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Human telomerase reverse transcriptase (hTERT; the catalytic protein subunit of telomerase) is subjected to numerous alternative splicing events, but the regulation and function of these splice variants is obscure. Full-length hTERT includes conserved domains that encode reverse transcriptase activity, RNA binding, and other functions. The major splice variant termed α+β− or β-deletion is highly expressed in stem and cancer cells, where it codes for a truncated protein lacking most of the reverse transcriptase domain but retaining the known RNA-binding motifs. In a breast cancer cell panel, we found that β-deletion was the hTERT transcript that was most highly expressed. Splicing of this transcript was controlled by the splice regulators SRSF11, HNRNPH2, and HNRNPL, and the β-deletion transcript variant was associated with polyribosomes in cells. When ectopically overexpressed, β-deletion protein competed for binding to telomerase RNA (hTR/TERC), thereby inhibiting endogenous telomerase activity. Overexpressed β-deletion protein localized to the nucleus and mitochondria and protected breast cancer cells from cisplatin-induced apoptosis. Our results reveal that a major hTERT splice variant can confer a growth advantage to cancer cells independent of telomere maintenance, suggesting that hTERT makes multiple contributions to cancer pathophysiology. Cancer Res; 73(9); 2817–28. ©2013 AACR.

PDF file - 516K, T1. Breast cell lines used in this study. T2. Summary of results for 45 breast cancer cell lines and 5 non-malignant cell lines. T3. Correlation of hTERT α/β splice variants, telomerase activity, telomere length and hTR in 50 breast cancer cell lines. T4. Sequences of primers used.

The telomerase ribonucleoprotein is a promising target for cancer therapy, as it is highly active in many human malignancies. A novel telomerase targeting approach combines short interfering RNA (siRNA) knockdown of endogenous human telomerase RNA (hTer) with expression of a mutant-template hTer (MT-hTer). Such combination MT-hTer/siRNA constructs induce a rapid DNA damage response, telomere uncapping, and inhibition of cell proliferation in a variety of human cancer cell lines. We tested which functional aspects of the protein catalytic component of telomerase [human telomerase reverse transcriptase (hTERT)] are required for these effects using human LOX melanoma cells overexpressing various hTERTs of known properties. Within 3 days of MT-hTer/siRNA introduction, both growth inhibition and DNA damage responses were significantly higher in the setting of wild-type hTERT versus catalytically dead hTERT or mutant hTERT that is catalytically competent but unable to act on telomeres. These effects were not attenuated by siRNA-induced knockdown of the telomeric protein human Rap1 and were additive with knockdown of the telomere-binding protein TRF2. Hence, the effects of MT-hTer/siRNA require a telomerase that is both catalytically competent to polymerize DNA and able to act on telomeres in cells. (Cancer Res 2006; 66(11): 5763-71)

In human cancers, telomeres are commonly maintained by elevated levels of the ribonucleoprotein enzyme telomerase, which contains an intrinsic templating RNA moiety (human telomerase RNA; hTER) and the core protein (human telomerase reverse transcriptase). We developed a lentiviral system for efficient overexpression of mutant-template human telomerase RNA (MT-hTer) to add mutant DNA to telomeres in cancer cells. We show that such MT-hTer overexpression rapidly inhibits cell growth and induces apoptosis in telomerase-positive precancerous or cancer cells but not in telomerase-negative cells. These rapid effects occurred independent of wild-type p53 and telomere length. Tumor growth and progression were significantly decreased in xenografts of human tumor cells overexpressing MT-hTers. Expression of a hairpin short-interfering RNA that specifically targeted the endogenous wild-type hTER template region, but spared the MT-hTers, also caused p53-independent cell growth inhibition and apoptosis, and when coexpressed with MT-hTer, synergistically killed cancer cells. Hence, anti-wild-type-hTER short-interfering RNA and MT-hTers may act through distinct pathways and, particularly in combination, represent a promising approach to anticancer therapies.

PDF file - 236K, S1. hTERT and SRSF3 splice variant enrichment after cycloheximide treatment. S2. Total SRSF3 and hTERT splice variant mRNA abundance in ribosome-containing fractions. S3. Unaltered microscopy image shown in Figure 3. S4. SRSF11 and hnRNPH2 binding sites in pSpliceExpress-hTERT. S5. hTR 3' end co-immunoprecipitates with FLAG-WT-hTERT, FLAG-D868A-hTERT and FLAG-β-deletion. S6. hTERT detection by Western blot in UM-UC-3 lysates from experiment 5C. S7. hTR RNA expression levels in breast cancer cell lines. S8. Modal telomere length stayed relatively constant after 20 continues passages in randomly selected breast cell lines. S9. Telomerase activity and relative expression of hTERT α+β+ and β-deletion mRNAs in breast cancer cell line subtypes.

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Supplementary Figures 1-5 from Assembly of Mutant-Template Telomerase RNA into Catalytically Active Telomerase Ribonucleoprotein That Can Act on Telomeres Is Required for Apoptosis and Cell Cycle Arrest in Human Cancer Cells

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Objective: In the context of the importance of elucidating the determinants of the initial, newborn setting of telomere length (TL), it is increasingly evident that maternal stress and stress-related processes during pregnancy play a major role. Although psychological resilience may function as a buffer, research in this area has not yet examined its potential role vis-à-vis that of stress. The authors examined the relationship between maternal psychological resilience during pregnancy and newborn TL. Methods: In a sample of 656 mother-child dyads from the Prediction and Prevention of Preeclampsia and Intrauterine Growth Restriction cohort, multiple serial assessments were conducted over the course of pregnancy to quantify maternal stress, negative and positive emotional responses to pregnancy events, positive affect, and perceived social support. Principal component analysis identified two latent factors: stress and positivity. A measure of resilience was computed by regressing the positivity factor on the stress factor, in order to quantify positivity after accounting for stress. TL was measured using quantitative polymerase chain reaction in leukocytes extracted from cord blood shortly after birth. Linear regression was used to predict newborn TL from maternal resilience during pregnancy, adjusting for other potential determinants. Results: Maternal stress significantly predicted shorter newborn TL (β=−0.079), and positivity significantly predicted longer TL (β=0.135). Maternal resilience (positivity accounting for stress) was significantly and positively associated with newborn TL (β=0.114, 95% CI=0.035, 0.189), with each standard deviation increase in resilience predicting 12% longer newborn TL. Conclusions: The results indicate that maternal psychological resilience may exert a salubrious effect on offspring telomere biology and highlight the importance of enhancing maternal mental health and well-being during pregnancy.

Background: Psychological stress is a risk factor for major adverse cardiovascular events in individuals with coronary artery disease (CAD). Accelerated biological aging, as indicated by telomere shortening, is a recognized pathway by which stress may lead to cardiovascular disease incidence and mortality. We sought to investigate brain correlates of acute psychological stress and short telomeres in men and women with CAD. Methods: Individuals with CAD (N = 170) underwent a validated mental stress protocol including public speaking and mental arithmetic. Imaging of the brain with [O-15] water positron emission tomography (PET) was performed during mental stress and control conditions. Telomere length in peripheral leucocytes was measured by quantitative PCR and expressed as T/S-units. Voxel-wise regression models were constructed to assess the association between brain areas and activity during rest and mental stress after adjustments for demographic factors and clinical characteristics. Methods: The mean (SD) age was 62 (8) years, and 69% were men. The median telomere length was 0.84 T/S-units. Increased activation with mental stress in the lingual gyrus, cerebellum and superior and inferior gyrus in the frontal lobe were associated with reduced telomere length; 1.6 higher voxel activation of the inferior frontal gyrus was associated with 0.1 T/S-units reduction in telomere length (P < 0.005). Additionally, higher resting activities of the precentral, middle and superior frontal gyri and middle temporal gyri were associated with short telomeres. Results remained consistent after adjustment for demographic and clinical risk factors. Conclusion: Increased resting brain activity and reactivity to mental stress within the frontal lobe is associated with short telomeres. These frontal areas may regulate biological aging at rest and in connection with stress, which may contribute to cardiovascular vulnerability.

The aim of this study was to determine the potential role of leukocyte telomere length as a biomarker for development of childhood obesity in a low-income Latino population. A birth cohort of Latino children (N = 201) in San Francisco (recruited May 2006-May 2007) was followed until age 9 and assessed annually for obesity and dietary intake. Leukocyte telomere length was measured at 4 and 5 years (n = 102) and assessed as a predictor for obesity at age 9, adjusting for known risk factors. Furthermore, leukocyte telomere length at age 4 and 5 was evaluated as a possible mediator of the relationship between excessive sugar-sweetened beverage consumption and obesity at age 9. Shorter leukocyte telomere length in preschoolers was associated with obesity at age 9 (adjusted odds ratio 0.35, 95% confidence interval 0.13-0.94) after adjustment for known risk factors. Telomere length mediated 11% of the relationship between excessive sugar-sweetened beverage consumption and obesity. Shorter leukocyte telomere length may be an indicator of future obesity risk in high-risk populations as it is particularly sensitive to damage from oxidative stress exposure, including those from sugar-sweetened beverages.

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.

Cytoskeletal forces acting upon telomeres promote active chromosome motion needed to pair homologous chromosomes during meiosis. The necessary components that allow this force to be applied to telomeres is still unclear, as are the roles of this motion and whether motion is needed primarily for increasing collisions of homologous regions, testing homolog pairing fidelity, or some other role. Here, we show a novel role for telomerase, previously known to be responsible for telomeric end replication, in anchoring telomeres to the nuclear envelope (NE) to provide proper transmission of cytoskeletal forces during meiosis. Reduction in telomerase function inSaccharomyces cerevisiaeresults in a dramatic decrease in the frequency of high velocity “pulls” resulting in earlier homolog synapsis and increased recombination. These observations are consistent with a model in which telomeric cytoskeletal engagement ensures homolog pairing fidelity by pulling apart improperly associated regions whereas general chromosomal motion aids in increasing homologous contacts.

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.

Telomere length, a marker of biological aging, has been associated with cardiovascular disease (CVD). Increased arterial stiffness, an indicator of arterial aging, predicts adverse CVD outcomes. However, the relationship between telomere length and arterial stiffness is less well studied. Here we examined the cross-sectional association between leukocyte telomere length (LTL) and arterial stiffness in 2,165 American Indians in the Strong Heart Family Study (SHFS). LTL was measured by qPCR. Arterial stiffness was assessed by stiffness index β. The association between LTL and arterial stiffness was assessed by generalized estimating equation model, adjusting for sociodemographics (age, sex, education level), study site, metabolic factors (fasting glucose, lipids, systolic blood pressure, and kidney function), lifestyle (BMI, smoking, drinking, and physical activity), and prevalent CVD. Results showed that longer LTL was significantly associated with a decreased arterial stiffness (β=-0.070, P=0.007). This association did not attenuate after further adjustment for hsCRP (β=-0.071, P=0.005) or excluding participants with overt CVD (β=-0.068, P=0.012), diabetes (β=-0.070, P=0.005), or chronic kidney disease (β=-0.090, P=0.001). In summary, shorter LTL was significantly associated with an increased arterial stiffness, independent of known risk factors. This finding may shed light on the potential role of biological aging in arterial aging in American Indians.

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.

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 selective serotonin reuptake inhibitor (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. The subjects then underwent open-label treatment with an SSRI antidepressant for 8 weeks, after which clinical ratings were repeated. The analyses were corrected for age, sex, and body mass index. ‘Non-responders' to treatment (HDRS improvement

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

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., Chromatin dynamics is thought to play an important role in the maintenance of telomeres, yet how has remained poorly understood. Here the authors locally enrich heterochromatin protein 1α (HP1α) at human telomeres to provide insights into the crosstalk between epigenetic regulations and structural dynamics at the telomeres.

Aims: Shorter telomere length is associated with increased chronic disease risk in adulthood including diabetes mellitus and cardiovascular risk. Few studies have evaluated the relationship between telomere length change and incident disease risk in populations with a high percentage of overweight and obesity. Results: In an urban Latina population recruited in San Francisco (n = 82) with a high prevalence of overweight and obesity (78.4%), we assessed leukocyte telomere length and telomere length change over a 1-year period in relation to obesity, chronicity of obesity, and incident metabolic disease risk 5–6 years later. We also assessed the relationship between telomere length change over a 1-year period and weight loss. There were no significant associations between baseline telomere length and socio-demographics including age and ethnicity, or current weight status. Telomere length change, however, was associated with being obese at baseline and previous years of chronic obesity. A high percentage of women who were obese at baseline were also obese the year before (90%) and 2 years before (85%). Obesity at baseline was an independent predictor for increased telomere length attrition (β = −346.9, −568.4 to −125.4; P

AB 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

Telomeres are the protective caps at the ends of eukaryotic chromosomes. Each time a somatic cell divides, a portion of the telomeric DNA fails to replicate; thus, telomeres naturally shorten with mitosis.1,2 Telomerase, the cellular enzyme that can counteract shortening by elongating and protecting telomeres, is kept at low levels in normal human cells.3 When telomeres become too short, cells lose the ability to grow and divide.4,5 Human genetic mutations that result in short telomeres are associated with a group of conditions collectively called “telomere syndromes” that resemble premature onset of diseases of aging, 6 consistent with a role of telomere shortening in human aging in the general population.7 Recent studies have found that shorter leukocyte telomere length is associated with numerous age-related diseases, including cardiovascular disease,8–11 type 2 diabetes,12,13 dementia,14–16 and cancer,17,18 independent of chronological age. While a number of studies have also reported that shorter telomeres are associated with increased mortality,17,19–30 others have failed to find an association between telomere length and survival 31–34 (see the appendix for a summary of findings). In general, studies that have not found an association between telomere length and mortality have examined older populations. Inconsistencies in the literature may be due to differences in sample size and measurement techniques, the use of population versus clinical samples, or unknown biologic differences between those who survive to extreme old age and those with earlier mortality.35,36 Using data from the National Health and Nutrition Examination Survey (NHANES) 1999–2002, the current study examined the association between leukocyte telomere length and mortality in a large, nationally representative, socioeconomically and ethnically diverse sample of US adults. This study addressed the following research questions: (1) Is telomere length associated with all-cause mortality in adults aged 50–84? (2) Is telomere length associated with cause-specific mortality? (3) Do associations between telomere length and mortality vary according to age, sex, race/ethnicity, or socioeconomic status (SES)? Although prior research has shown that older age, male sex, white race, and low SES are associated with shorter telomere length,37,38 it is not known whether the relationship between telomere length and mortality differs according to sociodemographic characteristics. Answering this question could help determine whether telomere length is a comparable indicator of mortality risk across population subgroups.

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.

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.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.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.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.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.

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.

BackgroundEusociality is the highest level of social organization and naked mole-rats (NMR)s are amongst the few mammals showing this unique social behavior; nevertheless, little is known about the molecular mechanisms underlying the eusociality of NMRs.ResultsGene expression profiling of NMR brain and gonads (ovary and testis), from animals belonging to different reproductive castes, revealed robust gene expression differences between reproductive and non-reproductive members of NMR colonies. In the brain, dopaminergic pathways appear to be potential players in NMR eusocial behaviour. Breeding animals (queens and breeding males) showed increased expression of genes involved in dopamine metabolism. Using immunohistochemistry, we notably found these differences to be in dopaminergic hypothalamic areas, which provide inhibitory control over the secretion of prolactin, amongst other regions. Furthermore, plasma prolactin concentrations were elevated in many non-breeders (of both sexes), often reaching levels exceeding that of pregnant or lactating queens, suggesting a role for hyperprolactinaemia in socially-induced reproductive suppression. We also found that the ovaries of non-breeding females are arrested at pre-pubertal stage. They contained fewer supporting stromal cells compared to queens, and had very low expression of the aromatase geneCyp19A1(a key enzyme in estrogen synthesis) compared to non-breeding females. In the testes, genes involved in post meiosis spermatogenesis and sperm maturation (Prm1, Prm2, Odf3andAkap4) were highly expressed in breeding males compared to non-breeders, explaining the low sperm number and impaired sperm motility characteristic of non-breeding males.ConclusionsOur study suggests that extreme reproductive skew, one of the defining features of eusociality, is associated with changes in expression of key components of dopamine pathways, which could lead to hypogonadism and a lifetime of socially-induced sterility for most NMRs.

Objective: The discovery of telomere length (TL) as a biomarker of cellular aging and correlate of age-related disease has generated a new field of research in the biology of healthy aging. Although the most common method of sample collection for TL is venous blood draw, less-invasive DNA collection methods are becoming more widely used. However, how TL relates across tissues derived from these sample collection methods is poorly understood. The current study is the first to characterize the associations in TL across three sample collection methods: venous whole blood, finger prick dried blood spot and saliva.Methods: TL was measured in 24 healthy young adults using three modes of sample collection for each participant: venous whole blood, finger prick dried blood spot and saliva. Relative TL was measured using quantitative polymerase chain reaction.Results: TL in finger prick dried blood spots (DBS) washighly correlated with TL in whole blood (r = 0.84, p < 0.001). Salivary TL was also correlated with whole blood TL (r = 0.56, p = 0.005), but this association was not as strong as that of dried blood spot TL (Steiger’s Z = 2.12, p = 0.034). TL was longer in saliva than in whole blood or DBS (p’s < 0.001).Conclusions: These findings have important implications for future study design by supporting the validity of less-invasive methods that can be implemented with vulnerable populations or in the field. Further, these findings aid in interpreting the burgeoning area of biological aging research and may shed light on our understanding of inconsistencies in the empirical literature.

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.

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.

Telomere length has been hypothesized to be a marker of cumulative exposure to stress, and stress is an established cause of depression and anxiety disorders. The goal of this study was to examine the relationship between depression, anxiety and telomere length, and to assess whether this relationship is moderated by race/ethnicity, gender, and/or antidepressant use. Data were from the National Health and Nutrition Examination Survey, 1999–2002. Telomere length was assessed using the quantitative polymerase chain reaction method of telomere length relative to standard reference DNA. Past year major depression (MD), generalized anxiety disorder (GAD) and panic disorder (PD), as well as depressed affect and anxious affect, were assessed using the Composite International Diagnostic Inventory (N=1,290). Multiple linear regression was used to assess the relationship between depression and anxiety disorders and telomere length. Among women, those with GAD or PD had shorter telomeres than those with no anxious affect (β: −0.07, p0.05). Among respondents currently taking an antidepressant, those with MD had shorter telomeres than those without (β: −.26, p.05). Neither depressive nor anxiety disorders were directly associated with telomere length in young adults. There was suggestive evidence that pharmacologically-treated MD is associated with shorter telomere length, likely reflecting the more severe nature of MD that has come to clinical attention.

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.

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

Recent work has linked psychological stress with premature cellular aging as indexed by reduced leukocyte telomere length. The combination of shorter telomeres with high telomerase activity (TA) may be indicative of active cell stress. We hypothesized that older individuals characterized by shorter telomeres with high TA in unstimulated leukocytes would show signs of high allostatic load and low levels of protective psychosocial resources. We studied 333 healthy men and women aged 54-76 y who underwent laboratory testing in which we measured cardiovascular, neuroendocrine, and inflammatory responses to standardized mental stress tasks. The tasks elicited prompt increases in blood pressure (BP), heart rate, cortisol, and mediators of inflammation and reductions in heart rate variability, returning toward baseline levels following stress. However, men having shorter telomeres with high TA showed blunted poststress recovery in systolic BP, heart rate variability, and monocyte chemoattractant protein-1, together with reduced responsivity in diastolic BP, heart rate, and cortisol, in comparison to men with longer telomeres or men with shorter telomeres and low TA. Shorter telomeres with high TA were also associated with reduced social support, lower optimism, higher hostility, and greater early life adversity. These effects were independent of age, socioeconomic status, and body mass index. We did not observe differences among older women. Our findings suggest that active cell stress is associated with impaired physiological stress responses and impoverished psychosocial resources, reflecting an integration of cellular, systemic, and psychological stress processes potentially relevant to health in older men.

Author(s): Rehkopf, David H; Dow, William H; Rosero-Bixby, Luis; Lin, Jue; Epel, Elissa S; Blackburn, Elizabeth H | Abstract: ObjectivesPeripheral blood leukocyte telomere length (LTL) 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 LTL. We examined whether there was monthly variation in LTL in Costa Rica, a country with strong seasonal differences in precipitation and infection.MethodsWe 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. LTL was assayed from these samples using the quantitative PCR method. Multivariate regression models were used to examine correlations between month of blood draw and LTL.ResultsTelomere 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.ConclusionsThere are two possible explanations of our findings. First, there could be relatively rapid month-to-month changes in LTL. 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 LTL use methods to account for the potential impact of constituent cell type.

Background Leukocyte telomere length (LTL) is an indicator of general systemic aging, with shorter LTL being associated with several chronic diseases of aging and earlier mortality. Identifying factors related to LTL among African Americans may yield insights into mechanisms underlying racial disparities in health. Purpose To test whether the combination of more frequent reports of racial discrimination and holding a greater implicit anti-black racial bias is associated with shorter LTL among African-American men. Methods Cross-sectional study of a community sample of 92 African-American men aged between 30 and 50 years. Participants were recruited from February to May 2010. Ordinary least squares regressions were used to examine LTL in kilobase pairs in relation to racial discrimination and implicit racial bias. Data analysis was completed in July 2013. Results After controlling for chronologic age and socioeconomic and health-related characteristics, the interaction between racial discrimination and implicit racial bias was significantly associated with LTL (b=−0.10, SE=0.04, p =0.02). Those demonstrating a stronger implicit anti-black bias and reporting higher levels of racial discrimination had the shortest LTL. Household income-to-poverty threshold ratio was also associated with LTL (b=0.05, SE=0.02, p Conclusions Results suggest that multiple levels of racism, including interpersonal experiences of racial discrimination and the internalization of negative racial bias, operate jointly to accelerate biological aging among African-American men. Societal efforts to address racial discrimination in concert with efforts to promote positive in-group racial attitudes may protect against premature biological aging in this population.

Supplemental Digital Content is available in the text., 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 log2 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.

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.

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.

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.