No abstract

A baseline diagnosis of MDD prospectively predicted LTL shortening over two years. Our results provide further support for MDD as a disease associated with accelerated aging in a well-characterized sample using validated, clinician-rated measures.

Background Telomere length in blood or buccal cell DNA has been associated with risk of various cancers. Glioma can be a highly malignant brain tumor and has few known risk factors. Genetic variants in or near RTEL1 and TERT, key components of telomere biology, are associated with glioma risk. Therefore, we evaluated the association between relative telomere length (RTL) and glioma in a prospective study. Materials and Methods We performed a nested case-control study within the Prostate, Lung, Colorectal, and Ovarian (PLCO) Cancer Screening Trial. RTL was determined by quantitative PCR on blood or buccal cell DNA obtained at least two years prior to diagnosis from 101 individuals with glioma cases. Healthy controls (n=198) were matched to cases (2:1) on age, gender, smoking status, calendar year, and DNA source. Conditional logistic regression was used to investigate the association between RTL and glioma. Results As expected, RTL declined with increasing age in both cases and controls. There was no statistically significant association between RTL and glioma overall. An analysis stratified by gender suggested that short RTL (1st tertile) in males was associated with glioma (odds ratio, [OR] = 2.29, 95% confidence interval [CI] 1.02-5.11); this association was not observed for females (OR=0.41, 95% CI 0.14-1.17). Conclusions This prospective study did not identify significant associations between RTL and glioma risk, but there may be gender-specific differences. Larger, prospective studies are needed to evaluate these findings.

Allogeneic hematopoietic stem cell transplantation is the only potentially curative treatment for patients with myelodysplastic syndrome (MDS), but long-term survival is limited by the risk of transplant-related complications. Short telomere length, mediated by inherited or acquired factors, impairs cellular response to genotoxic and replicative stress and could identify patients at higher risk for toxicity after transplantation. We measured relative telomere length in pre-transplant recipient blood samples in 1514 MDS patients and evaluated the association of telomere length with MDS disease characteristics and transplantation outcomes. Shorter telomere length was significantly associated with older age, male sex, somatic mutations that impair the DNA damage response, and more severe pre-transplant cytopenias, but not with bone marrow blast count, MDS treatment history, or history of prior cancer therapy. Among 1267 patients ≥40 years old, telomere length in the shortest quartile was associated with inferior survival (p<0.001) due to a high risk of non-relapse mortality (p=0.001) after adjusting for significant clinical and genetic variables. The adverse impact of shorter telomeres on NRM was independent of recipient comorbidities and was observed selectively among patients receiving more intensive conditioning, including myeloablative regimens and higher-dose melphalan-based reduced-intensity regimens. The effect of shorter telomeres on NRM was prominent among patients who developed severe acute graft-versus-host disease, suggesting that short telomere length may limit regenerative potential of mucosal tissues after acute injury. MDS patients with shorter telomere length, who have inferior survival driven by excess toxicity, could be considered for strategies focused on minimizing toxic effects of transplantation.

No abstract

Germline pathogenic TERT variants are associated with short telomeres and an increased risk of developing myelodysplastic syndrome (MDS) among patients with a telomere biology disorder. We identified TERT rare variants in 41 of 1514 MDS patients (2.7%) without a clinical diagnosis of a telomere biology disorder who underwent allogeneic transplantation. Patients with a TERT rare variant had shorter telomere length (p<0.001) and younger age at MDS diagnosis (52 vs. 59 years, p=0.03) than patients without a TERT rare variant. In multivariable models, TERT rare variants were associated with inferior overall survival (p=0.034) driven by an increased incidence of non-relapse mortality (NRM) (p=0.015). Death from a non-infectious pulmonary cause was more frequent among patients with a TERT rare variant. The majority of variants were missense substitutions and classified as variants of unknown significance (VUS). Therefore, we cloned all rare missense variants and quantified their impact on telomere elongation in a cell-based assay. We found that 90 percent of TERT rare variants had severe or intermediate impairment in their capacity to elongate telomeres. Using a homology model of human TERT bound to the shelterin protein TPP1, we inferred that TERT rare variants disrupt domain-specific functions, including catalysis, protein-RNA interactions, and recruitment to telomeres. Our results indicate that the contribution of TERT rare variants to MDS pathogenesis and NRM risk is underrecognized. Routine screening for TERT rare variants in MDS patients regardless of age or clinical suspicion may identify clinically inapparent telomere biology disorders and improve transplant outcomes through risk-adapted approaches.

Traumatic stress is thought to be associated with shortened telomere length (TL) in leukocytes, an age-related marker of increased risk for cellular senescence, though findings to date have been mixed. This study assessed associations between PTSD symptom severity, temperament, and TL in a sample of 453 white, non-Hispanic middle-aged, trauma-exposed male and female veterans and civilians. Given prior work suggesting an association between PTSD and accelerated cellular age, we also examined associations between TL and an index of accelerated cellular age derived from DNA methylation data (“DNAm age”). Analyses revealed that, controlling for chronological age, PTSD was not directly associated with TL, but rather, this association was moderated by age (β = −.14, p =.003, Δ R2 = .02). Specifically, PTSD severity evidenced a stronger negative association with TL among relatively older participants (≥ 55 years). In a subset of veterans with data pertaining to temperament (n = 150), positive emotionality, and specifically, a drive towards achievement (β = .26, p = .002, Δ R2 = .06), were positively associated with TL. There was no evidence of an association between age-adjusted TL and accelerated DNAm age. Collectively, these results indicate that older adults may be more vulnerable to the negative health effects of PTSD, but that traits such as achievement, resilience, and psychological hardiness may be protective. Findings underscore the importance of identifying reliable biomarkers of cellular aging and senescence and of determining the biological mechanisms that contribute to stress-related disease and decline.

In conclusion, weight loss increases the mortality risk in frail, disabled NH residents, even if they are overweight or obese.