Interindividual variation in mean leukocyte telomere length (LTL) is associated with cancer and several age-associated diseases. We report here a genome-wide meta-analysis of 37,684 individuals with replication of selected variants in an additional 10,739 individuals. We identified seven loci, including five new loci, associated with mean LTL (P < 5 × 10−8). Five of the loci contain candidate genes (TERC, TERT, NAF1, OBFC1 and RTEL1) that are known to be involved in telomere biology. Lead SNPs at two loci (TERC and TERT) associate with several cancers and other diseases, including idiopathic pulmonary fibrosis. Moreover, a genetic risk score analysis combining lead variants at all 7 loci in 22,233 coronary artery disease cases and 64,762 controls showed an association of the alleles associated with shorter LTL with increased risk of coronary artery disease (21% (95% confidence interval, 5–35%) per standard deviation in LTL, P = 0.014). Our findings support a causal role of telomere-length variation in some age-related diseases.

Identification of seven loci affecting mean telomere length and their association with disease

Objective
Previous research on the physical health consequences of childhood abuse and other adversities has been based on data from young or middle-aged adults. This study addressed the question of whether childhood abuse and other adversities have lasting, detectable consequences for inflammation and cell aging late in life, and whether the effects are large enough to be discernible beyond that of a major chronic stressor, dementia family caregiving.

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Childhood Adversity Heightens the Impact of Later-Life Caregiving Stress on Telomere Length and Inflammation

Background: Depression is associated with an unusually high rate of aging-related illnesses and early mortality. One aspect of ‘‘accelerated aging’’ in depression may be shortened leukocyte telomeres. When telomeres critically shorten, as often occurs with repeated mitoses or in response to oxidation and inflammation, cells may die. Indeed, leukocyte telomere shortening predicts early mortality and medical illnesses in non-depressed populations. We sought to determine if leukocyte telomeres are shortened in Major Depressive Disorder (MDD), whether this is a function of lifetime depression exposure and whether this is related to putative mediators, oxidation and inflammation. Methodology: Leukocyte telomere length was compared between 18 unmedicated MDD subjects and 17 controls and was correlated with lifetime depression chronicity and peripheral markers of oxidation (F2-isoprostane/Vitamin C ratio) and inflammation (IL-6). Analyses were controlled for age and sex. Principal Findings: The depressed group, as a whole, did not differ from the controls in telomere length. However, telomere length was significantly inversely correlated with lifetime depression exposure, even after controlling for age (p,0.05). Average telomere length in the depressed subjects who were above the median of lifetime depression exposure ($9.2 years’ cumulative duration) was 281 base pairs shorter than that in controls (p,0.05), corresponding to approximately seven years of ‘‘accelerated cell aging.’’ Telomere length was inversely correlated with oxidative stress in the depressed subjects (p,0.01) and in the controls (p,0.05) and with inflammation in the depressed subjects (p,0.05). Conclusions: These preliminary data indicate that accelerated aging at the level of leukocyte telomeres is proportional to lifetime exposure to MDD. This might be related to cumulative exposure to oxidative stress and inflammation in MDD. This suggest that telomere shortening does not antedate depression and is not an intrinsic feature. Rather, telomere shortening may progress in proportion to lifetime depression exposure.

/pdf/leukocyte-telomere-length-in-major-depression-correlations-23g5jut2lu.pdf

Leukocyte telomere length in major depression: correlations with chronicity, inflammation and oxidative stress--preliminary findings.

Atrial fibrillation (AF) is associated with significant morbidity and mortality. It is also a progressive disease secondary to continuous structural remodelling of the atria due to AF itself, to changes associated with ageing, and to deterioration of underlying heart disease. Current management aims at preventing the recurrence of AF and its consequences (secondary prevention) and includes risk assessment and prevention of stroke, ventricular rate control, and rhythm control therapies including antiarrhythmic drugs and catheter or surgical ablation. The concept of primary prevention of AF with interventions targeting the development of substrate and modifying risk factors for AF has emerged as a result of recent experiments that suggested novel targets for mechanism-based therapies. Upstream therapy refers to the use of non-antiarrhythmic drugs that modify the atrial substrate- or target-specific mechanisms of AF to prevent the occurrence or recurrence of the arrhythmia. Such agents include angiotensin-converting enzyme inhibitors (ACEIs), angiotensin receptor blockers (ARBs), statins, n-3 (ω-3) polyunsaturated fatty acids, and possibly corticosteroids. Animal experiments have compellingly demonstrated the protective effect of these agents against electrical and structural atrial remodelling in association with AF. The key targets of upstream therapy are structural changes in the atria, such as fibrosis, hypertrophy, inflammation, and oxidative stress, but direct and indirect effects on atrial ion channels, gap junctions, and calcium handling are also applied. Although there have been no formal randomized controlled studies (RCTs) in the primary prevention setting, retrospective analyses and reports from the studies in which AF was a pre-specified secondary endpoint have shown a sustained reduction in new-onset AF with ACEIs and ARBs in patients with significant underlying heart disease (e.g. left ventricular dysfunction and hypertrophy), and in the incidence of AF after cardiac surgery in patients treated with statins. In the secondary prevention setting, the results with upstream therapies are significantly less encouraging. Although the results of hypothesis-generating small clinical studies or retrospective analyses in selected patient categories have been positive, larger prospective RCTs have yielded controversial, mostly negative, results. Notably, the controversy exists on whether upstream therapy may impact mortality and major non-fatal cardiovascular events in patients with AF. This has been addressed in retrospective analyses and large prospective RCTs, but the results remain inconclusive pending further reports. This review provides a contemporary evidence-based insight into the role of upstream therapies in primary (Part I) and secondary (Part II) prevention of AF.

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Upstream therapies for management of atrial fibrillation: review of clinical evidence and implications for European Society of Cardiology guidelines. Part I: primary prevention.

OBJECTIVES\nThis study sought to test the hypothesis that patients with chronic heart failure (CHF) have shorter telomeres compared with age-balanced and gender-balanced healthy individuals.\n\n\nBACKGROUND\nTelomere length is considered to be a marker of biological aging. Chronic heart failure might be viewed as a condition associated with accelerated biological aging.\n\n\nMETHODS\nThe telomere length ratio of leukocytes was determined prospectively by a quantitative polymerase chain reaction-based method in a case-control setting involving 803 participants: 183 healthy individuals and 620 CHF patients, ages 40 to 80 years, New York Heart Association functional class II to IV, and left ventricular ejection fraction of 0.40 or less.\n\n\nRESULTS\nThe median telomere length ratio was 0.64 (interquartile range [IQR] 0.47 to 0.88) in CHF patients compared with 1.05 (IQR 0.86 to 1.29) in control patients (p < 0.001). The telomere length ratio in CHF patients related to severity of disease (median value [IQR] of patients with New York Heart Association class II, III, or IV function was 0.67 [0.48 to 0.92], 0.63 [0.46 to 0.86], and 0.55 [0.46 to 0.75], respectively; p for trend <0.05). In addition, telomeres were shorter in patients with an ischemic compared with a nonischemic etiology of CHF. Patients with none, 1 (coronary, cerebral, or peripheral vascular disease), 2 (any combination of the previous), or 3 atherosclerotic manifestations had a median (IQR) telomere length of 0.72 (0.51 to 1.01), 0.65 (0.48 to 0.87), 0.48 (0.39 to 0.72), and 0.43 (0.27 to 0.67), respectively (p for trend <0.001).\n\n\nCONCLUSIONS\nTelomere length is shorter in patients with CHF compared with age-balanced and gender-balanced control patients, and related to the severity of disease. In addition, telomere length was incrementally shorter according to the presence and extent of atherosclerotic disease manifestations.

Telomere length of circulating leukocytes is decreased in patients with chronic heart failure

ObjectivesHuman age-dependent telomere attrition and telomere shortening are associated with several age-associated diseases and poorer overall survival. The aim of this study was to determine longitudinal leucocyte telomere length dynamics and identify factors associated with temporal changes in telomere length. Design and MethodsLeucocyte telomere length was measured by quantitative polymerase chain reaction in 8074 participants from the Prevention of Renal and Vascular End-stage Disease (PREVEND) study, an ongoing community-based prospective cohort study initiated in 1997. Follow-up data were available at two time-points up to 2007. Leucocyte telomere length was measured, on between one and three separate occasions, in a total of 16783 DNA samples. Multilevel growth models were created to identify the factors that influence leucocyte telomere dynamics. ResultsWe observed an average attrition rate of 0.470.16 relative telomere length units (RTLUs) per year in the study population aged 48 (range 39-60) years at baseline. Annual telomere attrition rate increased with age (P ConclusionsSmoking and variables linked to the metabolic syndrome are modifiable lifestyle factors that accelerate telomere attrition in humans. The higher rate of cellular ageing may mediate the link between smoking and the metabolic syndrome to an increased risk of several age-associated diseases.

https://onlinelibrary.wiley.com/doi/pdf/10.1111/joim.12149

Telomere length loss due to smoking and metabolic traits

Background. Telomeres are causally involved in senescence. Senescence is a potential factor in the pathogenesis and progression of heart failure. In heart failure telomeres are shorter, but the prognostic value associated with telomere length has not been defi ned. Methods. Telomere length was prospectively determined by quantitative polymerase chain reaction in 890 patients with New York Heart Association (NYHA) functional class II to IV heart failure. After 18 months, we examined the association between telomere length and the predefi ned primary end-point: time to death or hospitalization for heart failure. Results. Mean age of the patients was 71 years, 39% were women, 51% were in NYHA class II, and 49% were in class III/IV. A total of 344 patients reached the primary end-point (130 deaths and 214 hospitalizations). Patients with shorter telomeres were at an increased risk of reaching the primary end-point (hazard ratio 1.79; 95% confi dence interval (CI) 1.21–2.63). In multivariate analysis shorter telomere length remained associated with a higher risk for death or hospitalization (hazard ratio, 1.74; 95% CI 1.07–2.95) after adjustment for age of heart failure onset, gender, hemoglobin, renal function, and N-terminal pro-B-type natriuretic peptide level, a history of stroke, atrial fi brillation, and diabetes. Conclusions. Shorter length of telomeres predicts the occurrence of death or hospitalization in patients with chronic heart failure.

https://www.researchgate.net/profile/Rudolf_De_Boer2/publication/232091302_Telomere_length_and_outcome_in_heart_failure/links/5493e5a90cf286fe3126a02a.pdf

Liza S. Wong

Papers

Telomere length loss due to smoking and metabolic traits

Telomere Length and Outcome in Heart Failure

Atherosclerotic plaque telomere length predicts the occurrence of restenosis after carotid endarterectomy

Telomere length is an independent risk factor for anaemia in patients with chronic heart failure