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Shorter telomeres with high telomerase activity are associated with raised allostatic load and impoverished psychosocial resources.

ABSTRACT: 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.

SUBMITTER: Zalli A

PROVIDER: S-EPMC3970484 | biostudies-literature | 2014 Mar

REPOSITORIES: biostudies-literature

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Shorter telomeres with high telomerase activity are associated with raised allostatic load and impoverished psychosocial resources.

Zalli Argita A Carvalho Livia A LA Lin Jue J Hamer Mark M Erusalimsky Jorge D JD Blackburn Elizabeth H EH Steptoe Andrew A

Proceedings of the National Academy of Sciences of the United States of America 20140310 12

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 un ...[more]

PMID: 24616496

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Project description:Telomeres are protein-DNA complexes that protect chromosome ends from illicit ligation and resection. Telomerase is a ribonucleoprotein enzyme that synthesizes telomeric DNA to counter telomere shortening. Human telomeres are composed of complexes between telomeric DNA and a six-protein complex known as shelterin. The shelterin proteins TRF1 and TRF2 provide the binding affinity and specificity for double-stranded telomeric DNA, while the POT1-TPP1 shelterin subcomplex coats the single-stranded telomeric G-rich overhang that is characteristic of all our chromosome ends. By capping chromosome ends, shelterin protects telomeric DNA from unwanted degradation and end-to-end fusion events. Structures of the human shelterin proteins reveal a network of constitutive and context-specific interactions. The shelterin protein-DNA structures reveal the basis for both the high affinity and DNA sequence specificity of these interactions, and explain how shelterin efficiently protects chromosome ends from genome instability. Several protein-protein interactions, many provided by the shelterin component TIN2, are critical for upholding the end-protection function of shelterin. A survey of these protein-protein interfaces within shelterin reveals a series of "domain-peptide" interactions that allow for efficient binding and adaptability towards new functions. While the modular nature of shelterin has facilitated its part-by-part structural characterization, the interdependence of subunits within telomerase has made its structural solution more challenging. However, the exploitation of several homologs in combination with recent advancements in cryo-EM capabilities has led to an exponential increase in our knowledge of the structural biology underlying telomerase function. Telomerase homologs from a wide range of eukaryotes show a typical retroviral reverse transcriptase-like protein core reinforced with elements that deliver telomerase-specific functions including recruitment to telomeres and high telomere-repeat addition processivity. In addition to providing the template for reverse transcription, the RNA component of telomerase provides a scaffold for the catalytic and accessory protein subunits, defines the limits of the telomeric repeat sequence, and plays a critical role in RNP assembly, stability, and trafficking. While a high-resolution definition of the human telomerase structure is only beginning to emerge, the quick pace of technical progress forecasts imminent breakthroughs in this area. Here, we review the structural biology surrounding telomeres and telomerase to provide a molecular description of mammalian chromosome end protection and end replication.

Project description:Background Prevention of hearing loss via addressing potentially modifiable risk factors may offer means of reducing the global burden of hearing loss. Prior studies reported associations between individual markers of inflammation and risk of hearing impairment. Allostatic load is an index of cumulative physiological stressors, including inflammation, to multiple biological systems. Our aims were to investigate associations between allostatic load and both audiometric and self-reported hearing impairment and examine whether associations are stronger over time due to prolonged high allostatic load. Methods Data were taken from the English Longitudinal Study of Ageing (ELSA), a nationally representative study of people aged 50+ living in England over 3 time points between 2008 and 2014. Allostatic load score was comprised of thirteen different measures available at baseline and 4 years post-baseline (high-density lipoprotein/total cholesterol, triglyceride, fibrinogen, haemoglobin A1c, C-reactive protein, insulin-like growth factor 1 (IGF-1), systolic and diastolic blood pressure, mean arterial pressure, resting pulse rate, peak expiratory flow, BMI and waist circumference), measured using clinical cut-off points for normal biomarker parameters. Hearing acuity was measured with a simple handheld tone-producing device at follow-up 7 years post-baseline, while self-reported hearing impairment was measured at time point. Results We included samples of 4373 and 4430 for the cross-sectional and longitudinal analysis, respectively. In the cross-sectional model high allostatic load was associated both self-reported (OR = 1.08, 95% CI 1.0,1.1; p < 0.01) and objective hearing loss (OR = 1.10, 95% CI 1.1,1.2; p < 0.001) adjusting for age and sex. Cross-sectional associations between allostatic load and hearing were not significant after further adjustment for covariates (qualification, physical activity and smoking). In longitudinal modelling, high allostatic load was associated with both audiometric (Z score OR = 1.11, 95% CI 1.1,1.2; p < 0.001) and self-reported hearing impairment (OR = 1.08, 95% CI 1.0,1.1; p < 0.001) adjusting for age and sex. Allostatic load was no longer associated with self-reported hearing loss but the association with audiometric hearing impairment (OR = 1.08, 95% CI 1.03,1.13; p < 0.001) remained following additional adjustment for baseline self-reported hearing, education, physical activity, and smoking. Conclusions Prolonged high allostatic load was associated with risk of hearing impairment. Reducing allostatic load via healthy lifestyle changes including non-smoking, healthy diet and exercise may offer an opportunity to reduce the risk of hearing impairment in later life. Highlights • Allostatic load captures cumulative physiological stress which has consequence for subsequent hearing function.• Prolonged high allostatic load was associated with risk of objectively measured hearing impairment.• This association is shown in nationally representative longitudinal ageing study.

Project description:Allostatic load is commonly operationalized using a sum-score of high-risk biomarkers. However, this method implies that biomarkers contribute equally to allostatic load, as each is given equal weight. Our goal in this methodological paper is to evaluate this, and complementarily, to identify biomarkers that are most informative and least informative for developing an allostatic load index. Item response theory models provide an alternate approach to calculating the allostatic load score, by treating individual biomarkers (e.g. “items”) as indicators of a latent allostatic load construct. Item response theory scores account for the data-driven discriminating power of each biomarker, and an individual’s pattern of biomarker responses. To demonstrate feasibility of this approach, we used data from the 2015–2016 National Health Examination and Nutrition Survey (NHANES; N = 3751), with twelve allostatic load biomarkers representing immune response, metabolic function and cardiovascular health. Item response theory models revealed that body-mass-index and C-reactive protein were the most informative biomarkers for allostatic load. Both higher allostatic load sum-score and allostatic load item response theory score were associated with lower socio-economic status (p = 0.008; p<0.001, respectively). Further, both formulations of allostatic load were positively associated with a nine-item depression screener (p<0.001 for both), but only the item response theory score was also positively associated with the impact of depressive symptoms on daily life (p = 0.045). Item response theory scores may be more finely tuned to tease out effects, compared to sum-scores, and also provide more flexibility when there are missing biomarker measurements. Supplemental R code for our approach are included. Highlights • Methodological paper to introduce item response theory for calculating allostatic load.• Biomarker data from NHANES 2015–2016 representative of United States adults.• Body-mass-index and C-reactive protein most informative for allostatic load.• Item response theory captures more variability in allostatic load compared to sum-scores.• Future work - item response theory can standardize allostatic load across datasets.

Dataset Information

Shorter telomeres with high telomerase activity are associated with raised allostatic load and impoverished psychosocial resources.

Publications

Shorter telomeres with high telomerase activity are associated with raised allostatic load and impoverished psychosocial resources.

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