3.1). There was no association between telomere length and cancer mortality.

Conclusions: The association between leukocyte telomere length and mortality differs by race/ethnicity and cause of death.
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http://dx.doi.org/10.1097/EDE.0000000000000299DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4679150PMC
July 2015

Psychiatric disorders and leukocyte telomere length: Underlying mechanisms linking mental illness with cellular aging.

Neurosci Biobehav Rev 2015 Aug 18;55:333-64. Epub 2015 May 18.

Department of Psychiatry, University of California San Francisco (UCSF), School of Medicine, San Francisco, CA, USA. Electronic address:

Many psychiatric illnesses are associated with early mortality and with an increased risk of developing physical diseases that are more typically seen in the elderly. Moreover, certain psychiatric illnesses may be associated with accelerated cellular aging, evidenced by shortened leukocyte telomere length (LTL), which could underlie this association. Shortened LTL reflects a cell's mitotic history and cumulative exposure to inflammation and oxidation as well as the availability of telomerase, a telomere-lengthening enzyme. Critically short telomeres can cause cells to undergo senescence, apoptosis or genomic instability, and shorter LTL correlates with poorer health and predicts mortality. Emerging data suggest that LTL may be reduced in certain psychiatric illnesses, perhaps in proportion to exposure to the psychiatric illnesses, although conflicting data exist. Telomerase has been less well characterized in psychiatric illnesses, but a role in depression and in antidepressant and neurotrophic effects has been suggested by preclinical and clinical studies. In this article, studies on LTL and telomerase activity in psychiatric illnesses are critically reviewed, potential mediators are discussed, and future directions are suggested. A deeper understanding of cellular aging in psychiatric illnesses could lead to re-conceptualizing them as systemic illnesses with manifestations inside and outside the brain and could identify new treatment targets.
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http://dx.doi.org/10.1016/j.neubiorev.2015.05.007DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4501875PMC
August 2015

Movement-Based Behaviors and Leukocyte Telomere Length among US Adults.

Med Sci Sports Exerc 2015 Nov;47(11):2347-52

1Center for Health Behavior Research, Department of Health, Exercise Science, and Recreation Management, University of Mississippi, University, MS; 2Kevser Ermin Applied Physiology Laboratory, Department of Health, Exercise Science, and Recreation Management, University of Mississippi, University, MS; and 3Blackburn Laboratory, Department of Biochemistry and Biophysics, University of California, San Francisco, San Francisco, CA.

Introduction: Short leukocyte telomere length (LTL) has become a hallmark characteristic of aging. Some, but not all, evidence suggests that physical activity (PA) may play an important role in attenuating age-related diseases and may provide a protective effect for telomeres. The purpose of this study was to examine the association between PA and LTL in a national sample of US adults from the National Health and Nutrition Examination Survey.

Methods: National Health and Nutrition Examination Survey data from 1999 to 2002 (n = 6503; 20-84 yr) were used. Four self-report questions related to movement-based behaviors (MBB) were assessed. The four MBB included whether individuals participated in moderate-intensity PA, vigorous-intensity PA, walking/cycling for transportation, and muscle-strengthening activities. An MBB index variable was created by summing the number of MBB an individual engaged in (range, 0-4).

Results: A clear dose-response relation was observed between MBB and LTL; across the LTL tertiles, respectively, the mean numbers of MBB were 1.18, 1.44, and 1.54 (Ptrend < 0.001). After adjustments (including age) and compared with those engaging in 0 MBB, those engaging in 1, 2, 3, and 4 MBB, respectively, had a 3% (P = 0.84), 24% (P = 0.02), 29% (P = 0.04), and 52% (P = 0.004) reduced odds of being in the lowest (vs highest) tertile of LTL; MBB was not associated with being in the middle (vs highest) tertile of LTL.

Conclusions: Greater engagement in MBB was associated with reduced odds of being in the lowest LTL tertile.
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http://dx.doi.org/10.1249/MSS.0000000000000695DOI Listing
November 2015

Race-Ethnicity, Poverty, Urban Stressors, and Telomere Length in a Detroit Community-based Sample.

J Health Soc Behav 2015 Jun 30;56(2):199-224. Epub 2015 Apr 30.

University of California San Francisco, San Francisco, CA, USA.

Residents of distressed urban areas suffer early aging-related disease and excess mortality. Using a community-based participatory research approach in a collaboration between social researchers and cellular biologists, we collected a unique data set of 239 black, white, or Mexican adults from a stratified, multistage probability sample of three Detroit neighborhoods. We drew venous blood and measured telomere length (TL), an indicator of stress-mediated biological aging, linking respondents' TL to their community survey responses. We regressed TL on socioeconomic, psychosocial, neighborhood, and behavioral stressors, hypothesizing and finding an interaction between poverty and racial-ethnic group. Poor whites had shorter TL than nonpoor whites; poor and nonpoor blacks had equivalent TL; and poor Mexicans had longer TL than nonpoor Mexicans. Findings suggest unobserved heterogeneity bias is an important threat to the validity of estimates of TL differences by race-ethnicity. They point to health impacts of social identity as contingent, the products of structurally rooted biopsychosocial processes.
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http://dx.doi.org/10.1177/0022146515582100DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4621968PMC
June 2015

PBMC telomerase activity, but not leukocyte telomere length, correlates with hippocampal volume in major depression.

Psychiatry Res 2015 Apr 19;232(1):58-64. Epub 2015 Jan 19.

Department of Radiology, UCSF School of Medicine, San Francisco, CA, USA; San Francisco Veterans Administration Medical Center, San Francisco, CA, USA.

Accelerated cell aging, indexed in peripheral leukocytes by telomere shortness and in peripheral blood mononuclear cells (PBMCs) by telomerase activity, has been reported in several studies of major depressive disorder (MDD). However, the relevance of these peripheral measures for brain indices that are presumably more directly related to MDD pathophysiology is unknown. In this study, we explored the relationship between PBMC telomerase activity and leukocyte telomere length and magnetic resonance imaging-estimated hippocampal volume in un-medicated depressed individuals and healthy controls. We predicted that, to the extent peripheral and central telomerase activity are directly related, PBMC telomerase activity would be positively correlated with hippocampal volume, perhaps due to hippocampal telomerase-associated neurogenesis, neuroprotection or neurotrophic facilitation, and that this effect would be clearer in individuals with increased PBMC telomerase activity, as previously reported in un-medicated MDD. We did not have specific hypotheses regarding the relationship between leukocyte telomere length and hippocampal volume, due to conflicting reports in the published literature. We found, in 25 un-medicated MDD subjects, that PBMC telomerase activity was significantly positively correlated with hippocampal volume; this relationship was not observed in 18 healthy controls. Leukocyte telomere length was not significantly related to hippocampal volume in either group (19 unmedicated MDD subjects and 17 healthy controls). Although the nature of the relationship between peripheral telomerase activity and telomere length and the hippocampus is unclear, these preliminary data are consistent with the possibility that PBMC telomerase activity indexes, and may provide a novel window into, hippocampal neuroprotection and/or neurogenesis in MDD.
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http://dx.doi.org/10.1016/j.pscychresns.2015.01.007DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4404215PMC
April 2015

Early telomerase inactivation accelerates aging independently of telomere length.

Cell 2015 Feb;160(5):928-939

Department of Biochemistry and Biophysics, University of California, San Francisco, San Francisco, CA 94158, USA. Electronic address:

Telomerase is required for long-term telomere maintenance and protection. Using single budding yeast mother cell analyses we found that, even early after telomerase inactivation (ETI), yeast mother cells show transient DNA damage response (DDR) episodes, stochastically altered cell-cycle dynamics, and accelerated mother cell aging. The acceleration of ETI mother cell aging was not explained by increased reactive oxygen species (ROS), Sir protein perturbation, or deprotected telomeres. ETI phenotypes occurred well before the population senescence caused late after telomerase inactivation (LTI). They were morphologically distinct from LTI senescence, were genetically uncoupled from telomere length, and were rescued by elevating dNTP pools. Our combined genetic and single-cell analyses show that, well before critical telomere shortening, telomerase is continuously required to respond to transient DNA replication stress in mother cells and that a lack of telomerase accelerates otherwise normal aging.
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http://dx.doi.org/10.1016/j.cell.2015.02.002DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4496004PMC
February 2015

Associations of cadmium and lead exposure with leukocyte telomere length: findings from National Health and Nutrition Examination Survey, 1999-2002.

Am J Epidemiol 2015 Jan 10;181(2):127-36. Epub 2014 Dec 10.

Cadmium and lead are ubiquitous environmental contaminants that might increase risks of cardiovascular disease and other aging-related diseases, but their relationships with leukocyte telomere length (LTL), a marker of cellular aging, are poorly understood. In experimental studies, they have been shown to induce telomere shortening, but no epidemiologic study to date has examined their associations with LTL in the general population. We examined associations of blood lead and cadmium (n = 6,796) and urine cadmium (n = 2,093) levels with LTL among a nationally representative sample of US adults from the National Health and Nutrition Examination Survey (1999-2002). The study population geometric mean concentrations were 1.67 µg/dL (95% confidence interval (CI): 1.63, 1.70) for blood lead, 0.44 µg/L (95% CI: 0.42, 0.47) for blood cadmium, and 0.28 µg/L (95% CI: 0.27, 0.30) for urine cadmium. After adjustment for potential confounders, the highest (versus lowest) quartiles of blood and urine cadmium were associated with -5.54% (95% CI: -8.70, -2.37) and -4.50% (95% CI: -8.79, -0.20) shorter LTLs, respectively, with evidence of dose-response relationship (P for trend < 0.05). There was no association between blood lead concentration and LTL. These findings provide further evidence of physiological impacts of cadmium at environmental levels and might provide insight into biological pathways underlying cadmium toxicity and chronic disease risks.
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http://dx.doi.org/10.1093/aje/kwu293DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4351349PMC
January 2015

Telomere length and the risk of atrial fibrillation: insights into the role of biological versus chronological aging.

Circ Arrhythm Electrophysiol 2014 Dec 8;7(6):1026-32. Epub 2014 Nov 8.

From the Section of Cardiac Electrophysiology, Division of Cardiology, Department of Medicine (J.D.R., T.A.D., J.E.O., G.M.M.), Institute of Human Genetics and Department of Medicine (E.Z., D.H.), Department of Biochemistry and Biophysics (J.L., E.H.B.), Department of Epidemiology and Biostatistics (D.V.G.), Department of Medicine (E.G.B.), and Department of Bioengineering and Therapeutic Sciences (E.G.B.), University of California, San Francisco; Division of Cardiovascular Surgery, Sutter Health, Sacramento, CA (J.L.); Department of Epidemiology (A.L.F., S.R.H.) and Cardiovascular Health Research Unit (B.M.P., S.R.H.), University of Washington, Seattle; and Departments of Medicine and Health Services, University of Washington and Group Health Research Institute, Group Health, Seattle (B.M.P., S.R.H.).

Background: Advanced age is the most important risk factor for atrial fibrillation (AF); however, the mechanism remains unknown. Telomeres, regions of DNA that shorten with cell division, are considered reliable markers of biological aging. We sought to examine the association between leukocyte telomere length (LTL) and incident AF in a large population-based cohort using direct LTL measurements and genetic data. To further explore our findings, we compared atrial cell telomere length and LTL in cardiac surgery patients.

Methods And Results: Mean LTL and the TERT rs2736100 single nucleotide polymorphism were assessed as predictors of incident AF in the Cardiovascular Health Study (CHS). Among the surgical patients, within subject comparison of atrial cell telomere length versus LTL was assessed. Among 1639 CHS participants, we observed no relationship between mean LTL and incident AF before and after adjustment for potential confounders (adjusted hazard ratio, 1.09; 95% confidence interval: 0.92-1.29; P=0.299); chronologic age remained strongly associated with AF in the same model. No association was observed between the TERT rs2736100 single nucleotide polymorphism and incident AF (adjusted hazard ratio: 0.95; 95% confidence interval: 0.88-1.04; P=0.265). In 35 cardiac surgery patients (26 with AF), atrial cell telomere length was longer than LTL (1.19 ± 0.20 versus 1.02 ± 0.25 [T/S ratio], P<0.001), a finding that remained consistent within the AF subgroup.

Conclusions: Our study revealed no evidence of an association between LTL and incident AF and no evidence of relative atrial cell telomere shortening in AF. Chronological aging independent of biological markers of aging is the primary risk factor for AF.
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http://dx.doi.org/10.1161/CIRCEP.114.001781DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4294941PMC
December 2014

Maternal estriol concentrations in early gestation predict infant telomere length.

J Clin Endocrinol Metab 2015 Jan;100(1):267-73

Departments of Pediatrics (S.E., C.B., P.D.W.), Obstetrics and Gynecology (P.D.W.), Epidemiology (P.D.W.), and Psychiatry and Human Behavior (P.D.W.), University of California, Irvine; California 92697; Department of Obstetrics, Gynecology, and Reproductive Sciences (H.N.S.), University of Pittsburgh, Pittsburgh, Pennsylvania 15213; Departments of Psychiatry (E.S.E.), and Biochemistry and Biophysics (E.H.B.), University of California, San Francisco, San Francisco, California 94143; and Institute for Medical Psychology (S.E., C.B.), Charité University Medicine, 10117 Berlin, Germany.

Context: Telomere biology plays a fundamental role in genomic integrity, cellular regeneration, physiology, aging, disease risk, and mortality. The initial setting of telomere length (TL) in early life has important implications for telomere maintenance and related disorders throughout the life span. However, little is known about the predictors of this initial setting.

Objective: Given the established role of estrogen on adult TL and the role of estriol (E3) in the context of fetal development, the goal of this study was to test the hypothesis that higher maternal E3 concentration during early pregnancy is associated with longer infant telomere length.

Design, Participants, And Setting: Study participants comprised a cohort of N = 100 infants followed prospectively from intrauterine life and birth through early childhood from a population-based, representative sample of pregnant mothers recruited in early pregnancy at university-based obstetric clinics in Southern California. Maternal unconjugated E3 concentrations were assessed in plasma in early gestation (around wk 15). Infant TL was assessed in buccal cells at approximately 15 months of age.

Results: After accounting for the effects of potential confounding maternal and infant variables, there was a significant, independent effect of maternal E3 concentration on infant TL (unstandardized β = 0.297; P = .001; 95% Cl, 0.121-0.473). Specifically, a one-multiple-of-the-median (MoM) increase in maternal E3 concentration during early pregnancy was associated with a 14.42% increase in infant TL.

Conclusions: This study supports the concept of developmental plasticity of the telomere biology system and highlights specifically the role of a potentially modifiable intrauterine factor for additional mechanistic and clinical investigation.
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http://dx.doi.org/10.1210/jc.2014-2744DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4283015PMC
January 2015

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.

Am J Public Health 2014 Dec 16;104(12):2425-31. Epub 2014 Oct 16.

Cindy W. Leung is with the Center for Health and Community, School of Medicine, University of California, San Francisco. Barbara A. Laraia is with the School of Public Health, University of California, Berkeley. Belinda Needham is with the Department of Epidemiology, School of Public Health, University of Michigan, Ann Arbor. David H. Rehkopf is with the Department of Medicine, Stanford University, Palo Alto, CA. Nancy E. Adler and Elissa S. Epel are with the Center for Health and Community and the Department of Psychiatry, School of Medicine, University of California, San Francisco. Jue Lin and Elizabeth H. Blackburn are with the Department of Biochemistry and Biophysics, University of California, San Francisco.

Objectives: We tested whether leukocyte telomere length maintenance, which underlies healthy cellular aging, provides a link between sugar-sweetened beverage (SSB) consumption and the risk of cardiometabolic disease.

Methods: We examined cross-sectional associations between the consumption of SSBs, diet soda, and fruit juice and telomere length in a nationally representative sample of healthy adults. The study population included 5309 US adults, aged 20 to 65 years, with no history of diabetes or cardiovascular disease, from the 1999 to 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 (b = -0.010; 95% confidence interval [CI] = -0.020, -0.001; P = .04). Consumption of 100% fruit juice was marginally associated with longer telomeres (b = 0.016; 95% CI = -0.000, 0.033; P = .05). No significant associations were observed between consumption of diet sodas or noncarbonated SSBs and telomere length.

Conclusions: Regular consumption of sugar-sweetened sodas might influence metabolic disease development through accelerated cell aging.
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http://dx.doi.org/10.2105/AJPH.2014.302151DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4229419PMC
December 2014

An antiapoptotic role for telomerase RNA in human immune cells independent of telomere integrity or telomerase enzymatic activity.

Blood 2014 Dec 15;124(25):3675-84. Epub 2014 Oct 15.

Department of Biophysics and Biochemistry, University of California, San Francisco, San Francisco, CA.

Telomerase is a ribonucleoprotein complex that adds telomeric DNA to the ends of linear chromosomes. It contains two core canonical components: the essential RNA component, hTR, which provides the template for DNA synthesis, and the reverse transcriptase protein component, hTERT. Low telomerase activity in circulating peripheral blood mononuclear cells has been associated with a variety of diseases. It is unknown, however, whether telomerase, in addition to its long-term requirement for telomere maintenance, is also necessary for short-term immune cell proliferation and survival. We report that overexpression of enzymatically inactive hTR mutants protected against dexamethasone-induced apoptosis in stimulated CD4 T cells. Furthermore, hTR knockdown reproducibly induced apoptosis in the absence of any detectable telomere shortening or DNA damage response. In contrast, hTERT knockdown did not induce apoptosis. Strikingly, overexpression of hTERT protein caused apoptosis that was rescued by overexpression of enzymatically inactive hTR mutants. Hence, we propose that hTR can function as a noncoding RNA that protects from apoptosis independent of its function in telomerase enzymatic activity and long-term telomere maintenance in normal human immune cells. These results imply that genetic or environmental factors that alter hTR levels can directly affect immune cell function to influence health and disease.
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http://dx.doi.org/10.1182/blood-2014-06-582254DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4263978PMC
December 2014
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