Reduced telomere length variation in healthy oldest old

Telomeres protect against DNA degradation at the ends of linear chromosomes. The number of telomere repeats is reduced over time in human aging. Using flow FISH we have assessed telomere length in 134 exceptionally healthy seniors aged 85 or older who have never been diagnosed with cancer, cardiovascular disease, major pulmonary disease, diabetes or Alzheimer disease (the ‘Super-seniors’) and 47 randomly-ascertained mid-life individuals aged 40-50 years. We compared their telomere lengths to a reference interval based on 400 individuals aged 1-100 years and show that Super-seniors do not have exceptionally long telomeres for their age. Consistent with the known trend of telomere shortening over time; however, they have shorter telomeres than the younger control group.Furthermore, we show that variability in telomere length was lower in the Super-seniors than in the mid-life controls or the reference data. Reduced telomere length variation was observed for lymphocytes, CD45RA-positive T-cells and memory T-cells. These results suggest that individuals, some types of their somatic cells, or both, may be selected for an optimal rather than extreme telomere length. Selection of individuals and/or cells that have an optimal telomere repeat length could contribute to disease resistance and promote healthy aging.     

Attachment and telomere length: more evidence for psychobiological connections between close relationships,health, and aging

Individuals with a history of poor interpersonal relationships are more likely to demonstrate negative health outcomes than those who have had high quality relationships. We sought to evaluate how attachment orientations, stress-induced respiratory sinus arrhythmia (RSA), and self-reported stress were associated with length of telomeres measured from peripheral blood mononuclear cells. Participants (N = 213) completed self-report measures of attachment and stress. Measurement of RSA was conducted before and after a stressful task and a blood draw was completed for analysis of telomere length. Attachment orientations were not directly associated with telomere length; however, we found that high attachment anxiety was associated with shorter length of telomeres via high self-reported stress. Attachment avoidance was also associated with telomere length via self-reported stress, but only among those with high stress-induced RSA. Exploratory analyses of T cell subsets indicated that stress was most strongly associated with telomeres from CD8CD28+ cells in comparison to CD8CD28? and CD4 cells. Study findings indicate that attachment orientations are associated with telomere length via stress, providing novel insights into the mechanisms through which close relationships can impact health and aging.     

No evidence of substantia nigra telomere shortening in Parkinson's disease

Telomeres are repetitive tracts of DNA which protect chromosomal integrity. Increased oxidative stress leads to shorter telomeres, which have been associated with several late-onset human diseases. Given independent evidence of oxidative stress and Parkinson's disease (PD), and conflicting reports of the role of telomere length in PD, we measured telomere length in both PD peripheral blood monocytes and in substantia nigra from affected individuals and controls. We confirmed previous findings of a paradoxically longer telomere length in blood from PD patients, but found no difference in telomere length in substantia nigra. Confounding factors provide a likely explanation for the findings in blood, and possibly the reduced frequency of cigarette smoking in PD patients. We conclude that telomere shortening is unlikely to be involved in the pathogenesis of PD.     

Effects of physical activity in telomere length: Systematic review and meta-analysis

The aim of this systematic review is to assess the effects of exercise on telomeres length. We searched the following databases: MEDLINE, EMBASE, Cochrane Central Register of Controlled Trials (CENTRAL, The Cochrane Library), Scopus, LILACS, SPORTDiscus and Web of Science from inception to August 2014. All articles that assessed the effects of exercise in telomere length were included in this review. The search strategy used the following combinations of terms: telomere AND “motor activity” OR exercise OR “physical activity”. Two reviewers, working independently, screened all titles and abstracts to identify studies that could meet inclusion criteria. Whenever possible, and if appropriate, we performed a random-effect meta-analysis of study outcomes. Thirty-seven original studies were included in this systematic review, including 41,230 participants. Twenty articles did not find statistically significant association, whereas 15 described a positive association. Two papers found an inverted “U” correlation. There is a tendency toward demonstrating an effect of exercise on telomere length. Few prospective studies were found, many studies did not reach statistical significance and there was an important methodological diversity. For this reason, a possible significant association between physical activity and telomere length remains an open question.     

Aging-associated alteration of telomere length and subtelomeric status in female patients with Parkinson's disease

A telomere is a repetitive DNA structure at chromosomal ends that stabilizes the chromosome structure and prevents harmful end-to-end recombinations. The telomere length of somatic cells becomes shorter with aging because of the "end replication problem." This telomere shortening is accelerated by pathophysiological conditions including daily mental stress. Living with Parkinson's disease (PD) causes physical and mental stress; therefore, the authors hypothesized that the telomere length of somatic cells was shortened excessively in patients with PD. In order to detect PD-associated somatic telomeric alterations, the telomere length and subtelomeric methylation status of peripheral leukocytes of PD patients were assessed by Southern blotting, using methylation-sensitive and -insensitive isoschizomers. The results demonstrated that the peripheral leukocytes of Japanese female patients with PD bore fewer long telomeres and a proportional increase of hypomethylated subtelomeres in short telomeres in comparison with the healthy controls. This study indicates that with the neurodegeneration associated with PD, telomeric and subtelomeric structural alterations occur. These structural telomere alterations most likely occur secondary to the acceleration of aging-associated telomeric changes and the accelerated loss of cells bearing short telomeres.     

Aging-Associated Alteration of Telomere Length and Subtelomeric Status in Female Patients With Parkinson's Disease

Abstract: A telomere is a repetitive DNA structure at chromosomal ends that stabilizes the chromosome structure and prevents harmful end-to-end recombinations. The telomere length of somatic cells becomes shorter with aging because of the “end replication problem.” This telomere shortening is accelerated by pathophysiological conditions including daily mental stress. Living with Parkinson's disease (PD) causes physical and mental stress; therefore, the authors hypothesized that the telomere length of somatic cells was shortened excessively in patients with PD. In order to detect PD-associated somatic telomeric alterations, the telomere length and subtelomeric methylation status of peripheral leukocytes of PD patients were assessed by Southern blotting, using methylation-sensitive and -insensitive isoschizomers. The results demonstrated that the peripheral leukocytes of Japanese female patients with PD bore fewer long telomeres and a proportional increase of hypomethylated subtelomeres in short telomeres in comparison with the healthy controls. This study indicates that with the neurodegeneration associated with PD, telomeric and subtelomeric structural alterations occur. These structural telomere altertions most likely occur secondary to the acceleration of aging-associated telomeric changes and the accelerated loss of cells bearing short telomeres.     

Association of kidney function and brain health: A systematic review and meta-analysis of cohort studies

ObjectiveThis study aimed to evaluate the bidirectional association between the kidney dysfunction and the brain health, including structural and functional abnormalities.DesignSystematic review and meta-analysis with network meta-analysis for outcomes with different estimated glomerular filtration rate (eGFR) ranges.Data sourcesPubMed, Embase database, Cochrane library and Web of Science (up to Dec. 2021).Eligibility criteria for selecting studiesLongitudinal studies that provided evidence of the impact of kidney function estimated from eGFR and urine albumin-to-creatinine ratio (UACR) or chronic kidney disease (CKD) on structural and functional brain abnormalities, and those that provided evidence of the opposite relationship. Studies with study population mean age under 18 years old were excluded.Main outcome measuresTwo independent reviewers screened the included studies, extracted the data, and assessed the risk of bias. We performed a random-effects meta-analysis and a network meta-analysis for outcomes with compatible data. We assessed the risk of bias using the Newcastle–Ottawa Quality Assessment Scale criteria (NOS). Subgroup and sensitivity analyses were conducted to explore heterogeneity in the meta-analyses. Inconsistency analyses using the node-splitting method were performed to confirm the results of network meta-analysis.ResultsA total of 53 studies with 3037,357 participants were included in the current systematic review. Among these, 16 provided evidence of structural brain abnormalities, and 38 provided evidence of cognitive impairment and dementia. Analysis of evidence of categorical kidney function showed a positive association between kidney dysfunction and cerebral small vessel disease (cSVD) (relative risk (RR) 1.77, 95% confidence interval (CI) 1.40–2.24, I² = 0.0%), but such results were not found in the analyses of evidence where the kidney function was measured as a continuous variable. Meanwhile, analysis of 28 prior longitudinal studies with 194 compatible sets of data showed that the worse kidney function as categorical variables was related to a greater risk of global brain cognitive disorder (RR 1.28, 95% CI 1.20–1.36, I² = 82.5%).ConclusionsIn this systematic review and meta-analysis, we found a positive association between CKD and functional brain disorders. However, the relationship between the kidney dysfunction and structural abnormalities in the brain remains controversial. As for the opposite relationship, structural brain abnormalities, especially cerebral microbleeds and silent infarction, but not functional brain abnormalities, are associated with worse renal function. In addition, a higher UACR, but not a lower eGFR, was associated with a higher risk of Alzheimer’s disease and vascular dementia.     

Mononuclear Cell Telomere Attrition Is Associated with Overall Survival after Nonmyeloablative Allogeneic Hematopoietic Cell Transplantation for Hematologic Malignancies

After allogeneic hematopoietic cell transplantation (allo-HCT), transplanted cells rapidly undergo multiple rounds of division. This may cause extensive telomere attrition, which could potentially prohibit further cell division and lead to increased mortality. We therefore characterized the development in telomere length after nonmyeloablative allo-HCT in 240 consecutive patients transplanted because of hematologic malignancies and tested the hypothesis that extensive telomere attrition post-transplant is associated with low overall survival. Telomere length was measured using quantitative PCR in mononuclear cells obtained from donors and recipients pretransplant and in follow-up samples from recipients post-transplant. Telomere attrition at 9 to 15 months post-transplant was calculated as the difference between recipient telomere length at 9 to 15 months post-transplant and donor pretransplant telomere length, divided by donor pretransplant telomere length. Although allo-HCT led to shorter mean telomere length in recipients when compared with donors, recipients had longer mean telomere length 9 to 15 months post-transplant than they had pretransplant. When compared with donor telomeres, recipients with extensive telomere attrition at 9 to 15 months post-transplant had low overall survival (10-year survival from 9 to 15 months post-transplant and onward: 68% in the tertile with least telomere attrition, 57% in the middle tertile, and 39% in the tertile with most attrition; log-rank P?=?.01). Similarly, after adjusting for potential confounders, recipients with extensive telomere attrition had high all-cause mortality (multivariable adjusted hazard ratio, 1.84 per standard deviation of telomere attrition at 9 to 15 months post-transplant; 95% confidence interval, 1.25 to 2.72; P?=?.002) and high relapse-related mortality (subhazard ratio, 2.07; 95% confidence interval, 1.14 to 3.76; P?=?.02). Taken together, telomere attrition may be a clinically relevant marker for identifying patients at high risk of mortality.     

Mild cognitive impairment identified in older individuals with down syndrome by reduced telomere signal numbers and shorter telomeres measured in microns

Previously, we established that short-term T lymphocyte cultures from people with Down syndrome (DS) and dementia (Alzheimer's disease) had shorter telomeres than did those from age- and sex-matched people with DS only, quantified as significantly reduced numbers of signals of peptide nucleic acid (PNA) telomere probes in whole metaphases [Jenkins et al. (2008); Neurosci Lett 440:340-343] as well as reduced telomere probe light intensity values in interphases [Jenkins et al. (2010); Neurobiol Aging 31:765-771]. We now describe shorter telomere length in adults with DS and mild cognitive impairment (MCI) compared to age- and sex-matched individuals with DS without MCI. Telomere length is quantified by reduced telomere signal numbers and shorter chromosome 1 telomeres measured in micrometers (microns). These findings were in agreement with quantitative light intensity measurements of chromosome 1 and chromosome 21 PNA telomere probes with and without the use of a "normalizing ratio" involving the fluorescence exhibited by a PNA probe for centromere 2, and with the use of light intensity measurements of interphase preparations. Most importantly, the distributions of chromosome 1 telomere lengths (in microns) were completely non-overlapping for adults with and without MCI, indicating that this measure has great promise as a biomarker for MCI as well as dementia in this population.     

Protection of telomeres 1 protein levels are associated with telomere length in gastric cancer

Protection of telomeres 1 (Pot1) is a telomere-associated protein, which binds to the single-stranded DNA extensions of telomeres and regulates telomere length. Pot1 production was examined and compared with telomere length in gastric cancer. Pot1 production and telomere lengths were assessed in 5 human gastric cancer cell lines by immunoblotting and Southern blotting, respectively. Pot1 intracellular localization was examined with protein fractionation. Pot1 index and telomere volume were examined in human gastric mucosa and cancer by immunohistochemistry and in situ hybridization. Pot1 protein levels, which were lower than those in the lymphocytes of healthy persons, were significantly correlated with telomere length in gastric cancer cells (P=0.0167). Pot1 protein was mainly detected in the nuclear fraction and increased by G2/M blocking with nocodazole in MKN28 cells. Pot1 indexes were correlated with telomere volumes in gastric cancers (P<0.0001). Pot1 index was decreased in gastric epithelia distant from cancer (84+/-14%), in peritumoral epithelia (72+/-24%), and in stage I-II (39+/-14%) and stage III-IV (23+/-14%) gastric cancers (P<0.0001). Pot1 index was lower in stage III-IV than in stage I-II gastric cancers (P<0.05). Pot1-low cases showed advanced cancer invasion (P<0.05). Thus, Pot1 production was closely associated with telomere length in gastric mucosa and cancers. Pot1 might be a good in situ marker for the examination of cell-specific telomere length.     

Shared decision-making and outcomes in type 2 diabetes: A systematic review and meta-analysis

ObjectiveType 2 diabetes is a chronic disease which necessitates the development of a therapeutic alliance between patient and provider. This review systematically examines the association between treatment shared decision-making (SDM) and outcomes in diabetes.MethodsA range of bibliographic databases and gray literature sources was searched. Included studies were subjected to dual data extraction and quality assessment. Outcomes were synthesized using meta-analyses where reporting was sufficiently homogenous or alternatively synthesized in narrative fashion.ResultsThe search retrieved 4592 records, which were screened by title, abstract, and full text to identify 16 studies with a range of study designs and populations. We found evidence of an association between SDM and improved decision quality, patient knowledge and patient risk perception. We found little evidence of an association between SDM and glycemic control, patient satisfaction, quality of life, medication adherence or trust in physician.ConclusionsThis work elucidates the potential clinical utility of SDM interventions in the management of Type 2 Diabetes and helps inform future research on the topic.Practice implicationsA more complete understanding of the associations between SDM and outcomes will guide and motivate efforts aimed at improving uptake of the SDM paradigm.     

Telomerase, senescence and ageing

Telomeres serve to camouflage chromosome ends from the DNA damage response machinery. Telomerase activity is required to maintain telomeres. One consequence of telomere dysfunction is cellular senescence, a permanent growth arrest state. We review the key regulators of cellular senescence and recent in vivo evidence which supports p53-dependent senescence induced by short telomeres as a potent tumor suppressor pathway. The in vivo link between cellular senescence and tumor regression is also discussed. The relationship between short telomere length and ageing or disease states in various cells of the body is increasingly reported. Paradoxically, the introduction of telomerase is proposed as a method to combat ageing via cell therapy and a possible method to regenerate tissue, while telomerase inhibition and telomere shortening is suggested as a possible therapy to defeat cancers with intact p53. Researchers thus face the challenge of understanding the complex processes which regulate the potential benefits of both telomerase inhibition and activation.     

Distinct telomere length regulation in premalignant cervical and endometrial lesions: implications for the roles of telomeres in uterine carcinogenesis

Mouse models show that progressive shortening of telomeres with ageing causes chromosomal instability, which can lead to the initiation of cancer. However, it is unclear what roles telomere shortening plays in human carcinogenesis. The present study has investigated the involvement of telomere dynamics in uterine carcinogenesis. Using telomere-FISH (telo-FISH) assays, telomere lengths in premalignant and malignant cervical and endometrial lesions were measured and compared with chromosomal arm loss or gain. Telo-FISH signals were visualized with Cy3-labelled telomere-specific probes and presented as telomere intensity (TI). Early-stage cervical intraepithelial neoplasias (CINs), especially CIN2, had significantly shorter telomeres than corresponding normal squamous epithelia (p = 0.019), together with increased rates of chromosomal arm loss/gain (p < 0.001). Cervical cancers had relatively short telomeres, but they also showed greater heterogeneity than other sampled tissues, including those with long telomeres. In contrast, there was no significant difference between the telomere length of normal endometrium and of endometrial hyperplasia and endometrial cancer. There was no significant difference in the rate of chromosomal arm loss/gain between normal endometrium and endometrial hyperplasia. These findings suggest that progressive shortening of telomeres occurs in CIN, in association with chromosomal instability, which may play critical roles in cervical carcinogenesis. In contrast, endometrial hyperplasias have relatively stable telomeres without widespread chromosome alteration, implying that endometrial carcinogenesis involves mechanisms distinct from those of cervical carcinogenesis, possibly including microsatellite instability.     

Questioning causal involvement of telomeres in aging

Multiple studies have demonstrated that telomere length predicts mortality and that telomeres shorten with age. Although rarely acknowledged these associations do not dictate causality. I review telomerase knockout and overexpression studies and find little support that telomeres cause aging. In addition, the causality hypothesis assumes that there is a critical telomere length at which senescence is induced. This generates the prediction that variance in telomere length decreases with age. In contrast, using meta-analysis of human data, I find no such decline. Inferring the causal involvement of telomeres in aging from current knowledge is therefore speculative and could hinder scientific progress.     

Telomere shortening and chromosomal instability in myelodysplastic syndromes

Telomere shortening and chromosomal instability are believed to play an important role in the development of myeloid neoplasia. So far, published data are only available on the average telomere length in myelodysplastic syndromes (MDS) and acute myeloid leukemia (AML), but not on the telomere length of individual chromosomes. We used a new technique, telomere/centromere‐fluorescence in situ hybridization (T/C‐FISH), which combines fluorescence R‐banding and FISH using a probe against the telomere repeats to measure the telomere length of each chromosome arm in 78 patients with MDS. In line with the previous results, patients with MDS showed significantly shorter telomeres than those of healthy controls. Telomere lengths did not differ significantly between distinct morphological subtypes of MDS. However, there was a significant difference in telomere length between patients with an isolated monosomy 7 and patients with a normal karyotype (P < 0.05). Notably, patients with an isolated monosomy 7 showed significantly longer telomeres than patients with a normal karyotype in many chromosome arms, among them 7p and 7q. Neo‐telomeres were found in two patients with a complex karyotype, in one case at the fusion site of a dic(14;20). Normal and aberrant metaphases of the same patient did not differ in telomere length, thus indicating to telomere shortening as a basic mechanism affecting all hematopoietic cells in patients with MDS. In some MDS subtypes, like MDS with isolated monosomy 7, telomeres may be stabilized and even increase in length because of the activation of telomerase or alternative mechanisms. © 2009 Wiley‐Liss, Inc.     

Luminal and cancer cells in the breast show more rapid telomere shortening than myoepithelial cells and fibroblasts

Critically shortened, dysfunctional telomeres may play a role in the genetic instabilities commonly found in cancer. We analyzed 30 surgical specimens of invasive breast carcinoma from women aged 34 to 91 years and estimated telomere lengths as telomere-to-centromere ratio values in the 5 different cell types comprising breast tissue in order to clarify telomere length variations within and between individuals using our tissue quantitative fluorescence in situ hybridization method. We obtained 3 novel findings. (1) In corresponding normal tissues, telomere length decreased in the order myoepithelial cells > normal-appearing fibroblasts > luminal epithelial cells, and telomere lengths were characteristic in these 3 cell types within each individual. (2) As expected, cancer cells had significantly shorter telomeres than myoepithelial cells (P < .0001) and normal-appearing fibroblasts (P = .0161), but there was no significant difference in telomere length between luminal cells and cancer cells (P = .6270). (3) Fibroblasts adjacent to cancer had longer telomeres than normal-appearing fibroblasts distant from cancer (P < .0001). This study, which represents the first reported assessment of telomere length variations in the 5 cell types comprising breast tissue within and between individuals, revealed that normal luminal epithelial cells and cancer cells had the shortest telomeres. Our new findings indicate that telomeres of background luminal cells are as short as those of cancer cells. Tissue quantitative fluorescence in situ hybridization, applicable to analysis of individual cells in tissue sections, is considered to be a powerful technique with considerable promise for studies in oncology.     

Reduced telomere length in older men with premutation alleles of the fragile X mental retardation 1 gene

Reduced telomere length has recently been reported in T lymphocytes of individuals with trisomy 21 Down syndrome (DS) and dementia. Shorter telomeres also have been documented in dyskeratosis congenita, cell senescence, Alzheimer disease, and neoplastic transformation. These observations suggest that similar shortening may occur in people with fragile X-associated tremor/ataxia syndrome (FXTAS), which frequently is accompanied by dementia. To test this hypothesis, telomere length has been quantified in T lymphocytes from older male carriers of premutation FMR1 alleles, with or without FXTAS, and FXTAS with dementia. Shorter telomeres (relative to age-matched controls) were observed in 5/5 individuals with FXTAS and dementia, in 2/2 individuals with FXTAS without dementia, and in 3/3 individuals with the fragile X premutation only (P values ranged from <0.001 to <0.05; Student's t-test), indicating that telomere shortening is associated with the premutation expansion of the FMR1 gene. The current study design allowed simultaneous comparisons among control, premutation, FXTAS, and FXTAS with dementia samples, and showed nearly equal degrees of shortening relative to controls among the three premutation sample groups. Thus, telomere shortening may serve as a biomarker for cellular dysregulation that may precede the development of the symptoms of FXTAS.     

Telomere length variation in biliary tract metaplasia, dysplasia, and carcinoma.

Biliary tract carcinoma, including carcinoma of the gallbladder, intrahepatic bile ducts (cholangiocarcinoma), and extrahepatic bile ducts, affects 7500 people in the United States annually, and has an overall 32% 5-year survival rate for disease limited to the mucosa, and a dismal 10% 5-year survival for more advanced disease. The identification of factors involved in the pathogenesis and progression of biliary tract carcinoma is critical for devising effective methods of screening and treatment. Recent evidence suggests that reduction of the length of telomeres, which normally help maintain chromosomal stability, may promote the development and progression of a variety of carcinomas. Using a novel, recently validated telomere fluorescence in situ hybridization method, we examined telomere length in normal and inflamed gallbladder epithelium, metaplasia and dysplasia of the gallbladder, and biliary tract carcinoma to determine whether telomere shortening is associated with neoplastic progression in the biliary tract. Although normal and inflamed gallbladder epithelium demonstrated uniform normal telomere lengths, over half of all metaplastic lesions demonstrated shortened telomeres, supporting prior evidence that metaplastic lesions of the gallbladder are pre-neoplastic. Dysplastic epithelium and invasive carcinomas demonstrated almost universally abnormally short telomeres, indicating that telomere shortening occurs at an early, preinvasive stage of cancer development. In addition, invasive adenocarcinoma of the biliary tract frequently demonstrated intratumoral heterogeneity of telomere lengths. We conclude that telomere shortening is a consistent and early finding in the development of biliary tract carcinoma.