senescence

Human mesenchymal stem cells (hMSCs) are multipotent non-hematopoietic precursor cells with the ability to differentiate into several tissue types. The use of hMSCs has gained significant importance in cancer therapies as well as a large number of degenerative disease therapies due to their homing abilities. However, these cells may undergo spontaneous transformation leading to them bypassing naturally built-in cell controls that could lead to senescence and carcinogenesis. Therefore, although...

Aging is associated with the onset of several diseases in various organ systems; however, different tissues may age differently, rendering some of them dysfunctional sooner than others. Placental membranes (fetal amniochorionic membranes) protect the fetus throughout pregnancy, but their longevity is limited to the duration of pregnancy. The age-associated dysfunction of these membranes is postulated to trigger parturition. Here, we investigated whether cellular senescence-the loss of cell...

In both biomedicine in general and biomedical gerontology in particular, cell replacement therapy is traditionally proposed as an intervention for cell loss. This article presents a proposed intervention-whole-body induced cell turnover (WICT)-for use in biomedical gerontology that combines cell replacement therapy with a second therapeutic component (targeted cell ablation) so as to broaden the therapeutic utility of cell therapies and increase the categories of age-related damage that are...

Cell senescence is dependent on the arrest in cell cycle. Here we studied the role of mitochondrial retrograde response signaling in yeast cell survival under a prolonged arrest. We have found that, unlike G1, long-term arrest in mitosis or S phase results in a loss of colony-forming abilities. Consistent with previous observations, loss of mitochondrial DNA significantly increased the survival of arrested cells. We found that this was because the loss increases the duration of G1 phase....

Insomnia, particularly in later life, may raise the risk for chronic diseases of aging and mortality through its effect on cellular aging. The current study examines the effects of insomnia on telomere length, a measure of cellular aging, and tests whether insomnia interacts with chronological age to increase cellular aging....

Declining health in the oldest-old takes an energy toll for the simple maintenance of body functions. The underlying mechanisms, however, differ in males and females. In females, the declines are explained by loss of muscle mass; but this is not the case in males, in whom they are associated with increased levels of circulating creatine kinase. This relationship raises the possibility that muscle damage rather than muscle loss is the cause of the increased energy demands of unhealthy aging in...

The epigenetic clock, in particular epigenetic pre-aging quantified by the so-called DNA methylation age acceleration, has recently been suggested to closely correlate with a variety of disease phenotypes. There remains a dearth of data, however, on its association with telomere length and frailty, which can be considered major correlates of age on the genomic and clinical level, respectively....

Telomeres are tandem repeat DNA sequences located at distal ends of chromosomes that protect against genomic DNA degradation and chromosomal instability. Excessive telomere shortening leads to cellular senescence and for this reason telomere length is a marker of biological age. Abnormally short telomeres may culminate in the manifestation of a number of cardio-metabolic diseases. Age-related cardio-metabolic diseases attributable to an inactive lifestyle, such as obesity, type 2 diabetes...

Histone variants and histone modifications are essential components in the establishment and maintenance of the repressed status of heterochromatin. Among these histone variants and modifications, acetylation at histone H4K16 is uniquely important for the maintenance of silencing at telomere and mating type loci but not at the ribosomal DNA locus. Here we show that mutations at H3 N-terminal acetylation site K14 specifically disrupt rDNA silencing. However, the mutant ion at H3K14R doesn't...

We prospectively examined the relation of relative telomere lengths (RTLs), a marker of biological aging, to phobic anxiety in later-life. RTLs in peripheral blood leukocytes were measured among 3194 women in the Nurses' Health Study who provided blood samples in 1989/90. The Crown-Crisp Phobic Index (CCI, range=0–16) was assessed in 1988 and 2004. Only participants with CCI≤3 (consistent with no meaningful anxiety symptoms) in 1988 were included. We related baseline RTLs to odds ratios...

Telomere uncapping is thought to be the fundamental cause of replicative cellular senescence, but the cellular machineries mediating this process have not been fully understood. In the present study, we present the role of Sp1 transcription factor in the state of telomere uncapping using the TRF2(ΔBΔM)-induced senescence model in human diploid fibroblasts. We observed that the expression of Sp1 is down-regulated in the TRF2(ΔBΔM)-induced senescence, which was mediated by ATM and p38 MAPK. In...

In a graying world, there is an increasing interest in correlates of aging, especially those found in early life. Leukocyte telomere length (LTL) is an emerging marker of aging at the cellular level, but little is known regarding its link with poor decision making that often entails being overly impatient. Here we investigate the relationship between LTL and the degree of impatience, which is measured in the laboratory using an incentivized delay discounting task. In a sample of 1,158 Han...

Telomere length shortening is modulated not only by aging, but also by both genetic and environmental factors. The aim of this study was to investigate the interactions between antioxidant nutrient metabolism-related gene single nucleotide polymorphisms (the genetic factors) and nutrient intake (the environmental factors) in their effects on telomere length shortening....

Telomerase is a ribonucleoprotein enzyme which is required for the maintenance of telomere repeats. Although overexpression of telomerase in normal human somatic cells is sufficient to overcome replicative senescence, the ability of telomerase to promote tumorigenesis requires additional activities that are independent of its role in telomere extension. Here we identify NOL1 (proliferation-associated nucleolar antigen 120) as a TERC-binding protein, which is found in association with...

Interference with telomerase and telomere maintenance is emerging as an attractive target for anticancer therapies. Ligand-induced stabilization of G-quadruplex formation by the telomeric DNA 3'-overhang inhibits telomerase from catalyzing telomeric DNA synthesis and from capping telomeric ends, making these ligands good candidates for chemotherapeutic purposes. BRACO-19 is one of the most effective and specific ligand for telomeric G4. It is shown here that BRACO-19 suppresses proliferation and...

Senescence has been hypothesized to arise in part from age-related declines in immune performance, but the patterns and drivers of within-individual age-related changes in immunity remain virtually unexplored in natural populations. Here, using a long-term epidemiological study of wild European badgers (Meles meles), we (i) present evidence of a within-individual age-related decline in the response of a key immune-signalling cytokine, interferon-gamma (IFNγ), to ex vivo lymphocyte stimulation,...

Naturally occurring telomerase reverse transcriptase (TERT) isoforms may regulate telomerase activity, and possibly function independently of telomeres to modulate embryonic stem (ES) cell self-renewal and differentiation....

The cellular senescence definition comes to the fact of cells irreversible proliferation disability. Besides the cell cycle arrest, senescent cells go through some morphological, biochemical, and functional changes which are the signs of cellular senescence. The senescent cells (including replicative senescence and stress-induced premature senescence) of all the tissues look alike. They are metabolically active and possess the set of characteristics in vitro and in vivo, which are known as...

Stem cells are endowed with the awesome power of self-renewal and multi-lineage differentiation that allows them to be major contributors to tissue homeostasis. Owing to their longevity and self-renewal capacity, they are also faced with a higher risk of genomic damage compared to differentiated cells. Damage on the genome, if not prevented or repaired properly, will threaten the survival of stem cells and culminate in organ failure, premature aging, or cancer formation. It is therefore of...

The aging process is accompanied by an accumulation of cellular damage, which compromises the viability and function of cells and tissues. We aim to further explore the association between in vitro DNA damage markers and the chronological age of the donor, as well as long-lived family membership and presence of cardiovascular diseases. Therefore, numbers of 53BP1 foci, telomere-associated foci (TAF) and micronuclei were measured in cultured dermal fibroblasts obtained from three age groups of...

Telomere shortening occurs when cells divide, both in vitro and in vivo. On the other hand, telomerase is able to maintain telomere length in cells by adding TTAGGG repeats to the ends of telomeres. However, the interrelationships existing among telomere length, telomerase activity and growth in vertebrates remain to be clarified. In the present study we measured telomere length (terminal restriction fragment length), telomerase activity and body growth of Oryzias latipes from the embryo stage...

Leukocyte telomere length (LTL) is considered one of the most predictive markers of biological aging. The aim of this study was to identify novel pathways regulating LTL using a metabolomics approach. To this end, we tested associations between 280 blood metabolites and LTL in 3511 females from TwinsUK and replicated our results in the KORA cohort. We furthermore tested significant metabolites for associations with several aging-related phenotypes, gene expression markers and epigenetic markers...

Cellular senescence is the state of permanent proliferation cessation. There are two types of cell senescence. One is replicative senescence, which relies on telomere length-dependent limit of cell divisions. The second is stress-induced premature senescence (SIPS) which is telomere- independent. Cell senescence is a barrier to cancer. Paradoxically senescent cells, which are metabolically active secrete factors which can be procancerogenic. The main culprit of cell senescence is DNA damage and...

Normal human stem cells rely on low levels of active telomerase to sustain their high replicative requirements. Deficiency in telomere maintenance mechanisms leads to the development of premature aging diseases, such as dyskeratosis congenita (DC) and aplastic anemia (AA). Mutations in the unique insertion in fingers domain (IFD) in the human telomerase catalytic subunit (hTERT) have previously been identified and shown to be associated with DC and AA. However, little is known about the...

Dyskeratosis congenita (DKC) is associated with impaired telomere maintenance and with clinical features of premature aging. In this study, we analysed global DNA methylation (DNAm) profiles of DKC patients. Age-associated DNAm changes were not generally accelerated in DKC, but there were significant differences to DNAm patterns of healthy controls, particularly in CpG sites related to an internal promoter region of PR domain containing 8 (PRDM8). Notably, the same genomic region was also...

Nutrition and lifestyle, known to modulate aging process and age-related diseases, might also affect telomerase activity. Short and dysfunctional telomeres rather than average telomere length are associated with longevity in animal models, and their rescue by telomerase maybe sufficient to restore cell and organismal viability. Improving telomerase activation in stem cells and potentially in other cells by diet and lifestyle interventions may represent an intriguing way to promote health-span in...

Senescence was originally identified by the finite lifespan of normal cells that is a consequence of telomere shortening with each cycle of DNA replication. Cells undergoing replicative senescence display pronounced morphological and biochemical changes such as flattening and/or enlargement, increases in p21(WAF1) and/or p16(INK4A), a senescence-associated secretory phenotype, and often senescence-associated heterochromatic foci. Senescence also occurs in tumor cells in response to various forms...

NAD(+) levels are markedly reduced when blood alcohol levels are high during binge drinking. This causes liver injury to occur because the enzymes that require NAD(+) as a cofactor such as the sirtuin de-acetylases cannot de-acetylate acetylated proteins such as acetylated histones. This prevents the epigenetic changes that regulate metabolic processes and which prevent organ injury such as fatty liver in response to alcohol abuse. Hyper acetylation of numerous regulatory proteins develops....

Telomere length has been proposed as a biomarker of biological aging. This study examined the relationship between body weight status and telomere length in U.S. middle-aged and older adults....

A confounding aspect of biological ageing is the nature and role of senescent cells. It is unclear whether the three major types of cellular senescence, namely replicative senescence, oncogene-induced senescence and DNA damage-induced senescence are descriptions of the same phenomenon instigated by different sources, or if each of these is distinct, and how they are associated with ageing. Recently, we devised an epigenetic clock with unprecedented accuracy and precision based on very specific...

Caloric restrictive feeding prolongs the lifespan of a variety of model organisms like rodents and invertebrates. It has been shown that caloric restriction reduces age-related as well as overall-mortality, reduces oxidative stress and influences DNA repair ability positively. There are numerous studies underlining this, but fewer studies involving humans exist. To contribute to a better understanding of the correlation of calorie reduction and DNA repair in humans, we adapted the host cell...

In this paper we present cellular senescence as the ultimate driver of the aging process, as a "causal nexus" that bridges microscopic subcellular damage with the phenotypic, macroscopic effect of aging. It is important to understand how the various types of subcellular damage correlated with the aging process lead to the larger, visible effects of anatomical aging. While it has always been assumed that subcellular damage (cause) results in macroscopic aging (effect), the bridging link between...

Telomeres are the terminal part of the chromosome containing a long repetitive and non-codifying sequence that has as function protecting the chromosomes. In normal cells, telomeres lost part of such repetitive sequence in each mitosis, until telomeres reach a critical point, triggering at that time senescence and cell death. However, in most of tumor cells in each cell division a part of the telomere is lost, however the appearance of an enzyme called telomerase synthetize the segment that just...

Short leukocyte telomere length (TL) and accelerated telomere attrition have been associated with various deleterious health outcomes, although their determinants have not been explored collectively in a large-scale study....

Cellular senescence is a multifactorial phenomenon of growth arrest and distorted function, which has been recognized as an important feature during tumor suppression mechanisms and a contributor to aging. Senescent cells have an altered secretion pattern called Senescence-Associated Secretory Phenotype (SASP) that comprises a complex mix of factors including cytokines, growth factors, chemokines, and matrix metalloproteinases. SASP has been related with local inflammation that leads to cellular...

Cellular senescence is a complex stress response that leads to an irreversible state of cell growth arrest. Senescence may be induced by different stimuli such as telomere shortening, DNA damage or oncogenic insult among others. Senescent cells are metabolically highly active producing a wealth of cytokines and chemokines that depending on the context may have a beneficial or deleterious impact on the organism. Senescence is considered a tightly regulated stress response that is largely governed...

Studies indicate that exercise might delay human biological aging, but the effects of long-term exercise on T cell function are not well known. We tested the hypothesis that moderate or intense exercise lifestyle may attenuate the effects of aging on the telomere length and the survival and composition of T cell subpopulations. Elderly (65-85 years) with intense training lifestyle (IT, n = 15), moderate training lifestyle (MT, n = 16), and who never trained (NT, n = 15) were...

Dyskeratosis Congenita (DC) is an inherited multisystem premature aging disorder with characteristic skin and mucosal findings as well as a predisposition to cancer and bone marrow failure. DC arises due to gene mutations associated with the telomerase complex or telomere maintenance, resulting in critically shortened telomeres. The pathogenesis of DC, as well as several congenital bone marrow failure (BMF) syndromes, converges on the DNA damage response (DDR) pathway and subsequent elevation of...

Glioblastomas are resistant to many kinds of treatment, including chemotherapy, radiation and other adjuvant therapies. As2O3 reportedly induces ROS generation in cells, suggesting it may be able to induce telomerase suppression and telomere dysfunction in glioblastoma cells. We show here that As2O3 induces ROS generation as well as telomerase phosphorylation in U87, U251, SHG4 and C6 glioma cells. It also induces translocation of telomerase from the nucleus to the cytoplasm, thereby decreasing...

Longer telomeres in the somatic cells of an individual have been regarded as a marker of youth and biological fitness within a population. Yet, several research groups have reported the surprising findings of longer telomeres in the germ cells of older men, which translated into longer leukocyte telomere length in their offspring. Although all these studies were purely cross-sectional, a longitudinal trend in the aging testes of individual males was taken for granted. Recently, a high-profile...

Accelerated telomere shortening is associated with stress-related cell damage and aging. Patients with depression have been shown to have shortened life expectancy and to be associated with multiple age-related systemic diseases. Previous studies have examined leukocyte telomere length (LTL) in patients with depression, but have shown inconsistent results....

Senescence stimuli activate multiple tumor suppressor pathways to initiate cycle arrest and a differentiation program characteristic of senescent cells. We performed a two-stage, gain-of-function screen to select for the genes whose enhanced expression can bypass replicative senescence. We uncovered multiple genes known to be involved in p53 and Rb regulation and ATM regulation, two components of the CST (CTC1-STN1-TEN1) complex involved in preventing telomere erosion, and genes such as REST and...

Homeostatic mechanisms to maintain the T cell compartment diversity indicate an ongoing process of thymic activity and peripheral T cell renewal during human life. These processes are expected to be accelerated after childhood thymectomy and by the influence of cytomegalovirus (CMV) inducing a prematurely aged immune system. The study aimed to investigate proportional changes and replicative history of CD8+ T cells, of recent thymic emigrants (RTEs) and CD103+ T cells (mostly gut-experienced)...

Human genetic disorders and transgenic mouse models have shown that mitochondrial DNA (mtDNA) mutations and telomere dysfunction instigate the aging process. Epidemiologically, exercise is associated with greater life expectancy and reduced risk of chronic diseases. While the beneficial effects of exercise are well established, the molecular mechanisms instigating these observations remain unclear....

Body mass index (BMI), bone mineral density (BMD), and telomere length are phenotypes that modulate the course of aging. Over 40% of their phenotypic variance is determined by genetics. Genome-wide association studies (GWAS) have recently uncovered >100 independent single-nucleotide polymorphisms (SNPs) showing genome-wide significant (p < 5 × 10-8) association with these traits....

Aging is a multifactorial and tissue-specific process involving diverse alterations regarded as the "hallmarks of aging", which include genomic instability, telomere attrition, epigenetic alterations, loss of proteostasis, deregulated nutrient sensing, mitochondrial dysfunction, cellular senescence, stem cell exhaustion and altered intracellular communication. Virtually all these hallmarks are targeted by dietary olive oil, particularly by virgin olive oil, since many of its beneficial effects...

The length of the chromosome ends, telomeres, is widely accepted as a biomarker of aging. However, the dynamic of the relationship between telomere length and hematopoietic parameters in the normal aging process, which is of particular interest with respect to age-related anemia, is not well understood....

Folate, vitamin B12, and homocysteine (HCY) are involved in the metabolism of nucleic acid precursors and it has been hypothesized that they also influence telomere length, a biomarker of aging. However, previous studies have reported inconsistent findings, and data for older adults are limited. Our study aimed to evaluate associations between leukocyte telomere length (LTL) and serum folate, vitamin B12, and HCY levels among adults aged 55 years and over. In a cross-sectional study in 798 men...

Telomere attrition and corresponding cellular senescence of the retinal pigment epithelium contribute to the changes of age-related macular degeneration. Activation of the enzyme telomerase can add telomeric DNA to retinal pigment epithelium chromosomal ends and has been proposed as a treatment for age-related macular degeneration. We report the use of a small molecule, oral telomerase activator (TA)-65 in early macular degeneration. This study, focusing on early macular degeneration, provides a...

Cancer cells overcome replicative senescence by exploiting mechanisms of telomere elongation, a process often accomplished by reactivation of the enzyme telomerase. However, a subset of cancer cells lack telomerase activity and rely on the alternative lengthening of telomeres (ALT) pathway, a recombination-based mechanism of telomere elongation. Although the mechanisms regulating ALT are not fully defined, chronic replication stress at telomeres might prime these fragile regions for...

Telomere length is a biomarker for aging. It is known that oxidative stress can accelerate telomere shortening, whereas antioxidants can delay their shortening. Carotenoids as antioxidants are favorably associated with health- and aging-related diseases caused by oxidative stress, but their association with telomere length is less certain. We investigated the association between blood carotenoid levels and leukocyte telomere length in a representative sample of US adults....

Age induces a progressive decline in functional reserve and impacts cancer treatments. Telomere attrition leads to tissue senescence. We tested the hypothesis that telomere length (TL) could predict patient vulnerability and outcome with cancer treatment....

Stress has been associated with biological aging and numerous age-related diseases. This may be due, in part, to accelerated shortening of telomeres, which are critical genomic structures that cap and protect chromosomal ends. Dysfunction of the hypothalamic-pituitary-adrenal axis may indirectly contribute to telomere shortening if an animal reacts too strongly or weakly to a stressor, leading to accelerated biological aging. In this study, outbred Rideau-Arcott sheep were stress challenged with...

Telomerase is a ribonucleoprotein that maintains the ends of linear chromosomes in most eukaryotes. Loss of telomerase activity results in shortening of telomeric DNA and eventually a specific G2/M cell-cycle arrest known as senescence. In humans, telomere shortening occurs during aging, while inappropriate activation of telomerase is associated with approximately 90% of cancers. Previous studies have identified several classes of noncoding RNAs (ncRNA) also associated with aging-related...

Authors: Stella S. Hurtley, Leslie L. Roberts, L Bryan LB. Ray, Beverly A BA. Purnell, Caroline C. Ash Published: 01/20/2016, Science (New York, N.Y.) PubMed Full Text...

Telomeres are the protective end-complexes at the termini of eukaryotic chromosomes. Telomere attrition can lead to potentially maladaptive cellular changes, block cell division, and interfere with tissue replenishment. Recent advances in the understanding of human disease processes have clarified the roles of telomere biology, especially in diseases of human aging and in some aging-related processes. Greater overall telomere attrition predicts mortality and aging-related diseases in inherited...

Telomeres shorten with each cell division and telomere dysfunction is a recognized hallmark of aging. Tissue proliferation is expected to dictate the rate at which telomeres shorten. We set out to test whether proliferative tissues age faster than non-proliferative due to telomere shortening during zebrafish aging. We performed a prospective study linking telomere length to tissue pathology and disease. Contrary to expectations, we show that telomeres shorten to critical lengths only in specific...

Authors: Emily E. Underwood Published: 01/20/2016, Science (New York, N.Y.) PubMed Full Text...

Higher vitamin D status, lower adiposity, and longer telomere length are each reportedly associated with lower risk of several chronic diseases and all-cause mortality. However, direct relationships between vitamin D status (measured by circulating 25-hydroxyvitamin D (25(OH)D) concentration), adiposity, and telomere length are not well established. We conducted a cross-sectional analysis of associations of 25(OH)D and body mass index (BMI; weight (kg)/height (m)(2)) with mean relative leukocyte...

Ageing is the inevitable time-dependent decline in physiological organ function that eventually leads to death. Age is a major risk factor for many of the most common medical conditions, such as cardiovascular disease, cancer, diabetes and Alzheimer's disease. This study reviews currently known hallmarks of ageing and their clinical implications....

Social support is associated with better health but it is unknown whether the health advantages of social support depend on the support source. Using a probability sample of older U.S. adults (n=1430) we compared leukocyte telomere length, a biomarker of cellular aging, between married adults whose support sources either did or did not include their spouse. Despite having social support from other sources, participants who lacked spousal support had shorter telomeres relative to those with...

Breast cancer is the most common malignant disease in women, but some basic questions remain in breast cancer biology. To answer these, several cell models were developed. Recently, the use of improved cell-culture conditions has enabled the development of a new primary cell model with certain luminal characteristics. This model is relevant because, after the introduction of a specific set of genetic elements, the transformed cells yielded tumors resembling human adenocarcinomas in mice. The use...

Previous research demonstrates that physical activity participation is associated with longer leukocyte telomere length, with shorter leukocyte telomere length being a hallmark characteristic of cellular aging. What remains under-investigated, however, is whether there is a mode-specific association of physical activity on leukocyte telomere length, which was this study's purpose....

Knowledge of the biology of cellular senescence has improved markedly in recent years, helping us to understand the aging process. It is now clear that cellular senescence is involved in the pathogenesis of many age-related diseases, including respiratory diseases such as chronic obstructive pulmonary disease (COPD). COPD occupies a special place among chronic respiratory diseases because of its frequency and socio-economic impact. The high morbidity and mortality associated with COPD are...

Telomere integrity is essential to maintain genome stability, and telomeric dysfunctions are associated with cancer and aging pathologies. In human, the shelterin complex binds TTAGGG DNA repeats and provides capping to chromosome ends. Within shelterin, RAP1 is recruited through its interaction with TRF2, and TRF2 is required for telomere protection through a network of nucleic acid and protein interactions. RAP1 is one of the most conserved shelterin proteins although one unresolved question...

Chronic cardiotoxicity is less common in male than in female patients receiving doxorubicin and other anthracyclines at puberty and adolescence. We hypothesized that this sex difference might be secondary to distinct activities of sex hormones on cardiomyocyte senescence, which is thought to be central to the development of long-term anthracycline cardiomyopathy....

An altered prenatal environment during maternal obesity predisposes offspring to insulin resistance, obesity, and their consequent comorbidities, type 2 diabetes and cardiovascular disease. Telomere shortening and frailty are additional risk factors for these conditions. The aim of this study was to evaluate the effects of resistance training on hepatic metabolism and ectopic fat accumulation. Thirty-five frail elderly women, whose mothers' body mass index (BMI) was known, participated in a 4-mo...

The shelterin proteins protect telomeres against activation of the DNA damage checkpoints and recombinational repair. We show here that a dimer of the shelterin subunit TRF2 wraps ∼90 bp of DNA through several lysine and arginine residues localized around its homodimerization domain. The expression of a wrapping-deficient TRF2 mutant, named Top-less, alters telomeric DNA topology, decreases the number of terminal loops (t-loops), and triggers the ATM checkpoint, while still protecting...

Accelerated aging has been proposed as a pathologic mechanism of various chronic diseases, including COPD. This concept has almost exclusively been approached by analyses of individual markers. We investigated whether COPD is associated with accelerated aging using a panel of markers representing various interconnected aspects of the aging process....

Life history theory (LHT) predicts a trade-off between reproductive effort and the pace of biological aging. Energy invested in reproduction is not available for tissue maintenance, thus having more offspring is expected to lead to accelerated senescence. Studies conducted in a variety of non-human species are consistent with this LHT prediction. Here we investigate the relationship between the number of surviving children born to a woman and telomere length (TL, a marker of cellular aging) over...

Anxiety disorders (AnxDs) are highly prevalent throughout the lifespan, with detrimental effects on daily-life functioning, somatic health, and quality of life. An emerging perspective suggested that AnxDs may be associated with accelerated aging. In this paper, we explored the association between AnxDs and hallmarks of accelerated aging, with a specific focus on neuroprogression. We reviewed animal and human findings that suggest an overlap between processes of impaired neurogenesis,...

Telomere length (TL) is an indicator of cellular aging associated with longevity and psychosocial stress. We examine here the relationship between religious involvement and TL in 251 stressed female family caregivers recruited into a 2-site study. Religious involvement, perceived stress, caregiver burden, depressive symptoms, and social support were measured and correlated with TL in whole blood leukocytes. Results indicated a U-shaped relationship between religiosity and TL. Those scoring in...

Telomere maintenance, achieved by the binding of protective shelterin capping proteins to telomeres and by either telomerase or a recombination-based alternative lengthening of telomere (ALT) mechanism, is critical for cell proliferation and survival. Extensive telomere shortening or loss of telomere integrity activates DNA damage checkpoints, leading to cell senescence or death. Although telomerase upregulation is an attractive target for anti-cancer therapy, the lag associated with telomere...

The nucleolus is the most prominent nuclear substructure assigned to produce ribosomes; molecular machines that are responsible for carrying out protein synthesis. To meet the increased demand for proteins during cell growth and proliferation the cell must increase protein synthetic capacity by upregulating ribosome biogenesis. While larger nucleolar size and number have been recognized as hallmark features of many tumor types, recent evidence has suggested that, in addition to overproduction of...

Data on the association between snoring and telomere length, an indicator of biological aging, are very limited. Moreover, no polysomnography (PSG) studies on this association in a general population have been conducted. Our study aimed to evaluate the association between snoring and leukocyte telomere length (LTL) using PSG and a questionnaire....

Werner syndrome (WS) is a progeroid or premature aging syndrome characterized by early onset of age-related pathologies and cancer. The average life expectancy of affected people is 52.8 years and tends to increase. The major causes of death are malignancy and myocardial infarction. Increased telomere attrition and decay are thought to play a causative role in the clinical and pathological manifestations of the disease. Although telomere length, with or without germline mutation, is known to be...

Age-related progressive loss of muscle mass is an increasing problem in our aging society, affecting physical ability, risk of falls, and need for health care. Telomere length has been recognized as a marker of biological age on the population level. The relation between muscle mass in advanced age and telomere length, however, has rarely been examined....

Mesenchymal stem cells (MSCs) are a source of adult multipotent cells important in tissue regeneration. Murine MSCs are known to proliferate poorly in vitro under normoxia. The aim of this study is to analyze the interaction of nonphysiological high oxygen and low-dose γ-irradiation onto growth, senescence, and DNA damage. Tri-potent bone marrow-derived MSCs from p53 wildtype and p53-/- mice were cultured under either 21% or 2% O2. Long-term observations revealed a decreasing ability of...

The telomerase is responsible for adding telomeric repeats to chromosomal ends and consists of the reverse transcriptase TERT and the RNA subunit TERC. The expression and activity of the telomerase are tightly regulated, and aberrant activation of the telomerase has been observed in >85% of human cancers. To better understand telomerase regulation, we performed immunoprecipitations coupled with mass spectrometry (IP-MS) and identified cold inducible RNA-binding protein (CIRP or hnRNP A18) as a...

Telomere length and mitochondrial DNA (mtDNA) content are markers of aging and aging-related diseases. There is inconclusive evidence concerning the mechanistic effects of airborne particulate matter (PM) exposure on biomolecular markers of ageing OBJECTIVE: The present study examines the association between short- and long-term PM exposure with telomere length and mtDNA content in elderly and investigates to what extend this association is mediated by expression of genes playing a role in the...

Potential molecular alterations based on age and sex are not well defined in diffuse large B-cell lymphoma (DLBCL). We examined global transcriptome DLBCL data from The Cancer Genome Atlas (TCGA) via a systems biology approach to determine the molecular differences associated with age and sex. Collectively, sex and age revealed striking transcriptional differences with older age associated with decreased metabolism and telomere functions and female sex was associated with decreased interferon...

Mesenchymal stem cells (MSCs) have the ability to differentiate into multi-lineage cells, which confers great promise for use in regenerative medicine. In this study, canine adipose MSCs (cAD-MSCs) were isolated from canine adipose tissue. These cells clearly represented stemness (Oct4, Sox2, and Nanog) and differentiation potential into the mesoderm (adipocytes, chondrocytes, and osteoblasts) at early passages. The aim of this study was to evaluate the effects of hypoxia on the differentiation...

Telomerase activity controls telomere length, and this plays an important role in stem cells, aging and tumors. Antioxidant was shown to protect telomerase activity in normal cells but inhibit that in cancer cells, but the underlying mechanism is elusive. Here we found that 7721 hepatoma cells held a higher redox homeostasis threshold than L02 normal liver cells which caused 7721 cells to have a higher demand for ROS; MnSOD over-expression in 7721 decreased endogenous reactive oxygen species...

The low reprogramming efficiency in cells from elderly patients is a challenge that must be overcome. Recently, it has been reported that senescence-associated microRNA (miR)-195 targets Sirtuin 1 (SIRT1) to advance cellular senescence. Thus, we hypothesized that a blockade of miR-195 expression could improve reprogramming efficiency in old skeletal myoblasts (SkMs). We found that miR-195 expression was significantly higher in old SkMs (24 months) isolated from C57BL/6 mice as compared to young...

Telomeres are located at chromosome ends and their length (TL) has been associated with aging and human diseases such as cancer. Whole blood DNA is frequently used for TL measurements but the influence of preanalytical conditions and DNA isolation methods on TL quantification has not been thoroughly investigated. To evaluate potential preanalytical as well as methodological bias on TL, anonymized leftover EDTA-whole blood samples were pooled according to leukocyte counts and were incubated with...

Aging is the universal, intrinsic, genetically-controlled, evolutionarily-conserved and time-dependent intricate biological process characterised by the cumulative decline in the physiological functions and their coordination in an organism after the attainment of adulthood resulting in the imbalance of neurological, immunological and metabolic functions of the body. Various biological processes and mechanisms along with altered levels of mRNAs and proteins have been reported to be involved in...

Telomere length, shape and function depend on a complex of six core telomere-associated proteins referred to as the telosome or shelterin complex. We here demonstrate that the isoform β2 of the heregulin family of growth factors (HRGβ2) is a novel interactor of the telosome/shelterin complex in human telomeres. Analysis of protein-protein interactions using a high-throughput yeast two-hybrid (Y2H) screen identified RAP1, the only telomere protein that is conserved from yeasts to mammals, as a...

The growth factor heregulin (HRG) promotes breast cancer (BC) tumorigenesis and metastasis and differentially modulates BC cell responses to DNA-damaging agents via its dual extracellular and nuclear localization. Given the central role of telomere dysfunction to drive carcinogenesis and to alter the chemotherapeutic profile of transformed cells, we hypothesized that an unanticipated nuclear function of HRG might be to regulate telomere length. Engineered overexpression of the HRGβ2 isoform in...

Reproductive aging involves declines both in oocyte number and developmental capacity. Declining oocyte number alone cannot explain the manifestations of reproductive aging in women. We have proposed the Telomere Theory of Reproductive Aging to explain the complex phenotype found in oocytes from older women. Telomeres are TTAGGG repeats and associated proteins, which form loops at the ends of chromosomes to provide structural and genomic stability. Studies in mice and women show that telomere...

Cellular senescence is a state of irreversible growth arrest that can be triggered by multiple mechanisms, including telomere shortening, the epigenetic derepression of the INK4α/ARF locus and DNA damage. Senescence has been considered a tumor‑suppressing mechanism that permanently arrests cells at risk for malignant transformation. However, accumulating evidence shows that senescent cells have deleterious effects on the tissue microenvironment. Some of these effects could be attributed to...

Several recent studies have investigated the relationship between telomere length and depression with inconsistent results. This meta-analysis examined whether telomere length and depression are associated and explored factors that might affect this association....

Physical activity and sports have repeatedly been reported to be associated with telomere length. We studied the association of different types of sports across different stages of life on relative leukocyte telomere length (rLTL) in advanced age.815 participants (397 men) from the Berlin Aging Study II aged over 61 years were included in the analysis. rLTL was measured by real time PCR and physical activity was determined retrospectively by questionnaire, assessing type and duration of sports...

Aging is a major factor predisposing for multiple diseases. Telomeres at the ends of chromosomes protect the integrity of chromosomal DNA. A specialized six-protein complex termed shelterin protects the telomere from unwanted interaction with DNA damage pathways. The aim of our study was to evaluate the integrity of telomeres and the stability of telomere protection during aging in endothelial cells (EC). We describe that aging EC can be characterized by an increased cell size (40%, p=0.02) and...

Ageing is linked to a number of changes in how the body and its organs function. On a molecular level, ageing is associated with a reduction of telomere length, changes in metabolic and gene-transcription profiles and an altered DNA-methylation pattern. Lifestyle factors such as smoking or stress can impact some of these molecular processes and thereby affect the ageing of an individual. Here we demonstrate by analysis of 77 plasma proteins in 976 individuals, that the abundance of circulating...

The scope of this review is to revise recent advances of the cell-based therapies of liver diseases with an emphasis on cell donor's and patient's age. Regenerative medicine with cell-based technologies as its integral part is focused on the structural and functional restoration of tissues impaired by sickness or aging. Unlike drug-based medicine directed primarily at alleviation of symptoms, regenerative medicine offers a more holistic approach to disease and senescence management aimed to...

With advancing age the left ventricle (LV) undergoes structural and functional changes, thereby creating the substrate for the development of diseases. One possible mechanism of the ageing of the heart is cellular senescence. Leukocyte telomere length (LTL) is a marker of replicative ageing. The purpose of this study was to evaluate the diastolic function of LV and level of NT-proBNP in people of different ages free of cardiovascular diseases and to assess their relationship with LTL. Our data...

Telomere length (TL) has been proposed as a biomarker of ageing, which might be used to identify individuals at higher risk of age-related diseases. Obesity is a well-known risk factor for several diseases. This study aims to analyse the associations of BMI with TL and the rate of TL change in older adults....

Telomeres consist of exanucleotide tandem repeats and proteins complexes at the end of chromosome ends. Telomeres shorten at each cell division, and as such telomere length is a marker of cellular age. Accelerated telomere shortening and cell senescence have been associated with a number of chronic medical conditions, including psychiatric disorders, where increased prevalence of age-related disorders and shorter telomere length have been reported. Shorter telomeres in psychiatric patients are...

Telomeres are nucleoprotein complexes comprised of tandem arrays of repetitive DNA sequence that serve to protect chromosomal termini from inappropriate degradation, as well as to prevent these natural DNA ends from being recognized as broken DNA (double-strand breaks) and triggering of inappropriate DNA damage responses. Preservation of telomere length requires telomerase, the specialized reverse transcriptase capable of maintaining telomere length via template-mediated addition of telomeric...

Children with congenital heart disease are exposed by repeated imaging to ionizing radiation, which may have important implications for lifetime health risks. Leukocyte telomere length (LTL), a reliable biomarker of genomic instability, is associated with increased risk of cancer and cardiovascular disease. We investigated LTL in grown-up patients with CHD (GUCHs) and a positive history of medical radiation exposure as well as the influence of functional polymorphisms of genes involved in DNA...

Telomeres are the heterochromatic repeat regions at the ends of eukaryotic chromosomes, whose length is considered to be a determinant of biological ageing. Normal ageing itself is associated with telomere shortening. Here, critically short telomeres trigger senescence and eventually cell death. This shortening rate may be further increased by inflammation and oxidative stress and thus affect the ageing process. Apart from shortened or dysfunctional telomeres, cells undergoing senescence are...

Previous studies have suggested that Alzheimer's disease (AD) causes an accelerated shortening of telomeres, the ends of chromosomes consisting of highly conserved TTAGGG repeats that, because of unidirectional 5'-3' DNA synthesis, lose end point material with each cell division. Our own previous work suggested that telomere length of T-lymphocytes might be a remarkably accurate biomarker for "mild cognitive impairment" in adults with Down syndrome (MCI-DS), a population at dramatically high...

Despite considerable evidence that RNA-binding proteins (RBPs) regulate mRNA transport and local translation in dendrites, roles for axonal RBPs are poorly understood. Here we demonstrate that a non-telomeric isoform of telomere repeat-binding factor 2 (TRF2-S) is a novel RBP that regulates axonal plasticity. TRF2-S interacts directly with target mRNAs to facilitate their axonal delivery. The process is antagonized by fragile X mental retardation protein (FMRP). Distinct from the current...

Long noncoding telomeric repeat-containing RNA (TERRA) has been implicated in telomere maintenance in a telomerase-dependent and a telomerase-independent manner during replicative senescence and cancer. TERRA's proposed activities are diverse, thus making it difficult to pinpoint the critical roles that TERRA may have. We propose that TERRA orchestrates different activities at chromosome ends in a manner that depends on the state of the telomere....

We propose a DNA-hairpin model for the processivity of telomeric-repeat addition. Concomitantly with template-RNA translocation after each repeat synthesis, the complementary DNA repeat, for example, AGGGTT, loops out in a noncanonical base-paired hairpin, thus freeing the RNA template for the next round of repeat synthesis. The DNA hairpin is temporarily stabilized by telomerase and the incoming dGTP but becomes realigned for processive telomere synthesis....

The guanine-rich sequences are able to fold into G-quadruplexes in living cells, making these structures promising anti-cancer drug targets. In the current study, we identified a small molecule, Ber8, from a series of 9-substituted berberine derivatives and found that it could induce acute cell growth arrest and senescence in cancer cells, but not in normal fibroblasts. Further analysis revealed that the cell growth arrest was directly associated with apparent cell cycle arrest, cell senescence,...

Leukocyte telomeres shorten with age, and excessive shortening is associated with age-related cardiometabolic diseases. Exercise training may prevent disease through telomere length maintenance although the optimal amount of exercise that attenuates telomere attrition is unknown. Furthermore, the underlying molecular mechanisms responsible for the enhanced telomere maintenance observed in endurance athletes is poorly understood. We quantified the leukocyte telomere length and analyzed the...

Telomere uncapping increases with advancing age in human arteries and this telomere uncapping is associated with increased markers of senescence, independent of mean telomere length. However, whether there are sex specific differences in arterial telomere uncapping is unknown. We found that telomere uncapping (serine 139 phosphorylated histone γ-H2A.X in telomeres) in arteries was ~2.5 fold greater in post-menopausal women (n=17, 63±2years) compared with pre-menopausal women (n=11, 30±2years,...

Telomerase inactivation causes loss of the male germline in worms, fish, and mice, indicating a conserved dependence on telomere maintenance in this cell lineage. Here, using telomerase reverse transcriptase (Tert) reporter mice, we found that very high telomerase expression is a hallmark of undifferentiated spermatogonia, the mitotic population where germline stem cells reside. We exploited these high telomerase levels as a basis for purifying undifferentiated spermatogonia using...

The influence of physical activity (PA) and physical fitness (PF) at older ages on changes in telomere length (TL)--repetitive DNA sequences that may mark biologic aging--is not well-established. Few prior studies (mainly cross-sectional) have been conducted in older adults, and few studies have evaluated PF....

Ageing is considered as a major risk factor for the development of chronic diseases. Among these, heart failure seems to be particularly important for both triggering and accelerating pathological ageing. In the present review, we give a general overview of the most relevant results concerning the mechanism of normal and premature senescence of cardiomyocytes and cardiac stromal cells. In particular, we will address the role of telomere dysfunction, DNA damage response, impairment of...

Telomerase reverse transcriptase (TERT) maintains telomeres and is rate limiting for replicative life span. While most somatic tissues silence TERT transcription resulting in telomere shortening, cells derived from cancer or cardiovascular diseases express TERT and activate telomerase. In the present study, we demonstrate that histone deacetylase (HDAC) inhibition induces TERT transcription and promoter activation. At the protein level in contrast, HDAC inhibition decreases TERT protein...

The nucleolus is considered to be a stress sensor and rDNA-based regulation of cellular senescence and longevity has been proposed. However, the role of rDNA in the maintenance of genome integrity has not been investigated in detail. Using genomically diverse industrial yeasts as a model and array-based comparative genomic hybridization (aCGH), we show that chromosome level may be balanced during passages and as a response to alcohol stress that may be associated with changes in rDNA pools....

Telomeres are conserved DNA-protein structures at the termini of eukaryotic chromosomes which contribute to maintenance of genome integrity, and their shortening leads to cell senescence, with negative consequences for organismal functions. Because telomere erosion is influenced by extrinsic and endogenous factors, telomere dynamics may provide a mechanistic basis for evolutionary and physiological trade-offs. Yet, knowledge of fundamental aspects of telomere biology under natural selection...

MicroRNAs (miRNAs) have been considered important regulators in both physiological and disease contexts. Among all miRNAs, the miR-34 family (miR-34a, -34b, -34c), which has been well characterized as a tumor suppressor, displays diverse functions in noncancerous diseases. MiR-34 levels are relatively low in the cardiovascular system, but recently they have been reported to function in cardiovascular disorders by regulating apoptosis, telomere attrition, DNA damage, and inflammatory response. In...

Short telomeres induce a DNA damage response, senescence, and apoptosis, thus maintaining telomere length equilibrium is essential for cell viability. Telomerase addition of telomere repeats is tightly regulated in cells. To probe pathways that regulate telomere addition, we developed the ADDIT assay to measure new telomere addition at a single telomere in vivo. Sequence analysis showed telomerase-specific addition of repeats onto a new telomere occurred in just 48 hr. Using the ADDIT assay, we...

Cell senescence contributes to organismal aging and is induced by telomere erosion and an ensuing DNA damage signal as cells reach the end of their replicative lifespan in vitro or in vivo. Stresses induced by oncogene or tumor suppressor hyperactivation, oxidative stress, ionizing radiation and other DNA damaging agents result in forms of stress induced premature senescence (SIPS) that show similarities to replicative senescence. Since replicative senescence and SIPS occur over many days and...

Replicative senescence, associated with telomere shortening, plays an important role in aging and cardiovascular disease. The relation between telomere length, cardiovascular risk, and renal disease is unknown....

TO summarize the researcn situation or mesenchymal stem cells (MSCs) senescence, including the characteristics and mechanisms of senescence....

Although exposure to stressors is known to increase disease susceptibility and accelerate ageing, evidence is accumulating that these effects can span more than one generation. Stressors experienced by parents have been reported to negatively influence the longevity of their offspring and even grand offspring. The mechanisms underlying these long-term, cross-generational effects are still poorly understood, but we argue here that telomere dynamics are likely to play an important role. In this...

Inhibition of intimal hyperplasia plays an important role in preventing restenosis. Previously, we reported the provocative role of Pin1 in regulating vascular smooth muscle cell (VSMC) proliferation. Here we intended to identify whether locally delivered lentivirus-mediated siPin1 via pluronic F127 (PF127) could inhibit neointimal formation and further explore the potential mechanisms thereof. In vitro studies revealed that lentivirus-mediated siPin1 dispersed in PF127 suppressed proliferation...

Western societies are aging due to an increasing life span, decreased birth rates, and improving social and health conditions. On the other hand, the prevalence of cardiovascular (CV) and cerebrovascular (CBV) diseases rises with age. Thus, in view of the ongoing aging pandemic, it is appropriate to better understand the molecular pathways of aging as well as age-associated CV and CBV diseases. Oxidative stress contributes to aging of organs and the whole body by an accumulation of reactive...

Late-life aging in humans is often associated with severe frailty. This suggests catastrophic events reaching an undeniable biological threshold in cellular stability and a rapidly diminished homeostasis. The driving force of the syndrome is likely 'genetic instability' or 'genomic instability', a high frequency of mutations and deletions within the genome (both nuclear and mitochondrial DNA) of bodily somatic cells caused by DNA damage and inefficient repair. Reactive oxygen species, calcium...

Telomeres play a fundamental role in the maintenance of genomic integrity at a cellular level, and average leukocyte telomere length (LTL) has been proposed as a biomarker of organismal aging. However, studies tracking LTL across the entire life course of individuals are lacking. Here, we examined lifelong patterns of variation in LTL among four birth cohorts of female Soay sheep (Ovis aries) that were longitudinally monitored and sampled from birth to death. Over the first 4 months of life,...

Replication stress causes DNA damage at fragile sites in the genome. DNA damage at telomeres can initiate breakage-fusion-bridge cycles and chromosome instability, which can result in replicative senescence or tumor formation. Little is known about the extent of replication stress or telomere dysfunction in human embryonic stem cells (hESCs). hESCs are grown in culture with the expectation of being used therapeutically in humans, making it important to minimize the levels of replication stress...

Mutations of human telomerase RNA component (TERC) and telomerase reverse transcriptase (TERT) are associated with a subset of lung aging diseases, but the mechanisms by which TERC and TERT participate in lung diseases remain unclear. In this report, we show that knock-out (KO) of the mouse gene Terc or Tert causes pulmonary alveolar stem cell replicative senescence, epithelial impairment, formation of alveolar sacs, and characteristic inflammatory phenotype. Deficiency in TERC or TERT causes a...

The human telomerase reverse transcriptase (hTERT) promoter promotes differential hTERT gene expression in tumor cells and normal cells. However, information on the mechanisms underlying the differential hTERT transcription and induction of telomerase activity in tumor cells is limited. In the present study, suppressor of Ty homolog-5 (SPT5), a protein encoded by the SUPT5H gene, was identified as a novel tumor-specific hTERT promoter-binding protein and activator in colon cancer cells. We...

Human syndromes and mouse mutants that exhibit accelerated but bona fide aging in multiple organs and tissues have been invaluable for the identification of nine denominators of aging: telomere attrition, genome instability, epigenetic alterations, mitochondrial dysfunction, deregulated nutrient sensing, altered intercellular communication, loss of proteostasis, cellular senescence and adult stem cell exhaustion. However, whether and how these instigators of aging interrelate or whether they...

Given the irreversible nature of nephron loss, aging of the kidney is of special interest to diagnostic and toxicologic pathologists. There are many similarities among histologic lesions in aged human and canine kidneys, including increased frequency of glomerulosclerosis, interstitial fibrosis, and tubular atrophy. Unfortunately, there are few studies in which renal tissue from aged healthy dogs was adequately examined with advanced diagnostics-namely, transmission electron microscopy and...

Short telomeres are associated with increased risk of cardiovascular disease. Here we studied cardiomyocyte telomere length at key ages during the ontogeny of cardiac hypertrophy and failure in the hypertrophic heart rat (HHR) and compared these with the normal heart rat (NHR) control strain. Key ages corresponded with the pathophysiological sequence beginning with fewer cardiomyocytes (2 days), leading to left ventricular hypertrophy (LVH) (13 wk) and subsequently progression to heart failure...

In most human cancer cells, cellular immortalization relies on the activation and recruitment of telomerase to telomeres. The telomere-binding protein TPP1 and the TEN domain of the telomerase catalytic subunit TERT regulate telomerase recruitment. TERT contains a unique domain, called the insertion in fingers domain (IFD), located within the conserved reverse transcriptase domain. We report the role of specific hTERT IFD residues in the regulation of telomerase activity and processivity,...

Telomere repeat binding factor TRF2 is a member of shelterin complex with an important role in protecting and stabilizing chromosomal ends. In the present study, we investigated the effect of partial knockdown of TRF2 on radiosensitivity of telomerase immortalized human mesenchymal stem cells (hMSC-telo1), which have a higher radioresistance compared to non telomerized counterpart. Partial knockdown of the protein achieved 15-20% reduction in TRF2 protein levels. The study compared the effect of...

Stem cells of intensely regenerative tissues are susceptible to cellular damage. Although the response to this process in hematopoietic stem cells (HSCs) is crucial, the mechanisms by which hematopoietic homeostasis is sustained are not completely understood. Aging increases reactive oxygen species (ROS) levels and inflammation, which contribute to increased proliferation, senescence and/or apoptosis, leading to self-renewal premature exhaustion. In this study, we assessed ROS production, DNA...

Conceptualizations of links between stress and cellular aging in childhood suggest that accumulating stress predicts shorter leukocyte telomere length (LTL). At the same time, several models suggest that emotional reactivity to stressors may play a key role in predicting cellular aging. Using intensive repeated measures, we tested whether exposure or emotional "reactivity" to conflict and warmth in the family were related to LTL. Children (N=39; 30 target children and 9 siblings) between 8 and...

Meibomian gland carcinoma (MGC) and basal cell carcinoma (BCC) are common eyelid carcinomas that exhibit highly dissimilar degrees of proliferation and prognoses. We address here the question of the differential mechanisms between these two eyelid cancers that explain their different outcome. A total of 102 confirmed MGC and 175 diagnosed BCC cases were analyzed. Twenty confirmed MGC and twenty diagnosed BCC cases were collected to determine the telomere length, the presence of senescent cells,...

Telomerase maintains ends of eukaryotic chromosomes, telomeres. Telomerase loss results in replicative senescence and a switch to recombination-dependent telomere maintenance. Telomerase insufficiency in humans leads to telomere syndromes associated with premature ageing and cancer predisposition. Here we use yeast to show that the survival of telomerase insufficiency differs from the survival of telomerase loss and occurs through aneuploidy. In yeast grown at elevated temperatures, telomerase...

Telomerase is an enzyme that adds repeats of DNA sequences to the ends of chromosomes, thereby preventing their shortening. Telomerase activity is associated with proliferative status of cells, organismal development, and aging. We report an analysis of telomerase activity and telomere length in the honeybee, Apis mellifera. Telomerase activity was found to be regulated in a development and caste-specific manner. During the development of somatic tissues of larval drones and workers, telomerase...

Telomeres, the repetitive sequences at chromosomal ends, protect intact chromosomes. Telomeres progressively shorten through successive rounds of cell divisions, and critically shortened telomeres trigger senescence and apoptosis. The enzyme that elongates telomeres and maintains their structure is known as telomerase. The catalytic subunit of this enzyme (telomerase reverse transcriptase [TERT]) is expressed at a high level in malignant cells, but at a very low level in normal cells. Although...

Reduced telomere length with increasing age in dividing cells has been implicated in contributing to the pathologies of human aging, which include cardiovascular and metabolic disorders, through induction of cellular senescence. Telomere shortening results from the absence of telomerase, an enzyme required to maintain telomere length. Telomerase reverse transcriptase (TERT), the protein subunit of telomerase, is expressed only transiently in a subset of adult somatic cells, which include stem...

To investigate the prevalence of endocrine disturbances in a group of HIV-positive (HIV+) women and to identify factors affecting presence of these disorders. To examine specifically whether cellular ageing, as measured by leukocyte telomere length (LTL), is correlated with the presence of endocrine disturbance....

Cellular senescence is a barrier to tumorigenesis in normal cells, and tumor cells undergo senescence responses to genotoxic stimuli, which is a potential target phenotype for cancer therapy. However, in this setting, mixed-mode responses are common with apoptosis the dominant effect. Hence, more selective senescence inducers are required. Here we report a machine learning-based in silico screen to identify potential senescence agonists. We built profiles of differentially affected biological...

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....

Atherosclerosis is associated with reduced mononuclear cell (MNC) telomere length, and senescent cells have been detected in atherosclerotic plaques. Rice bran is a source of γ-oryzanol, phytosterols and tocols with potential lipid-lowering, antioxidant and anti-inflammatory activities. Here, we tested the hypothesis that rice bran enzymatic extract (RBEE) impacts on apoptosis, telomere length and atherogenesis in mice....

In eukaryotes, the absence of telomerase results in telomere shortening, eventually leading to replicative senescence, an arrested state that prevents further cell divisions. While replicative senescence is mainly controlled by telomere length, the heterogeneity of its onset is not well understood. This study proposes a mathematical model based on the molecular mechanisms of telomere replication and shortening to decipher the causes of this heterogeneity. Using simulations fitted on experimental...

Authors: I I. Hadj Salem, J J. Dubé, L-P LP. Boulet, J J. Chakir Published: 10/15/2015, Clinical and experimental allergy : journal of the British Society for Allergy and Clinical Immunology PubMed Full Text...

Neuroblastoma is a malignant paediatric tumour of the sympathetic nervous system. Roughly half of these tumours regress spontaneously or are cured by limited therapy. By contrast, high-risk neuroblastomas have an unfavourable clinical course despite intensive multimodal treatment, and their molecular basis has remained largely elusive. Here we have performed whole-genome sequencing of 56 neuroblastomas (high-risk, n = 39; low-risk, n = 17) and discovered recurrent genomic rearrangements...

Chronic exposure to psychosocial stressors is related to worse somatic health. This association applies both to stressors early in life, such as childhood adversities, and more recent life stress, such as stressful life events. This study examined whether accelerated telomere shortening, as an indicator of cellular aging, might be an explanatory mechanism....

The telomere shortening in chromosomes implies the senescence, apoptosis, or oncogenic transformation of cells. Since detecting telomeres in aging and diseases like cancer, is important, the direct detection of telomeres has been a very useful biomarker. We propose a telomere detection method using a newly synthesized quantum dot (QD) based probe with oligonucleotide conjugation and direct fluorescence in situ hybridization (FISH). QD-oligonucleotides were prepared with metal coordination...

Previously, we reported that a novel subpopulation of young mesenchymal stem cells (YMSCs) existed in old bone marrow, which possessed high antiaging properties as well as excellent efficacy for cardiac repair. MicroRNAs (miRNAs) have emerged as key regulators in post-transcriptional gene expression programs, and however, it is unknown whether miRNAs directly control stem cell senescence. Here we present the first evidence that miR-195 overexpressed in old MSCs (OMSCs) induces stem cell...

Patients with acromegaly exhibit reduced life expectancy and increased prevalence of age-related diseases, such as diabetes, hypertension, and cardiovascular disease. However, the underlying mechanism has not been fully elucidated. Telomere shortening is reportedly associated with reduced life expectancy and increased prevalence of these age-related diseases....

Telomere length (TL) is considered a marker of biological aging and has been associated with the presence of various coronary risk factors in patients. Much less is known about the relationships between TL and classic coronary risk factors in other populations. We measured TL in peripheral blood leukocytes of 343 middle-aged blood donors (mean age 40.2 ± 12.4 years; 201 men, 142 women) using quantitative polymerase chain reaction. Median TL was 0.86 (range: 0.48-1.85) relative TL units. In...

Aging is a complex biological process characterized by a progressive decline of organ functions leading to an increased risk of age-associated diseases and death. Decades of intensive research have identified a range of molecular and biochemical pathways contributing to aging. However, many aspects regarding the regulation and interplay of these pathways are insufficiently understood. Telomere dysfunction and genomic instability appear to be of critical importance for aging at a cellular level....

While telomerase (hTERT) activity is absent from normal somatic cells, reactivation of hTERT expression is a hallmark of cancer cells. Telomerase activity is required for avoiding replicative senescence and supports immortalization of cellular proliferation. Only a minority of cancer cells rely on a telomerase-independent process known as alternative lengthening of telomeres, ALT, to sustain cancer cell proliferation. Multiple genetic, epigenetic, and viral mechanisms have been found to...

Many stress-related and depressive disorders have been shown to be associated with one or more of the following; shortened telomeres, raised cortisol levels and increased susceptibility to age-related dysfunction. It is suggested here that insufficient availability of the neurological peptide, carnosine, may provide a biochemical link between stress- and depression-associated phenomena: there is evidence that carnosine can enhance cortisol metabolism, suppress telomere shortening and exert...

Aberrant MSC function was shown to contribute to the pathophysiology of myelodysplastic syndromSe (MDS). In comparison to adult MDS, pediatric MDS displayed different features both in biologically and clinically. The mechanisms for adult MDS may not be applicable in pediatric MDS. However, understanding of the MSCs in pediatric MDS is lacking. In this study, we investigated the proliferation capacity of MSCs from pediatric MDS patients at clone cell level....

The chronological age of an individual animal predicts many of its biological characteristics, and these in turn influence population-level ecological processes. Animal age information can therefore be valuable in ecological research, but many species have no external features that allow age to be reliably determined. Molecular age biomarkers provide a potential solution to this problem. Research in this area of molecular ecology has so far focused on a limited range of age biomarkers. The most...

Telomeric abnormalities caused by loss of function of the RecQ helicase WRN are linked to the multiple premature ageing phenotypes that characterize Werner syndrome. Here we examine WRN's role in telomeric maintenance, by comparing its action on a variety of DNA structures without or with telomeric sequences. Our results show that WRN clearly prefers to act on strand invasion intermediates in a manner that favours strand invasion and exchange. Moreover, WRN unwinding of these recombination...

Replicative senescence, associated with telomere shortening, plays an important role in aging and cardiovascular disease. The relation between telomere length, cardiovascular risk, and renal disease is unknown....

Although vascular smooth muscle cell (VSMC) proliferation is implicated in atherogenesis, VSMCs in advanced plaques and cultured from plaques show evidence of VSMC senescence and DNA damage. In particular, plaque VSMCs show shortening of telomeres, which can directly induce senescence. Senescence can have multiple effects on plaque development and morphology; however, the consequences of VSMC senescence or the mechanisms underlying VSMC senescence in atherosclerosis are mostly unknown....

Telomere length is considered as a biological marker for aging. It is expected that telomeres shorten with age and with conditions associated with oxidative stress and inflammation. Both are present in patients with chronic kidney disease (CKD) who have a very high cardiovascular risk. We investigated whether CKD duration is associated with relative telomere length (RTL) in 4802 patients from the German Chronic Kidney Disease (GCKD) study. We measured RTL in each sample in quadruplicates using a...

Chromosome 21 nondisjunction in oocytes is the most common cause of trisomy 21, the primary chromosomal abnormality responsible for Down syndrome (DS). This specific type of error is estimated to account for over 90 % of live births with DS, with maternal age being the best known risk factor for chromosome 21 nondisjunction. The loss of telomere length and the concomitant shortening of chromosomes are considered a biological marker for aging. Thus, we tested the hypothesis that mothers who had a...

Photoageing represents the addition of extrinsic chronic ultraviolet radiation-induced damage on intrinsic ageing and accounts for most age-associated changes in skin appearance. In this study, we evaluated the effect of 38% BPF, a highly concentrated extract of the bergamot fruit (Citrus bergamia) on UVB-induced photoageing by examining inflammatory cytokine expression, telomere length/telomerase alterations and cellular viability in human immortalized HaCaT keratinocytes. Our results suggest...

Age and short leukocyte telomeres have been associated with a higher risk of Alzheimer's disease (AD). Inflammation is involved in AD and it is suggested that anti-inflammatory interleukin-10 (IL-10) may partly antagonize these processes....

Reduced telomere length is a measure of biological aging that is predictive of cardiac events in adults, and has been mechanistically implicated in the onset and progression of atherosclerosis. We sought to describe the early life factors associated with leukocyte telomere length in early childhood, and to determine whether telomere length measured during early childhood is associated with arterial wall thickening later in childhood....

Authors: Simon S. Verhulst, Ezra E. Susser, Pam R PR. Factor-Litvak, Mirre J P MJ. Simons, Athanase A. Benetos, Troels T. Steenstrup, Jeremy D JD. Kark, Abraham A. Aviv Published: 09/24/2015, International journal of epidemiology PubMed Full Text...

Chronic inflammation negatively impacts all physiological functions, causing an array of degenerative conditions including diabetes; cancer; cardiovascular, osteo-articular, and neurodegenerative diseases; autoimmunity disorders; and aging. In particular, there is a growing knowledge of the role that gene transcription factors play in the inflammatory process. Obesity, metabolic syndrome, and diabetes represent multifactorial conditions resulting from improper balances of hormones and gene...

Oxidative stress (OS)-induced senescence of the amniochorion has been associated with parturition at term. We investigated whether telomere fragments shed into the amniotic fluid (AF) correlated with labor status and tested if exogenous telomere fragments (T-oligos) could induce human and murine amnion cell senescence. In a cross-sectional clinical study, AF telomere fragment concentrations quantitated by a validated real-time PCR assay were higher in women in labor at term compared to those not...

The proliferation and differentiation potential of bone marrow mesenchymal stem cells (BMMSCs) declines with age and with in vitro passages. However, the underlying mechanisms and putative approaches to maintain their function are not fully understood. Recent studies have revealed telomere attrition as the core initiator determining functional decline in aging of BMMSCs. Telomere attrition activates downstream p53 signaling and compromises mitochondrial metabolism via the peroxisome...

Human umbilical endothelial cells (HUVECs) have been proven to be effective in tumor anti-angiogenesis but the mechanism remained to be further demonstrated. The restricted ability of HUVECs to proliferate in vitro also limits their application on a large scale. In the present study, we immortalized HUVECs with hTERT genes by lentiviral infection and explored the antitumor immunity of hTERT-expressing HUVECs (HUVEC-TERTs). Results showed that HUVEC-TERTs maintained high telomere activity and...

Cardiac aging has been confounded by the concept that the heart is a postmitotic organ characterized by a predetermined number of myocytes, which is established at birth and largely preserved throughout life until death of the organ and organism. Based on this premise, the age of cardiac cells should coincide with that of the organism; at any given time, the heart would be composed of a homogeneous population of myocytes of identical age. The discovery that stem cells reside in the heart and...

Cellular senescence has been associated with the structural and functional decline observed during physiological lung aging and in chronic obstructive pulmonary disease (COPD). Airway epithelial cells are the first line of defense in the lungs and are important to COPD pathogenesis. However, the mechanisms underlying airway epithelial cell senescence, and particularly the role of telomere dysfunction in this process, are poorly understood. We aimed to investigate telomere dysfunction in airway...

A longer leukocyte telomere length (LTL) in women than men has been attributed to a slow rate of LTL attrition in women, perhaps due to high estrogen exposure during the premenopausal period....

Telomeres form protective caps at the ends of linear chromosomes to prevent nucleolytic degradation, end-to-end fusion, irregular recombination, and chromosomal instability. Telomeres are composed of repetitive DNA sequences (TTAGGG)n in humans, that are bound by specialized telomere binding proteins. Telomeres lose capping function in response to telomere shortening, which occurs during each division of cells that lack telomerase activity-the enzyme that can synthesize telomeres de novo....

Rotenone inhibits the electron transfer from complex I to ubiquinone, in this way interfering with the electron transport chain in mitochondria. This chain of events induces increased levels of intracellular reactive oxygen species, which in turn can contribute to acceleration of telomere shortening and induction of DNA damage, ultimately resulting in aging. In this study, we investigated the effect of rotenone treatment in human fibroblast strains....

Stress can be a predisposing factor to psychiatric disorders and has been associated with decreased neurogenesis and reduced hippocampal volume especially in depression. Similarly, in white blood cells chronic psychological stress has been associated with telomere shortening and with mood disorders and schizophrenia (SZ). However, in previous post-mortem brain studies from occipital cortex and cerebellum, no difference in telomere length was observed in depression. We hypothesized that in...

Biomagnifying organohalogenated compounds (OHCs) may have adverse effects on the health of birds, especially marine avian top predators that accumulate high OHC loads. Contaminants may impair the humoral immunity and also influence the antioxidant enzyme activity (i.e. oxidative stress). Moreover, physical conditions and oxidative stress during development may reduce telomere lengths, one of the main mechanisms explaining cell senescence. To examine the potential effects of environmental...

Authors: Robertina R. Giacconi, Marco M. Malavolta, Laura L. Costarelli, Mauro M. Provinciali Published: 09/11/2015, EBioMedicine PubMed Full Text...

Telomere shortening is associated with increasing age, male gender and lifestyle factors such as obesity and smoking. Inflammation has also been implicated in cellular senescence and may promote telomere shortening in chronic conditions such as obesity and diabetes. However, little is known about the relationship between markers of obesity and inflammation, and leukocyte telomere length (LTL)....

DNA is organized into complex three-dimensional chromatin structures, but how this spatial organization regulates gene expression remains a central question. These DNA/chromatin looping structures can range in size from 10-20 kb (enhancers/repressors) to many megabases during intra- and inter-chromosomal interactions. Recently, the influence of telomere length on chromatin organization prior to senescence has revealed the existence of long-distance chromatin loops that dictate the expression of...

Dietary factors can affect telomere length (TL), a biomarker of aging, through oxidation and inflammation-related mechanisms. A Dietary Inflammatory Index (DII) could help to understand the effect of the inflammatory potential of the diet on telomere shortening....

Ageing is characterized by a progressive deterioration of multiple physiological and molecular pathways, which impair organismal performance and increase risks of death with advancing age. Hence, ageing studies must identify physiological and molecular pathways that show signs of age-related deterioration, and test their association with the risk of death and longevity. This approach necessitates longitudinal sampling of the same individuals, and therefore requires a minimally invasive sampling...

The aim of this study was to investigate the anti-aging effects of exogenous estrogen on telomerase activity in ovariectomized female Sprague-Dawley rats....

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...

Research on the physiological causes of senescence aim to identify common physiological mechanisms that explain age-related declines in fitness across taxonomic groups. Telomeres are repetitive nucleotide sequences found on the ends of eukaryotic chromosomes. Past research indicates that telomere attrition is strongly correlated with inter-specific rates of aging, though these studies cannot distinguish whether telomere attrition is a cause or consequence of the aging process. We extend previous...

In mammals, DNA methylation is essential for protecting repetitive sequences from aberrant transcription and recombination. In some developmental contexts (e.g., preimplantation embryos) DNA is hypomethylated but repetitive elements are not dysregulated, suggesting that alternative protection mechanisms exist. Here we explore the processes involved by investigating the role of the chromatin factors Daxx and Atrx. Using genome-wide binding and transcriptome analysis, we found that Daxx and Atrx...

Telomeres are repetitive DNA sequences located at the ends of chromosomes. Chromosomal and genomic instability due to telomere dysfunction has been known to play an important role in the carcinogenesis of some organs....

Aged and degenerated intervertebral discs are characterised by a significant increase in the number of senescent cells, which may be associated with the deterioration of this tissue due to their catabolic phenotype. On the other hand, carboxymethyl-lysine has been found to be accumulated with ageing in the proteins of the disc, evidencing the existence of oxidative stress in this tissue. Accordingly, here we investigated the effect of oxidative stress on the physiology of human nucleus pulposus...

Senescence--the progressive age-dependent decline in performance--occurs in most organisms. There is considerable variation in the onset and rate of senescence between and within species. Yet the causes of this variation are still poorly understood, despite being central to understanding the evolution of senescence. Long-term longitudinal studies on wild animals are extremely well-suited to studying the impact of environmental and individual characteristics (and the interaction between the two)...

Head and neck squamous cell carcinoma (HNSCC) is a very heterogeneous disease resulting in huge differences in the treatment response. New individualized therapy strategies including molecular targeting might help to improve treatment success. In order to identify potential targets, we developed a HNSCC radiochemotherapy cell culture model of primary HNSCC cells derived from two different patients (HN1957 and HN2092) and applied an integrative microRNA (miRNA) and mRNA analysis in order to gain...

Mouse embryonic stem cells (mESCs) have a remarkable capacity to maintain normal genome stability and karyotype in culture. We previously showed that infrequent bursts of Zscan4 expression (Z4 events) are important for the maintenance of telomere length and genome stability in mESCs. However, the molecular details of Z4 events remain unclear. Here we show that Z4 events involve unexpected transcriptional derepression in heterochromatin regions that usually remain silent. During a Z4 event, we...

Both COPD and lung cancer are major worldwide health concerns owing to cigarette smoking, and represent a huge, worldwide, preventable disease burden. Whilst the majority of smokers will not develop either COPD or lung cancer, they are closely related diseases, occurring as co-morbidities at a higher rate than if they were independently triggered by smoking. Lung cancer and COPD may be different aspects of the same disease, with the same underlying predispositions, whether this is an underlying...

Telomeres are nucleoprotein structures, essential for chromosome stability and cell survival. Telomeres are progressively shortened with each cell division and by environmental factors. Telomere loss has been linked to age and stress-induced premature senescence. Dysfunctional telomeres tend to form aggregates, which consist of the end-to-end fusion of telomeres. Telomere elongation is carried out by telomerase, which is a specific reverse transcriptase capable of adding telomeric repeats to...

Reductions in DNA integrity, genome stability, and telomere length are strongly associated with the aging process, age-related diseases as well as the age-related loss of muscle mass. However, in people reaching an age far beyond their statistical life expectancy the prevalence of diseases, such as cancer, cardiovascular disease, diabetes or dementia, is much lower compared to "averagely" aged humans. These inverse observations in nonagenarians (90-99 years), centenarians (100-109 years) and...

Hutchinson-Gilford progeria (HGPS) is a premature ageing syndrome caused by a mutation in LMNA, resulting in a truncated form of lamin A called progerin. Progerin triggers loss of the heterochromatic marker H3K27me3, and premature senescence, which is prevented by telomerase. However, the mechanism how progerin causes disease remains unclear. Here, we describe an inducible cellular system to model HGPS and find that LAP2α (lamina-associated polypeptide-α) interacts with lamin A, while its...

Leukocyte telomere length (LTL) shortening is characteristic of aging and is associated with morbidity and mortality, independent of age. Research demonstrates that lower extremity muscular strength is associated with mobility, morbidity and mortality; however, no study, to our knowledge, had examined the association between lower extremity muscular strength and LTL, which was the purpose of this brief study....

Chronic inflammation and oxidative stress might be considered the key mechanisms of aging. Insulin resistance (IR) is a phenomenon related to inflammatory and oxidative stress. We tested the hypothesis that IR may be associated with cellular senescence, as measured by leukocyte telomere length (LTL), and arterial stiffness (core feature of arterial aging), as measured by carotid-femoral pulse wave velocity (c-f PWV)....

Highly active antiretroviral therapy has remarkably improved quality of life of HIV-1-infected patients. However, this treatment has been associated with the so-called lipodystrophic syndrome, which conveys a number of adverse metabolic effects and morphological alterations. Among them, lipoatrophy of subcutaneous fat in certain anatomical areas and hypertrophy of visceral depots are the most common. Less frequently, lipomatous enlargements of subcutaneous fat at distinct anatomic areas occur....

Cancer was recognized as a genetic disease at least four decades ago, with the realization that the spontaneous mutation rate must increase early in tumorigenesis to account for the many mutations in tumour cells compared with their progenitor pre-malignant cells. Abnormalities in the deoxyribonucleotide pool have long been recognized as determinants of DNA replication fidelity, and hence may contribute to mutagenic processes that are involved in carcinogenesis. In addition, many anticancer...

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...

Cellular senescence and organismal aging predispose age-related chronic diseases, such as neurodegenerative, metabolic, and cardiovascular disorders. These diseases emerge coincidently from elevated oxidative/electrophilic stress, inflammation, mitochondrial dysfunction, DNA damage, and telomere dysfunction and shortening. Mechanistic linkages are incompletely understood. Here, we show that ablation of peroxisome proliferator-activated receptor γ coactivator-1α (PGC-1α) accelerates vascular...

The key step of carcinogenesis is the malignant transformation which is fundamentally a telomere biology dysfunction permitting cells to bypass the Hayflick limit and to divide indefinitely and uncontrollably. Thus all partners and structures involved in normal and abnormal telomere maintenance, protection and lengthening can be considered as potential anti-cancer therapeutic targets. In this Point of View we discuss, highlight and provide new perspectives from the current knowledge and...

The lifespan of humans has increased drastically over the last decades; considerable effort has been applied to delineate the mechanisms behind aging in order to find strategies for longevity. As the benefits of the gained knowledge might extend to diseases, where accelerated aging is suspected, the role of aging in the systemic autoimmune disease Systemic Lupus Erythematosus (SLE) is of particular interest. In this review the immunological similarities of SLE and aging are analyzed on three...

Gout is the most common auto-inflammatory arthritis that leads to severe comorbidities such as cardiovascular diseases, renal impairment and metabolic disorders at an early age. We hypothesize that chronic as well as frequent flares of intermittent inflammation, caused by uric acid contribute to an early onset of cardiovascular-, renal- and metabolic diseases. Persistent exposure of the cells to such inflammatory events elaborates DNA damage, excessive cell turnover inconsistent with age and...

Immunosenescence, characterized by complex modifications of immunity with age, could be related to frailty syndrome in elderly individuals, leading to an inadequate response to minimal aggression. Functional decline (i.e., the loss of ability to perform activities of daily living) is related to frailty and decreased physiological reserves and is a frequent outcome of hospitalization in older patients. Links between immunosenescence and frailty have been explored and 20 immunological parameters,...

Individuals rarely grow as fast as their physiologies permit despite the fitness advantages of being large. One reason may be that rapid growth is costly, resulting for example in somatic damage. The chromosomal ends, the telomeres, are particularly vulnerable to such damage, and telomere attrition thus influences the rate of ageing. Here, we used a transgenic salmon model with an artificially increased growth rate to test the hypothesis that rapid growth is traded off against the ability to...

Chronic kidney disease (CKD) affects 10-15% of the general population and affected individuals are at an increased risk for cardiovascular disease (CVD). Since telomere length is considered to be involved in biological aging, we tested whether relative telomere length (RTL) might be a marker for these two diseases....

With advancing age the left ventricle (LV) undergoes structural and functional changes, thereby creating the substrate for the development of diseases. One possible mechanism of the ageing heart is a cellular senescence. Leukocyte telomere length (LTL) is a marker of replicative ageing. The purpose of this study was to evaluate the structure and function of the LV in people of different ages free of cardiovascular diseases (CVD) and regular drug medication and to assess their relationship with...

Accumulated data indicate that wound-care products should have a composition equivalent to that of the skin: a combination of particular growth factors and extracellular matrix (ECM) proteins endogenous to the skin, together with viable epithelial cells, fibroblasts, and mesenchymal stem cells (MSCs). Strategies consisting of bioengineered dressings and cell-based products have emerged for widespread clinical use; however, their performance is not optimal because chronic wounds persist as a...

Psychosocial stress has been associated with an increased risk for mental and somatic health problems across the life span. Some studies in younger adults linked this to accelerated cellular aging, indexed by shortened telomere length (TL). In older adults, the impact of psychosocial stress on TL may be different due to the lifetime exposure to competing causes of TL-shortening. This study aims to assess whether early and recent psychosocial stressors (childhood abuse, childhood adverse events,...

Telomere shortening in the kidney explains the impaired regenerative capacity, but may not drive the ageing phenotype itself. We investigated kidneys from young and old Terc(+/+) and Terc(-/-) mice of early (G1) and late (G4, G5) generations. Functional parameters declined and age-related morphological changes increased in late generation Terc(-/-) mice and with further age. Podocyte loss was only seen in old G4 Terc(-/-). Whereas p21(CIP1/WAF1) was highest in old G1 and G4 Terc(-/-), telomere...

A longitudinal study was conducted to examine sex-specific associations between changes in adiposity over a 10-year period, the FTO rs9939609 polymorphism, and leukocyte telomere length (LTL)....

The objective of this study was to find the key regulatory molecules in the cell senescence process through observing the expression of telomere-associated factor during the normal cell replicative senescence process. Based on the established cell replicative senescence model, reverse transcription-polymerase chain reaction and western blot analyses were used to detect telomere-associated factor expression at the mRNA and protein levels, including that of human telomere binding protein 1,...

Chronic jet lag or shift work is deleterious to human metabolic health, in that such circadian desynchronization is associated with being overweight and the prevalence of altered glucose metabolism. Similar metabolic changes are observed with age, suggesting that chronic jet lag and accelerated cell aging are intimately related, but the association remains to be determined. We addressed whether jet lag induces metabolic and cell aging impairments in young grass rats (2-3 mo old), using control...

To assess the cardiovascular health, markers of cardiovascular aging and telomere length in survivors of the siege of Leningrad, who were either born during the siege or lived in the besieged city in their early childhood....

Telomeres are regions at the ends of chromosomes that maintain chromosomal structural integrity and genomic stability. In studies of mainly older, white populations, shorter leukocyte telomere length (LTL) is associated with cardiometabolic risk factors and increased risks of mortality and coronary heart disease (CHD). On average, African Americans (AfAm) have longer LTL than whites, but the LTL-CHD relationship in AfAm is unknown. We investigated the relationship of LTL with CHD and mortality...

Leukocyte telomere length (LTL) shortens with age and short LTL has been associated with increased mortality and increased risk for some age-related outcomes. This study aims to analyse the associations of smoking habits with LTL and rate of LTL change per year in older adults....

Vascular dysfunction is an early feature of diabetic vascular disease, due to increased oxidative stress and reduced nitric oxide (NO) bioavailability. This can lead to endothelial cell senescence and clinical complications such as stroke. Cells can become senescent by shortened telomeres and oxidative stress is known to accelerate telomere attrition. Sirtuin 1 (SIRT1) has been linked to vascular health by upregulating endothelial nitric oxide synthase (eNOS), suppressing oxidative stress, and...

Why mammalian cells possess multiple DNA glycosylases (DGs) with overlapping substrate ranges for repairing oxidatively damaged bases via the base excision repair (BER) pathway is a long-standing question. To determine the biological role of these DGs, null animal models have been generated. Here, we report the generation and characterization of mice lacking Neil2 (Nei-like 2). As in mice deficient in each of the other four oxidized base-specific DGs (OGG1, NTH1, NEIL1, and NEIL3), Neil2-null...

Microglia are a proliferative population of resident brain macrophages that under physiological conditions self-renew independent of hematopoiesis. Microglia are innate immune cells actively surveying the brain and are the earliest responders to injury. During aging, microglia elicit an enhanced innate immune response also referred to as 'priming'. To date, it remains unknown whether telomere shortening affects the proliferative capacity and induces priming of microglia. We addressed this issue...

Pauline Abdallah, Pierre Luciano, Kurt W. Runge, Michael Lisby, Vincent Géli, Eric Gilson and M. Teresa Teixeira Telomeres protect chromosome ends from fusion and degradation. In the absence of a specific telomere elongation mechanism, their DNA shortens progressively with every round of replication, leading to replicative senescence. Here,...

Christian Werner MD, Tobias Fürster MD, Thomas Widmann MD, Janine Pöss MD, Cristiana Roggia MD, Milad Hanhoun MD, Jürgen Scharhag MD, Nicole Büchner DBBSc, Tim Meyer MD, Wilfried Kindermann MD, Judith Haendeler PhD, Michael Böhm MD, and Ulrich Laufs MD C57/Bl6 mice were randomized to voluntary running or...

Sheila A. Stewart - Departments of Cell Biology and Physiology and of Medicine, Washington University School of Medicine, St. Louis, Missouri 63110, and Robert A. Weinberg - Whitehead Institute for Biomedical Research and Department of Biology, Massachusetts Institute of Technology, Cambridge, Massachusetts 02142. Annu Rev Cell Dev Biol. 2006;22:531-57 ...

Judith Campis and Fabrizio d'Adda di Fagagna; Nature Reviews | Molecular Cell Biology Volume 8 | 729 Cells continually experience stress and damage from exogenous and endogenous sources, and their responses range from complete recovery to cell death. Proliferating cells can initiate an additional response by adopting a...

Kajstura J, Rota M, Urbanek K, Hosoda T, Bearzi C, Anversa P, Bolli R, Leri A. Cardiovascular Research Institute, Department of Medicine, New York Medical College, Valhalla, New York 10595, USA. The preservation of myocyte number and cardiac mass throughout life is dependent on the balance between cell...

Minamino T, Komuro I.:Department of Cardiovascular Science and Medicine, Chiba University Graduate School of Medicine, 1-8-1 Inohana, Chuo-ku, Chiba, Japan. Front. Biosci. 1;13:2971-9. Telomeres are DNA regions composed of TTAGGG repeats that are located at the ends of chromosomes. Specific proteins associate with the telomeres and form non-nucleosomal...

By John Gever, Senior Editor, MedPage Today Published: September 21, 2010 Reviewed by Zalman S. Agus, MD; Emeritus Professor University of Pennsylvania School of Medicine and Dorothy Caputo, MA, RN, BC-ADM, CDE, Nurse Planner Shortened telomeres in peripheral blood leukocytes may predict relapse, malignant progression, and poorer survival in patients with...

To determine the most important drivers of successful ageing at extreme old age, we combined community-based prospective cohorts: Tokyo Oldest Old Survey on Total Health (TOOTH), Tokyo Centenarians Study (TCS) and Japanese Semi-Supercentenarians Study (JSS) comprising 1554 individuals including 684 centenarians and (semi-)supercentenarians, 167 pairs of centenarian offspring and spouses, and 536 community-living very old (85 to 99 years). We combined z scores from multiple biomarkers to describe...

Chronic obstructive pulmonary disease (COPD) is characterized by airflow limitation that is not completely reversible by administration of inhaled bronchodilators. Many studies propose that telomere length shortening might have occurred in COPD patients. We aimed to determine the telomere length in COPD patients and compare the results of non-smoking and smoking control subjects....

Moods are enduring affective states that we hypothesise should be affected by an individual's developmental experience and its current somatic state. We tested whether early-life adversity, induced by manipulating brood size, subsequently altered juvenile European starlings' (Sturnus vulgaris) decisions in a judgment bias task designed to provide a cognitive measure of mood. We predicted that starlings from larger broods, specifically those that had experienced more nest competitors larger than...

A schizophrenia phenotype for paternal and maternal age effects on illness risk could benefit etiological research. As odor sensitivity is associated with variability in symptoms and cognition in schizophrenia, we examined if it was related to parental ages in patients and healthy controls. We tested Leukocyte Telomere Length (LTL) as an explanatory factor, as LTL is associated with paternal age and schizophrenia risk. Seventy-five DSM-IV patients and 46 controls were assessed for detection of...

Authors: Phaedra M PM. Tachtatzis, Aileen A. Marshall, Aloysious A. Aravinthan, Suman S. Verma, Sue S. Penrhyn-Lowe, Marianna M. Mela, Cinzia C. Scarpini, Susan E SE. Davies, Nicholas N. Coleman, Graeme J M GJ. Alexander Published: 07/28/2015, PloS one PubMed Full Text...

Cardiovascular disease is a severe threat to human health and life. Among many risk factors of cardiovascular disease, genetic or gene-based ones are drawing more and more attention in recent years. Accumulated evidence has demonstrated that the loss or mutation of ataxia telangiectasia mutated (ATM) gene can result in DNA damage repair dysfunctions, telomere shortening, decreased antioxidant capacity, insulin resistance, increased lipid levels, etc., and thus can promote the occurrence of...

Bipolar disorder (BD) is associated with a reduced life expectancy compared to the general population mainly due to a high prevalence of comorbid somatic illnesses. A model of accelerated aging has been proposed as a potential explanation to these epidemiological findings. Nevertheless, studies measuring telomere length (TL) in patients with BD compared to healthy controls have provided mixed results....

Telomeric repeat containing RNAs (TERRA) are small RNA molecules synthesized from telomeric regions which were previously considered as silent genomic domains. In normal cells, these RNAs are transcribed in a direction from subtelomeric region towards the chromosome ends, but in case of cancer cells, their expression remains limited or absent. Telomerase is a rate limiting enzyme for cellular senescence, cancer and aging. Most of the studies deal with the manipulation of telomerase enzyme in...

Cytomegalovirus (CMV) infection profoundly affects the T cell compartment and is associated with alterations in T cell aging parameters and generation of cytotoxic CD4(+) CD28null T cells. Hence, the effect of a primary CMV infection post-kidney transplantation (KT) on the peripheral T cell compartment was examined. As aging parameters, we determined the T cell differentiation status, T cell receptor excision circle (TREC) content, CD31(+) naïve T cell numbers and relative telomere length (RTL)...

Telomerase reverse transcriptase (TERT) maintains telomere ends during DNA replication by catalyzing the addition of short telomere repeats. The expression of telomerase is normally repressed in somatic cells leading to a gradual shortening of telomeres and cellular senescence with aging. Interindividual variation in leukocyte telomere length has been previously associated with susceptibility to cardiovascular disease. The aim of the present study was to determine whether six variants in the...

The caps on the ends of chromosomes, called telomeres, keep the ends of chromosomes from appearing as DNA double-strand breaks (DSBs) and prevent chromosome fusion. However, subtelomeric regions are sensitive to DSBs, which in normal cells is responsible for ionizing radiation-induced cell senescence and protection against oncogene-induced replication stress, but promotes chromosome instability in cancer cells that lack cell cycle checkpoints. We have previously reported that I-SceI...

Aging is the most prominent risk factor contributing to the development of neurodegenerative disorders. In the United States, over 35 million of elderly people suffer from age-related diseases. Aging impairs the self-repair ability of neuronal cells, which undergo progressive deterioration. Once initiated, this process hampers the already limited regenerative power of the central nervous system, making the search for new therapeutic strategies particularly difficult in elderly affected patients....

Age-at-menopause and leukocyte telomere length (LTL) are both associated with biologic aging. Therefore, it would be reasonable to hypothesize that LTL may also serve as a marker for reproductive aging as shorter LTL may be associated with earlier age-at-menopause....

Clonal evolutionary processes can drive pathogenesis in human diseases, with cancer being a prominent example. To prevent or treat cancer, mechanisms that can potentially interfere with clonal evolutionary processes need to be understood better. Mathematical modeling is an important research tool that plays an ever-increasing role in cancer research. This paper discusses how mathematical models can be useful to gain insights into mechanisms that can prevent disease initiation, help analyze...

Multipotent mesenchymal stem cells (MSCs) are widely used as seed cells in studies of tissue engineering and regenerative medicine; however, their clinical application is limited due to replicative senescence. It has been demonstrated that telomerase expression extends the lifespan and maintains the bone-forming ability of MSCs; however, the detailed role and the underlying molecular mechanisms in MSCs remain largely unknown. In the present study, we found that senescence was associated with...

Atherosclerosis is a disease of ageing in that its incidence and prevalence increase with age. However, atherosclerosis is also associated with biological ageing, manifest by a number of typical hallmarks of ageing in the atherosclerotic plaque. Thus, accelerated biological ageing may be superimposed on the effects of chronological ageing in atherosclerosis. Tissue ageing is seen in all cells that comprise the plaque, but particularly in vascular smooth muscle cells (VSMCs). Hallmarks of ageing...

Energy restriction in prenatal life has detrimental effects on later life health and longevity. Studies in rats have shown that the shortening of telomeres in key tissues plays an important role in this association....

Telomeres are essential for chromosomal integrity and stability. Shortened telomere length (TL) has been associated with risk of cancers and aging-related diseases. Several studies have explored associations between TL and cancer prognosis, but the results are conflicting....

There is a well-established association between aging and the onset of metastasis. Although the mechanisms through which age impinges upon the malignant phenotype remain uncharacterized, the role of a senescent microenvironment has been emphasized. We reported previously that human epithelial cells that undergo telomere-driven chromosome instability (T-CIN) display global microRNA (miR) deregulation and develop migration and invasion capacities. Here, we show that post-crisis cells are not able...

The aging kidney undergoes profound changes that lead to a reduction in stress resistance and impaired repair capacity. In order to improve the outcome of acute and chronic kidney damage, it is instrumental to understand the mechanisms that cause these changes. Cellular senescence has emerged as an important cellular process that contributes to age-associated kidney changes and chronic kidney disease progression....

Telomere length (TL) is highly heritable, and a shorter telomere at birth may increase the risk of age-related problems. Additionally, a shorter TL may represent a biomarker of chronic stress and has been associated with psychiatric disorders. However, no study has explored whether there is an association between TL and the symptoms of one of the most common neurodevelopmental disorders in childhood: Attention Deficit/Hyperactive Disorder (ADHD). We evaluated 61 (range, 6-16 years) ADHD children...

In eukaryotes, telomeres cap chromosome ends to maintain genomic stability. Failure to maintain telomeres leads to their progressive erosion and eventually triggers replicative senescence, a pathway that protects against unrestricted cell proliferation. However, the mechanisms underlying the variability and dynamics of this pathway are still elusive. Here we use a microfluidics-based live-cell imaging assay to investigate replicative senescence in individual Saccharomyces cerevisiae cell...

Ever since the first demonstration of their repetitive sequence and unique replication pathway, telomeres have beguiled researchers with how they function in protecting chromosome ends. Of course much has been learned over the years, and we now appreciate that telomeres are comprised of the multimeric protein/DNA shelterin complex and that the formation of t-loops provides protection from DNA damage machinery. Deriving their name from D-loops, t-loops are generated by the insertion of the 3'...

Older cancer patients are a highly heterogeneous population in terms of global health and physiological reserves, and it is often difficult to determine the best treatment. Moreover, clinical tools currently used to assess global health require dedicated time and lack a standardized end score. Circulating markers of biological age and/or fitness could complement or partially substitute the existing screening tools. In this study we explored the relationship of potential ageing/frailty biomarkers...

Short leukocyte telomere length (LTL) has become a hallmark characteristic of aging and is associated with higher morbidity and mortality. Physical activity (PA) has been implicated in attenuating age-induced diseases by, for example, preserving LTL. Results from studies of the relationship between PA and LTL have been mixed, which might be because PA was assessed over a short period of time. There have been few studies in which investigators have examined the association between LTL and...

Authors: K K. Hartmann, A A. Illing, F F. Leithäuser, A A. Baisantry, L L. Quintanilla-Martinez, K L KL. Rudolph Published: 07/02/2015, Leukemia PubMed Full Text...

Deterioration of metabolic syndrome (MetS) has been associated with short telomere length (TL). Large-scale longitudinal studies with repeated measures of MetS and TL are lacking....

Telomeres interact with numerous proteins, including components of the shelterin complex, whose alteration, similarly to proliferation-induced telomere shortening, initiates cellular senescence. In tumors, telomere length is maintained by Telomerase activity or by the Alternative Lengthening of Telomeres mechanism, whose hallmark is the telomeric localization of the promyelocytic leukemia (PML) protein. Whether PML contributes to telomeres maintenance in normal cells is unknown. We show that in...

Tumour formation is blocked by two barriers: replicative senescence and crisis. Senescence is triggered by short telomeres and is bypassed by disruption of tumour-suppressive pathways. After senescence bypass, cells undergo crisis, during which almost all of the cells in the population die. Cells that escape crisis harbour unstable genomes and other parameters of transformation. The mechanism of cell death during crisis remains unexplained. Here we show that human cells in crisis undergo...

Although BRCA1 function is essential for maintaining genomic integrity in all cell types, it is unclear why increased risk of cancer in individuals harbouring deleterious mutations in BRCA1 is restricted to only a select few tissues. Here we show that human mammary epithelial cells (HMECs) from BRCA1-mutation carriers (BRCA1(mut/+)) exhibit increased genomic instability and rapid telomere erosion in the absence of tumour-suppressor loss. Furthermore, we uncover a novel form of...

Short leukocyte telomere length (LTL) is associated with atherosclerosis in adults and diminished survival in the elderly. The prevailing view is that LTL is associated with accelerated aging since it serves as a biomarker of the cumulative burden of inflammation and oxidative stress during adult life. However LTL dynamics are mainly defined by LTL at birth, which is highly variable, and its age-dependent attrition thereafter, which is rapid during the first 20 years of life. We examined whether...

'Cellular senescence', a term originally defining the characteristics of cultured cells that exceed their replicative limit, has been broadened to describe durable states of proliferative arrest induced by disparate stress factors. Proposed relationships between cellular senescence, tumour suppression, loss of tissue regenerative capacity and ageing suffer from lack of uniform definition and consistently applied criteria. Here, we highlight caveats in interpreting the importance of suboptimal...

The elevation of circulating LPS has been associated with obesity and aging. However, whether and how LPS contributes to adipose tissue dysfunction is unclear. In this study, we investigated the effect of LPS on the adipogenic capacity and cellular senescence of adipocyte progenitors. Stromal-vascular cells were isolated from inguinal adipose tissue of C57BL/6 mice and treated with LPS during the different time periods of adipocyte differentiation. We found that LPS treatment for 24 h prior to...

The global population is aging with significant gains in life expectancy particularly in the developed world. Consequently, greater focus on understanding the processes that underlie physiological aging has occurred. Key facets of advancing age include genomic instability, telomere shortening, epigenetic changes, and declines in immune function termed immunosenescence. Immunosenescence and its associated chronic low grade systemic "inflamm-aging" contribute to the development and progression of...

Telomere shortening is strongly associated with higher mortality rates and has been shown in a number of age-related diseases, such as cardiovascular disorders, diabetes mellitus, Alzheimer's disease, and psychiatric disorders. Oxidative stress is known to induce DNA breaks and genome instability. Telomeric DNA rich in guanosine is particularly sensitive to such oxidative damages. Psychosis is associated with a disequilibrium between free radical production and antioxidative defense. Although...

Human telomeres are G-rich tandem repeats that assume G-quadruplex structures at the ends of chromosomes. Stabilization of telomeric G-quadruplex represents a significant drug target for inhibiting the telomerase activity that is required in ~85% of cancers. Metal ions have been revealed as important stabilizers to DNA G-quadruplexes, but their binding process with human telomeric G-quadruplex remains unclear. In this report, we show that K(+) traverses into the G-tetrads center of two G-tetrad...

The Kaiser Permanente Research Program on Genes, Environment, and Health (RPGEH) Genetic Epidemiology Research on Adult Health and Aging (GERA) cohort includes DNA specimens extracted from saliva samples of 110,266 individuals. Because of its relationship to aging, telomere length measurement was considered an important biomarker to develop on these subjects. To assay relative telomere length (TL) on this large cohort over a short time period, we created a novel high throughput robotic system...

Cellular senescence--defined as a stable cell-cycle arrest combined with stereotyped phenotypic changes--might play a causal role in various lung diseases, including chronic obstructive pulmonary disease (COPD), which is predicted to become the third leading cause of death worldwide by 2020. COPD is characterized by slowly progressive airflow obstruction and emphysema due to destruction of the lung parenchyma and is often complicated by pulmonary hypertension (PH). No curative treatment is...

Chromosomal telomere length shortens with repeated cell divisions. Human leukocyte DNA telomere length (LTL) has been shown to shorten during aging. LTL shortening has correlated with decreased longevity, dementia, and other age-associated processes. Because LTL varies widely between individuals in a given age group, it has been hypothesized to be a marker of biological aging. However, the principal basis for the variation of human LTL has not been established, although various studies have...

Strong evidence supports that living in disadvantaged neighborhoods has direct unfavorable impact on mental and physical health. However, whether it also has direct impact on cellular health is largely unknown. Thus we examined whether neighborhood quality was associated with leukocyte telomere length, an indicator of cellular aging....

Visual impairment broadly impacts the ability of affected people to maintain their function and to remain independent during their daily occupations as they grow older. Visual impairment affects survival of older patients, quality of life, can affect a person's self-ranking of health , may be associated with social and functional decline, use of community support services, depression , falls , nursing home placement , and increased mortality. It has been hypothesized that senile cataract may...

Evidence for an association of leukocyte telomere length (LTL) with cognitive function, predominantly in older adults, is inconsistent. No report has examined the association of LTL dynamics (age-specific LTL and its attrition rate) with cognitive function. We aimed to examine the association of LTL dynamics over 13 years in young adulthood with cognitive function in midlife. 497 individuals who had LTL measured at ages 28-32 and 41-46 years were assessed at ages 48-52 for global cognitive...

Cellular DNA is organized into chromosomes and capped by a unique nucleoprotein structure, the telomere. Both oxidative stress and telomere shortening/dysfunction cause aging-related degenerative pathologies and increase cancer risk. However, a direct connection between oxidative damage to telomeric DNA, comprising <1% of the genome, and telomere dysfunction has not been established. By fusing the KillerRed chromophore with the telomere repeat binding factor 1, TRF1, we developed a novel...

During DNA replication, the enzyme telomerase maintains the ends of chromosomes, called telomeres. Shortened telomeres trigger cell senescence, and cancer cells often have increased telomerase activity to promote their ability to proliferate indefinitely. The catalytic subunit, human telomerase reverse transcriptase (hTERT), is stabilized by phosphorylation. We found that the lysophospholipid sphingosine 1-phosphate (S1P), generated by sphingosine kinase 2 (SK2), bound hTERT at the nuclear...

Telomere length and telomerase activity are important indicators of cellular senescence and replicative ability. Loss of telomerase is associated with ageing and the development of osteoarthritis. Implantation of telomerase-positive cells, chondrocytes, or stem cells expressing a normal chondrocyte phenotype is desired for cartilage repair procedures. The objective of this study was to identify at what age chondrocytes and at what passage bone marrow-derived mesenchymal stem cells (MSCs) become...

The integrity of the nuclear lamina has emerged as an important factor in the maintenance of genome stability. In particular, mutations in the LMNA gene, encoding A-type lamins (lamin A/C), alter nuclear morphology and function, and cause genomic instability. LMNA gene mutations are associated with a variety of degenerative diseases and devastating premature aging syndromes such as Hutchinson-Gilford Progeria Syndrome (HGPS) and Restrictive Dermopathy (RD). HGPS is a severe laminopathy, with...

We first aimed to generate transformed cell lines from a human induced pluripotent stem cell (hiPSC)-teratoma, and then examined the tumorigenic risks of the differentiated cells from hiPSC explant, because hiPSC-derivatives give rise to tumors in immune-deficient mice when transplanted. The colonies isolated from sparse cultures of hiPSC-teratoma cells expressed NANOG and OCT3/4 strongly, and telomerase reverse transcriptase (TERT) weakly. However, soft agar assay demonstrated that only one of...

Acrylamide (AAM) has been recently discovered in food as a Maillard reaction product. AAM and glycidamide (GA), its metabolite, have been described as probably carcinogenic to humans. It is widely established that senescence and carcinogenicity are closely related. In vitro, endothelial aging is characterized by replicative senescence in which primary cells in culture lose their ability to divide. Our objective was to assess the effects of AAM and GA on human endothelial cell senescence. Human...

During the last decade, our understanding of the molecular mechanisms regulating the cellular environment has made significant advances. With the new dynamical description of the functionalities of the cell, several processes known to play a crucial role in the onset of aging such as cell senescence, the increase of ROS level and telomere shortening appear to be a consequence of the disruption of a systemic dynamical equilibrium established within the cellular environment. In this short review,...

Advancing age is a well-known risk factor for tendon disease. Energy-storing tendons [e.g., human Achilles, equine superficial digital flexor tendon (SDFT)] are particularly vulnerable and it is thought that injury occurs following an accumulation of micro-damage in the extracellular matrix (ECM). Several authors suggest that age-related micro-damage accumulates due to a failure of the aging cell population to maintain the ECM or an imbalance between anabolic and catabolic pathways. We...

It is supposed that the development and aging of multicellular animals and humans are controlled by a special form of the clock mechanism - a chronograph. The development of animals and their aging are interconnected by the program of the species lifespan that has been selected in the evolution of each species to fit the resources of its ecological niche.

Aging is characterized by a decrease in genome integrity, impaired organ maintenance, and an increased risk of cancer, which coincide with clonal dominance of expanded mutant stem and progenitor cell populations in aging tissues, such as the intestinal epithelium, the hematopoietic system, and the male germline. Here we discuss possible explanations for age-associated increases in the initiation and/or progression of mutant stem/progenitor clones and highlight the roles of stem cell quiescence,...

This study examined the association between leukocyte telomere length--a marker of cell aging--and mortality in a nationally representative sample of US adults ages 50-84 years. We also examined moderating effects of age, sex, race/ethnicity, and education....

Hypoxic areas are a common feature of rapidly growing malignant tumors and their metastases and are typically spatially heterogeneous. Hypoxia has a strong impact on tumor cell biology and contributes to tumor progression in multiple ways. To date, only a few molecular key players in tumor hypoxia, such as hypoxia-inducible factor-1 (HIF-1), have been discovered. The distribution of biomolecules is frequently heterogeneous in the tumor volume and may be driven by hypoxia and HIF-1α....

In adults, bone hematopoietic cells are responsible for the lifelong production of all blood cells. It is affected in aging, with progressive loss of physiological integrity leading to impaired function by cellular intrinsic and extrinsic factors. However, intervention measures, which directly inhibit the aging of hematopoietic cells, remain to be investigated. In the present study, 10 µmol/l ginsenoside Rg1 (Rg1) markedly alleviated the aging phenotypes of Sca‑1+ hematopoietic cells...

A new holistic paradigm is proposed for slowing our genomic-based biological clocks (e.g. regulation of telomere length), and decreasing heat energy exigencies for maintenance of physiologic homeostasis. Aging is considered the result of a progressive slow burn in small volumes of tissues with increase in the quantum entropic states; producing desiccation, microscopic scarring, and disruption of cooperative coherent states. Based upon piezoelectricity, i.e. photon-phonon transductions,...

The belief that beekeepers live longer than anyone else is present since ages. However, no research has been done to explore the longevity of life in beekeepers. Here, we investigated the telomere length in 30 male beekeepers and 30 male non-beekeepers and associated them with the longevity of life using Southern analysis of terminal restriction fragments (TRFs) generated by Hinf I/Rsa I digestion of human genomic DNA using TeloTAGGG Telomere Length Assay. Interestingly, we found that the...

It is known that glucose disturbances contribute to micro- and macrovascular complications and vascular aging. Telomere length is considered to be a cellular aging biomarker. It is important to determine the telomere length role in vascular structural and functional changes in patients with diabetes mellitus. We conducted a cross-sectional observational study in a high-risk population from Moscow, Russia. The study included 50 patients with diabetes and without clinical cardiovascular disease...

The telomeric 3'-overhang (G-tail) length is essential for the biological effects of telomere dysfunction in vitro, but the association of length with aging and cardiovascular risk is unclear in humans. We investigated the association between the telomere G-tail length of leukocytes and cardiovascular risk, age-related white matter changes (ARWMCs), and endothelial function....

Dyskeratosis congenita (DC) and related diseases are a heterogeneous group of disorders characterized by impaired telomere maintenance, known collectively as the telomeropathies. Disease-causing variants have been identified in 10 telomere-related genes including the reverse transcriptase (TERT) and the RNA component (TERC) of the telomerase complex. Variants in TERC and TERT can impede telomere elongation causing stem cells to enter premature replicative senescence and/or apoptosis as telomeres...

Aging is a process that depends on a variety of both external and internal factors. The biological age of a person determines body deterioration and the risk of age-related diseases. Currently, as indicators of biological age are considered different characteristics including average length of telomeres in cells and the level DNA methylation. We propose to combine the two approaches to create a model to assess the biological age of the person. Application of qPCR to determina the length of...

The incidence of CVD increases with aging, because of long-term exposure to risk factors/stressors. Aging is a complex biological process resulting in progressive loss of physiological integrity, leading to impaired function and increased vulnerability to death. The main hallmarks of aging are cellular senescence, stem cell exhaustion, and altered intracellular communication. The major hallmarks of senescence are mitochondrial dysfunction, genomic instability, telomere attrition and epigenetic...

Chronic Hepatitis B virus (HBV) infection can lead to the development of chronic hepatitis, cirrhosis and hepatocellular carcinoma. We hypothesized that HBV might accelerate hepatocyte ageing and investigated the effect of HBV on hepatocyte cell cycle state and biological age. We also investigated the relation between inflammation, fibrosis and cell cycle phase....

The researches in the dynamic changes of the progress of HSCs aging are very limited and necessary. In this study, male C57BL/6 mice were divided into 5 groups by age. We found that the superoxide damage of HSPCs started to increase from the middle age (6 months old), with notably reduced antioxidation ability. In accordance with that, the senescence of HSPCs also started from the middle age, since the self-renewal and differentiation ability remarkably decreased, and senescence-associated...

Early-life intelligence has been shown to predict multiple causes of death in populations around the world. This finding suggests that intelligence might influence mortality through its effects on a general process of physiological deterioration (i.e., individual variation in "biological age"). We examined whether intelligence could predict measures of aging at midlife before the onset of most age-related disease....

The objective of this study is to investigate placental telomere shortening in unexplained stillbirths (SBs) as an indication of premature senescence....

Telomere shortening is considered a cellular marker of health status and biological ageing. Exercise may influence the health and lifespan of an individual by affecting telomere length (TL). However, it is unclear whether different endurance exercise levels may have beneficial or detrimental effects on biological aging. The aims of the study were to assess both chronic and acute effects of endurance training on TL after an exceptional and extreme trail race. TL was assessed in 20 endurance...

Psychiatric diseases are associated with an increased rate of somatic age-related illness. A new study sheds light on putative mediating cellular mechanisms by linking increased mitochondrial DNA copy number and decreased telomere length to childhood stress and major depression....

The ends of eukaryotic chromosomes need to be protected from the activation of a DNA damage response that leads the cell to replicative senescence or apoptosis. In mammals, protection is accomplished by a six-factor complex named shelterin, which organizes the terminal TTAGGG repeats in a still ill-defined structure, the telomere. The stable interaction of shelterin with telomeres mainly depends on the binding of two of its components, TRF1 and TRF2, to double-stranded telomeric repeats....

Telomeres usually shorten during an organism's lifespan and have thus been used as an aging and health marker. When telomeres become sufficiently short, senescence is induced. The most common method of restoring telomere length is via telomerase reverse transcriptase activity, highly expressed during embryogenesis. However, although asexual reproduction from adult tissues has an important role in the life cycles of certain species, its effect on the aging and fitness of wild populations, as well...

SLX4 assembles a toolkit of endonucleases SLX1, MUS81 and XPF, which is recruited to telomeres via direct interaction of SLX4 with TRF2. Telomeres present an inherent obstacle for DNA replication and repair due to their high propensity to form branched DNA intermediates. Here we provide novel insight into the mechanism and regulation of the SLX4 complex in telomere preservation. SLX4 associates with telomeres throughout the cell cycle, peaking in late S phase and under genotoxic stress....

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...

Transplantation is the preferred method of end stage renal insufficiency treatment due to better quality of life and extended life of transplanted patients. Currently a non-invasive test, which evaluates the risk of acute or chronic rejection or deterioration of the transplanted organ's function, is being sought. An increase of the transrenal DNA concentration in the urine of urinary tract infection patients and in renal graft recipients during an episode of acute rejection was observed. There...

Both short telomere length and mitochondrial dysfunction have been associated with pregnancy complications, such as preeclampsia and intrauterine growth restriction. However, the relationship between these two biomarkers of oxidative stress, during pregnancy, is unknown. This study investigated the association of leukocyte telomere length with mitochondrial DNA (mtDNA) copy number, an indicator of mitochondrial density and possible mitochondrial dysfunction, using maternal blood samples...

Schizophrenia has been suggested as a syndrome of accelerated aging. Telomere length (TL) decrease is considered one biological marker associated with age and can be accelerated by pathological characteristics present in schizophrenia. Several studies evaluated TL in schizophrenia, but the results are still controversial. The aim of this study was to conduct a meta-analysis of the existing results of TL in leukocytes of individuals with schizophrenia compared to healthy controls. A search was...

Telomeres, comprised of short repetitive sequences, are essential for genome stability and have been studied in relation to cellular senescence and aging. Telomerase, the enzyme that adds telomeric repeats to chromosome ends, is essential for maintaining the overall telomere length. A lack of telomerase activity in mammalian somatic cells results in progressive shortening of telomeres with each cellular replication event. Mammals exhibit high rates of cell proliferation during embryonic and...

Ovarian aging is closely tied to the decline in ovarian follicular reserve and oocyte quality. During the prolonged reproductive lifespan of the female, granulosa cells connected with oocytes play critical roles in maintaining follicle reservoir, oocyte growth and follicular development. We tested whether double-strand breaks (DSBs) and repair in granulosa cells within the follicular reservoir are associated with ovarian aging....

Many adverse pregnancy outcomes (APOs), including spontaneous preterm birth (PTB), are associated with placental dysfunction. Recent clinical and experimental evidences suggest that premature aging of the placenta may be involved in these events. Although placental aging is a well-known concept, the mechanisms of aging during normal pregnancy and premature aging in APOs are still unclear. This review was conducted to assess the knowledge on placental aging related biochemical changes leading to...

A career as an elite-class male athlete seems to improve metabolic heath in later life and is also associated with longer life expectancy. Telomere length is a biomarker of biological cellular ageing and could thus predict morbidity and mortality. The main aim of this study was to assess the association between vigorous elite-class physical activity during young adulthood on later life leukocyte telomere length (LTL). The study participants consist of former male Finnish elite athletes (n = 392)...

Post-traumatic stress disorder (PTSD) has major public health significance. Evidence that PTSD may be associated with premature senescence (early or accelerated aging) would have major implications for quality of life and healthcare policy. We conducted a comprehensive review of published empirical studies relevant to early aging in PTSD....

Telomere length shortens with aging, and short telomeres have been linked to a wide variety of pathologies. Previous studies suggested a discrepancy in age-associated telomere shortening rate estimated by cross-sectional studies versus the rate measured in longitudinal studies, indicating a potential bias in cross-sectional estimates. Intergenerational changes in initial telomere length, such as that predicted by the previously described effect of a father's age at birth of his offspring (FAB),...

Aging continuously remodels the immune system, a process known as immunosenescence. Here, we review evidence of premature immunosenescence in younger individuals under conditions of chronic psychological stress, chronic inflammation, or exposure to certain persistent viral infections. Chronic stress may accelerate various features of immunosenescence by activating key allostatic systems, notably the hypothalamic-pituitary-adrenal axis and increased cortisol levels. Chronic stress is associated...

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...

The field of sedentary behavior epidemiology is emerging. Short leukocyte telomere length (LTL) is a hallmark characteristic of aging, but LTL is also associated with morbidity and mortality independent of age. To my knowledge, only one study has examined the association between sedentary behavior and LTL. The purpose of this study was to examine the association between screen-based sedentary behavior and LTL. Data from the 1999-2002 National Health and Nutrition Examination Survey were used...

The Suv39h1 and Suv39h2 H3K9 histone methyltransferases (HMTs) have a conserved role in the formation of constitutive heterochromatin and gene silencing. Using a transgenic mouse model system we demonstrate that elevated expression of Suv39h1 increases global H3K9me3 levels in vivo. More specifically, Suv39h1 overexpression enhances the imposition of H3K9me3 levels at constitutive heterochromatin at telomeric and major satellite repeats in primary mouse embryonic fibroblasts. Chromatin...

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...

The cornea protects the anterior eye and accounts for two thirds of the eyes refractive capacity. The homeostasis of corneal epithelium is thought to be maintained by putative stem cells residing in the epithelial basal layer. As a tissue constantly exposed to environmental stress, the cornea is hypothesised to accumulate persistent DNA damage events with time in stem cell populations. Recently, telomere associated DNA damage foci (TAFs) have been suggested as a marker for persistent DNA damage...

Telomeres are the ends of eukaryotic chromosomes, consisting of consecutive short repeats that protect chromosome ends from degradation. Telomeres shorten with each cell division, leading to replicative cell senescence. Deregulation of telomere length homeostasis is associated with the development of various age-related diseases and cancers. A number of experimental techniques exist for telomere length measurement; however, until recently, the absence of tools for extracting telomere lengths...

The telomeric end structures of the DNA are known to contain tandem repeats of TTAGGG sequence bound with specialised protein complex called the "shelterin complex". It comprises six proteins, namely TRF1, TRF2, TIN2, POT1, TPP1 and RAP1. All of these assemble together to form a complex with double strand and single strand DNA repeats at the telomere. Such an association contributes to telomere stability and its protection from undesirable DNA damage control-specific responses. However, any...

Genetic studies have bestowed insight into the biological mechanisms underlying inter-individual differences in susceptibility to (or resistance to) organisms’ aging. Recent advances in molecular and genetic epidemiology provide tools to explore the genetic sources of the variability in biological aging in humans. To be successful, the genetic study of a complex condition such as aging requires the clear definition of essential traits that can characterize the aging process phenotypically....

Personality traits have been associated with cardiometabolic diseases and mental disorders as well as with longevity. However, the underlying mechanisms are not fully understood. Accelerated cellular aging may play a role in this process. We studied whether personality traits in late adulthood, as defined in the five-factor model (FFM), were associated with a biomarker of cellular vitality, leukocyte telomere length (LTL)....

A critical function of the telomere is to disguise chromosome ends from cellular recognition as double strand breaks, thereby preventing aberrant chromosome fusion events. Such chromosome end-to-end fusions are known to initiate genomic instability via breakage-fusion-bridge cycles. Telomere dysfunction and other forms of genomic assault likely result in misregulation of genes involved in growth control, cell death, and senescence pathways, lowering the threshold to malignancy and likely drive...

Telomeric diseases are a group of rare progeroid genetic syndromes, presenting premature aging phenotypes, characterized for defects on telomere maintenance. In humans, telomeres are heterochromatic structures consisting of long TTAGGG repeats located at the chromosomal ends, which shorten progressively after each DNA replication because of the 'end replication problem'. Critically short telomeres activate a DNA damage response that leads to the arrest of the cell cycle and resulting in cellular...

The process of aging results in a host of changes at the cellular and molecular levels, which include senescence, telomere shortening, and changes in gene expression. Epigenetic patterns also change over the lifespan, suggesting that epigenetic changes may constitute an important component of the aging process. The epigenetic mark that has been most highly studied is DNA methylation, the presence of methyl groups at CpG dinucleotides. These dinucleotides are often located near gene promoters and...

This study sought to assess the association between long-term radiation exposure in the catheterization laboratory (cath lab) and early signs of subclinical atherosclerosis....

Expression of type I interferons (IFNs) can be induced by DNA-damaging agents, but the mechanisms and significance of this regulation are not completely understood. We found that the transcription factor IRF3, activated in an ATM-IKKα/β-dependent manner, stimulates cell-autonomous IFN-β expression in response to double-stranded DNA breaks. Cells and tissues with accumulating DNA damage produce endogenous IFN-β and stimulate IFN signaling in vitro and in vivo. In turn, IFN acts to amplify...

Telomere dysfunction plays a complex role in tumorigenesis. While dysfunctional telomeres can block the proliferation of incipient cancer clones by inducing replicative senescence, fusion of dysfunctional telomeres can drive genome instability and oncogenic genomic rearrangements. Therefore, it is important to define the regulatory pathways that guide these opposing effects. Recent work has shown that the autophagy pathway regulates both senescence and genome instability in various contexts....

The alternative lengthening of telomeres (ALT) mechanism allows cancer cells to escape senescence and apoptosis in the absence of active telomerase. A characteristic feature of this pathway is the assembly of ALT-associated promyelocytic leukemia (PML) nuclear bodies (APBs) at telomeres. Here, we dissected the role of APBs in a human ALT cell line by performing an RNA interference screen using an automated 3D fluorescence microscopy platform and advanced 3D image analysis. We identified 29...

It is supposed that the development and aging of multicellular animals and humans are controlled by a special form of the clock mechanism - a chronograph. The development of animals and their aging are interconnected by the program of the species lifespan that has been selected in the evolution of each species to fit the resources of its ecological niche. The theory is based on the idea about a controlled loss by the neurons in the brain of hypothetical organelles - chronomeres that represent...

During the last decade, our understanding of the molecular mechanisms regulating the cellular environment has made significant advances. With the new dynamical description of the functionalities of the cell, several processes known to play a crucial role in the onset of aging such as cell senescence, the increase of ROS level and telomere shortening appear to be a consequence of the disruption of a systemic dynamical equilibrium established within the cellular environment. In this short review,...

By maintaining genome integrity, controlling cell proliferation, and regulating tissue homeostasis, telomerase plays a critical role in the pathology of aging and cancer. Telomerase is composed of telomerase RNA, or telomerase RNA component (TERC), which serves as a template for telomeric DNA synthesis, and a catalytic subunit, telomerase reverse transcriptase (TERT). The canonical function of TERT is the synthesis of telomeric DNA repeats and the maintenance of telomere length. Recent studies...

Telomere shortening to a critical limit is associated with replicative senescence. This process is prevented by the enzyme telomerase. Oxidative stress and chronic inflammation are factors accelerating telomere loss. Chronic hemodialysis, typically accompanied by oxidative stress and inflammation, may be also associated with replicative senescence. To test this hypothesis, we determined telomere length and telomerase activity in peripheral blood mononuclear cells (PBMCs) in a cross-sectional...

Patients with histories of myocardial infarction display shortened leukocyte telomere length (LTL), but conflicting findings have been reported on the relation between LTL and subclinical coronary artery atherosclerosis, as expressed by coronary artery calcium (CAC). The aim of this study was to examine the relation between LTL, measured by Southern blots, and CAC in 3,169 participants in the National Heart, Lung, and Blood Institute Family Heart Study. Participants consisted of 2,556 whites,...

Telomere assumes intra-molecular G-quadruplex that is a significant drug target for inhibiting telomerase maintenance of telomeres in cancer. Metal cations have been recognized as playing important roles in stabilizing G-quadruplex, but their binding processes to human telomeric G-quadruplex remain uncharacterized. To investigate the detailed binding procedures, molecular dynamics simulations were conducted on the hybrid [3 + 1] form-one human telomeric intra-molecular G-quadruplex. We show here...

Werner Syndrome (WS) is a rare inherited disease characterized by premature aging and increased propensity for cancer. Mutations in the WRN gene can be of several types, including nonsense mutations, leading to a truncated protein form. WRN is a RecQ family member with both helicase and exonuclease activities, and it participates in several cell metabolic pathways, including DNA replication, DNA repair, and telomere maintenance. Here, we reported a novel homozygous WS mutation (c.3767 C > G) in...

Combination antiretroviral therapy (cART) has extended the longevity of human immunodeficiency virus (HIV)-infected individuals. However, this has resulted in greater awareness of age-associated diseases such as chronic obstructive pulmonary disease (COPD). Accelerated cellular senescence may be responsible, but its magnitude as measured by leukocyte telomere length is unknown and its relationship to HIV-associated COPD has not yet been established. We measured absolute telomere length (aTL) in...

The old age population is increasing worldwide as well as age related diseases, including neurodegenerative disorders, such as Alzheimer's disease (AD), which negatively impacts on the health care systems. Aging represents per se a risk factor for AD. Thus, the study and identification of pathways within the biology of aging represent an important end point for the development of novel and effective disease-modifying drugs to treat, delay, or prevent AD. Cellular senescence and telomere...

Impaired glucose tolerance characterized by postprandial hyperglycemia, which occurs frequently in elderly persons and represents an important preliminary step in diabetes mellitus, poses an independent risk factor for the development of atherosclerosis. Endothelial cellular senescence is reported to precede atherosclerosis. We reported that continuous high glucose stimulus causes endothelial senescence more markedly than hypertension or dyslipidemia stimulus. In the present study, we evaluated...

Human cardiac progenitor cells (hCPC) improve heart function after autologous transfer in heart failure patients. Regenerative potential of hCPCs is severely limited with age, requiring genetic modification to enhance therapeutic potential. A legacy of work from our laboratory with Pim1 kinase reveals effects on proliferation, survival, metabolism, and rejuvenation of hCPCs in vitro and in vivo. We demonstrate that subcellular targeting of Pim1 bolsters the distinct cardioprotective effects of...

There are limited data on the association between dietary information and leukocyte telomere length (LTL), which is considered an indicator of biological aging. In this study, we aimed at determining the association between dietary patterns or consumption of specific foods and LTL in Korean adults....

Telomere erosion leading to replicative senescence has been well documented in human and anthropoid primates, and provides a clue against tumorigenesis. In contrast, other mammals, such as laboratory mice, with short lifespan and low body weight mass have different telomere biology without replicative senescence. We analyzed telomere biology in the grey mouse lemur, a small prosimian model with a relative long lifespan currently used in ageing research. We report an average telomere length by...

Telomeres are dynamic nucleoprotein structures that protect the ends of chromosomes from degradation and activation of DNA damage response. For this reason, telomeres are essential to genome integrity. Chromosome ends are enriched in heterochromatic marks and proper organization of telomeric chromatin is important to telomere stability. Despite their heterochromatic state, telomeres are transcribed giving rise to long noncoding RNAs (lncRNA) called TERRA (telomeric repeat-containing RNA). TERRA...

Telomere shortening has an important role in cellular aging. However, the impact of high sodium intake, an important risk factor of age-related diseases, on telomere shortening remains unknown. Therefore, we examined the relationship between high dietary sodium intake and leukocyte telomere length (LTL), particularly in the context of obesity, as obesity increases salt sensitivity....

Authors: João H JH. Duarte Published: 04/14/2015, Nature reviews. Rheumatology PubMed Full Text...

Accelerated telomere shortening may cause cancer via chromosomal instability, making it a potentially useful biomarker. However, publications on blood telomere length (BTL) and cancer are inconsistent. We prospectively examined BTL measures over time and cancer incidence....

One of the hallmarks of malignant cell populations is the ability to undergo continuous proliferation. This property allows clonal lineages to acquire sequential aberrations that can fuel increasingly autonomous growth, invasiveness, and therapeutic resistance. Innate cellular mechanisms have evolved to regulate replicative potential as a hedge against malignant progression. When activated in the absence of normal terminal differentiation cues, these mechanisms can result in a state of...

Leukocyte telomere length (LTL) and bone mineral density (BMD) are associated with health and mortality. Because osteoporosis is an age-related condition and LTL is considered to be a biomarker of aging, we hypothesized that shorter LTL could predict lower BMD. The aim of our study was to assess whether there is an association of LTL with BMD and to determine whether this possible association is independent of age. The BMDs of the lumbar spine (LS), femoral neck (FN) and total hip (TH) were...

The actions of transcription factors, chromatin modifiers and noncoding RNAs are crucial for the programming of cell states. Although the importance of various epigenetic machineries for controlling pluripotency of embryonic stem (ES) cells has been previously studied, how chromatin modifiers cooperate with specific transcription factors still remains largely elusive. Here, we find that Pontin chromatin remodelling factor plays an essential role as a coactivator for Oct4 for maintenance of...

Telomere length, a highly heritable trait, is longer in offspring of older fathers. This perplexing feature has been attributed to the longer telomeres in sperm of older men and it might be an 'epigenetic' mechanism through which paternal age plays a role in telomere length regulation in humans. Based on two independent (discovery and replication) twin studies, comprising 889 twin pairs, we show an increase in the resemblance of leukocyte telomere length between dizygotic twins of older fathers,...

Neurodegenerative disease is common and frequently occurs in elderly patients. Previous studies have shown that ginsenoside Rg1 was able to inhibit senescent of brain, but the mechanism on the brain during the treatment remains elucidated. To study the mechanism of ginsenoside Rg1 in the process of anti-aging of brain, forty male SD rats were randomly divided into normal group, Rg1 normal group, brain aging model group and Rg1 brain aging model group, each group with 10 rats (brain aging model...

Human ageing is associated with a gradual decline in the physiological functions of the body at multiple levels and it is a key risk factor for many diseases, including cancer. Ageing process is intimately related to widespread cellular senescence, characterised by an irreversible loss of proliferative capacity and altered functioning associated with telomere attrition, accumulation of DNA damage and compromised mitochondrial and metabolic function. Tumour and senescent cells may be generated in...

Cellular aging plays a role in longevity and senescence, and has been implicated in medical and psychiatric conditions, including heart disease, cancer, major depression and posttraumatic stress disorder. Telomere shortening and mitochondrial dysfunction are thought to be central to the cellular aging process. The present study examined the association between mitochondrial DNA (mtDNA) copy number and telomere length in a sample of medically healthy adults. Participants (total n=392) were...

Authors: Abraham A. Aviv, Jeremy D JD. Kark, Ezra E. Susser Published: 04/03/2015, Epidemiology (Cambridge, Mass.) PubMed Full Text...

Telomere syndromes have their most common manifestation in lung disease that is recognized as idiopathic pulmonary fibrosis and emphysema. In both conditions, there is loss of alveolar integrity, but the underlying mechanisms are not known. We tested the capacity of alveolar epithelial and stromal cells from mice with short telomeres to support alveolar organoid colony formation and found that type 2 alveolar epithelial cells (AEC2s), the stem cell-containing population, were limiting. When...

Our investigation aims to assess the impact of symptoms of maternal sleep-disordered breathing, specifically sleep apnea risk and daytime sleepiness, on fetal leukocyte telomere length....

Mature adipocytes have shown dynamic plasticity to be converted into fibroblast-like and lipid-free cells. After the dedifferentiation process, these cells re-entered the cell cycle and acquired a high proliferation potential, becoming a valid source of stem cells. However, many aspects of the cellular biosafety about dedifferentiated fat cells remained unclear. This study aimed to elucidate their potential susceptibility to malignant transformation and to ascertain the safety of these cells for...

Telomeres are structures of tandem TTAGGG repeats that are found at the ends of chromosomes and preserve genomic DNA by serving as a disposable buffer to protect DNA termini during chromosome replication. In this process, the telomere itself shortens with each cell division and can consequently be thought of as a cellular 'clock', reflecting the age of a cell and the time until senescence. Telomere shortening and changes in the levels of telomerase, the enzyme that maintains telomeres, occur in...

DNA double strand break (DSB) is one of the major damages that cause genome instability and cellular aging. The homologous recombination (HR)-mediated repair of DSBs plays an essential role in assurance of genome stability and cell longevity. Telomeres resemble DSBs and are competent for HR. Here we show that in budding yeast Saccharomyces cerevisiae telomere recombination elicits genome instability and accelerates cellular aging. Inactivation of KEOPS subunit Cgi121 specifically inhibits...

The psychosomatic approach arose in antiquity as mankind looked for explanations for illness and death. With the rise of modern medicine, the links between emotions and medical conditions, such as cardiac disease and diabetes, were described by astute clinical observers, but the mechanisms for these conditions were based on correlation from observations rather than on experimental design. Psychoanalytic theory was often utilized to explain many common diseases. For example, peptic ulcer disease...

Most molecular hallmarks of cellular senescence have been identified in studies of cells aged in vitro by driving them into replicative or stress-induced senescence. Comparatively, less is known about the characteristic features of cells that have aged in vivo. Here we provide a systematic molecular analysis of normal human dermal fibroblasts (NHDFs) that were isolated from intrinsically aged human skin of young versus middle aged versus old donors. Intrinsically aged NHDFs in culture exhibited...

The causal role of aneuploidy in cancer initiation remains under debate since mutations of euploidy-controlling genes reduce cell fitness but aneuploidy strongly associates with human cancers. Telomerase activation allows immortal growth by stabilizing telomere length, but its role in aneuploidy survival has not been characterized. Here, we analyze the response of primary human cells and murine hematopoietic stem cells (HSCs) to aneuploidy induction and the role of telomeres and the telomerase...

Obesity is a risk factor for diabetes and its consequences, including accelerated ageing and mortality. The underlying factor could be accumulation of certain lipid moieties, such as ceramides (CER) and diacylgycerol (DAG) within muscle tissue, which are known to promote insulin resistance (IR), induce inflammation and oxidative injury, ultimately altering muscle function....

SIRT6, a member of the sirtuin family of nicotinamide adenine dinucleotide (NAD(+))-dependent protein deacetylases, has been implicated as a key factor in aging-related diseases. However, the role of SIRT6 in chondrocytes has not been fully explored. The purpose of this study was to examine the role of SIRT6 in human chondrocytes by inhibiting SIRT6 in vitro....

To study the impact of simulated climatic conditions of the 2010 summer in Moscow on the telomere repeats of chromosomes in human blood cells....

The WRAP53 gene encodes both an antisense transcript (WRAP53α) that stabilizes the tumor suppressor p53 and a protein (WRAP53β) involved in maintenance of Cajal bodies, telomere elongation and DNA repair. WRAP53β is one of many proteins containing WD40 domains, known to mediate a variety of cellular processes. These proteins lack enzymatic activity, acting instead as platforms for the assembly of large complexes of proteins and RNAs thus facilitating their interactions. WRAP53β mediates...

Prediabetes increases cardiovascular risk and is associated with excess mortality. In preclinical models, metformin has been shown to exert anti-ageing effects. In this study, we sought to assess whether metformin modulates putative effector longevity programs in prediabetic subjects....

Cushing's syndrome (CS) increases cardiovascular risk (CVR) and adipocytokine imbalance, associated with an increased inflammatory state. Telomere length (TL) shortening is a novel CVR marker, associated with inflammation biomarkers. We hypothesized that inflammatory state and higher CVR in CS might be related to TL shortening, as observed in premature aging....

Culture microenvironment plays a critical role in the propagation and differentiation of human embryonic stem cells (hESCs) and their differentiated progenies. Although high efficiency of hESC differentiation to keratinocytes (hESC-Kert) has been achieved, little is known regarding the effects of early culture microenvironment and pertinent extracellular matrix (ECM) interactions during epidermal commitment on subsequent proliferative capacity of hESC-Kert. The aim of this study is to evaluate...

Increasing evidence suggests that miRNAs can act as either tumor suppressors or oncogenes in carcinogenesis. In the present study, we identified the role of miR-34a in regulating telomerase activity, with subsequent effect on cellular senescence and viability. We found the higher expression of miR-34a was significantly correlated with the advanced clinicopathologic parameters in hepatocellular carcinoma. Furthermore, tumor tissues of 75 HCC patients demonstrated an inverse correlation between...

Chronic obstructive pulmonary disease (COPD) is often associated with age-related systemic abnormalities that adversely affect the prognosis. Whether these manifestations are linked to the lung alterations or are independent complications of smoking remains unclear....

Many women now choose to develop their careers before having children. Thus, it is becoming increasingly important to assess a woman's potential for extended fertility and to understand the health consequences of having children at a late age. In particular, there is a striking positive correlation between extended fertility and longevity in women, which poses important implications for medicine, biology, and evolution. In this article we review the diverse epidemiologic evidence for the link...

Down syndrome (DS) is one of the most common aneuploidy. In general population, its prevalence is 1:600-1:800 live births. It is caused by a trisomy of chromosome 21. DS is phenotypically manifested by premature aging, upward slant to the eyes, epicanthus, flattened face, and poor muscle tone. In addition to physical changes, this syndrome is characterized by early onset of diseases specific to old age, such as Alzheimer's disease, vision and hearing problems, and precocious menopause. Since DS...

The human telomere repeat sequence 5'-TTAGGG-3' is a hot spot for oxidation at guanine, yielding 8-oxo-7,8-dihydroguanine (OG), a biomarker of oxidative stress. Telomere shortening resulting from oxidation will ultimately induce cellular senescence. In this study, α-hemolysin (α-HL) nanopore technology was applied to detect and quantify OG in the human telomeric DNA sequence. This repeat sequence adopts a basket G-quadruplex in the NaCl electrolyte used for analysis that enters the α-HL...

Authors: Alexander K AK. Koliada, Dmitry S DS. Krasnenkov, Alexander M AM. Vaiserman Published: 03/16/2015, Frontiers in genetics PubMed Full Text...

The susceptibility of the aging brain to neurodegenerative disease may in part be attributed to cellular aging of the microglial cells that survey it. We investigated the effect of cellular aging induced by telomere shortening on microglia by the use of mice lacking the telomerase RNA component (TERC) and design-based stereology. TERC knockout (KO) mice had a significantly reduced number of CD11b(+) microglia in the dentate gyrus. Because of an even greater reduction in dentate gyrus volume,...

Nonsense-mediated mRNA decay (NMD) is a post-transcriptional mechanism that targets aberrant transcripts and regulates the cellular RNA reservoir. Genetic modulation in vertebrates suggests that NMD is critical for cellular and tissue homeostasis, although the underlying mechanism remains elusive. Here, we generate knockout mice lacking Smg6/Est1, a key nuclease in NMD and a telomerase cofactor. While the complete loss of Smg6 causes mouse lethality at the blastocyst stage, inducible deletion of...

Leucocyte telomere length (LTL) is a complex trait associated with ageing and longevity. LTL dynamics are defined by LTL and its age-dependent attrition. Strong, but indirect evidence suggests that LTL at birth and its attrition during childhood largely explains interindividual LTL variation among adults. A number of studies have estimated the heritability of LTL, but none has assessed the heritability of age-dependent LTL attrition....

In general, nanoparticle-based materials are promising candidates for use in biological systems for diagnostic and therapeutic approaches. However, these materials' actions at the molecular level remain poorly understood. Nanoparticle (silica, silver and diamond)-induced oxidative stress and activation of the NF-κB pathway lead to the depletion of lamin B1 pools, which, in turn, results in upregulation of telomeric repeat binding factor (TRF) protein expression and maintenance of telomere...

The aged population suffers increased morbidity and higher mortality in response to episodes of acute kidney injury (AKI). Aging is associated with telomere shortening, and both telomerase reverse transcriptase (TerT) and RNA (TerC) are essential to maintain telomere length. To define a role of telomerase deficiency in susceptibility to AKI, we used ischemia/reperfusion injury in wild-type mice or mice with either TerC or TerT deletion. Injury induced similar renal impairment at day 1 in each...

When defective or absent, Werner syndrome protein (WRN) causes a genetic premature aging disorder called Werner syndrome. Several studies have reported that defects in WRN function are responsible for not only progeria syndrome but also genomic instability via the deregulation of DNA repair, replication, recombination, and telomere stability. Given the importance of WRN in the repair process, we herein investigated the potential role of WRN in drug response by evaluating the DNA repair following...

In this study, we analyzed 100 cases of renal cell carcinoma (RCC) for telomerase activity, telomere length and alternative lengthening of telomeres (ALT) using the TRAP assay, TeloTTAGGG assay kit and immunohistochemical analysis of ALT associated promyelocytic leukemia (PML) bodies respectively. A significantly higher (P=0.000) telomerase activity was observed in 81 cases of RCC which was correlated with clinicopathological features of tumor for instance, stage (P=0.008) and grades (P=0.000)...

Antigen-specific multifunctional T cells that secrete interferon-γ, interleukin-2 and tumour necrosis factor-α simultaneously after activation are important for the control of many infections. It is unclear if these CD8(+) T cells are at an early or late stage of differentiation and whether telomere erosion restricts their replicative capacity. We developed a multi-parameter flow cytometric method for investigating the relationship between differentiation (CD45RA and CD27 surface phenotype),...

Dermal fibroblasts provide a paradigmatic model of cellular adaptation to long-term exogenous stress and ageing processes driven thereby. Here we addressed whether fibroblast ageing analysedex vivo entails genome instability. Dermal fibroblasts from human female donors aged 20-67 years were studied in primary culture at low population doubling. Under these conditions, the incidence of replicative senescence and rates of age-correlated telomere shortening were insignificant. Genome-wide gene...

Persistent ATG-induced CD4(+) T cell lymphopenia is associated with serious clinical complications. We tested the hypothesis that ATG induces accelerated immune senescence in renal transplant recipients (RTR). Immune senescence biomarkers were analyzed at transplant and one-year later in 97 incident RTR -62 patients receiving ATG and 35 receiving anti-CD25 mAb (α-CD25). This consisted in: (i) thymic output; (ii) bone marrow renewal of CD34(+) hematopoietic progenitor cells (CD34(+) HPC) and...

Telomeres are gene sequences present at chromosomal ends and are responsible for maintaining genome integrity. Telomere length is maximum at birth and decreases progressively with advancing age and thus is considered as a biomarker of chronological aging. This age associated decrease in the length of telomere is linked to various ageing associated diseases like diabetes, hypertension, Alzheimer's disease, cancer etc. and their associated complications. Telomere length is a result of combined...

Hypothalamic releasing and inhibiting hormones are major neuroendocrine regulators of human body metabolism being driven directly to the anterior pituitary gland via hypothalamic-hypophyseal portal veins. The alternative physiological or therapeutic interventions utilizing the pharmaco-nutritional boost of imidazole-containing dipeptides (non-hydrolized oral form of carnosine, carcinine, N-acetylcarnosine lubricant eye drops) can maintain health, enhance physical exercise performance and prevent...

Leukocyte telomere length (LTL) is considered as the marker of biological aging and may be related to environmental factors. The current study aimed to examine the relation between Mediterranean-type diet and LTL. We used a cross-sectional study of 1743 multi-ethnic community residents of New York aged 65 years or older. Mediterranean-type diet (MeDi) was calculated from dietary information collected using a food frequency questionnaire. LTL was measured from leukocyte DNA using a real-time PCR...

High variation in telomere length between individuals is already present before birth and is as wide among newborns as in adults. Environmental exposures likely have an impact on this observation, but remain largely unidentified. We hypothesize that placental telomere length in twins is associated with residential traffic exposure, an important environmental source of free radicals that might accelerate aging. Next, we intend to unravel the nature-nurture contribution to placental telomere...

Telomeric repeat binding factor 2 (TRF2) is essential for telomere maintenance and has been implicated in DNA damage response and aging. Telomere dysfunction induced by TRF2 inhibition can accelerate cellular senescence in human fibroblasts. While previous work has demonstrated that a variety of factors can regulate TRF2 expression transcriptionally and post-translationally, whether microRNAs (miRNAs) also participate in post-transcriptionally modulating TRF2 levels remains largely unknown. To...

It has been documented that telomere-associated cellular senescence may contribute to certain age-related disorders, and telomere length (TL) may be an informative biomarker of healthy aging. Hormone-brain-aging behavior-modulated telomere dynamics and changes in telomerase activity are consistent elements of cellular alterations associated with changes in proliferative state, and these processes are consequently considered as the new therapeutic drug targets for physiological control with...

Subjective age, or how young or old individuals experience themselves to be relative to their chronological age, is a crucial construct in gerontology. Subjective age is a significant predictor of important health outcomes, but little is known about the criteria by which individuals' subjectively evaluate their age. To identify psychosocial and biomedical factors linked to the subjective evaluation of age, this study examined whether perceived age discrimination and markers of biological aging...

The enzymatic ribonucleoprotein telomerase maintains telomeres in many eukaryotes, including humans, and plays a central role in aging and cancer. Saccharomyces cerevisiae telomerase RNA, TLC1, is a flexible scaffold that tethers telomerase holoenzyme protein subunits to the complex. Here we test the hypothesis that a lengthy conserved region of the Est1-binding TLC1 arm contributes more than simply Est1-binding function. We separated Est1 binding from potential other functions by tethering TLC1...

Age is a risk factor for cardiovascular disease, suggesting a causal relationship between age-related changes and vascular damage. Endothelial dysfunction is an early pathophysiological hallmark in the development of cardiovascular disease. Senescence, the cellular equivalent of aging, was proposed to be involved in endothelial dysfunction, but functional data showing a causal relationship are missing.Endothelium-dependent vasodilation was measured in aortic rings ex vivo. We investigated aortas...

Yoga is a mind-body modulation technique that has been shown to have beneficial effects on various diseases related to various systems in the body. However, the molecular basis of mechanism of action is not clear. Hence, this study was designed to study the leukocyte telomere biology and its relation with homocysteine and oxidative stress in yoga practitioners....

The questions about why and how senescence occurs in the wild are among the most pertinent ones in evolutionary ecology. Telomere length is a commonly used marker for aging, while other biomarkers of aging have received considerably less attention. Here we studied how another potent indicator of aging-skin pentosidine concentration-relates to age and blood telomere length in a long-lived seabird with well-documented reproductive senescence. We found no associations between telomere length, skin...

Telomerase is required for long-term telomere maintenance and protection. Using single budding yeast mother cell analyses we found that, even early after telomerase inactivation (ETI), yeast mother cells show transient DNA damage response (DDR) episodes, stochastically altered cell-cycle dynamics, and accelerated mother cell aging. The acceleration of ETI mother cell aging was not explained by increased reactive oxygen species (ROS), Sir protein perturbation, or deprotected telomeres. ETI...

Experimental evidence shows that telomere shortening induces mitochondrial damage but so far studies in humans are scarce. Here, we investigated the association between leukocyte telomere length (LTL) and mitochondrial DNA (mtDNA) content in elderly and explored possible intermediate mechanisms by determining the gene expression profile of candidate genes in the telomere-mitochondrial axis of ageing. Among 166 non-smoking elderly, LTL, leukocyte mtDNA content and expression of candidate genes:...

At a cellular level, oxidative stress is known to increase telomere attrition, and hence cellular senescence and risk of disease. It has been proposed that dietary micronutrients play an important role in telomere protection due to their antioxidant properties. We experimentally manipulated dietary micronutrients during early life in zebra finches (Taeniopygia guttata). We found no effects of micronutrient intake on telomere loss during chick growth. However, females given a diet high in...

Telomeres are regarded as important biomarkers of ageing and serve as useful tools in revealing how stress acts at the cellular level. However, the effects of social and ecological factors on telomere length remain poorly understood, particularly in free-ranging mammals. Here, we investigated the influences of within-group dominance rank and group membership on telomere length in wild adult spotted hyenas (Crocuta crocuta). We found large effects of both factors; high-ranking hyenas exhibited...

Authors: Johann J. Steurer Published: 02/25/2015, Praxis PubMed Full Text...

Regular exercise has multi-system anti-aging effects. Here we summarize how exercise impacts the major hallmarks of aging. We propose that, besides searching for novel pharmaceutical targets of the aging process, more research efforts should be devoted to gaining insights into the molecular mediators of the benefits of exercise and to implement effective exercise interventions for elderly people....

Much like an individual's hairstyle, hair fibers along the scalp see a number of changes over the course of one's lifetime. As the decades pass, the shine and volume synonymous with youthful hair may give way to thin, dull, and brittle hair commonly associated with aging. These changes are a result of a compilation of genetic and environmental elements influencing the cells of the hair follicle, specifically the hair follicle stem cells and melanocytes. Telomere shortening, decrease in cell...

The outcome of kidney allograft transplantation is associated with numerous donor-dependent and recipient-dependent immunological and non-immunological factors. Studies on genetic factors affecting the non-immunological aspects, like ageing of the kidney allograft and patient outcome are still lacking. The aim of this study was the analysis of relative telomere length (RTL; T/S ratio) in the biopsy specimens of the transplanted kidney allograft and its correlation with the delayed graft function...

Authors: Steven C SC. Hunt, Jeremy D JD. Kark, Abraham A. Aviv Published: 02/18/2015, Circulation. Cardiovascular genetics PubMed Full Text...

Since its first description over 50 years ago, cellular senescence has gained increasing attention. The number of research publications on cellular senescence last year alone is more than the number of publications in the decade in 1990s. Laboratories solely studying senescence, scientific conferences and organisations dedicated to field of cellular senescence are also on the rise. These not only indicate the growing interest in this field but also highlight the importance of cellular senescence...

Research links psychosocial stress to premature telomere shortening and accelerated human aging; however, this association has only been demonstrated in so-called "WEIRD" societies (Western, educated, industrialized, rich, and democratic), where stress is typically lower and life expectancies longer. By contrast, we examine stress and telomere shortening in a non-Western setting among a highly stressed population with overall lower life expectancies: poor indigenous people--the Sahariya--who...

To investigate the possible occurrence of early thymic failure and premature senescence of naïve and memory T-cells in patients with axial spondyloarthritis (aSpA)....

The identification of biological markers that allow the early diagnosis, or even the prevention of age-related diseases, is an important goal that is being actively pursued in the research community. Sleep is one of the physiological processes that is most affected by aging, and there is a strong relationship between age-related sleep alterations and diseases. Changes in cellular senescence and the linked changes in telomere length might be potential markers of age-related sleep changes. In this...

Disruption of telomere maintenance pathways leads to accelerated entry into cellular senescence, a stable proliferative arrest that promotes aging-associated disorders in some mammals. The budding yeast CST complex, comprising Cdc13, Stn1, and Ctc1, is critical for telomere replication, length regulation, and end protection. Although mammalian homologues of CST have been identified recently, their role and function for telomere maintenance in normal somatic human cells are still incompletely...

Stress induced premature senescence (SIPS) is a relative extension to the concept of exogenous cellular insult. Besides persistent double strand (ds) DNA breaks and increased β-galactosidase activity, biological significance of telomeric attrition in conjunction with senescence associated secretory phenotype (SASP) has been highlighted in SIPS. To gain insight on the potential role of this unique phenomenon invoked upon environmental stress, we sequentially validated the molecular repercussions...

Aging is a complex process that affects multiple organs. Modeling aging and age-related diseases in the lab is challenging because classical vertebrate models have relatively long lifespans. Here, we develop the first platform for rapid exploration of age-dependent traits and diseases in vertebrates, using the naturally short-lived African turquoise killifish. We provide an integrative genomic and genome-editing toolkit in this organism using our de-novo-assembled genome and the CRISPR/Cas9...

Bovine leukemia virus (BLV) is the causative agent of enzootic bovine leukosis (EBL). BLV can interact with telomerase and inhibits telomere shortening, contributing in leukemogenesis and tumour induction. The role of telomerase in BLV-induced lymphosarcoma and aging has been extensively studied. To date, the interaction of both BLV and aging on telomerase mis-regulation have, however, not been investigated. In the present study, telomerase activity in BLV positive and negative cows was compared...

Telomeres protect chromosome ends and are markers of cellular aging and replicative capacity....

Bloom syndrome helicase (BLM) has key roles in homologous recombination repair, telomere maintenance, and DNA replication. Germ-line mutations in the BLM gene causes Bloom syndrome, a rare disorder characterized by premature aging and predisposition to multiple cancers, including breast cancer. The clinicopathologic significance of BLM in sporadic breast cancers is unknown. We investigated BLM mRNA expression in the Molecular Taxonomy of Breast Cancer International Consortium cohort (n = 1,950)...

Many observers have noted that the morphological changes that occur in chronic kidney disease (CKD) patients resemble those seen in the geriatric population, with strikingly similar morbidity and mortality profiles and rates of frailty in the two groups, and shared characteristics at a pathophysiological level especially in respect to the changes seen in their vascular and immune systems. However, whilst much has been documented about the shared physical characteristics of aging and uremia, the...

Population studies have demonstrated that telomere length (TL) displays great diversity among different populations. Previously described controversial findings associated longevity with specific mitochondrial DNA haplogroups (hgs) (e.g., J and U). These observations may be influenced by population diversity, geographic location, and/or specific historic background. The aims of this study were to identify a specific hg which correlates with aging in a Latvian populating and to evaluate the...

The aims of this study were to investigate the impact of caloric restriction (CR) on cardiac telomere biology in an animal model of diabetes and to examine the signal transduction involved in cell senescence as well as cardiac function. Male 8-week-old Otsuka Long-Evans Tokushima fatty (OLETF) diabetic rats were divided into two groups: a group fed ad libitum (OLETF-AL) and a group fed with CR (OLETF-CR: 30% energy reduction). Long-Evans Tokushima Otsuka (LETO) non-diabetic rats were used as...

A large body of evidence supports a key role for telomere dysfunction in carcinogenesis due to the induction of chromosomal instability. To study telomere shortening in precancerous pancreatic lesions, we measured telomere lengths using quantitative fluorescence in situ hybridization in the normal pancreatic duct epithelium, pancreatic intraepithelial neoplasias (PanINs), and cancers. The materials employed included surgically resected pancreatic specimens without cancer (n = 33) and with...

Anxiety disorders increase the risk of onset of several ageing-related somatic conditions, which might be the consequence of accelerated cellular ageing....

Despite successful treatment and CD4+ T-cell recovery, HIV-infected individuals often experience a profound immune dysregulation characterized by a persistently low CD4:CD8 T-cell ratio. This residual immune dysregulation is reminiscent of the Immune Risk Phenotype (IRP) previously associated with morbidity and mortality in the uninfected elderly (>85 years). The IRP consists of laboratory markers that include: a low CD4:CD8 T-cell ratio, an expansion of CD8+CD28- T-cells and cytomegalovirus...

Leucocyte telomere length is considered a marker of biological ageing and has been suggested to be shorter in patients with CAD and heart failure compared with healthy controls. The aim of this study was to determine whether telomere length is associated with clinical outcomes in patients with ischaemic heart failure and whether this association is superior to chronological age as defined by date of birth....

Aging involves a deterioration of cell functions and changes that may predispose the cell to undergo an oncogenic transformation. The carcinogenic risks following radiation exposure rise with age among adults. Increasing inflammatory response, loss of oxidant/antioxidant equilibrium, ongoing telomere attrition, decline in the DNA damage response efficiency, and deleterious nuclear organization are age-related cellular changes that trigger a serious threat to genomic integrity. In this review, we...

Cardiovascular disease (CVD) is the leading cause of death in the United States and aging is a major risk factor for CVD development. One of the major age-related arterial phenotypes thought to be responsible for the development of CVD in older adults is endothelial dysfunction. Endothelial function is modulated by traditional CVD risk factors in young adults, but advancing age is independently associated with the development of vascular endothelial dysfunction. This endothelial dysfunction...

The current study aimed to investigate the association between telomere length in peripheral blood leukocytes and kidney function in various age groups of a healthy population. A total of 139 healthy individuals were divided into five groups according to their age: 35‑44, 45‑54, 55‑64, 65‑74 and >75 years old. Peripheral blood leukocytes were obtained and the telomere restriction fragment (TRF) length was assayed using a digoxigenin‑labeled hybridization probe in Southern blot assays....

We studied potential changes in the subventricular zone (SVZ) stem cell niche of the senescence-accelerated mouse prone-8 (SAM-P8) aging model. Bromodeoxyuridine (BrdU) assays with longtime survival revealed a lower number of label-retaining stem cells in the SAM-P8 SVZ compared with the SAM-Resistant 1 (SAM-R1) control strain. We also found that in SAM-P8 niche signaling is attenuated and the stem cell pool is less responsive to the self-renewal niche factor pigmented epithelium-derived factor...

Werner syndrome (WS) is a rare human autosomal recessive premature aging disorder characterized by early onset of aging-associated diseases, chromosomal instability, and cancer predisposition. The function of the DNA helicase encoded by WRN, the gene responsible for WS, has been studied extensively. WRN helicase is involved in the maintenance of chromosome integrity through DNA replication, repair, and recombination by interacting with a variety of proteins associated with DNA repair and...

Age-associated cardiovascular diseases are at least partially ascribable to vascular cell senescence. Replicative senescence (RS) and stress-induced premature senescence (SIPS) are provoked respectively by endogenous (telomere erosion) and exogenous (H2O2, UV) stimuli resulting in cell cycle arrest in G1 and G2 phases. In both scenarios, mitochondria-derived ROS are important players in senescence initiation. We aimed to define whether a mtDNA-transcribed long-non-coding-RNA (lncRNA),...

Cardiac atrial appendage stem cells (CASCs) have recently emerged as an attractive candidate for cardiac regeneration after myocardial infarction. As with other cardiac stem cells, CASCs have to be expanded ex vivo to obtain clinically relevant cell numbers. However, foetal calf serum (FCS), which is routinely used for cell culturing, is unsuitable for clinical purposes, and influence of long-term in vitro culture on CASC behaviour is unknown....

Leukocyte telomere length (LTL) has been observed to be hereditable and correlated with longevity. However, contrasting results have been reported in different populations on the value of LTL heritability and on how biology of telomeres influences longevity. We investigated whether the variability of genes correlated to telomere maintenance is associated with telomere length and affects longevity in a population from Southern Italy (20-106 years). For this purpose we analyzed thirty-one...

Genome maintenance (GM) is an essential defense system against aging and cancer, as both are characterized by increased genome instability. Here, we compared the copy number variation and mutation rate of 518 GM-associated genes in the naked mole rat (NMR), mouse, and human genomes. GM genes appeared to be strongly conserved, with copy number variation in only four genes. Interestingly, we found NMR to have a higher copy number of CEBPG, a regulator of DNA repair, and TINF2, a protector of...

Telomere length (TL) is an indicator of general systemic aging, with diminished TL associated with several chronic diseases of aging and with heightened mortality risk. Research has begun to focus on the ways in which stress contributes to telomere attrition. The purposes of this study were (a) to establish whether exposure to nonsupportive parenting, defined as high levels of conflict and rancor with low levels of warmth and emotional support, at age 17 would forecast TL 5 years later; and (b)...

Leucocyte telomere length (LTL), which is fashioned by multiple genes, has been linked to a host of human diseases, including sporadic melanoma. A number of genes associated with LTL have already been identified through genome-wide association studies. The main aim of this study was to establish whether DCAF4 (DDB1 and CUL4-associated factor 4) is associated with LTL. In addition, using ingenuity pathway analysis (IPA), we examined whether LTL-associated genes in the general population might...

Telomeres are protective DNA-protein complexes at the ends of each chromosome, maintained primarily by the enzyme telomerase. Shortening of the blood leukocyte telomeres is associated with aging, several chronic diseases, and stress, eg, major depression. Hippocampus is pivotal in the regulation of cognition and mood and the main brain region of telomerase activity. Whether there is telomere dysfunction in the hippocampus of depressed subjects is unknown. Lithium, used in the treatment and...

Ginseng, which is the root of Panax ginseng (Araliaceae), has been used in Oriental medicine as a stimulant and dietary supplement for more than 7,000 years. Older ginseng plants are substantially more medically potent, but ginseng age can be simulated using unscrupulous cultivation practices. Telomeres progressively shorten with each cell division until they reach a critical length, at which point cells enter replicative senescence. However, in some cells, telomerase maintains telomere length....

Recovery from infection is not always complete, and mild chronic infection may persist. Although the direct costs of such infections are apparently small, the potential for any long-term effects on Darwinian fitness is poorly understood. In a wild population of great reed warblers, we found that low-level chronic malaria infection reduced life span as well as the lifetime number and quality of offspring. These delayed fitness effects of malaria appear to be mediated by telomere degradation, a...

Authors: Gretchen G. Vogel Published: 01/23/2015, Science (New York, N.Y.) PubMed Full Text...

Here, with the aim of obtaining insight into the intriguing selectivity of G-quadruplex (G4) ligands toward cancer compared to normal cells, a genetically controlled system of progressive transformation in human BJ fibroblasts was analyzed. Among the different comparative evaluations, we found a progressive increase of DNA damage response (DDR) markers throughout the genome from normal toward immortalized and transformed cells. More interestingly, sensitivity to G4 ligands strongly correlated...

Conditions experienced during early life can have profound consequences for both short- and long-term fitness. Variation in the natal environment has been shown to influence survival and reproductive performance of entire cohorts in wild vertebrate populations. Telomere dynamics potentially provide a link between the early environment and long-term fitness outcomes, yet we know little about how the environment can influence telomere dynamics in early life. We found that environmental conditions...

In a broad range of species--including humans--it has been demonstrated that telomere length declines throughout life and that it may be involved in cell and organismal senescence. This potential link to ageing and thus to fitness has triggered recent interest in understanding how variation in telomere length is inherited and maintained. However, previous studies suffer from two main drawbacks that limit the possibility of understanding the relative importance of genetic, parental and...

Abstract Like most basic molecular mechanisms, programmed -1 ribosomal frameshifting (-1 PRF) was first identified in viruses. Early observations that global dysregulation of -1 PRF had deleterious effects on yeast cell growth suggested that -1 PRF may be used to control cellular gene expression, and the cell cycle in particular. Collection of sufficient numbers of viral -1 PRF signals coupled with advances in computer sciences enabled 2 complementary computational approaches to identify -1 PRF...

In ageing populations many patients have multiple diseases characterised by acceleration of the normal ageing process. Better understanding of the signalling pathways and cellular events involved in ageing shows that these are characteristic of many chronic degenerative diseases, such as chronic obstructive pulmonary disease (COPD), chronic cardiovascular and metabolic diseases, and neurodegeneration. Common mechanisms have now been identified in these diseases, which show evidence of cellular...

Cellular senescence is a state of irreversible cell cycle arrest that has been involved in many gastrointestinal diseases, including human cholestatic liver disorders. Senescence may play a role in biliary atresia, primary sclerosing cholangitis, cellular rejection, and primary biliary cirrhosis, four liver diseases affecting cholangiocytes and the biliary system. In this review, we examine proposed mechanisms of senescence-related biliary diseases, including hypotheses associated with the...

Telomere extension has been proposed as a means to improve cell culture and tissue engineering and to treat disease. However, telomere extension by nonviral, nonintegrating methods remains inefficient. Here we report that delivery of modified mRNA encoding TERT to human fibroblasts and myoblasts increases telomerase activity transiently (24-48 h) and rapidly extends telomeres, after which telomeres resume shortening. Three successive transfections over a 4 d period extended telomeres up to 0.9...

We sought to develop and validate a risk index for prospective cognitive decline in older adults based on blood-derived markers....

Accelerated cell aging, indexed in peripheral leukocytes by telomere shortness and in peripheral blood mononuclear cells (PBMCs) by telomerase activity, has been reported in several studies of major depressive disorder (MDD). However, the relevance of these peripheral measures for brain indices that are presumably more directly related to MDD pathophysiology is unknown. In this study, we explored the relationship between PBMC telomerase activity and leukocyte telomere length and magnetic...

It is well-known that aging is the most risk factor for Alzheimer's disease (AD). Recent studies have demonstrated that human telomerase is associated with pathological mechanisms of AD. In view of the central role of telomere and telomerase in the aging process, herein we found that the aggregated form Aβ (Aβ1-40 and Aβ1-42), not Aβ monomer, could inhibit telomerase activity both in vitro and in living cells. The β-sheet structures were essential for Aβ-induced telomerase inhibition....

Functional decline in stem cell-mediated regeneration contributes to aging associated with cellular senescence in c-kit+ cardiac progenitor cells (CPCs). Clinical implementation of CPC-based therapy in elderly patients would benefit tremendously from understanding molecular characteristics of senescence to antagonize aging. Nucleostemin (NS) is a nucleolar protein regulating stem cell proliferation and pluripotency....

Telomere shortening and alterations of mitochondrial biogenesis are involved in cellular aging. Childhood adversity is associated with telomere shortening, and several investigations have shown short telomeres in psychiatric disorders. Recent studies have examined whether mitochondria might be involved in neuropsychiatric conditions; findings are limited and no prior work has examined this in relation to stress exposure....

During aging, progressive deleterious changes increase the risk of disease and death. Prominent molecular hallmarks of aging are genomic instability, telomere attrition, epigenetic alterations, loss of proteostasis, cellular senescence, stem cell exhaustion, and altered intercellular communication. Long noncoding RNAs (lncRNAs) play important roles in a wide range of biological processes, including age-related diseases like cancer, cardiovascular pathologies, and neurodegenerative disorders....

Telomere length is a marker of biological aging that has been linked to cardiovascular disease risk. The black South African population is witnessing a tremendous increase in the prevalence of cardiovascular disease, part of which might be explained through urbanization. We compared telomere length between black South Africans and white South Africans and examined which biological and psychosocial variables played a role in ethnic difference in telomere length....

The use of targeted sequencing and unbiased whole exome sequencing has detected the presence of MDS-related mutations in nearly 20-25% of patients with bonafide AA, with mutations more commonly seen in epigenetic regulators such as DNMT3A, ASXL1 and BCOR. The implications of these mutations and their hierarchical order, especially in the context of predicting evolution to MDS, is still being explored and further data, especially with serial sampling at various time points during the course of...

Adipocyte hypertrophy and hyperplasia have been shown to be associated with shorter telomere length, which may reflect aging, altered cell proliferation and adipose tissue (AT) dysfunction. In individuals with obesity, differences in fat distribution and AT cellular composition may contribute to obesity related metabolic diseases. Here, we tested the hypotheses that telomere lengths (TL) are different between: (1) abdominal subcutaneous and omental fat depots, (2) superficial and deep abdominal...

Loss of telomere protection occurs during physiological cell senescence and ageing, due to attrition of telomeric repeats and insufficient retention of the telomere-binding factor TRF2. Subsequently formed telomere fusions trigger rampant genomic instability leading to cell death or tumorigenesis. Mechanistically, telomere fusions require either the classical non-homologous end-joining (C-NHEJ) pathway dependent on Ku70/80 and LIG4, or the alternative non-homologous end-joining (A-NHEJ), which...

Telomere attrition has been noted in many neuropsychiatric and neurodegenerative syndromes, and may indicate a shared molecular pathology across conditions. We evaluated telomere length in subjects with remitted and unremitted schizophrenia and in control subjects....

To determine associations between circulating markers of immune activation, immune cell senescence, and inflammation with HIV-associated abnormalities of pulmonary function....

To determine the mutation status of human telomerase reverse transcriptase gene (TERT) promoter region in hepatocellular carcinoma (HCC) from different geographical regions....

Telomere shortening occurs with human aging in many organs and tissues and is accelerated by rapid cell turnover and oxidative injury. We measured average telomere length using quantitative real-time PCR in non-neoplastic gastric mucosa and assessed its relationship to H. pylori-related gastritis, DNA methylation, ulcer disease, and nonsteroidal anti-inflammatory drug (NSAID) usage. Gastric biopsies were obtained from 151 cancer-free subjects including 49 chronic NSAID users and 102 nonusers....

Telomere shortening, a biomarker of cellular aging, has been associated with aging-related diseases. While psychological stress has been implicated in the process of telomere shortening, associations with activity of physiological stress systems have remained elusive. We studied whether leukocyte telomere length (LTL) is associated with hypothalamic-pituitary-adrenal (HPA) axis responses to psychosocial stress in elderly adults....

Cellular senescence is a cell cycle arrest accompanied by high expression of cyclin dependent kinase inhibitors which counteract overactive growth signals, which serves as a tumor suppressive mechanism. Senescence can be a result of telomere shortening (natural or replicative senescence) or DNA damage resulting from exogenous stressors (induced senescence). Here, we performed gene expression profiling through RNA-seq of replicative senescence, adriamycin-induced senescence, H2O2-induced...

Cognitive impairments are often related to aging and micronutrient deficiencies. Various essential micronutrients in the diet are involved in age-altered biological functions such as, zinc, copper, iron, and selenium that play pivotal roles either in maintaining and reinforcing the antioxidant performances or in affecting the complex network of genes (nutrigenomic approach) involved in encoding proteins for biological functions. Genomic stability is one of the leading causes of cognitive decline...

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....

Authors: Surabhi S. Dangi-Garimella Published: 12/31/2014, The American journal of managed care PubMed...

Genome instability represents a primary hallmark of aging and cancer. RecQL helicases (i.e., RECQL1, WRN, BLM, RECQL4, RECQL5) as well as poly(ADP-ribose) polymerases (PARPs, in particular PARP1) represent two central quality control systems to preserve genome integrity in mammalian cells. Consistently, both enzymatic families have been linked to mechanisms of aging and carcinogenesis in mice and humans. This is in accordance with clinical and epidemiological findings demonstrating that defects...

Cellular senescence is a stable cell cycle arrest that normal cells undergo in response to a variety of intrinsic and extrinsic stimuli, including progressive telomere shortening, changes in telomeric structure or other forms of genotoxic as well nongenotoxic stress. Senescence is thought to have originated as a remodelling program that is active in embryonic development and acts as a key tumour suppressor mechanism during the reproductive stage in early adult life, by leading to the removal of...

Early cell death is a feature of neurodegenerative disorders. Telomere shortening is related to premature cellular senescence and could be a marker for cellular pathology in neurological diseases. Relative telomere length in dementia (N=70), Huntington's disease (N=35), ataxia telangiectasia (N=9), and age-group matched control samples (N=105) was measured as relative telomere copy/single copy gene ratios. Individuals with Huntington's disease had the lowest relative telomere copy/single copy...

The endoplasmic reticulum (ER) is a multifunctional organelle critical for the proper folding and assembly of secreted and transmembrane proteins. Perturbations of ER functions cause ER stress, which activates a coordinated system of transcriptional and translational controls called the unfolded protein response (UPR), to cope with accumulation of misfolded proteins and proteotoxicity. It results in ER homeostasis restoration or in cell death. Senescence is a complex cell phenotype induced by...

The average length of telomeres as measured in genomic DNA from human peripheral blood leukocytes is proving to be a potential biomarker of great interest, particularly with respect to studies of aging, specific diseases, and the effects of various stresses on overall health....

Cellular senescence is described to be a consequence of telomere erosion during the replicative life span of primary human cells. Quiescence should therefore not contribute to cellular aging but rather extend lifespan. Here we tested this hypothesis and demonstrate that cultured long-term quiescent human fibroblasts transit into senescence due to similar cellular mechanisms with similar dynamics and with a similar maximum life span as proliferating controls, even under physiological oxygen...

The present study aims to investigate whether gastrokine 1 (GKN1) induces senescence and apoptosis in gastric cancer cells by regulating telomere length and telomerase activity. Telomere length, telomerase activity, and hTERT expression decreased significantly in AGSGKN1 and MKN1GKN1 cells. Both stable cell lines showed increased expression of TRF1 and reduced expression of the hTERT and c-myc proteins. In addition, TRF1 induced a considerable decrease in cell growth, telomerase activity, and...

Atherosclerosis is a complex disease which can be described as an excessive fibrofatty, proliferative, inflammatory response to damage to the artery wall involving several cell types such as smooth muscle cells, monocyte-derived macrophages, lymphocytes, dendritic cells and platelets. On the other hand, atherosclerosis is a typical age-related degenerative pathology, which is characterized by signs of cell senescence in the arterial wall including reduced cell proliferation, irreversible growth...

Poor sleep quality and short sleep duration are associated with increased incidence and progression of a number of chronic health conditions observed at greater frequency among the obese and those experiencing high levels of stress. Accelerated cellular aging, as indexed by telomere attrition in immune cells, is a plausible pathway linking sleep and disease risk. Prior studies linking sleep and telomere length are mixed. One factor may be reliance on leukocytes, which are composed of varied...

Telomere length (TL), the length of repeated DNA sequence that forms protective caps at the end of chromosomes, has emerged as a novel biomarker of cell aging and oxidative stress. There is increasing research exploring the associations of smoking and perceived stress with TL, and the results are inconsistent. This study aimed to examine whether smoking and perceived stress were associated with shortened salivary TL among primary caregivers of children with disabilities. Using a quantitative...

Senescence is a non-proliferative state reached by normal cells in response to various stresses, including telomere uncapping, oxidative stress or oncogene activation. In previous reports, we have highlighted that senescent human epidermal keratinocytes have two opposite outcomes: either they die by autophagic programmed cell death or they evade in the form of neoplastic postsenescence emergent (PSNE) cells. Herein, we show that partially reducing macroautophagy in senescent keratinocytes using...

Authors: Nathan N. Corbett, Martin M. Alda Published: 12/18/2014, Journal of psychiatry & neuroscience : JPN PubMed...

The increased level of chromosome instability in cancer cells is not only a driving force for oncogenesis but also can be the Achille's heel of the disease since many chemotherapies kill cells by inducing a nontolerable rate of DNA damage. A wealth of published evidence showed that telomere stability can be more affected than the bulk of the genome by several conventional antineoplastic drugs. In the present study, HT1080 cell lines compromised for either telomere repeats binding factor 2 (TRF2)...

Telomere length (TL) is regarded as a marker of cellular aging due to the gradual shortening by each cell division, but is influenced by a number of factors including oxidative stress and inflammation. Parkinson's disease and atypical forms of parkinsonism occur mainly in the elderly, with oxidative stress and inflammation in afflicted cells. In this study the relationship between blood TL and prognosis of 168 patients with idiopathic parkinsonism (136 Parkinson's disease [PD], 17 Progressive...

Dyskeratosis congenita (DC) is an inherited multisystem disorder, characterized by oral leukoplakia, nail dystrophy, and abnormal skin pigmentation, as well as high rates of bone marrow (BM) failure, solid tumors, and other medical problems such as osteopenia. DC and telomere biology disorders (collectively referred to as TBD here) are caused by germline mutations in telomere biology genes leading to very short telomeres and limited proliferative potential of hematopoietic stem cells. We found...

Telomeric DNA represents a novel target for the development of anticancer drugs. By application of a catalytic metallodrug strategy, a copper-acridine-ATCUN complex (CuGGHK-Acr) has been designed that targets G-quadruplex telomeric DNA. Both fluorescence solution assays and gel sequencing demonstrate the CuGGHK-Acr catalyst to selectively bind and cleave the G-quadruplex telomere sequence. The cleavage pathway has been mapped by matrix assisted laser desorption ionization time-of-flight mass...

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)...

Non-communicable diseases (NCDs) are a leading cause of death and disability, representing 63% of the total death number worldwide. A characteristic phenotype of these diseases is the accelerated aging, which is the result of phenomena such as accumulated DNA damage, telomere capping loss and subcellular irreversible/nonrepaired oxidative damage. DNA damage, mostly oxidative, plays a key role in the development of most common NCDs. The present review will gather some of the most relevant...

The telomerase complex and Telosome regulate, maintenance and repair telomeres. The telomerase complex is formed by complex of protein (TERT, Dyskerin, GAR, NHP2, NOP10) and nucleic acid (TERC) that together work as a reverse transcriptase. The Telosoma comprises a network of protein (TRF2, TRF1, TIN2, RAP1, TPP1 and POT1). Furthermore, dyskeratosis congenita (DC) (ORPHA1775) is a rare disease with similar characteristics to premature aging. DC is a genetically heterogeneous disease caused by...

Telomerase reactivation and immortalization are critical for human carcinoma progression. However, little is known about the mechanisms controlling this crucial step, due in part to the paucity of experimentally tractable model systems that can examine human epithelial cell immortalization as it might occur in vivo. We achieved efficient non-clonal immortalization of normal human mammary epithelial cells (HMEC) by directly targeting the 2 main senescence barriers encountered by cultured HMEC....

The stability of mammalian telomeres depends upon TRF2, which prevents inappropriate repair and checkpoint activation. By using a plasmid integration assay in yeasts carrying humanized telomeres, we demonstrated that TRF2 possesses the intrinsic property to both stimulate initial homologous recombination events and to prevent their resolution via its basic N-terminal domain. In human cells, we further showed that this TRF2 domain prevents telomere shortening mediated by the resolvase-associated...

Metabolic syndrome (MetS) clusters risk factors for age-related conditions including cardiovascular disease and diabetes. Shorter telomere length (TL), a cellular marker for biological age, may predict an individual's deteriorating metabolic condition....

Authors: Vera V. Gorbunova, Jef D JD. Boeke, Stephen L SL. Helfand, John M JM. Sedivy Published: 12/05/2014, Science (New York, N.Y.) PubMed Full Text...

Telomeres are tandem repeats of sequences present at the end of the chromosomes that maintain chromosomal integrity. After repeated cell division, telomeres shorten to a critical level, triggering replicative senescence or apoptosis, which is a key determinant of cellular aging. Short telomeres also contribute to genome instability and are a hallmark of many cancers. There are several methods for estimating telomere length (TL) from extracted DNA samples. Southern blot is accurate but requires a...

Telomeres are essential in maintaining chromosome integrity and in controlling cellular replication. Attrition of telomere length in peripheral blood mononuclear cells (PBMCs) with age is well documented from cross-sectional studies. But the actual in vivo changes in telomere lengths and its relationship with the contributing factors within the individuals with age have not been fully addressed. In the present paper, we report a longitudinal analysis of telomere length in the PBMCs, lymphocytes...

To examine whether adherence to the Mediterranean diet was associated with longer telomere length, a biomarker of aging....

Over the last 50 years, major improvements have been made in our understanding of the driving forces, both parallel and opposing, that lead to aging and cancer. Many theories on aging first proposed in the 1950s, including those associated with telomere biology, senescence, and adult stem-cell regulation, have since gained support from cumulative experimental evidence. These views suggest that the accumulation of mutations might be a common driver of both aging and cancer. Moreover, some tumor...

Authors: Peter M PM. Nilsson Published: 12/02/2014, BMJ (Clinical research ed.) PubMed...

Telomere length has been associated with longevity. As telomere length is partly determined by the human telomerase reverse transcriptase (hTERT), we investigated the association between an hTERT polymorphism located in its promoter region ((-) (1327)T/C) and longevity in two cohorts of older adults. Participants from the Kungsholmen project (KP; n = 1,205) and the Swedish National study of Aging and Care in Kungsholmen (SNAC-K; n = 2,764) were followed for an average period of 7.5 years. The...

Telomere length is emerging as a biomarker for aging and survival is paternally inherited and associated with parental lifespan. Telomere-associated cellular senescence may contribute to certain age-related disorders, including an increase in cancer incidence, wrinkling and diminished skin elasticity, atherosclerosis, osteoporosis, weight loss, age-related cataract, glaucoma and others. Shorter telomere length in leukocytes was associated cross-sectionally with cardiovascular disorders and its...

The relative length of telomeres measured in peripheral blood leukocytes is a commonly used system marker for biological aging and can also be used as a biomarker of cardiovascular aging. However, to what extent the telomere length in peripheral leukocytes reflects telomere length in different organ tissues is still unclear. Therefore, we have measured relative telomere length (rTL) in twelve different human tissues (peripheral blood leukocytes, liver, kidney, heart, spleen, brain, skin,...

Lipid peroxidation due to oxidative stress (OS) may play an important role in the pathogenesis of chronic systemic inflammatory diseases such as multiple sclerosis (MS). Telomeres, repeated sequences that cap chromosome ends, undergo shortening with each cycle of cell division, resulting in cellular senescence. Research regarding telomere shortening has provided novel insight into the pathogenesis of various diseases. We hypothesized that OS damage leads to inflammatory reactions, which...

We reported that suramin is an effective chemosensitizer at noncytotoxic concentrations (<50 μM); this effect was observed in multiple types of human xenograft tumors in vitro and in vivo. Clinical evaluation of noncytotoxic suramin is ongoing. Because (a) suramin inhibits reverse transcriptase, (b) telomerase is a reverse transcriptase, and (c) inhibition of telomerase enhances tumor chemosensitivity, we studied the pharmacodynamics of noncytotoxic suramin on telomerase activity and telomere...

The intrauterine environment, including the placenta, is influenced by a variety of factors, among which is diabetes during pregnancy. These factors can affect lifetime morbidity. Senescence is a state of cellular metabolic arrest, known to be correlated with age-related diseases and is usually accompanied by short telomeres. This study evaluated telomere characteristics in placentas and in cord blood from term pregnancies complicated by uncontrolled diabetes mellitus....

Geriatric patients are highly susceptible to infections. While reduced lymphocyte count has been associated with age, other studies found no change in WBC counts with age. Increased circulating white blood cell (WBC) count has been associated with cardiovascular (CV) diseases and frailty but there are discrepancies. Frailty, geriatric conditions, cardiovascular diseases and WBC count have also been associated with low grade inflammation. Association between geriatric conditions and WBC has been...

Authors: Marie Eve ME. Brault, Samuel M SM. Ohayon, Ricky R. Kwan, Howard H. Bergman, Mark J MJ. Eisenberg, Jean-François JF. Boivin, Jean-François JF. Morin, Yves Y. Langlois, Chantal C. Autexier, Jonathan J. Afilalo Published: 11/21/2014, Journal of the American Geriatrics Society ...

In this issue of Blood, Wang et al elegantly show that telomere shortening results in DNA damage that induces apoptosis and senescence in quiescent hematopoietic stem cells (HSCs)....

Depression is associated with an increased risk of mortality in patients with cancer; it has been hypothesized that depression-associated alterations in cell aging mechanisms, in particular, the telomere/telomerase maintenance system, may underlie this increased risk. We evaluated the association of depressive symptoms and telomere length to mortality and recurrence/progression in 464 patients with bladder cancer....

Adverse experiences in early life can exert powerful delayed effects on adult survival and health. Telomere attrition is a potentially important mechanism in such effects. One source of early-life adversity is the stress caused by competitive disadvantage. Although previous avian experiments suggest that competitive disadvantage may accelerate telomere attrition, they do not clearly isolate the effects of competitive disadvantage from other sources of variation. Here, we present data from an...

Telomere maintenance by telomerase is impaired in the stem cell disease dyskeratosis congenita and during human aging. Telomerase depends upon a complex pathway for enzyme assembly, localization in Cajal bodies, and association with telomeres. Here, we identify the chaperonin CCT/TRiC as a critical regulator of telomerase trafficking using a high-content genome-wide siRNA screen in human cells for factors required for Cajal body localization. We find that TRiC is required for folding the...

Autoimmune cytopenia is a frequent manifestation of primary immunodeficiencies. Two siblings presented with Evans syndrome, viral infections, and progressive leukopenia. DNA available from one patient showed a homozygous frameshift mutation in tripeptidyl peptidase II (TPP2) abolishing protein expression. TPP2 is a serine exopeptidase involved in extralysosomal peptide degradation. Its deficiency in mice activates cell death programs and premature senescence. Similar to cells from naïve,...

Telomere length predicts cardiovascular disease (CVD) possibly through an impact of telomere attrition on aortic stiffness. Whether reduced biological aging and a lack of telomere length-aortic stiffness relationships in women contribute to the lower prevalence of CVD in women, prior to menopause, is uncertain....

The gene variant Pro/Ala (rs1801282) in the PPARγ2 has been associated with lower cardiovascular risk and greater benefit from lifestyle interventions. This polymorphism also seems to be associated with longer lifespan, but no information on telomere length (TL) is available. Our aim was to study the association between the Ala allele and changes in TL in high cardiovascular risk subjects and the potential interaction with a Mediterranean dietary pattern....

Los of renal function is associated with uremia-associated immune deficiency, which contributes significantly to the mortality and morbidity of end-stage renal disease (ESRD) patients. In this review, the effect of ESRD on the adaptive cellular immune system is discussed. Progressive loss of renal function causes a preferential loss of number and function of lymphoid cells. More in depth analysis of these changes reveals a loss of thymic function, attrition of telomeres, and expanded memory T...

While global chromatin conformation studies are emerging, very little is known about the chromatin conformation of human telomeres. Most studies have focused on the role of telomeres as a tumor suppressor mechanism. Here we describe how telomere length regulates gene expression long before telomeres become short enough to produce a DNA damage response (senescence). We directly mapped the interactions adjacent to specific telomere ends using a Hi-C (chromosome capture followed by high-throughput...

Telomeres are repetitive, gene-poor regions that cap the ends of DNA and help maintain chromosomal integrity. Their shortening is caused by inflammation and oxidative stress within the cellular environment and ultimately leads to cellular senescence. Shortened leukocyte telomere length is hypothesized to be a novel biomarker for age and age-related diseases, yet reports on its association with cardiometabolic outcomes in the literature are conflicting....

The primary purpose of telomeres is to protect chromosome ends from erosion during cell division cycles. New observations suggest an additional function for telomeres, namely in gene silencing via formation of long-range chromatin interactions....

Telomeres protect the ends of linear genomes, and the gradual loss of telomeres is associated with cellular ageing. Telomere protection involves the insertion of the 3' overhang facilitated by telomere repeat-binding factor 2 (TRF2) into telomeric DNA, forming t-loops. We present evidence suggesting that t-loops can also form at interstitial telomeric sequences in a TRF2-dependent manner, forming an interstitial t-loop (ITL). We demonstrate that TRF2 association with interstitial telomeric...

Ageing is a major cause of illness, disease and mortality, mainly due to the shortening of telomeres, resulting in cells undergoing senescence and apoptosis. Increasing autophagy and the levels of antioxidants removes oxidants that cause DNA and telomere damage, thus reducing the rate at which telomeres shorten, resulting in a longer cellular lifespan. Phosphatase and tensin homolog (PTEN) has been shown to increase the lifespan of organisms by upregulating pathways involved in DNA damage...

Werner syndrome (WS) is a premature aging disorder characterized by chromosomal instability and cancer predisposition. Mutations in WRN are responsible for the disease and cause telomere dysfunction, resulting in accelerated aging. Recent studies have revealed that cells from WS patients can be successfully reprogrammed into induced pluripotent stem cells (iPSCs). In the present study, we describe the effects of long-term culture on WS iPSCs, which acquired and maintained infinite proliferative...

There is mounting evidence of a higher incidence of coronary heart disease in cytomegalovirus-seropositive individuals....

The biological mechanisms of aging, and more specifically cellular senescence, are increasingly a subject of research. Cellular senescence may be a common determinant of many age-related diseases, including some chronic lung diseases such as chronic obstructive pulmonary disease (COPD) or idiopathic pulmonary fibrosis. Many arguments suggest that these diseases are associated with premature senescence of lung cells, which may be involved in the pathophysiology of respiratory alterations....

Advanced age is the most important risk factor for atrial fibrillation (AF); however, the mechanism remains unknown. Telomeres, regions of DNA that shorten with cell division, are considered reliable markers of biological aging. We sought to examine the association between leukocyte telomere length (LTL) and incident AF in a large population-based cohort using direct LTL measurements and genetic data. To further explore our findings, we compared atrial cell telomere length and LTL in cardiac...

The skin is the body's largest organ and it is able to self-repair throughout an individual's life. With advanced age, skin is prone to degenerate in response to damage. Although cosmetic surgery has been widely adopted to rejuvinate skin, we are far from a clear understanding of the mechanisms responsible for skin aging. Recently, adult skin-resident stem/progenitor cells, growth arrest, senescence or apoptotic death and dysfunction caused by alterations in key signaling genes, such as...

Torpor is thought to slow age-related processes and to sustain growth and fattening of young individuals. Energy allocation into these processes represents a challenge for juveniles, especially for those born late in the season. We tested the hypothesis that late-born juvenile garden dormice (Eliomys quercinus) fed ad libitum ('AL', n = 9) or intermittently fasted ('IF', n = 9) use short torpor bouts to enhance growth and fat accumulation to survive winter. IF juveniles displayed more frequent...

Telomerase-negative yeasts survive via one of the two Rad52-dependent recombination pathways, which have distinct genetic requirements. Although the telomere pattern of type I and type II survivors is well characterized, the mechanistic details of short telomere rearrangement into highly evolved pattern observed in survivors are still missing. Here, we analyze immediate events taking place at the abruptly shortened VII-L and native telomeres. We show that short telomeres engage in pairing with...

The study of canine bone marrow-derived mesenchymal stem cells (MSCs) has a prominent position in veterinary cell-based applications. Yet the plethora of breeds, their different life spans, and interbreed variations provide unclearness on what can be achieved specifically by such therapies. In this study, we compared a set of morphological, physiological, and genetic markers of MSCs derived from large dog breeds, namely, Border collie, German shepherd, Labrador, Malinois, Golden retriever, and...

Osteoarthritis is the most common disease of joints caused by degradation of articular cartilage and subchondral bone. It is classified as primary form with unknown cause and as secondary form with known etiology. Genetic and epigenetic factors interact with environmental factors and contribute to the development of primary osteoarthritis. Thus far, many polymorphisms associated with osteoarthritis have been identified and recent studies also indicate the involvement of epigenetic factors (e.g.,...

Perinatal complications predict increased risk for morbidity and early mortality. Evidence of perinatal programming of adult mortality raises the question of what mechanisms embed this long-term effect. We tested a hypothesis related to the theory of developmental origins of health and disease: that perinatal complications assessed at birth predict indicators of accelerated aging by midlife....

Authors: Alan E AE. Guttmacher, Tonse N K TN. Raju Published: 11/03/2014, Pediatrics PubMed Full Text...

Telomere deprotection occurs during tumorigenesis and aging upon telomere shortening or loss of the telomeric shelterin component TRF2. Deprotected telomeres undergo changes in chromatin structure and elicit a DNA damage response (DDR) that leads to cellular senescence. The telomeric long noncoding RNA TERRA has been implicated in modulating the structure and processing of deprotected telomeres. Here, we characterize the human TERRA transcriptome at normal and TRF2-depleted telomeres and...

SIRT1 (silent information regulator two protein) is a type III protein deacetylase that regulates a variety of important metabolic and physiologic processes including stress resistance, metabolism, apoptosis and energy balance. It reverses cholesterol transport and reduces risk for development of atherosclerosis and cardiovascular disease. The following review highlights the potential role of SIRT1 on cardiovascular biology and function....

Homocysteine can accelerate the senescence of endothelial progenitor cells or endothelial cells (ECs) via telomerase inactivation and length shortening. However, the underlying mechanism is unclear. Here, we investigated whether homocysteine promotes endothelial senescence by reducing the expression and activity of human telomerase reverse transcriptase (hTERT) by DNA methylation to reduce ECs telomerase activity....

Telomeres which are formed by double-strand breaks and DNA under replication, cause cell cycle arrest resulting in cellular senescence and apoptosis. The erosion of telomeres is an important mechanism for regulating the aging process by limiting cell proliferation. Over the last decade, many investigations in the field of telomeric biology showed that telomeric DNA and telomeric proteins are involved in the pathogenesis of some human diseases. The aim of the study was to compare telomere length...

It has been hypothesized that chronic psychological stress is associated with shorter telomere length; however, the mechanisms that link stress and telomere length are not well understood. To examine the interplay between biochemical factors related to stress arousal and cellular aging, we investigate the association between anabolic/catabolic (A/C) imbalance and leukocyte telomere length (LTL) in the Social Environment and Biomarkers of Aging Study (SEBAS), conducted in Taiwan (N = 925). SEBAS...

The purpose of this study was to examine biological and behavioral explanations for gender differences in leukocyte telomere length (LTL), a biomarker of cell aging that has been hypothesized to contribute to women's greater longevity. Data are from a subsample (n = 851) of the Multi-Ethnic Study of Atherosclerosis, a population-based study of women and men aged 45 to 84. Mediation models were used to examine study hypotheses. We found that women had longer LTL than men, but the gender...

Telomeric repeat binding factor 2 (TRF2), which plays a central role in telomere capping, is frequently increased in human tumors. We reveal here that TRF2 is expressed in the vasculature of most human cancer types, where it colocalizes with the Wilms' tumor suppressor WT1. We further show that TRF2 is a transcriptional target of WT1 and is required for proliferation, migration, and tube formation of endothelial cells. These angiogenic effects of TRF2 are uncoupled from its function in telomere...

The DNA damage response (DDR) is activated upon DNA damage generation to promote DNA repair and inhibit cell cycle progression in the presence of a lesion. Cellular senescence is a permanent cell cycle arrest characterized by persistent DDR activation. However, some reports suggest that DDR activation is a feature only of early cellular senescence that is then lost with time. This challenges the hypothesis that cellular senescence is caused by persistent DDR activation. To address this issue, we...

Authors: Natália M NM. Perseguini, Rozangela R. Verlengia, Juliana C JC. Milan, Vinicius V. Minatel, Patrícia P. Rehder-Santos, Anielle C M AC. Takahashi, Bárbara A BA. Santana-Lemos, Rodrigo T RT. Calado, Pedro P. Ferreira Filho, Alberto A. Porta, Aparecida M AM. Catai Published: 10/22/2014, International journal of cardiology ...

Peripheral blood telomere length has been associated with age-related conditions including Alzheimer's disease (AD). This suggests that telomere length may identify subjects at increased risk of AD. Thus, we investigated the associations of peripheral blood telomere length with amnestic mild cognitive impairment (aMCI), a putative precursor of AD, among Mayo Clinic Study of Aging participants who were prospectively followed for incident aMCI. We matched 137 incident aMCI cases (mean age 81.1...

Cancer is a leading cause of death worldwide and an estimated 1 in 4 deaths in the United States is due to cancer. Despite recent advances in cancer treatment, adverse effects related to cancer therapy remain a limiting factor for many patients. The ideal cancer treatment would selectively target cancerous cells while sparing normal, healthy cells to offer maximal therapeutic benefit while minimizing toxicity. Telomeres are structurally unique DNA sequences at the end of human chromosomes, which...

It has been documented that telomere-associated cellular senescence may contribute to certain age-related disorders, including an increase in cancer incidence, wrinkling and diminished skin elasticity, atherosclerosis, osteoporosis, weight loss, age-related cataract, glaucoma and others. Shorter telomere length in leukocytes was associated crosssectionally with cardiovascular disorders and their risk factors, including pulse pressure and vascular aging, obesity, vascular dementia, diabetes,...

The immunosuppressant drug rapamycin was reported to have an antiaging activity, which was attributed to the TORC1 inhibition that inhibits cell proliferation and increases autophagy. However, rapamycin also exhibits a number of harmful adverse effects. Whether rapamycin can be developed into an antiaging agent remains unclear....

The ability to achieve sufficient restorative sleep is important in the maintenance of physical and mental health; however, disturbed sleep and insomnia symptoms are a common experience among women with breast cancer. In non-cancer populations, insufficient sleep quantity and quality has been associated with shortened telomere length (TL), a measure of accumulated cellular damage and human aging. This feasibility study compared TL in women previously diagnosed with breast cancer with clinically...

To review the discovery of chromothripsis and analyze its impact on human reproduction....

Recent studies have found mixed results regarding the association between leukocyte telomere length (LTL)--thought to be a marker of cellular aging--and all-cause mortality. Some studies have reported a significant inverse relationship, but others have not, perhaps in part owing to insufficient power. We examine the relationship using data from a nationally representative sample of older Taiwanese (54+ in 2000), which is larger (n = 942) than most previous studies, and which includes...

Replicative senescence is preceded by loss of repeat sequences of DNA from the telomeres that eventually leads to telomere dysfunction, the accumulation of irreparable DNA double strand breaks and a DNA damage response (DDR). However, we have previously reported that whilst telomere dysfunction in human keratinocytes is associated with a permanent cell cycle arrest, the DDR was very weak and transcriptional profiling also revealed several molecules normally associated with keratinocytes terminal...

We tested whether leukocyte telomere length maintenance, which underlies healthy cellular aging, provides a link between sugar-sweetened beverage (SSB) consumption and the risk of cardiometabolic disease....

Authors: Lorna L. Stewart Published: 10/16/2014, Nature PubMed Full Text...

Ageing is related to slowdown/breakdown of the somatotropic axis (i.e. the somatopause) leading to many physiological changes. The somatopause is accompanied by DNA and other macromolecule damage, and is characterized by a progressive decline in vitality and tissue function. We still do not have a definitive understanding of the mechanism( s) of ageing. Several overlapping theories have been proposed such as: 1) The free radical theory, 2) Mitochondrial Ageing, 3) The Glycation Theory, 4)...

Cellular senescence is the state of permanent inhibition of cell proliferation. Senescent cells are characterized by several features including increased activity of senescence-associated β-galactosidase (SA-β-GAL) and senescenceassociated secretory phenotype (SASP). In vitro, 2 types of senescence have been described. One is telomere-dependent replicative senescence and the second is stress-induced premature senescence (SIPS). Despite some tissue-specific characteristics many kinds of cells,...

Telomeres are DNA-protein structures that form protective caps at the end of eukaryotic chromosomes. They constitute the safeguards of chromosome degradation and are responsible for maintaining genomic integrity. The multifactorial nature of telomere length (TL) regulation increases the perplexity of studies in the field. TL is characterized by a high variability among individuals (birth and later life) and among species but it is unknown whether this is associated with their lifespan potential....

Telomere length has been associated with dementia and psychological stress, but its relationship with human brain size is unknown....

Animals and plants have biological clocks that help to regulate circadian cycles, seasonal rhythms, growth, development and sexual maturity. If aging is not a stochastic process of attrition but is centrally orchestrated, it is reasonable to suspect that the timing of senescence is also influenced by one or more biological clocks. Evolutionary reasoning first articulated by G. Williams suggests that multiple, redundant clocks might influence organismal aging. Some aging clocks that have been...

Incident atherothrombotic disease is predicted by leukocyte telomere length, a marker of biological age, and hemostatic factor levels, indicating a hypercoagulable state. We hypothesized that shorter telomeres are associated with elevated circulating levels of hemostatic factors....

Telomeres are specialized structures protecting chromosomes against genome instability. Telomeres shorten with cell division, and replicative senescence is induced when telomeres are badly eroded. Whereas TRF2 (telomeric-repeat binding factor 2), ATM (ataxia telangiectasia mutated) and p53 have been identified involved in senescence induction, how it is triggered remains unclear. Here, we propose an integrated model associating telomere loss with senescence trigger. We characterize the dynamics...

Vitamin D plays crucial roles in neuroprotection and neurodevelopment, and low levels are commonly associated with schizophrenia. We considered if the association was spurious or causal by examining the association of Vitamin D with Leukocyte Telomere Length (LTL), a marker of cellular aging. Vitamin D levels in 22 well-characterized schizophrenia cases were examined with respect to symptoms, cognition, and functioning. LTL was assessed using quantitative polymerase chain reaction (qPCR). The...

Telomeres can be considered a marker of biological aging. Studies have suggested that telomere shortening may be associated with aging related diseases and also psychiatric disorders....

To assess if there is an association between socioeconomic status and quality of life, functional status and markers of aging, we studied 86 women aged 73 ± 7 years, who answered the WHO Qol Bref quality of life survey. Mini mental state examination, timed up and go test, 12 minutes' walk, hand grip and quadriceps strength, dual X-ray absorptiometry (DEXA), carotid intima-media thickness and telomere length in peripheral leukocytes were measured. Successful aging was defined as a walking speed,...

Telomere length has been proposed as a marker of mitotic cell age and as a general index of human organism aging. Telomere shortening in peripheral blood lymphocytes has been linked to cardiovascular-related morbidity and mortality. The authors investigated the potential correlation of conventional risk factors, radiation dose and telomere shortening with the development of coronary artery disease (CAD) following radiation therapy in a large cohort of Hodgkin lymphoma (HL) patients. Multivariate...

A growing body of research demonstrates that individuals diagnosed with major depressive disorder (MDD) are characterized by shortened telomere length, which has been posited to underlie the association between depression and increased instances of medical illness. The temporal nature of the relation between MDD and shortened telomere length, however, is not clear. Importantly, both MDD and telomere length have been associated independently with high levels of stress, implicating dysregulation...

Aprataxin (APTX) deficiency causes progressive cerebellar degeneration, ataxia and oculomotor apraxia in man. Cell free assays and crystal structure studies demonstrate a role for APTX in resolving 5'-adenylated nucleic acid breaks, however, APTX function in vertebrates remains unclear due to the lack of an appropriate model system. Here, we generated a murine model in which a pathogenic mutant of superoxide dismutase 1 (SOD1(G93A)) is expressed in an Aptx-/- mouse strain. We report a delayed...

The uremia-induced inflammatory environment in end-stage renal disease (ESRD) patients is associated with premature T-cell aging resulting in a defective T-cell immunity. As kidney transplantation (KTx) reduces the pro-inflammatory environment, we hypothesized that KTx would rejuvenate the aged T-cell system. As aging parameters, we determined in 70 KTx recipients the differentiation status by immunophenotyping, thymic output by the T-cell receptor excision circle (TREC) content together with...

Immunosenescence, the deterioration of immune system capability with age, may play a key role in mediating age-related declines in whole-organism performance, but the mechanisms that underpin immunosenescence are poorly understood. Biomedical research on humans and laboratory models has documented age and disease related declines in the telomere lengths of leukocytes ('immune cells'), stimulating interest their having a potentially general role in the emergence of immunosenescent phenotypes....

Four-stranded DNA structures were structurally characterized in vitro by NMR, X-ray and Circular Dichroism spectroscopy in detail. Among the different types of quadruplexes (i-Motifs, minor groove quadruplexes, G-quadruplexes, etc.), the best described are G-quadruplexes which are featured by Hoogsteen base-paring. Sequences with the potential to form quadruplexes are widely present in genome of all organisms. They are found often in repetitive sequences such as telomeric ones, and also in...

Mild traumatic brain injury (mTBI) or concussion affects a large portion of the population and although many of these individuals recover completely, a small subset of people experience lingering symptomology and poor outcomes. Little is known about the factors that affect individual susceptibility or resilience to poor outcomes after mTBI and there are currently no biomarkers to delineate mTBI diagnosis or prognosis. Based upon the growing literature associated with caloric intake and altered...

Biomass smoke at higher concentrations is associated with respiratory symptoms and, after years of exposure, increased risk of respiratory disorders in adults, but its effects on cardiovascular diseases are not well characterized, particularly compared with other pollution sources like tobacco smoke or traffic....

Liver transplantation is used to treat patients with irreversible liver failure from a variety of causes. Long-term survival has been reported, particularly in the paediatric population, with graft survival longer than 20 years now possible. The goal for paediatric liver transplantation is to increase the longevity of grafts to match the normal life expectancy of the child. This paper reviews the literature on the current understanding of ageing of the liver and biomarkers that may predict...

Fibroblast growth factor 23 knockout mice develop premature aging and emphysema, indicating that dysregulation of the normal aging process is involved in the pathobiology of chronic obstructive pulmonary disease. Thus, we explored the association among a coding single-nucleotide polymorphism of fibroblast growth factor 23, its protein concentration in serum and telomere length in patients with chronic obstructive pulmonary disease....

Mesenchymal stem cells (MSCs) from various animals undergo spontaneous transformation in vitro,establishing some malignant characteristics. However,this phenomenon seems seldom appearing in human (h)MSCs. To address the question whether the hMSCs really do not undergo the spontaneous transformation and why,the present study compared MSCs from two species under the same conditions, the commercialized primary hMSCs whose in vitro life span is very uniform, and the rat (r)MSCs whose spontaneous...

Aging involves multiple biologically complex processes characterized by a decline in cellular homeostasis over time leading to a loss and impairment of physiological integrity and function. Specific cellular hallmarks of aging include abnormal gene expression patterns, shortened telomeres and associated biological dysfunction. Like all organs, the lung demonstrates both physiological and structural changes with age that result in a progressive decrease in lung function in healthy individuals....

Along with the increase in aging of our population, the proportion of older patients with chronic kidney disease (CKD) and end-stage renal disease (ESRD) is on the rise as a result of the accumulation of comorbidities as well as biological processes associated with aging. Older patients with acute kidney injury (AKI) comprise an increasing proportion of patients with CKD/ESRD as well. In this review, we will discuss biological processes of aging that predispose patients to AKI and CKD....

In patients with renal disease, uremia raises oxidative stress and senescence in endothelial cells, which can lead to endothelial dysfunction and cardiovascular disease. Klotho protein is a β-glucuronidase capable of hydrolyzing steroid β-glucuronides. This protein is recognized as an antiaging gene, that modulate both stress-induced senescence and functional response. The aim of the study was to investigate how senescence and oxidative stress induced by uremia in endothelial cells affects...

Telomeres are repetitive sequence structures at the ends of linear chromosomes that consist of double-stranded DNA repeats followed by a short single-stranded DNA protrusion. Telomeres need to be replicated in each cell cycle and protected from DNA-processing enzymes, tasks that cells execute using specialized protein complexes such as telomerase (that includes TERT), which aids in telomere maintenance and replication, and the shelterin complex, which protects chromosome ends. These complexes...

DNA damage and telomere dysfunction shorten organismal lifespan. Here we show that oral glucose administration at advanced age increases health and lifespan of telomere dysfunctional mice. The study reveals that energy consumption increases in telomere dysfunctional cells resulting in enhanced glucose metabolism both in glycolysis and in the tricarboxylic acid cycle at organismal level. In ageing telomere dysfunctional mice, normal diet provides insufficient amounts of glucose thus leading to...

Telomeric G-tails play a pivotal role in maintaining the intramolecular loop structure of telomeres. Previous in vitro studies have suggested that the erosion of telomeric G-tails triggers cellular senescence, leading to organ dysfunction and atherosclerosis. The authors recently established a method to measure telomeric G-tail length using a hybridization protection assay. Using this method, this study investigated whether telomeric G-tail length could be used as a novel predictor for future...

Our understanding of the pathophysiology of aplastic anemia is undergoing significant revision, with implications for diagnosis and treatment. Constitutional and acquired disease is poorly delineated, as lesions in some genetic pathways cause stereotypical childhood syndromes and also act as risk factors for clinical manifestations in adult life. Telomere diseases are a prominent example of this relationship. Accelerated telomere attrition is the result of mutations in telomere repair genes and...

A growing number of studies confirm an important effect of diet, lifestyle and physical activity on health status, the ageing process and many metabolic disorders. This study focuses on the influence of a diet supplement, NucleVital®Q10 Complex, on parameters related to redox homeostasis and ageing. An experimental group of 66 healthy volunteer women aged 35-55 supplemented their diet for 12 weeks with the complex, which contained omega-3 acids (1350 mg/day), ubiquinone (300 mg/day),...

Telomeres have recently been suggested to play important role in ageing and are considered to be a reliable ageing biomarkers. The life history theory predicts that costs of reproduction should be expressed in terms of accelerated senescence, and some empirical studies do confirm such presumption. Thus, a link between reproductive effort and telomere dynamics should be anticipated. Recent studies have indeed demonstrated that reproduction may trigger telomere loss, but actual impact of...

Decline in the gene expression of senescence repressor Bmi1, and telomerase, together with telomere shortening, underlay senescence of stem cells cultured for multiple passages. Here, we investigated whether the impairment of senescence preventing mechanisms can be efficiently counteracted by exposure of human adipose-derived stem cells to radio electric asymmetrically conveyed fields by an innovative technology, named Radio Electric Asymmetric Conveyer (REAC). Due to REAC exposure, the number...

Telomere shortening limits the proliferative capacity of human cells, and age-dependent shortening of telomeres occurs in somatic tissues including hematopoietic stem cells (HSCs). It is currently unknown whether genomic and molecular damage that occurs in HSCs induced by telomere shortening is transmitted to the progenitor cells. Here we show that telomere shortening results in DNA damage accumulation and gene expression changes in quiescent HSCs of aged mice. Upon activation, a subset of HSCs...

The progression of physiological ageing is driven by intracellular aberrations including telomere attrition, genomic instability, epigenetic alterations and loss of proteostasis. These in turn damage cells and compromise their functionality. Cellular senescence, a stable irreversible cell-cycle arrest, is elicited in damaged cells and prevents their propagation in the organism. Under normal conditions, senescent cells recruit the immune system which facilitates their removal from tissues....

MNS16A, a variable number of tandem repeats polymorphism in the TERT gene, has been suggested to regulate telomerase activity. As telomerase activity has been reported to be related to life-span, we hypothesized that this polymorphism might affect human longevity by controlling the length of the telomere. To test this hypothesis, we collected 446 unrelated pericentenarian individuals (age[Symbol: see text]90, mean 94.45±3.45 years) and 332 normal controls (age 22-53, mean 35.0±12.0 years) from...

Fibroblasts from the progeroid Nijmegen breakage syndrome that express a truncated version of the nibrin protein (NBN(p70)) undergo premature senescence and have an enlarged morphology with high levels of senescence-associated β-galactosidase, although they do not have F-actin stress fibres. Growth of these fibroblasts in the continuous presence of p38 inhibitors resulted in a large increase in replicative capacity and changed the cellular morphology so that the cells resembled young normal...

Limited resources for adult stem cells necessitate their in vitro culture prior to clinical use. Investigating mitochondrial DNA (mtDNA) and telomere shortening has proved to be important indications of stem cell validity. This study was designed to investigate these indicators in multiple passages of three adult stem cell lines which were produced in our stem cell laboratory....

The roles of p53 as "guardian of the genome" are extensive, encompassing regulation of the cell cycle, DNA repair, apoptosis, cellular metabolism, and senescence - ultimately steering cells through a balance of death and proliferation. The majority of sporadic cancers exhibit loss of p53 activity due to mutations or deletions of TP53, and alterations in its signaling pathway. Germline TP53 mutations have been identified in a group of families exhibiting a rare but highly penetrant familial...

Human telomeres associate with shelterin, a six-protein complex that protects chromosome ends from being recognized as sites of DNA damage. The shelterin subunit TRF2 (telomeric repeat-binding factor 2) protects telomeres by facilitating their organization into the protective capping structure. We have reported previously that the DNA-PKcs (DNA-dependent protein kinase catalytic subunit)-interacting protein KIP associates with telomerase through an interaction with hTERT (human telomerase...

Cellular senescence is a state of permanent replicative arrest that allows cells to stay viable and metabolically active but resistant to apoptotic and mitogenic stimuli. Specific, validated markers can identify senescent cells, including senescence-associated β galactosidase activity, chromatin alterations, cell morphology changes, activated p16- and p53-dependent signaling and permanent cell cycle arrest. Senescence is a natural consequence of DNA replication-associated telomere erosion, but...

Mitochondrial DNA deletions are prominent in human genetic disorders, cancer, and aging. It is thought that stalling of the mitochondrial replication machinery during DNA synthesis is a prominent source of mitochondrial genome instability; however, the precise molecular determinants of defective mitochondrial replication are not well understood. In this work, we performed a computational analysis of the human mitochondrial genome using the "Pattern Finder" G-quadruplex (G4) predictor algorithm...

With age, a person's cardio-vascular system changes gradually formed at different functional levels, which are the basis for the development of chronic heart failure. While aging itself does not lead to chronic heart failure, it is likely that age-related changes in the human body can accelerate the time onset of signs and symptoms of the disease. Different groups of patients start time and rate of progression of heart failure is extremely constant. Recently, particular attention is paid to the...

Telomeres, telomerase and tankyrase (TNKS) have an extremely important and special association with human cell aging and cancer. Telomerase activity is abnormally high in cancer cells and is accompanied by the overexpression of tankyrase 1 (TNKS1). TNKS1 is a positive regulator of telomerase activation and telomere extension in the human body, indicating that TNKS1 may be a possible therapeutic target for cancer. XAV939 is a small-molecule inhibitor of TNKS1. The objective of the present study...

Reactive oxygen species (ROS) can cause severe damage to DNA, proteins and lipids in normal cells, contributing to carcinogenesis and various pathological conditions. While cellular senescence arrests the early phase of cell cycle without any detectable telomere loss or dysfunction. ROS is reported to contribute to induction of cellular senescence, as evidence by its premature onset upon treatment with antioxidants or inhibitors of cellular oxidant scavengers. Although cellular senescence is...

Chronic obstructive pulmonary disease (COPD) is a major disease of the lungs. It primarily occurs after a prolonged period of cigarette smoking. Chronic inflammation of airways and the alveolar space as well as lung tissue destruction are the hallmarks of COPD. Recently it has been shown that cellular senescence might play a role in the pathogenesis of COPD. Cellular senescence comprises signal transduction program, leading to irreversible cell cycle arrest. The growth arrest in senescence can...

Low birth weight and rapid postnatal growth increases risk of cardiovascular-disease (CVD); however, underlying mechanisms are poorly understood. Previously, we demonstrated that rats exposed to a low-protein diet in utero that underwent postnatal catch-up growth (recuperated) have a programmed deficit in cardiac coenzyme Q (CoQ) that was associated with accelerated cardiac aging. It is unknown whether this deficit occurs in all tissues, including those that are clinically accessible. We...

Double strand break (DSB) repair is suppressed during mitosis because RNF8 and downstream DNA damage response (DDR) factors, including 53BP1, do not localize to mitotic chromatin. Discovery of the mitotic kinase-dependent mechanism that inhibits DSB repair during cell division was recently reported. It was shown that restoring mitotic DSB repair was detrimental, resulting in repair dependent genome instability and covalent telomere fusions. The telomere DDR that occurs naturally during cellular...

The mammalian protein kinase ataxia telangiectasia mutated (ATM) is a key regulator of the DNA double-strand-break response and belongs to the evolutionary conserved phosphatidylinositol-3-kinase-related protein kinases. ATM deficiency causes ataxia telangiectasia (AT), a genetic disorder that is characterized by premature aging, cerebellar neuropathy, immunodeficiency, and predisposition to cancer. AT cells show defects in the DNA damage-response pathway, cell-cycle control, and telomere...

Telomere shortening in peripheral blood mononuclear cells (PBMCs) has been associated with biological age and several chronic degenerative diseases. However, the relationship between telomere length and sarcopenia, a hallmark of the aging process, is unknown. The aim of the present study was therefore to determine whether PBMC telomeres obtained from sarcopenic older persons were shorter relative to non-sarcopenic peers. We further explored if PBMC telomere length was associated with frailty, a...

Defects in lamin A maturation result in premature aging syndromes and severe atherosclerosis as observed in the Hutchinson-Gilford Progeria Syndrome. In age-related atherosclerosis, several features of cellular senescence have been characterized in endothelial cells including telomere shortening and increased oxidative stress. However, to date, very little is known about lamin A alterations in these cells....

We sought to investigate whether maternal smoking during pregnancy affects telomere length of the fetus....

The notion that it is possible to eradicate age-related degeneration and live a life with a negligible rate of senescence solely by using a physical "repair-oriented" approach is flawed on a number of fronts. Here, I will argue that there are so many unknown variables embedded in this line of thinking that make the final result impossible to predict. Two relatively easy-to-research areas are the search for successful cross-link breakers and an effective lysosomal degradation therapy. A more...

The pathophysiological alterations of vascular endothelial cells induced by heat were studied. Human umbilical venous endothelial cells were cultured for 1 day at three different temperatures (37, 39, and 42 °C). The telomere lengths, the expressions of proteins associated with telomere length maintenance, apoptosis, heat shock, and vascular function were analyzed. The cell growth was not suppressed at 39 °C but suppressed at 42 °C. The mean telomere length did not change, whereas the...

Both telomere length and frailty were observed to be associated with aging. Whether and to what extent telomere length is related to frailty is essentially unknown. In this cross-sectional analysis of baseline data of 3537 community-dwelling adults aged 50 to 75 years of a large German cohort study, we assessed the hypothesis that shorter telomere length might be a biological marker for frailty. Using whole blood DNA we examined mean telomere repeat copy to single gene copy number (T/S ratio)...

Depression might be associated with accelerated cellular aging. However, does this result in an irreversible state or is the body able to slow down or recover from such a process? Telomeres are DNA-protein complexes that protect the ends of chromosomes and generally shorten with age; and therefore index cellular aging. The majority of studies indicate that persons with depression have shorter leukocyte telomeres than similarly aged non-depressed persons, which may contribute to the observed...

Human ageing is a complex and integrated gradual deterioration of cellular processes. There are nine major hallmarks of ageing, that include changes in DNA repair and DNA damage response, telomere shortening, changes in control over the expression and regulation of genes brought about by epigenetic and mRNA processing changes, loss of protein homeostasis, altered nutrient signaling, mitochondrial dysfunction, stem cell exhaustion, premature cellular senescence and altered intracellular...

Cellular senescence is a complex process associated with irreversible cell cycle arrest. We can distinguish replicative senescence, which is telomere dependent and stress-induced premature senescence (SIPS), which is telomere independent. Replicative senescence can be observed in culture after a few weeks or months, depending on the cell type. On the other hand SIPS can be observed a few days after treating with a senescence inducing agent. Till now a universal marker of senescence has not been...

The mesothelium is a specific group of cells having characteristics of both mesenchymal and epithelial cells. One of the most unique properties of these cells is a low proliferative capacity and a small number of achievable division. The purpose of this paper was to present the current state of knowledge on the causes of premature senescence of peritoneal mesothelial cells and to discuss the molecular events involved in this process. Particular attention was paid to the role of telomeres, the...

For hundreds of years natural compounds have been used in herbal medicine. They have been known for their antibacterial, antifungal, anticancer activities as well as for enhancing wound healing and improving immunity. Recently growing interest in natural compounds has been observed, due to their ability to modulate cellular senescence. Particularly interesting are these compounds that can induce tumor senescence, delay senescence of normal cells or reverse changes associated with senescence -...

Aging is accelerated by metabolic and cardiovascular diseases, and the risk of these diseases increases with age. Obesity is an important risk factor for many age-related diseases and is linked to reduced telomere length in white blood cells. We investigated whether cardiac senescence might be enhanced in DahlS.Z-Lepr(fa)/Lepr(fa) (DS/obese) rats, which we recently established as a new animal model of metabolic syndrome. The heart of DS/obese rats was compared with that of homozygous lean...

The possible regulation mechanism of red light was determined to discover how to retard UVA-induced skin photoaging. Human skin fibroblasts were cultured and irradiated with different doses of UVA, thus creating a photoaging model. Fibroblasts were also exposed to a subtoxic dose of UVA combined with a red light-emitting diode (LED) for five continuous days. Three groups were examined: control, UVA and UVA plus red light. Cumulative exposure doses of UVA were 25 J cm(-2), and the total doses of...

A large variability in occurrence, complications, and age/gender manifestations characterizes individual susceptibility of sporadic thoracic aortic aneurysms (TAA), even in subjects with the same risk factor profiles. The reasons are poorly understood. On the other hand, TAA pathophysiology mechanisms remain unclear than those involved in abdominal aorta aneurysms. However, recent evidence is suggesting a crucial role of biological ageing in inter-individual risk variation of cardiovascular...

Authors: Stefano S. Guerra Published: 08/16/2014, American journal of respiratory and critical care medicine PubMed Full Text...

Asthma is prospectively associated with age-related chronic diseases and mortality, suggesting the hypothesis that asthma may relate to a general, multisystem phenotype of accelerated aging....

Abused women, who suffer from chronic psychological stress, have been shown to have shorter telomeres than never abused women. Telomere shortening is associated with increased risk of cell death, and it is believed that adopting health-promoting behaviors can help to increase the activity of telomerase, an enzyme that counters telomere shortening. Qigong is an ancient Chinese mind-body integration, health-oriented practice designed to enhance the function of qi, an energy that sustains...

With the continued extension of lifespan, aging and age-related diseases have become a major medical challenge to our society. Aging is accompanied by changes in multiple systems. Among these, the aging process in the central nervous system is critically important but very poorly understood. Neurons, as post-mitotic cells, are devoid of replicative associated aging processes, such as senescence and telomere shortening. However, because of the inability to self-replenish, neurons have to...

The purpose of this study is to build a biological age (BA) equation combining telomere length with chronological age (CA) and associated aging biomarkers. In total, 139 healthy volunteers were recruited from a Chinese Han cohort in Beijing. A genetic index, renal function indices, cardiovascular function indices, brain function indices, and oxidative stress and inflammation indices (C-reactive protein [CRP]) were measured and analyzed. A BA equation was proposed based on selected parameters,...

The DNA damage response (DDR) orchestrates DNA repair and halts cell cycle. If damage is not resolved, cells can enter into an irreversible state of proliferative arrest called cellular senescence. Organismal ageing in mammals is associated with accumulation of markers of cellular senescence and DDR persistence at telomeres. Since the vast majority of the cells in mammals are non-proliferating, how do they age? Are telomeres involved? Also oncogene activation causes cellular senescence due to...

Social control in the health domain refers to attempts by social network members to get an individual to modify their health behaviors. According to the dual effects model of social control, having one's health behavior controlled by others should be related to healthier behavioral change, but might arouse psychological distress as one may resent being controlled. Despite potential healthy behavior change, the stress of social control may thus be detrimental as interpersonal stress has been...

Cancer cells are often immortal through up-regulation of the hTERT gene, which encodes the catalytic subunit of a special reverse transcriptase to overcome end-replication problem of chromosomes. This study demonstrates that papaverine, an isoquinoline alkaloid from the Papaveraceae, can overcome telomerase dependent immortality of HepG-2 cells that was used as a model of hepatocarcinoma. Although this alkaloid does not directly interact with telomeric sequences, papaverine inhibits telomerase...

A consistent association has been observed between leukocyte telomere length (LTL) and atherosclerosis, but the mechanisms underlying these associations are still not well understood. Premature biology aging was evident in atherosclerotic plaques, characterized by reduced cell proliferation, irreversible growth arrest and apoptosis, and telomere attrition. As atherosclerosis is a state of chronic low-grade inflammation and increased oxidative stress, shortened LTL in patients with...

Circadian clocks are fundamental machinery in organisms ranging from archaea to humans. Disruption of the circadian system is associated with premature aging in mice, but the molecular basis underlying this phenomenon is still unclear. In this study, we found that telomerase activity exhibits endogenous circadian rhythmicity in humans and mice. Human and mouse TERT mRNA expression oscillates with circadian rhythms and are under the control of CLOCK-BMAL1 heterodimers. CLOCK deficiency in mice...

Pediatric ependymomas are highly recurrent tumors resistant to conventional chemotherapy. Telomerase, a ribonucleoprotein critical in permitting limitless replication, has been found to be critically important for the maintenance of tumor-initiating cells (TICs). These TICs are chemoresistant, repopulate the tumor from which they are identified, and are drivers of recurrence in numerous cancers. In this study, telomerase enzymatic activity was directly measured and inhibited to assess the...

Shortening of telomere is associated with cellular senescence and cancer. This study aims to investigate the relationship between tumor grade and recurrence in relation to telomere length (TL), telomerase activity (TA) and telomere-binding proteins expression (TBPs) in patients with non-muscle invasive bladder cancer (NMIBC)....

Adverse childhood experiences (ACEs) are associated with poor physical and mental health outcomes in adulthood. Adverse childhood experiences are also associated with shortened leukocyte telomere length (LTL) in adults, suggesting accelerated cell aging. No studies have yet assessed the relationship of ACEs to LTL in individuals with major depressive disorder (MDD), despite the high incidence of antecedent ACEs in individuals with MDD. Further, no studies in any population have assessed the...

Age-related physiological, biochemical and functional changes in mammalian skeletal muscle have been shown to begin at the mid-point of the lifespan. However, the underlying changes in DNA methylation that occur during this turning point of the muscle aging process have not been clarified. To explore age-related genomic methylation changes in skeletal muscle, we employed young (0.5 years old) and middle-aged (7 years old) pigs as models to survey genome-wide DNA methylation in the longissimus...

Telomere length (TL) is a biomarker of accumulated cellular damage and human aging. Evidence in healthy populations suggests that TL is impacted by a host of psychosocial and lifestyle factors, including physical activity. This is the first study to evaluate the relationship between self-reported physical activity and telomere length in early stage breast cancer survivors....

Telomere protection and length regulation are important processes for aging, cancer and several other diseases. At the heart of these processes lies the single-stranded DNA (ssDNA)-binding protein Pot1, a component of the telomere maintenance complex shelterin, which is present in species ranging from fission yeast to humans. Pot1 contains a dual OB-fold DNA-binding domain (DBD) that fully confers its high affinity for telomeric ssDNA. Studies of S. pombe Pot1-DBD and its individual OB-fold...

In Belgium and in other countries, the Cancer Registry data show an increased incidence of cancers related to age, the majority of tumors being diagnosed beyond 60 years. However, the mechanisms responsible for this increase are not clear. Cancer could be chronologically associated with aging because of the long latency period between the exposition to carcinogenic agents and the appearance of clinical signs. Aging could also predispose directly to cancer by different mechanisms (impaired immune...

Ionizing radiation (IR) is known to be a cause of telomere dysfunction in tumor cells; however, very few studies have investigated X-ray-related changes in telomere length and the telomerase activity in normal human cells, such as umbilical vein endothelial cells (HUVECs). The loss of a few hundred base pairs from a shortened telomere has been shown to be important with respect to cellular senescence, although it may not be detected according to traditional mean telomere length [assessed as the...

CXCL12 encodes stromal cell-derived factor 1α (SDF-1), which binds to the receptor encoded by CXCR4. Variation at the CXCL12 locus is associated with coronary artery disease and endothelial progenitor cell numbers, whereas variation at the CXCR4 locus is associated with leukocyte telomere length, which has been shown to be associated with coronary artery disease. Therefore, we examined the relationships of plasma SDF-1 levels to cardiovascular disease (CVD)-related outcomes, risk factors,...

Telomeres are emerging as a biomarker for ageing and survival, and are likely important in shaping life-history trade-offs. In particular, telomere length with which one starts in life has been linked to lifelong survival, suggesting that early telomere dynamics are somehow related to life-history trajectories. This result highlights the importance of determining the extent to which telomere length is inherited, as a crucial factor determining early life telomere length. Given the scarcity of...

Several studies have reported an association between traumatic stress and telomere length suggesting that traumatic stress has an impact on ageing at the cellular level. A newly derived tool provides an additional means to investigate cellular ageing by estimating epigenetic age based on DNA methylation profiles. We therefore hypothesise that in a longitudinal study of traumatic stress both indicators of cellular ageing will show increased ageing. We expect that particularly in individuals that...

Given the established relation between testosterone and aging in older adults, we tested whether buccal telomere length (TL), an established cellular biomarker of aging, was associated with testosterone levels in youth....

In eutherian mammals and in humans, the female fetus may be masculinized while sharing the intra-uterine environment with a male fetus. Telomere length (TL), as expressed in leukocytes, is heritable and is longer in women than in men. The main determinant of leukocyte TL (LTL) is LTL at birth. However, LTL is modified by age-dependent attrition....

DNA double-strand breaks are highly toxic DNA lesions that cause genomic instability, if not efficiently repaired. RecQ helicases are a family of highly conserved proteins that maintain genomic stability through their important roles in several DNA repair pathways, including DNA double-strand break repair. Double-strand breaks can be repaired by homologous recombination (HR) using sister chromatids as templates to facilitate precise DNA repair, or by an HR-independent mechanism known as...

Human and other multicellular life species age, and ageing processes become dominant during the late phase of life. Recent studies challenge this dogma, suggesting that ageing does not occur in some animal species. In mammals, cell replicative senescence occurs as early as before birth (i.e. in embryos) under physiological conditions. How the molecular machinery operates and why ageing cells dominate under some circumstances are intriguing questions. Recent studies show that cell ageing involves...

We have analyzed the yeast replicative lifespan of a large number of open reading frame (ORF) deletions. Here, we report that strains lacking genes SGF73, SGF11, and UBP8 encoding SAGA/SLIK complex histone deubiquitinase module (DUBm) components are exceptionally long lived. Strains lacking other SAGA/SALSA components, including the acetyltransferase encoded by GCN5, are not long lived; however, these genes are required for the lifespan extension observed in DUBm deletions. Moreover, the...

Telomeres, the ends of our linear chromosomes, can function as 'replicometers', capable of counting cell division cycles as they progressively erode with every round of DNA replication. Once they are critically short, telomeres become dysfunctional and consequently activate a proliferative arrest called replicative senescence. For many years, telomeres were thought to be autonomous structures, largely isolated from cell intrinsic and extrinsic signals, whose function is to prevent limitless...

Ageing is associated with an overall decline in the functional capacity of tissues and stem cells, including haematopoietic stem and progenitor cells (HSPCs), as well as telomere dysfunction. Dietary restriction (DR) is a recognised anti-ageing intervention that extends lifespan and improves health in several organisms. To investigate the role of telomeres and telomerase in haematopoietic ageing, we compared the HSPC profile and clonogenic capacity of bone marrow cells from wild type with...

Oxidative stress is believed to be an important inducer of cellular senescence and aging. Zinc finger protein 637 (Zfp637), which belongs to the Krüppel-like protein family, has been hypothesized to play a role in oxidative stress. Nevertheless, the precise function of Zfp637 has seldom been reported, and it remains unclear whether Zfp637 is involved in oxidative stress-induced premature senescence. In this study, we show that the endogenous expression levels of Zfp637 and mouse telomerase...

Mutation is associated with developmental and hereditary disorders, aging, and cancer. While we understand some mutational processes operative in human disease, most remain mysterious. We used Caenorhabditis elegans whole-genome sequencing to model mutational signatures, analyzing 183 worm populations across 17 DNA repair-deficient backgrounds propagated for 20 generations or exposed to carcinogens. The baseline mutation rate in C. elegans was approximately one per genome per generation, not...

Authors: Emily G EG. Jacobs, Elissa S ES. Epel, Jue J. Lin, Elizabeth H EH. Blackburn, Natalie L NL. Rasgon Published: 07/15/2014, JAMA neurology PubMed Full Text...

Previous evidences support that increased oxidative stress (OxS) may play an important role in metabolic syndrome (MetS) and both are closely linked to vascular dysfunction. This study determined whether there is a relationship between endothelial function and relative telomere length (RTL) in MetS subjects. In this cross-sectional study from the LIPGENE cohort, a total of 88 subjects (36 men and 52 women) were divided into four groups by quartiles of telomere length. We measured ischemic...

The outcome of the Chernobyl nuclear power plant (CNPP) accident was that a huge number of people were exposed to ionizing radiation. Previous studies of CNPP clean-up workers from Latvia revealed a high occurrence of age-associated degenerative diseases and cancer in young adults, as well as a high mortality as a result of cardiovascular disorders at age 45-54 years. DNA tandem repeats that cap chromosome ends, known as telomeres, are sensitive to oxidative damage and exposure to ionizing...

Epigenetics is tissue-specific and potentially even cell-specific, but little information is available from human reproductive studies about the concordance of DNA methylation patterns in cord blood and placenta, as well as within-placenta variations. We evaluated methylation levels at promoter regions of candidate genes in biological ageing pathways (SIRT1, TP53, PPARG, PPARGC1A, and TFAM), a subtelomeric region (D4Z4) and the mitochondrial genome (MT-RNR1, D-loop)....

Epidermal stem cells have been in clinical application as a source of culture-generated grafts. Although applications for such cells are increasing due to aging populations and the greater incidence of diabetes, current keratinocyte grafting technology is limited by immunological barriers and the time needed for culture amplification. We studied the feasibility of using human fetal skin cells for allogeneic transplantation and showed that fetal keratinocytes have faster expansion times, longer...

Hydra present an interesting deviation from typical life histories: they have an extensive capacity to regenerate and self-renew and seem to defy the aging process. Hydra have the ability to decouple the aging process from their life history and therefore provide us with a unique opportunity to gain insight into the aging process not only for basal hydrozoans but also for other species across the tree of life. We argue that under steady feeding and asexual reproduction Hydra species are able to...

Placentas from pregnancies complicated with IUGR (intrauterine growth restriction) express altered telomere homeostasis. In the current study, we examined mechanisms of telomere shortening in these placentas....

Premature aging disorders, like Werner syndrome, Bloom's syndrome, and Hutchinson-Gilford Progeria Syndrome (HGPS), have been the subjects of immense interest as they recapitulate many of the phenotypes observed in physiological aging. They, therefore, not only provide model systems to study normal aging processes but also give valuable insights into the intricate mechanisms underlying senescence. Recent works on HGPS have revealed alterations in a spectrum of cellular and molecular pathways...

Telomeres are the physical ends of eukaryotic linear chromosomes. Telomeres form special structures that cap chromosome ends to prevent degradation by nucleolytic attack and to distinguish chromosome termini from DNA double-strand breaks. With few exceptions, telomeres are composed primarily of repetitive DNA associated with proteins that interact specifically with double- or single-stranded telomeric DNA or with each other, forming highly ordered and dynamic complexes involved in telomere...

The mechanisms that increase cardiovascular risk in individuals born small for gestational age (SGA) are not well understood. Telomere shortening has been suggested to be a predictor of disease onset. Our aim was to determine whether impaired intrauterine growth is associated with early signs of vascular aging and whether telomere length could be a biomarker of this pathway....

Telomeres consist of repetitive DNA-protein complexes that cap the ends of vertebrate linear chromosomes. Their capping function and dynamics both with regard to structure and length are carefully orchestrated by many regulatory mechanisms and factors, with likely more yet to be described. Telomere shortening has been shown to be a major measurable molecular characteristic of aging of cells in vitro and in vivo and is thought to have evolved as a tumor protection mechanism in long-lived species....

Ku is an abundant, highly conserved DNA binding protein found in both prokaryotes and eukaryotes that plays essential roles in the maintenance of genome integrity. In eukaryotes, Ku is a heterodimer comprised of two subunits, Ku70 and Ku80, that is best characterized for its central role as the initial DNA end binding factor in the "classical" non-homologous end joining (C-NHEJ) pathway, the main DNA double-strand break (DSB) repair pathway in mammals. Ku binds double-stranded DNA ends with high...

Telomeres are long nucleotide repeats and protein complexes at the ends of chromosomes that are essential for maintaining chromosomal stability. They shorten with each cell division, and therefore, telomere length is a marker for cellular aging and senescence. Epidemiological research of telomeres investigates the role that these genetic structures have in disease risk and mortality in human populations. This chapter provides an overview of the current telomere epidemiology research and...

In humans, telomere length studies have acquired great relevance because the length of telomeres has been related to natural processes like disease, aging and cancer. However, very little is known about the influence of telomere length on the biology of wild type plants. The length of plant telomeres has been usually studied by Terminal Restriction Fragment (TRF) analyses. This technique requires high amounts of tissue, including multiple cell types, which might be the reason why very little is...

DHX9 is an ATP-dependent DEXH box helicase with a multitude of cellular functions. Its ability to unwind both DNA and RNA, as well as aberrant, noncanonical polynucleotide structures, has implicated it in transcriptional and translational regulation, DNA replication and repair, and maintenance of genome stability. We report that loss of DHX9 in primary human fibroblasts results in premature senescence, a state of irreversible growth arrest. This is accompanied by morphological defects, elevation...

The predominant X-linked form of Dyskeratosis congenita results from mutations in DKC1, which encodes dyskerin, a protein required for ribosomal RNA modification that is also a component of the telomerase complex. We have previously found that expression of an internal fragment of dyskerin (GSE24.2) rescues telomerase activity in X-linked dyskeratosis congenita (X-DC) patient cells. Here we have found that an increased basal and induced DNA damage response occurred in X-DC cells in comparison...

Cellular senescence is a stable cell cycle arrest, caused by insults, such as: telomere erosion, oncogene activation, irradiation, DNA damage, oxidative stress, and viral infection. Extrinsic stimuli such as cell culture stress can also trigger this growth arrest. Senescence is thought to have evolved as an example of antagonistic pleiotropy, as it acts as a tumor suppressor mechanism during the reproductive age, but can promote organismal aging by disrupting tissue renewal, repair, and...

In living donor liver transplantation, the biological organ age of the donated allograft is unknown in young patients who receive grafts from older donors. Few studies have focused on the effects of aging on allografts in the state of tolerance. The purpose of this study was to assess the biological organ age of liver grafts....

Telomeres maintain chromosome stability and cell replicative capacity. Telomere shortening occurs concomitant with aging. Short telomeres are associated with some diseases, such as dyskeratosis congenita, idiopathic pulmonary fibrosis, and aplastic anemia. Telomeres are longer in pluripotent stem cells than in somatic cells and lengthen significantly during preimplantation development. Furthermore, telomere elongation during somatic cell reprogramming is of great importance in the acquisition of...

The present report examines several subcultures of a single sample of ARPE-19 cells to determine their status with respect to cell mortality. If a transformation from mortal to immortal has occurred in these cells, it may impact their characteristics and, thereby, their utility for modeling natural retinal pigment epithelial (RPE) cells....

Neurogenesis continues throughout the lifetime in the hippocampus, while the rate declines with brain aging. It has been hypothesized that reduced neurogenesis may contribute to age-related cognitive impairment. Ginsenoside Rg1 is an active ingredient of Panax ginseng in traditional Chinese medicine, which exerts anti-oxidative and anti-aging effects. This study explores the neuroprotective effect of ginsenoside Rg1 on the hippocampus of the D-gal (D-galactose) induced aging rat model. Sub-acute...

There is increasing evidence that chronic stress accelerates telomere erosion in leukocytes/peripheral blood mononuclear cells (PBMCs). However, functional changes associated with telomere shortening are poorly understood. We hypothesized that war veterans with PTSD would have shorter telomeres in PBMCs and that these cells might exhibit changes in measures of immune reactivity such as proliferation, cytokine production and expression of regulators of immune responses....

A higher prevalence of chronic atrophic gastritis (CAG) occurs in younger adults in Asia. We used Stomach Age to examine the different mechanisms of CAG between younger adults and elderly individuals, and established a simple model of cancer risk that can be applied to CAG surveillance....

Centenarians and their offspring are increasingly considered a useful model to study and characterize the mechanisms underlying healthy aging and longevity. The aim of this project is to compare the prevalence of age-related diseases and telomere length (TL), a marker of biological age and mortality, across five groups of subjects: semisupercentenarians (SSCENT) (105-109years old), centenarians (CENT) (100-104years old), centenarians' offspring (CO), age- and gender-matched offspring of parents...

Increased proliferation rates as well as resistance to apoptosis are considered major obstacles for the treatment of patients with chronic myelogenous leukemia (CML), thus highlighting the need for novel therapeutic approaches. Since senescence has been recognized as a physiological barrier against tumorigenesis, senescence-based therapy could represent a new strategy against CML. DNA demethylating agent 5-aza-2'-deoxycytidine (DAC) was reported to induce cellular senescence but underlying...

Chronic inflammation is associated with normal and pathological ageing. Here we show that chronic, progressive low-grade inflammation induced by knockout of the nfkb1 subunit of the transcription factor NF-κB induces premature ageing in mice. We also show that these mice have reduced regeneration in liver and gut. nfkb1(-/-) fibroblasts exhibit aggravated cell senescence because of an enhanced autocrine and paracrine feedback through NF-κB, COX-2 and ROS, which stabilizes DNA damage....

Cross-sectional studies reported associations between short leucocyte telomere length (LTL) and measures of vascular and cardiac damage. However, the contribution of LTL dynamics to the age-related process of cardiovascular (CV) remodelling remains unknown. In this study, we explored whether the rate of LTL shortening can predict CV phenotypes over 10-year follow-up and the influence of established CV risk factors on this relationship....

Age-related diastolic dysfunction is a major factor in the epidemic of heart failure. In patients hospitalized with heart failure, HFpEF is now as common as heart failure with reduced ejection fraction. We now have many successful treatments for heart failure with reduced ejection fraction, while specific treatment options for HFpEF patients remain elusive. The lack of treatments for HFpEF reflects our very incomplete understanding of this constellation of diseases. There are many...

Depressive disorders have been associated with increased risk for aging-related diseases, possibly as a consequence of accelerated cellular aging. Cellular aging, indexed by telomere length (TL) shortening, has been linked to depression in adults younger than 60 years; however, it remains unclear whether this is the case in late-life depression (age >60 years). The objective of this study was to assess differences in TL between persons with current late-life depression and never-depressed...

Downstream factors that regulate the decision between senescence and cell death have not been elucidated. Cells undergo senescence through three pathways, replicative senescence (RS), stress-induced premature senescence (SIPS) and oncogene-induced senescence. Recent studies suggest that the ataxia telangiectasia mutant (ATM) kinase is not only a key protein mediating cellular responses to DNA damage, but also regulates cellular senescence induced by telomere end exposure (in RS) or persistent...

Telomere shortening occurs with human aging in many organs and tissues and is accelerated by rapid cell turnover and oxidative injury. To clarify the clinical importance of telomere shortening in colonic mucosa in ulcerative colitis (UC), we measured average telomere length using quantitative real-time PCR in non-neoplastic colonic mucosa in UC patients and assessed its relationship to various clinical subtypes. Relative telomere length in genomic DNA was measured in colonic biopsies obtained...

Checkpoint kinase 2 (CHK2) is a downstream effector of the DNA damage response (DDR). Dysfunctional telomeres, either owing to critical shortening or disruption of the shelterin complex, activate a DDR, which eventually results in cell cycle arrest, senescence and/or apoptosis. Successive generations of telomerase-deficient (Terc) mice show accelerated aging and shorter lifespan due to tissue atrophy and impaired organ regeneration associated to progressive telomere shortening. In contrast, mice...

Prostaglandin E2 (PGE2), a pleiotropic immunomodulatory molecule, and its free radical catalyzed isoform, iso-PGE2, are frequently elevated in the context of cancer and chronic infection. Previous studies have documented the effects of PGE2 on the various CD4+ T cell functions, but little is known about its impact on cytotoxic CD8+ T lymphocytes, the immune cells responsible for eliminating virally infected and tumor cells. Here we provide the first demonstration of the dramatic effects of PGE2...

Telomeres protect chromosome ends from degradation and inappropriate DNA damage response activation through their association with specific factors. Interestingly, these telomeric factors are able to localize outside telomeric regions, where they can regulate the transcription of genes involved in metabolism, immunity and differentiation. These findings delineate a signalling pathway by which telomeric changes control the ability of their associated factors to regulate transcription. This...

The senescent cardiac phenotype is accompanied by changes in mitochondrial function and biogenesis causing impairment in energy provision. The relationship between myocardial senescence and Pim kinases deserves attention because Pim-1 kinase is cardioprotective, in part, by preservation of mitochondrial integrity. Study of the pathological effects resulting from genetic deletion of all Pim kinase family members could provide important insight about cardiac mitochondrial biology and the aging...

Glioblastoma is the most prevalent primary brain tumor and is essentially universally fatal within 2 years of diagnosis. Glioblastomas contain cellular hierarchies with self-renewing glioblastoma stem cells (GSCs) that are often resistant to chemotherapy and radiation therapy. GSCs express high amounts of repressor element 1 silencing transcription factor (REST), which may contribute to their resistance to standard therapies. Telomere repeat-binding factor 2 (TRF2) stablizes telomeres and REST...

Shorter leukocyte telomere length (LTL) has been associated with a wide range of age-related disorders including cardiovascular disease (CVD) and diabetes. Obesity is an important risk factor for CVD and diabetes. The association of LTL with obesity is not well understood. This study for the first time examines the association of LTL with obesity indices including body mass index, waist circumference, percent body fat, waist-to-hip ratio, and waist-to-height ratio in 3,256 American Indians...

In contrast to the postnatal period, little is known about telomere length (TL) during prenatal life. The decrease in placental TL remains unknown, although intra uterine growth retardation and preeclampsia are associated with shorter placental TL. The aim of this study is to assess the decrease of placental TL during the third trimester of gestation and to explore the role of potential "growth influencing factors"....

Aging is one of the contributing risk factors for kidney diseases. Accumulating evidence prompts the view that telomere length in kidney tissue cells is an indicator for organismal aging. Previously identified aging markers (cathelin-related antimicrobial peptide (CRAMP), stathmin, elongation factor-1α (EF-1α), and chitinase) were associated not only with telomere driven aging in mice but also with human aging and chronic diseases. This study focuses on the relationship between these...

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...

Recent evidence demonstrated a relevant role of adenosine deaminase (ADA) in replicative senescence of T cells through its capacity to modulate telomerase activity (TA). Herein, we tested the impact of the functional polymorphism ADA rs73598374:G>A (c.22G>A, p.Asp8Asn) on telomere biology, by measuring TA and leukocyte telomere length (LTL) in healthy subjects selected according to rs73598374 genotype. rs73598374-A carriers showed lower TA (P=0.019) and shorter LTL (P=0.003), respectively,...

Telomeres play an essential role in maintaining chromosomal integrity in the face of physiological stressors. Although the age-related shortening of TL (telomere length) in highly proliferative tissue is predominantly due to the replication process, the mechanism for telomere shortening in skeletal muscle, which is minimally proliferative, is unclear. By studying TL in both the upper and lower limbs of the young, old-mobile and old-immobile subjects and by virtue of the bipedal nature of human...

Mesenchymal stem cells (MSCs) senescence is an age-related process that impairs the capacity for tissue repair and compromises the clinical use of autologous MSCs for tissue regeneration. Here, we describe the effects of SIRT1, a NAD(+)-dependent deacetylase, on age-related MSCs senescence. Knockdown of SIRT1 in young MSCs induced cellular senescence and inhibited cell proliferation whereas overexpression of SIRT1 in aged MSCs reversed the senescence phenotype and stimulated cell proliferation....

Among diverse environmental factors that modify aging, diet has a profound effect. Calorie restriction (CR), which entails reduced calorie consumption without malnutrition, is the only natural regimen shown to extend maximum and mean lifespan, as well as healthspan in a wide range of organisms. Although the knowledge about the biological mechanisms underlying CR is still incipient, various approaches in biogerontology research suggest that CR can ameliorate hallmarks of aging at the cellular...

Werner syndrome (WS), caused by loss of function of the RecQ helicase WRN, is a hereditary disease characterized by premature aging and elevated cancer incidence. WRN has DNA binding, exonuclease, ATPase, helicase and strand annealing activities, suggesting possible roles in recombination-related processes. Evidence indicates that WRN deficiency causes telomeric abnormalities that likely underlie early onset of aging phenotypes in WS. Furthermore, TRF2, a protein essential for telomere...

The pathogenesis of liver cirrhosis is not completely elucidated. Although in the majority of patients, the risk factors may be identified in B and C viral hepatitis, alcohol intake, drugs or fatty liver disease, there is a small percentage of patients with no apparent risk factors. In addition, the evolution of chronic liver disease is highly heterogeneous from one patient to another. Among patient with identical risk factors, some rapidly progress to cirrhosis and hepatocellular carcinoma...

Ultraviolet A (UVA) radiation contributes to skin photoaging. Baicalin, a plant-derived flavonoid, effectively absorbs UV rays and has been shown to have anti-oxidant and anti-inflammatory properties that may delay the photoaging process. In the current study, cultured human skin fibroblasts were incubated with 50 μg/ml baicalin 24 hours prior to 10 J/cm(2) UVA irradiation. In order to examine the efficacy of baicalin treatment in delaying UVA-induced photoaging, we investigated aging-related...

Telomeres consist of DNA tandem repeats that recruit the multiprotein complex shelterin to build a chromatin structure that protects chromosome ends. Although cancer formation is linked to alterations in telomere homeostasis, there is little understanding of how shelterin function is limited in cancer cells. Using a small-scale screening approach, we identified miR-155 as a key regulator in breast cancer cell expression of the shelterin component TERF1 (TRF1). miR-155 targeted a conserved...

Age-dependent dysregulations of innate immunity impair effective priming of adaptive immunity. Alteration of helper functions of CD4 T cells during aging prevents them from sustaining cytotoxic responses of CD8 T cells against pathogens. The main characteristics of aged and/or differentiated T cells included telomere erosion, reduction of proliferation, decrease of IL-2 secretion and responsiveness, loss of CD28 and acquisition of cytotoxic properties. Phenotypic and functional modifications...

To replicate previously confirmed telomere-length loci in a Chinese Han population with coronary heart disease (CHD), and investigate these loci and the possibility of and age at onset of CHD....

Telomere attrition has been associated with age-related diseases, although causality is unclear and controversial; low-grade systemic inflammation (inflammaging) has also been implicated in age-related pathogenesis. Unpicking the relationship between aging, telomere length (TL), and inflammaging is hence essential to the understanding of aging and management of age-related diseases. This longitudinal study explored whether telomere attrition is a cause or consequence of aging and whether...

Replicative senescence is a fundamental tumor-suppressive mechanism triggered by telomere erosion that results in a permanent cell cycle arrest. To understand the impact of telomere shortening on gene expression, we analyzed the transcriptome of diploid human fibroblasts as they progressed toward and entered into senescence. We distinguished novel transcription regulation due to replicative senescence by comparing senescence-specific expression profiles to profiles from cells arrested by DNA...

Telomeres are the protective caps at the ends of eukaryotic chromosomes. Telomeres get shorter each time a cell divides, and critically shortened telomeres trigger cellular senescence. Thus, telomere length is hypothesized to be a biological marker of aging. The purpose of this study was to examine the association between neighborhood characteristics and leukocyte telomere length. Using data from a subsample (n=978) of the Multi-Ethnic Study of Atherosclerosis, a population-based study of women...

During recent years, it has become increasingly evident that donor leukemia following allogeneic transplant may be more common then realized in the past. We identified five cases of potential donor leukemia cases during past five years. The precise mechanism of the origin of such leukemias, however, remains poorly defined. In this short communication, we report a well documented case of donor-derived de novo acute myeloid leukemia (AML) that developed fourteen years after allogeneic stem cell...

Age-related bone loss is in large part the consequence of senescence mechanisms that impact bone cell number and function. In recent years, progress has been made in the understanding of the molecular mechanisms underlying bone cell senescence that contributes to the alteration of skeletal integrity during aging. These mechanisms can be classified as intrinsic senescence processes, alterations in endogenous anabolic factors, and changes in local support. Intrinsic senescence mechanisms cause...

The telomere structure in the Iberian shrew Sorex granarius is characterized by unique, striking features, with short arms of acrocentric chromosomes carrying extremely long telomeres (up to 300 kb) with interspersed ribosomal DNA (rDNA) repeat blocks. In this work, we investigated the telomere physiology of S. granarius fibroblast cells and found that telomere repeats are transcribed on both strands and that there is no telomere-dependent senescence mechanism. Although telomerase activity is...

Authors: Laura A LA. Villalobos, Anna A. Uryga, Tania T. Romacho, Alejandra A. Leivas, Carlos F CF. Sánchez-Ferrer, Jorge D JD. Erusalimsky, Concepción C. Peiró Published: 05/17/2014, International journal of cardiology PubMed Full Text...

A growing body of evidence indicates that aberrant activation of alveolar epithelial cells and fibroblasts in an aging lung plays a critical role in the pathogenesis of idiopathic pulmonary fibrosis (IPF). However, the biopathological processes linking aging with IPF and the mechanisms responsible for the abnormal activation of epithelial cells and fibroblasts have not been elucidated. Many of the hallmarks of aging (e.g., genomic instability, telomere attrition, epigenetic alterations,...

Aging, a time-dependent functional decline of biological processes, is the primary risk factor in developing diseases such as cancer, cardiovascular or degenerative diseases. There is a real need to understand the human aging process in order to increase the length of disease-free life, also known as "health span". Accumulation of progerin and prelamin A are the hallmark of a group of premature aging diseases but have also been found during normal cellular aging strongly suggesting similar...

Methylation of N-terminal arginines of the shelterin component TRF2 is important for cellular proliferation. While TRF2 is found at telomeres, where it plays an essential role in maintaining telomere integrity, little is known about the cellular localization of methylated TRF2. Here we report that the majority of methylated TRF2 is resistant to extraction by high salt buffer and DNase I treatment, indicating that methylated TRF2 is tightly associated with the nuclear matrix. We show that...

Maternal effects provide a mechanism to adapt offspring phenotype and optimize the mother's fitness to current environmental conditions. Transferring steroids to the yolk is one way mothers can translate environmental information into potential adaptive signals for offspring. However, maternally-derived hormones might also have adverse effects for offspring. For example, recent data in zebra finch chicks suggested that ageing related-processes (i.e. oxidative stress and telomere loss) were...

Age is one of the key parameters in establishing a physical characteristic profile of an individual. For biological evidence left in crime scenes such as blood, saliva, hair, etc, the evidence owner's age can be determined only by DNA extracted from these materials. Previous researches have found that there are certain DNA regions with specialized characteristic and function called telomere being able to predict age. The present study was to determine the correlation between telomere length and...

Cell senescence is one of the major paradigms of aging research. It started with the demonstration by L. Hayflick of the limited number of divisions by normal, nontransformed cells, not shown by transformed malignant cells, this processes being largely regulated by the telomere-telomerase system. A complete renewal of this discipline came from the demonstration that cells can enter senescence at any time by an anti-oncogene-triggered pathway, enabling them to escape malignancy. The senescent...

The observation that human fibroblasts have a limited number of cell population doublings in vitro led to the proposal that it is the expression of cellular aging. In vitro, the proliferation of human fibroblasts terminates with a postmitotic cell which was called senescent cell. Due to misinterpreted experiments, the latter was considered the hallmark of cellular aging, although obviously we do not age because our cells stop dividing. The so-called senescent cell has been the core of the...

FEN1 has key roles in Okazaki fragment maturation during replication, long patch base excision repair, rescue of stalled replication forks, maintenance of telomere stability and apoptosis. FEN1 may be dysregulated in breast and ovarian cancers and have clinicopathological significance in patients. We comprehensively investigated FEN1 mRNA expression in multiple cohorts of breast cancer [training set (128), test set (249), external validation (1952)]. FEN1 protein expression was evaluated in 568...

Telomeres play a central role in cell fate and aging by adjusting the cellular response to both biological and psychological stress. Human telomeres are regions of tandem TTAGGG repeats at chromosomal ends that protect chromosomes from degradation, fusion, and recombination. They are made up of approximately 1000-2500 copies of the repeated DNA sequence. Over time, at each cell division, the telomere ends become shorter. Thus, telomere length (TL) has been considered a cellular marker for...

Telomeres are specialised structures that cap the ends of chromosomes. They shorten with each cell division and have been proposed as a marker of cellular aging. Previous studies suggest that early life stressors increase the rate of telomere shortening with potential impact on disease states and mortality later in life. This study examined the associations between telomere length and exposure to a number of stressors that arise during development from the antenatal/perinatal period through to...

Impaired adipogenesis renders an adipose tissue unable to expand, leading to lipotoxicity and conditions such as diabetes and cardiovascular disease. While factors important for adipogenesis have been studied extensively, those that set the limits of adipose tissue expansion remain undetermined. Feeding a Western-type diet to apolipoprotein E2 knock-in mice, a model of metabolic syndrome, produced 3 groups of equally obese mice: mice with normal glucose tolerance, hyperinsulinemic yet...

Preterm infants develop an 'aged' phenotype in comparison with term-born infants, one component of which is adverse metabolic health and, therefore, long-term health follow-up is warranted to identify morbidity. In light of this, the identification and use of biomarkers to aid with prognosis would be a welcome development. Telomeres are repeat sequences at the ends of each chromosome arm known to shorten as a consequence of cellular aging, and in relation to several disease conditions. The...

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...

Telomere attrition and genomic instability are associated with organism aging. Concerns still exist regarding telomere length resetting in cloned embryos and ntES cells, and possibilities of premature aging of cloned animals achieved by somatic cell nuclear transfer (SCNT). Trichostatin A (TSA), a histone deacetylase inhibitor, effectively improves the developmental competence of cloned embryos and animals, and recently contributes to successful generation of human ntES cells by SCNT. To test...

Centrosomes direct spindle morphogenesis to assemble a bipolar mitotic apparatus to enable error-free chromosome segregation and preclude chromosomal instability (CIN). Amplified centrosomes, a hallmark of cancer cells, set the stage for CIN, which underlies malignant transformation and evolution of aggressive phenotypes. Several studies report CIN and a tumorigenic and/or aggressive transformation in mitochondrial DNA (mtDNA)-depleted cells. Although several nuclear-encoded proteins are...

Cryopreservation is the only method for long-term storage of viable cells and tissues used for cellular therapy, stem cell transplantation and/or tissue engineering. However, the freeze-thaw process strongly contributes to cell and tissue damage through several mechanisms, including oxidative stress, cell injury from intracellular ice formation and altered physical cellular properties. Our previous proteomics investigation was carried out on Wharton's Jelly Stem Cells (WJSCs) having similar...

Telomere length is a heritable trait, and short telomere length has been associated with multiple chronic diseases. We investigated the relationship of relative leukocyte telomere length with cardiometabolic risk and performed the first genome-wide association study and meta-analysis to identify variants influencing relative telomere length in a population of Sikhs from South Asia....

Bloom's syndrome is an autosomal recessive genome-instability disorder associated with a predisposition to cancer, premature aging and developmental abnormalities. It is caused by mutations that inactivate the DNA helicase activity of the BLM protein or nullify protein expression. The BLM helicase has been implicated in the alternative lengthening of telomeres (ALT) pathway, which is essential for the limitless replication of some cancer cells. This pathway is used by 10-15% of cancers, where...

Developmental stressors often have long-term fitness consequences, but linking offspring traits to fitness prospects has remained a challenge. Telomere length predicts mortality in adult birds, and may provide a link between developmental conditions and fitness prospects. Here, we examine the effects of manipulated brood size on growth, telomere dynamics and post-fledging survival in free-living jackdaws. Nestlings in enlarged broods achieved lower mass and lost 21% more telomere repeats...

Europe has the highest proportion of elderly people in the world. Cardiovascular disease, type 2 diabetes, sarcopenia and cognitive decline frequently coexist in the same aged individual, sharing common early risk factors and being mutually reinforcing. Among conditions which may contribute to establish early risk factors, this review focuses on maternal obesity, since the epidemic of obesity involves an ever growing number of women of reproductive age and children, calling for appropriate...

Telomere shortening in arteries could lead to telomere uncapping and cellular senescence, which in turn could promote the development of hypertension....

Leukocyte telomere length (LTL) is related to the aging of somatic cells. We hypothesized that LTL is inversely associated with mortality in elderly men. LTL was measured in 2744 elderly men (mean age 75.5, range 69-81years) included in the prospective population-based MrOS-Sweden study. Mortality data were obtained from national health registers with no loss of follow-up. During the follow-up (mean 6.0years), 556 (20%) of the participants died. Using Cox proportional hazards regression, tertile...

The effects of stress on ill health have become evident in recent years. Under acute stress situations, a cascade of physiological events helps the body mount an appropriate adaptive response. However, under chronic stress situations, this physiological response may lead to wear and tear on the body that accelerates the decline in physiological functioning and increases the risk of chronic conditions. Recent evidence for social stress experienced during childhood suggests serious consequences...

The pathophysiological consequences of caregiving have not been fully elucidated. We evaluated how caregiving, stress, and caregiver strain were associated with shorter relative telomere length (RTL), a marker of cellular aging. Caregivers (n = 240) and some noncaregivers (n = 98) in the 2008-2010 Survey of the Health of Wisconsin, comprising a representative sample of Wisconsin adults aged 21-74 years, reported their sociodemographic, health, and psychological characteristics. RTL was assayed...

Cellular senescence restricts the proliferative capacity of cells and is accompanied by the production of several proteins, collectively termed the "senescence-messaging secretome" (SMS). As senescent cells accumulate in tissue, local effects of the SMS have been hypothesized to disrupt tissue regenerative capacity. Klotho functions as an aging-suppressor gene, and Klotho-deficient (kl/kl) mice exhibit an accelerated aging-like phenotype that includes a truncated lifespan, arteriosclerosis, and...

Telomeres are specialized structures maintaining chromosome integrity during cellular division and preventing from premature senescence and apoptosis. The rate-limiting component of telomerase is human telomerase reverse transcriptase (hTERT), for which multiple transcripts exist. The aim of this work was to characterize hTERT splice variants in MDS and its relation to telomerase activity, telomere length and hTERT expression. The telomere length in PBMCs of patients with MDS cases was...

Human cells typically consist of 23 pairs of chromosomes. Telomeres are repetitive sequences of DNA located at the ends of chromosomes. During cell replication, a number of basepairs are lost from the end of the chromosome and this shortening restricts the number of divisions that a cell can complete before it becomes senescent, or non-replicative. In this paper, we use Monte Carlo simulations to form a stochastic model of telomere shortening to investigate how telomere shortening affects normal...

Telomeres are nucleoprotein complexes that cap the ends of all linear chromosomes and function to prevent aberrant repair and end-to-end chromosome fusions. In somatic cells, telomere shortening is a natural part of the aging process as it occurs with each round of cell division. In germ and stem cells, however, the enzyme telomerase synthesizes telomere DNA to counter-balance telomere shortening and help maintain cellular proliferation. Of the primary telomere end-binding proteins, TPP1 has...

Oxidative stress is involved in the pathogenesis of airway obstruction in α1-antitrypsin deficient patients. This may result in a shortening of telomere length, resulting in cellular senescence. To test whether telomere length differs in α1-antitrypsin deficient patients compared with controls, we measured telomere length in DNA from peripheral blood cells of 217 α1-antitrypsin deficient patients and 217 control COPD patients. We also tested for differences in telomere length between DNA from...

The somatic mutation burden in healthy white blood cells (WBCs) is not well known. Based on deep whole-genome sequencing, we estimate that approximately 450 somatic mutations accumulated in the nonrepetitive genome within the healthy blood compartment of a 115-yr-old woman. The detected mutations appear to have been harmless passenger mutations: They were enriched in noncoding, AT-rich regions that are not evolutionarily conserved, and they were depleted for genomic elements where mutations...

It has been shown that bone marrow mesenchymal stromal cells (MSCs) from patients with myelodysplastic syndromes (MDSs) display defective proliferative potential. We have probed the impaired replicative capacity of culture-expanded MSCs in MDS patients (n=30) compared with healthy subjects (n=32) by studying senescence characteristics and gene expression associated with WNT/transforming growth factor-β1 (TGFB1) signaling pathways. We have also explored the consequences of the impaired patient...

Telomeres are nucleoprotein structures that cap the ends of the linear eukaryotic chromosomes and thereby protect their stability and integrity. Telomeres play central roles in maintaining the genome's integrity, distinguishing between the natural chromosomal ends and unwanted double-stranded breaks. In addition, telomeres are replicated by a special reverse transcriptase called telomerase, in a complex mechanism that is coordinated with the genome's replication. Telomeres also play an important...

Telomeres are specialized nucleoprotein structures that protect chromosomal ends from degradation. These structures progressively shorten during cellular division and can signal replicative senescence below a critical length. Telomere length is predominantly maintained by the enzyme telomerase. Significant decreases in telomere length and telomerase activity are associated with a host of chronic diseases; conversely their maintenance underpins the optimal function of the adaptive immune system....

Acrolein is a ubiquitous environmental hazard to human health. Acrolein has been reported to activate the DNA damage response and induce apoptosis. However, little is known about the effects of acrolein on cellular senescence....

The heat shock 70 family protein, mortalin, has pancytoplasmic distribution pattern in normal and perinuclear in cancer human cells. Cancer cells when induced to senesce by either chemicals or stress showed shift in mortalin staining pattern from perinuclear to pancytoplasmic type. Using such shift in mortalin staining as a reporter, we screened human shRNA library and identified nine senescence-inducing siRNA candidates. An independent Comparative Genomic Hybridization analysis of 35 breast...

Hypercortisolism in Cushing's syndrome (CS) is associated with increased morbidity and mortality. Hypercortisolism also occurs in chronic depressive disorders and stress, where telomere length (TL) is shorter than in controls. We hypothesized that shortening of telomere might occur in CS and contribute to premature aging and morbidity....

Although accelerated β-cell telomere shortening may be associated with diabetes that shows a dramatically increased incidence with aging, β-cell telomere length in diabetes has never been explored....

Authors: A A. Zietzer, P P. Hillmeister Published: 04/15/2014, Acta physiologica (Oxford, England) PubMed Full Text...

TRF2 is a component of shelterin, the protein complex that protects the ends of mammalian chromosomes. TRF2 is essential for telomere capping owing to its roles in suppressing an ATM-dependent DNA damage response (DDR) at chromosome ends and inhibiting end-to-end chromosome fusions. Mice deficient for TRF2 are early embryonic lethal. However, the role of TRF2 in later stages of development and in the adult organism remains largely unaddressed, with the exception of liver, where TRF2 was found to...

We present a classic interactome bioinformatic analysis and a study on competing endogenous (ce) RNAs for hTERT. The hTERT gene codes for the catalytic subunit and limiting component of the human telomerase complex. Human telomerase reverse transcriptase (hTERT) is essential for the integrity of telomeres. Telomere dysfunctions have been widely reported to be involved in aging, cancer, and cellular senescence. The hTERT gene network has been analyzed using the BioGRID interaction database...

Recent studies have uncovered important aging clues, including free radicals, inflammation, telomeres, and life span pathways. Strategies to regulate aging-associated signaling pathways are expected to be effective in the delay and prevention of age-related disorders. For example, herbal polysaccharides with considerable anti-oxidant and anti-inflammation capacities have been shown to be beneficial in aging and age-related neurodegenerative diseases. Polysaccharides capable of reducing cellular...

The nucleolus is speculated to be a regulator of cellular senescence in numerous biological systems (Guarente, Genes Dev 11(19):2449-2455, 1997; Johnson et al., Curr Opin Cell Biol 10(3):332-338, 1998). In the budding yeast Saccharomyces cerevisiae, alterations in nucleolar architecture, the redistribution of nucleolar protein and the accumulation of extrachromosomal ribosomal DNA circles (ERCs) during replicative aging have been reported. However, little is known regarding rDNA stability and...

The serotonin transporter gene (5-HTT)-linked polymorphic region (5-HTTLPR) plays an important role in modulating mood and behavior by regulating 5-HTT expression and thereby controlling the concentration of serotonin (5-HT) in brain synapses: The homozygous shorter allele (S/S) in 5-HTTLPR results in lower 5-HTT expression coupled with stronger psycho-pathological reactions to stressful experiences compared to the homozygous long (L/L) and heterozygous (S/L) alleles. Psychological insults and...

Disadvantaged social environments are associated with adverse health outcomes. This has been attributed, in part, to chronic stress. Telomere length (TL) has been used as a biomarker of chronic stress: TL is shorter in adults in a variety of contexts, including disadvantaged social standing and depression. We use data from 40, 9-y-old boys participating in the Fragile Families and Child Wellbeing Study to extend this observation to African American children. We report that exposure to...

A novel rice mutant, lesion mimic and early senescence 1 (lmes1), was induced from the rice 93-11 cultivar in a γ-ray field. This mutant exhibited spontaneous disease-like lesions in the absence of pathogen attack at the beginning of the tillering stage. Moreover, at the booting stage, lmes1 mutants exhibited a significantly increased MDA but decreased chlorophyll content, soluble protein content and photosynthetic rate in the leaves, which are indicative of an early senescence phenotype. The...

Telomeres, the caps of eukaryotic chromosomes, control chromosome stability and cellular senescence, but aging and exposure to chronic stress are suspected to cause attrition of telomere length. We investigated the effect of social isolation on telomere length in the highly social and intelligent African Grey parrot (Psittacus erithacus erithacus). Our study population consisted of single-housed (n = 26) and pair-housed (n = 19) captive individuals between 0.75 to 45 years of age. Relative...

Authors: Emily E. Anthes Published: 04/03/2014, Nature PubMed Full Text...

Repetitive DNA sequences, such as those present in microsatellites and minisatellites, telomeres, and trinucleotide repeats (linked to fragile X syndrome, Huntington disease, etc.), account for nearly 30% of the human genome. These domains exhibit enhanced susceptibility to oxidative attack to yield base modifications, strand breaks, and abasic sites; have a propensity to adopt non-canonical DNA forms modulated by the positions of the lesions; and, when not properly processed, can contribute to...

Despite the fact that telomeres carry chromatin marks typically associated with silent heterochromatin, they are actively transcribed into TElomeric Repeat containing RNA (TERRA). TERRA transcription is conserved from yeast to man, initiates in the subtelomeric region and proceeds through the telomeric tract of presumably each individual telomere. TERRA levels are increased in yeast survivors and in cancer cells employing ALT as a telomere maintenance mechanism (TMM). Thus, TERRA may be a...

Telomeres, ribonucleoprotein complexes that cap eukaryotic chromosomes, typically shorten in leukocytes with aging. Aging is a primary risk factor for neurodegenerative disease (ND), and a common assumption has arisen that leukocyte telomere length (LTL) can serve as a predictor of neurological disease. However, the evidence for shorter LTL in Alzheimer's and Parkinson's patients is inconsistent. The diverse causes of telomere shortening may explain variability in LTL between studies and...

Cataracts in small animals are shown to be at least partially caused by oxidative damage to lens epithelial cells (LECs) and the internal lens; biomarkers of oxidative stress in the lens are considered as general biomarkers for life expectancy in the canine and other animals. Telomeres lengths and expressed telomerase activity in canine LECs may serve as important monitors of oxidative damage in normal LECs with documented higher levels of telomerase activity in cataractous LECs during cells'...

Although CDKN2A is the most frequent high-risk melanoma susceptibility gene, the underlying genetic factors for most melanoma-prone families remain unknown. Using whole-exome sequencing, we identified a rare variant that arose as a founder mutation in the telomere shelterin gene POT1 (chromosome 7, g.124493086C>T; p.Ser270Asn) in five unrelated melanoma-prone families from Romagna, Italy. Carriers of this variant had increased telomere lengths and numbers of fragile telomeres, suggesting that...

Recent work suggests that leukocyte telomere length (LTL), a marker of cellular aging, is sensitive to effects of social stress and may also provide early indication of premature aging. Using data from a birth cohort with LTL information at birth and in middle adulthood we examined a potential source of race-based health disparity by testing the hypothesis that Blacks would demonstrate a faster rate of telomere shortening than Whites. Linear regression analyses were conducted and adjusted for...

Dyskerin is a conserved, nucleolar RNA-binding protein implicated in an increasing array of fundamental cellular processes. Germline mutation in the dyskerin gene (DKC1) is the cause of X-linked dyskeratosis congenita (DC). Conversely, wild-type dyskerin is overexpressed in sporadic cancers, and high-levels may be associated with poor prognosis. It was previously reported that acute loss of dyskerin function via siRNA-mediated depletion slowed the proliferation of transformed cell lines....

Senescent cells, which express p16 (INK4a) , accumulate with aging and contribute to age-related pathology. To understand whether cytotoxic agents promote molecular aging, we measured expression of p16 (INK4a) and other senescence markers in breast cancer patients treated with adjuvant chemotherapy....

Advances in medical science and technology allow people live longer lives, which results in age-related problems. Humans cannot avoid the various aged-related alterations of aging; in other words, humans cannot remain young at molecular and cellular levels. In 1956, Harman proposed the "free radical theory of aging" to explain the molecular mechanisms of aging. Telomere length, and accumulation of DNA or mitochondrial damage are also considered to be mechanisms of aging. On the other hand, stem...

Werner syndrome (WS) patients exhibit premature aging predominantly in mesenchyme-derived tissues, but not in neural lineages, a consequence of telomere dysfunction and accelerated senescence. The cause of this lineage-specific aging remains unknown. Here, we document that reprogramming of WS fibroblasts to pluripotency elongated telomere length and prevented telomere dysfunction. To obtain mechanistic insight into the origin of tissue-specific aging, we differentiated iPSCs to mesenchymal stem...

Homozygous ABCA1 gene mutation causes Tangier disease (TD). The effects reported in heterozygous state regard plasma HDL, cell cholesterol efflux and coronary artery disease. We investigated whether in vitro replicative skin fibroblast senescence shown in TD proband (Hom), his father (Het), and in a healthy control might be induced in a "gene-dosage way"....

Lack of weight gain throughout adult life could mimic the beneficial effects of energy restriction in humans. The present study aimed to assess the effects of weight stability or gain, over a period of 10 years, on telomere length, sirtuin 1 and 6 expression, and carotid intima media thickness....

In this issue, Soudet et al. show that the actual mechanistic details of the chromosomal end-replication problem, the principle linking telomere biology with human cellular senescence and cancer, match previous predictions almost to the nucleotide....

Arsenic (As) induces pre-malignant and malignant dermatological lesions, non-dermatological health effects and cancers in humans. Senescence involves telomere length changes and acquisition of senescence-associated secretory phenotype (SASP), which promotes carcinogenesis. Though in vitro studies have shown that As induces senescence, population based studies are lacking. We investigated the arsenic-induced senescence, telomere length alteration and its contribution towards development of...

Cellular senescence is a stable proliferation arrest associated with an altered secretory pathway, the senescence-associated secretory phenotype. However, cellular senescence is initiated by diverse molecular triggers, such as activated oncogenes and shortened telomeres, and is associated with varied and complex physiological endpoints, such as tumor suppression and tissue aging. The extent to which distinct triggers activate divergent modes of senescence that might be associated with different...

Exposure to stressors early in life is associated with faster ageing and reduced longevity. One important mechanism that could underlie these late life effects is increased telomere loss. Telomere length in early post-natal life is an important predictor of subsequent lifespan, but the factors underpinning its variability are poorly understood. Recent human studies have linked stress exposure to increased telomere loss. These studies have of necessity been non-experimental and are consequently...

Structural and functional analysis of telomeres is very important for understanding basic biological functions such as genome stability, cell growth control, senescence and aging. Recently, serious concerns have been raised regarding the reliability of current telomere measurement methods such as Southern blot and quantitative polymerase chain reaction. Since telomere length is associated with age related pathologies, including cardiovascular disease and cancer, both at the individual and...

Dyskeratosis congenita (DC) is a clinically and genetically heterogeneous multisystem bone marrow failure disorder of telomere maintenance, which may present with dermatological features. The main cause of mortality is bone marrow failure, often developing in the second decade of life, although pulmonary disease and malignancies such as squamous cell carcinomas (SCCs) may also prove fatal. We report the case of a 28-year-old man with X-linked DC and confirmed DKC1 gene mutation. In addition to...

Slower rates of aging distinguish humans from our nearest living cousins. Chimpanzees rarely survive their forties while large fractions of women are postmenopausal even in high-mortality hunter-gatherer populations. Cellular and molecular mechanisms for these somatic aging differences remain to be identified, though telomeres might play a role. To find out, we compared telomere lengths across age-matched samples of female chimpanzees and women....

Progressive telomere shortening with cell division is a hallmark of aging. Short telomeres are associated with increased cancer risk, but there are conflicting reports about telomere length and mortality in breast cancer survivors....

A major medical challenge in the elderly is osteoporosis and the high risk of fracture. Telomere dysfunction is a cause of cellular senescence and telomere shortening, which occurs with age in cells from most human tissues, including bone. Telomere defects contribute to the pathogenesis of two progeroid disorders characterized by premature osteoporosis, Werner syndrome and dyskeratosis congenital. It is hypothesized that telomere shortening contributes to bone aging. We evaluated the skeletal...

In the United States, there will be an estimated 96,830 new cases of colorectal cancer (CRC) and 50,310 deaths in 2014. CRC is often detected at late stages of the disease, at which point there is no effective chemotherapy. Thus, there is an urgent need for effective novel therapies that have minimal effects on normal cells. T-oligo, an oligonucleotide homologous to the 3'-telomere overhang, induces potent DNA damage responses in multiple malignant cell types, however, its efficacy in CRC has...

Exposure to total body irradiation (TBI) induces not only acute hematopoietic radiation syndrome but also long-term or residual bone marrow (BM) injury. This residual BM injury is mainly attributed to permanent damage to hematopoietic stem cells (HSCs), including impaired self-renewal, decreased long-term repopulating capacity, and myeloid skewing. These HSC defects were associated with significant increases in production of reactive oxygen species (ROS), expression of p16(Ink4a) (p16) and Arf...

A variety of human tumors employ alternative and recombination-mediated lengthening for telomere maintenance (ALT). Human RecQ helicases, such as BLM and WRN, can efficiently unwind alternate/secondary structures during telomere replication and/or recombination. Here, we report a novel role for RECQL1, the most abundant human RecQ helicase but functionally least studied, in telomere maintenance. RECQL1 associates with telomeres in ALT cells and actively resolves telomeric D-loops and Holliday...

Leukocyte telomere length (LTL) is longer in association with advanced paternal age, but this association has not been examined along with family history (FH) in schizophrenia. LTL was measured by PCR and compared across cases and controls as part of a study to examine the characteristics of paternal age related schizophrenia. The 53 schizophrenia cases had similar mean LTL as 20 controls, although cases were significantly older than controls and overwhelmingly smoked cigarettes. Multivariate...

Colorectal cancer (CRC) is the third most common cancer worldwide and, despite improved treatments, is still an important cause of cancer-related deaths. CRC encompasses a complex of diseases arising from a multi-step process of genetic and epigenetic events. Besides heterogeneity in the molecular and biological features of CRC, chromosomal instability is a hallmark of cancer and cancer cells may also circumvent replicative senescence and acquire the ability to sustain unlimited proliferation....

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...

Telomere biology is frequently associated with disease evolution in human cancer and dysfunctional telomeres have been demonstrated to contribute to genetic instability. In BCR-ABL(+) chronic myeloid leukemia (CML), accelerated telomere shortening has been shown to correlate with leukemia progression, risk score and response to treatment. Here, we demonstrate that proliferation of murine CML-like bone marrow cells strongly depends on telomere maintenance. CML-like cells of telomerase knockout...

Telomeres play a key role in replicative ageing and undergo age-dependent attrition in vivo. Here, we report a novel method, TelSeq, to measure average telomere length from whole genome or exome shotgun sequence data. In 260 leukocyte samples, we show that TelSeq results correlate with Southern blot measurements of the mean length of terminal restriction fragments (mTRFs) and display age-dependent attrition comparably well as mTRFs....

Therapeutic use of multipotent mesenchymal stromal stem cells (MSC) is a promising venue for a large number of degenerative diseases and cancer. Their availability from many different adult tissues, ease of expansion in culture, the ability to avoid immune rejection and their homing ability, are some of the properties of MSCs that make them a great resource for therapy. However, the challenges and risks for cell-based therapies are multifaceted. The blessing of cell culture expansion also comes...

The post-translational modification of histones has been implicated in the regulation of cellular lifespan. Previously, we reported that cellular aging is associated with increased ubiquitylation of histone H2B and methylation of histone H3 at lysines 4 and 79 in yeast telomeric heterochromatin. Here, we show the antagonistic role of Set2 methyltransferase, which is specific for histone H3 at lysine 36, in regulating telomeric silencing and cellular lifespan. We observed that an intermediate...

Telomeres are DNA-protein complexes that cap chromosomal ends, promoting chromosome stability. Telomerase is a ribonucleoprotein complex with a direct telomere protective function. Telomere shortening represents lifetime exposure to oxidative stress and is negatively correlated with age, smoking, and mortality. Smoking increases oxidative DNA modification and thus may influence telomere dynamics and human telomerase reverse transcriptase (hTERT) activity....

Telomeres are nucleoprotein structures that cap the end of chromosomes and shorten with sequential cell divisions in normal aging. Short telomeres are also implicated in the incidence of many cancers, but the evidence is not conclusive for colorectal cancer (CRC). Therefore, the aim of this study was to assess the association of CRC and telomere length....

Telomerase plays a pivotal role in bypassing cellular senescence and maintaining telomere homeostasis, essential properties required for the sustenance and progression of cancer. However, recent investigations have uncovered extratelomeric properties of telomerase that are independent of its role in telomere extension. This review summarizes recent insights to the noncanonical functions of telomerase reverse transcriptase (TERT) catalytic subunit, in particular in cancer progression, and...

The most important risk factor for developing Parkinson's disease (PD) is age. Aging is ascribed to different mechanisms, including telomere shortening. Telomeres consist of repetitive DNA sequences and stabilize chromosome integrity. Currently, however, the data reported on telomere shortening in PD patients are inconsistent. We investigated the effect of telomere shortening in the MPTP mouse model of PD using late-generation telomerase-deficient mice (G3 Terc mice). G3 Terc mice showed a...

A major objective of biobehavioral research is defining the mechanisms that underlie linkages among behavior, biology, health, and disease. The genomic revolution has demonstrated the importance of studying the role of the environment in (epi)genetic mechanisms. The idea that interactions between environment and genetics influence health outcomes is a central concept of the exposome, a measure of environmental exposures throughout a lifetime. Research suggests that telomere length (TL) and...

Through implementation of combination antiretroviral therapy (cART) remarkable gains have been achieved in the management of HIV infection; nonetheless, the neurocognitive consequences of infection remain a pivotal concern in the cART era. Research has often employed norm-referenced neuropsychological scores, derived from healthy populations (excluding many seronegative individuals at high risk for HIV infection), to characterize impairments in predominately male HIV-infected populations....

In telomerase negative yeast cells, Rad52-dependent recombination is activated to maintain telomeres. This recombination-mediated telomere elongation usually involves two independent pathways, type I and type II, and leads to generation of type I and type II survivors. It remains elusive whether the recombination-mediated telomere elongation prefers to take place on shorter or longer telomeres. In this study, we exploited the de novo telomere addition system to examine the telomere recombination...

Telomeres play a fundamental role in the protection of chromosomal DNA and in the regulation of cellular senescence. Recent work in human epidemiology and evolutionary ecology suggests adult telomere length (TL) may reflect past physiological stress and predict subsequent morbidity and mortality, independent of chronological age.Several different methods have been developed to measure TL, each offering its own technical challenges. The aim of this review is to provide an overview of the...

Mutations accumulate as a result of DNA damage and imperfect DNA repair machinery. In higher eukaryotes the accumulation and spread of mutations is limited in two primary ways: through p53-mediated programmed cell death and cellular senescence mediated by telomeres. Telomeres shorten at every cell division and cell stops dividing once the shortest telomere reaches a critical length. It has been shown that the rate of telomere attrition is accelerated when cells are exposed to DNA damaging...

The etiopathogenesis of schizophrenia is poorly understood. Within the proposed "neurodegeneration paradigm", observations have been put forth for "accelerated aging" in this disorder. This proposition is largely based on the neuroscience research that demonstrates progressive changes in brain as well as other systemic abnormalities supportive of faster aging process in patients with this disorder. In this review, we have summarized the literature related to the concept of early aging in...

Over the last 40 years it has become clear that telomeres, the end of the chromosomes, and the enzyme telomerase reverse transcriptase (TERT), which is required to counteract their shortening, play a pivotal role in senescence and aging. However, over the last years several studies demonstrated that TERT belongs to the group of dual-targeted proteins. It contains a bipartite nuclear localization signal as well as a mitochondrial targeting sequence and, under physiological conditions, is found in...

Telomere shortening and telomerase deficiency have been linked with several age related degenerative diseases. Moreover, degenerative changes in various tissues/organs have been attributed to derangement of stem cell functions causing regenerative tragedy. Bone marrow stromal cells (BMSCs) are considered the ideal candidates for regenerative approaches owing to their beneficial effects in numerous clinical applications. Thus, the effect of telomerase deficiency in perpetrating age related...

Telomeres protect and cap linear chromosome ends, yet these genomic buffers erode over an organism's lifespan. Short telomeres have been associated with many age-related conditions in humans, and genetic mutations resulting in short telomeres in humans manifest as syndromes of precocious aging. In women, telomere length limits a fertilized egg's capacity to develop into a healthy embryo. Thus, telomere length must be reset with each subsequent generation. Although telomerase is purportedly...

Peripheral 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....

Cellular senescence is a physiological process of irreversible cell-cycle arrest that contributes to various physiological and pathological processes of aging. Whereas replicative senescence is associated with telomere attrition after repeated cell division, stress-induced premature senescence occurs in response to aberrant oncogenic signaling, oxidative stress, and DNA damage which is independent of telomere dysfunction. Recent evidence indicates that cellular senescence provides a barrier to...

Telomerase is the enzyme responsible for the maintenance of telomere length by adding guanine-rich repetitive sequences. Its activity can be seen in gametes, stem cells and tumor cells. In human somatic cells the proliferative potential is limited, reaching senescence after 50-70 cell divisions, because the DNA polymerase is not able to copy the DNA at the ends of chromosomes. By contrast, in most tumor cells the replicative potential is unlimited due to the maintenance of the telomeric length...

The spatial and temporal organization of the genome has emerged as an additional level of regulation of nuclear functions. Structural proteins associated with the nuclear envelope play important roles in the organization of the genome. The nuclear lamina, a polymeric meshwork formed by lamins (A- and B-type) and lamin-associated proteins, is viewed as a scaffold for tethering chromatin and protein complexes regulating a variety of nuclear functions. Alterations in lamins function impact DNA...

Telomeres are biomarkers of biological aging. Shorter telomeres have been associated with increased adiposity in adults. However, this relationship remains unclear in children and adolescents....

Heterochromatin displays repressive histone marks that down-regulate transcription. In the absence of specialized barriers, these repressive marks spread onto nearby nucleosomes and induce transcriptional silencing of these regions. Accordingly, in various species, transgenes that are experimentally inserted directly next to telomeric repeats are silenced. Transcriptional repression induced by the spreading of telomeric heterochromatin is known as the "telomere position effect". Although it is...

Telomeric DNA has been intensely investigated for its role in chromosome protection, aging, cell death, and disease. In humans the telomeric tandem repeat (TTAGGG)n is found at the ends of chromosomes and provides a novel target for the development of new drugs in the treatment of age related diseases such as cancer. These telomeric sequences show slight sequence variations from species to species; however, each contains repeats of 3 to 4 guanines allowing the G-rich strands to fold into compact...

The elderly population is increasing progressively. Along with this increase the number of age related diseases, such as cardiovascular, neurodegenerative diseases, metabolic impairment and cancer, is also on the rise thereby negatively impacting the burden on health care systems. Telomere shortening and dysfunction results in cellular senescence, an irreversible proliferative arrest that has been suggested to promote organismal aging and disabling age-related diseases. Given that telomerase,...

Human telomeric regions are packaged as constitutive heterochromatin, characterized by extensive subtelomeric DNA methylation and specific histone modifications. ICF (immunodeficiency, centromeric instability, facial anomalies) type I patients carry mutations in DNA methyltransferase 3B (DNMT3B) that methylates de novo repetitive sequences during early embryonic development. ICF type I patient fibroblasts display hypomethylated subtelomeres, abnormally short telomeres and premature senescence....

In human somatic cells or yeast cells lacking telomerase, telomeres are shortened upon each cell division. This gradual shortening of telomeres eventually leads to senescence. However, a small population of telomerase-deficient cells can survive by bypassing senescence through the activation of alternative recombination pathways to maintain their telomeres. Although genes involved in telomere recombination have been identified, mechanisms that trigger telomere recombination are less known. The...

Introduction. Fatigue is often present in older adults with no identified underlying cause. The accruing burden of oxidative stress and inflammation might be underlying factors of fatigue. We therefore hypothesized that leukocyte telomere length (LTL) is relatively short in older adults who experience fatigue. Materials and Methods. We assessed 439 older nondisabled Danish twins. LTL was measured using Southern blots of terminal restriction fragments. Fatigue was measured by the Mob-T Scale...

Bipolar Disorder (BD) has been conceptualized as both a cyclic and a progressive disorder. Mechanisms involved in neuroprogression in BD remain largely unknown although several non-mutually exclusive models have been proposed as explanatory frameworks. In the present paper, we propose that the pathophysiological changes observed in BD (e.g. brain structural alterations, cognitive deficits, oxidative stress imbalance, amyloid metabolism, immunological deregulation, immunosenescence, neurotrophic...

Authors: Emma R ER. Drašar, Jie J. Jiang, Kate K. Gardner, Jo J. Howard, Tom T. Vulliamy, Nisha N. Vasavda, Swee Lay SL. Thein Published: 02/14/2014, British journal of haematology PubMed Full Text...

Telomeres are structures that cap the ends of chromosomes. The integrity of the telomere structure and its DNA hexamer (TTAGGG)n repeat sequence is critical for protecting the ends of chromosomes from degradation and in maintaining overall chromosomal stability. Currently, there are limited data on the influence that nutrition has on telomere length. Recent studies have suggested that micronutrients may influence telomere length. Here we examined the relationship between telomere length in...

Telomeres protect chromosome ends from being recognized as sites of DNA damage. Upon telomere shortening or telomere uncapping induced by loss of telomeric repeat-binding factor 2 (TRF2), telomeres elicit a DNA-damage response leading to cellular senescence. Here, we show that following TRF2 depletion, the levels of the long noncoding RNA TERRA increase and LSD1, which binds TERRA, is recruited to telomeres. At uncapped telomeres, LSD1 associates with MRE11, one of the nucleases implicated in...

DNA-damage response and repair are crucial to maintain genetic stability, and are consequently considered central to aging and longevity. Here, we investigate whether this pathway overall associates to longevity, and whether specific sub-processes are more strongly associated with longevity than others. Data were applied on 592 SNPs from 77 genes involved in nine sub-processes: DNA-damage response, base excision repair (BER), nucleotide excision repair, mismatch repair, non-homologous...

Telomeres are nucleoprotein structures that cap the ends of eukaryotic chromosomes, protecting them from degradation and activation of DNA damage response. For this reason, functional telomeres are vital to genome stability. For years, telomeres were assumed to be transcriptionally silent, because of their heterochromatic state. It was only recently shown that, in several organisms, telomeres are transcribed, giving rise to a long noncoding RNA (lncRNA) called telomeric repeat-containing RNA...

Epidemiological and experimental studies indicate that early vascular dysfunction occurs in low-birth-weight subjects, especially preterm (PT) infants. We recently reported impaired angiogenic activity of endothelial colony-forming cells (ECFCs) in this condition. We hypothesized that ECFC dysfunction in PT might result from premature senescence and investigated the underlying mechanisms. Compared with ECFCs from term neonates (n = 18), ECFCs isolated from PT (n = 29) display an accelerated...

Early life stress (ELS) poses a risk for mental disorders and aging-related diseases. Accelerated biological aging, reflected in shorter leukocyte telomere length (LTL), may underlie these risks. We examined whether objectively recorded ELS and retrospectively self-reported traumatic experiences across the lifespan are associated with LTL in later adulthood. Of 1486 participants, 215 had been exposed to ELS, namely to temporary separation from both parents in childhood. Participants...

Cornelia de Lange syndrome (CdLS) is the prototype for the cohesinopathy disorders that have mutations in genes associated with the cohesin subunit in all cells. Roberts syndrome is the next most common cohesinopathy. In addition to the developmental implications of cohesin biology, there is much translational and basic research, with progress towards potential treatment for these conditions. Clinically, there are many issues in CdLS faced by the individual, parents and caretakers,...

BDNF plays an important role in the development and maintenance of visual circuitries in the retina and brain visual centers. In adulthood, BDNF signaling is involved in neural protection and regeneration of retina. In this survey, we investigated the expression of BDNF in the retina of adult Nothobranchius furzeri, a teleost fish employed for age research. After describing the retina of N. furzeri and confirming that the structure is organized in layers as in all vertebrates, we have studied...

Dyskeratosis congenita (DC) is an inherited disorder with mutations affecting telomerase or telomeric proteins. DC patients usually die of bone marrow failure. Here we show that genetic depletion of the telomerase RNA component (TR) in the zebrafish results in impaired myelopoiesis, despite normal development of haematopoietic stem cells (HSCs). The neutropenia caused by TR depletion is independent of telomere length and telomerase activity. Genetic analysis shows that TR modulates the...

Telomeres are protective nucleoprotein structures at the ends of eukaryotic chromosomes. Despite the heterochromatic state of telomeres they are transcribed, generating non-coding telomeric repeat-containing RNA (TERRA). Strongly induced TERRA transcription has been shown to cause telomere shortening and accelerated senescence in the absence of both telomerase and homology-directed repair (HDR). Moreover, it has recently been demonstrated that TERRA forms RNA-DNA hybrids at chromosome ends. The...

Uncontrolled growth of cells, a main criterion of cancer, is merged with pathologic telomere length alteration. Thereby, measurement of telomere length could provide important information on cell proliferation and senescence in cancer tissues. Telomere shortening and its potential correlation with clinicopathological predictive markers in sporadic colorectal cancer (CRC) with normal expression of mismatch repair (MMR) proteins (including Mlh1, Msh2, Pms2, and Msh6) and normal p53 expression was...

Charles Darwin knew that the fossil record is not overwhelmingly supportive of genetic and phenotypic gradualism; therefore, he developed the core of his theory on the basis of breeding experiments. Here, I present evidence for the existence of a cell biological mechanism that strongly points to the almost forgotten European concept of saltatory evolution of nonadaptive characters, which is in perfect agreement with the gaps in the fossil record. The standard model of chromosomal evolution has...

Human aging is associated with DNA methylation changes at specific sites in the genome. These epigenetic modifications may be used to track donor age for forensic analysis or to estimate biological age....

To investigate the relationship between telomere length in peripheral blood white cells and cardiovascular function in a healthy, aging Han Chinese population....

Mindfulness-based stress reduction (MBSR) reduces symptoms of depression, anxiety, and fear of recurrence among breast cancer (BC) survivors. However, the effects of MBSR (BC) on telomere length (TL) and telomerase activity (TA), known markers of cellular aging, psychological stress, and disease risk, are not known. This randomized, wait-listed, controlled study, nested within a larger trial, investigated the effects of MBSR (BC) on TL and TA. BC patients (142) with Stages 0-III cancer who had...

The ageing process is strongly influenced by nutrient balance, such that modest calorie restriction (CR) extends lifespan in mammals. Irisin, a newly described hormone released from skeletal muscles after exercise, may induce CR-like effects by increasing adipose tissue energy expenditure. Using telomere length as a marker of ageing, this study investigates associations between body composition, plasma irisin levels and peripheral blood mononuclear cell telomere length in healthy, non-obese...

8-oxo-2'-deoxyguanosine (8-oxo-dG) is a nucleoside resulting from oxidative damage and is known to be mutagenic. 8-Oxo-dG has been related to aging and diseases, including neurological disorders and cancer. Recently, we reported that a fluorescent nucleoside derivative, adenosine-1,3-diazaphenoxazine (Adap), forms a stable base pair with 8-oxo-dG in DNA with accompanying efficient quenching. In this study, a new Adap derivative having an additional 2-amino group on the adenosine moiety...

Tumor viruses promote cell proliferation in order to gain access to an environment suitable for persistence and replication. The expression of viral products that promote growth transformation is often accompanied by the induction of multiple signs of telomere dysfunction, including telomere shortening, damage of telomeric DNA and chromosome instability. Long-term survival and progression to full malignancy require the bypassing of senescence programs that are triggered by the damaged telomeres....

Clinical studies suggest that hypercholesterolemia may cause ageing in hematopoietic stem cells (HSCs) because ageing-associated alterations were found in peripheral blood cells and their bone marrow residing precursors in patients with advanced atherosclerosis. We hypothesized that hypercholesterolemia induces oxidant stress in hematopoietic stems cells that accelerates their ageing....

Lamellarin D (LamD) is a marine alkaloid with broad spectrum antitumor activities. Multiple intracellular targets of LamD, which affect cancer cell growth and induce apoptosis, have been identified. These include nuclear topoisomerase I, relevant kinases (such as cyclin-dependent kinase 2) and the mitochondrial electron transport chain. While we have previously demonstrated that LamD at micromolar range deploys strong cytotoxicity by inducing mitochondrial apoptosis, mechanisms of its cytostatic...

Telomerase plays a pivotal role in the pathology of aging and cancer by maintaining genome integrity, controlling cell proliferation, and regulating tissue homeostasis. Telomerase is essentially composed of an RNA component, Telomerase RNA or TERC, which serves as a template for telomeric DNA synthesis, and a catalytic subunit, telomerase reverse transcriptase (TERT). The canonical function of TERT is the synthesis of telomeric DNA repeats, and the maintenance of telomere length. However,...

Ghrelin regulates homeostatic food intake, hedonic eating, and is a mediator in the stress response. In addition, ghrelin has metabolic, cardiovascular, and anti-aging effects. This cross-sectional study examined associations between total plasma ghrelin, caloric intake based on 3day diet diaries, hedonic eating attitudes, stress-related and metabolic factors, and leukocyte telomere length in overweight (n=25) and obese women (n=22). We hypothesized associations between total plasma ghrelin and...

Individuals infected with human immunodeficiency virus (HIV) appear to age faster than the general population, possibly related to HIV infection, antiretroviral therapy, and/or social/environmental factors. We evaluated leukocyte telomere length (LTL), a marker of cellular aging, in HIV-infected and uninfected adults....

Telomeric attrition has repeatedly been found to correlate with the ageing of organisms; however, recent research is increasingly showing that the determinants of attrition dynamics are not well understood. This study examined the relative telomere lengths in Eastern mosquitofish, Gambusia holbrooki, kept at different temperatures and at different ages. Newly born fry were randomly selected for one of four treatment groups: 20, 30, 20-30, and 30-20 °C, where the third and fourth treatment...

Leukocyte telomere length (LTL) is a predictor of aging and a number of age-related diseases. We performed genome-wide association studies of mean LTL in 2632 individuals,with a two-stage replication in 3917 individuals from Chinese populations. To further validate our findings, we get the results of 696 samples from a cohort of European ancestry. We identified two loci associated with LTL that map in telomerase reverse transcriptase (TERT; rs2736100, P = 1.93×10(-5)) on chromosome 5p15.33...

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....

To investigate the association between genetic variation in telomerase RNA component (TERC) and leukocyte telomere length (LTL) with risk of coronary heart disease (CHD)....

Selection for large body size in mink (Neovison vison) can result in obesity, which is associated with poor reproduction and metabolic disorders. Caloric restriction is effective in diminishing oxidative stress and delaying aging-related diseases. This study investigated the effects of moderate diet restriction on body condition, health, and reproductive success of mink breeder females. One-hundred control females were fed according to conventional feeding practice, while the feed allowance of...

Leukocyte telomere length is believed to measure cellular aging in humans, and short leukocyte telomere length is associated with increased risks of late onset diseases, including cardiovascular disease, dementia, etc. Many studies have shown that leukocyte telomere length is a heritable trait, and several candidate genes have been identified, including TERT, TERC, OBFC1, and CTC1. Unlike most studies that have focused on genetic causes of chronic diseases such as heart disease and diabetes in...

Human RecQ4 (hRecQ4) affects cancer and aging but is difficult to study because it is a fusion between a helicase and an essential replication factor. Budding yeast Hrq1 is homologous to the disease-linked helicase domain of RecQ4 and, like hRecQ4, is a robust 3'-5' helicase. Additionally, Hrq1 has the unusual property of forming heptameric rings. Cells lacking Hrq1 exhibited two DNA damage phenotypes: hypersensitivity to DNA interstrand crosslinks (ICLs) and telomere addition to DNA breaks....

Life expectancy, as well as the average age of patients undergoing solid organ transplantation, increases constantly. Consequently, immunosuppressive therapy is no longer limited to young organ recipients....

To examine the association between plasma concentrations of antioxidative micronutrients and leukocyte telomere length (LTL) in elderly adults....

Enzymatic activity of Telomerase Reverse Transcriptase (TERT) is important in maintaining the telomere length and has been implicated in cancer and aging related pathology. Since cancer susceptibility as well as longevity of dogs vary between breeds, this study involved sequencing the entire TERT gene of Canis familiaris from DNA samples obtained from forty dogs, with ten dogs each of four breeds: Shih Tzu, Dachshund, Irish Wolfhound, and Newfoundland, each with different life expectancies and...

There is evidence that persistent psychiatric disorders lead to age-related disease and premature mortality. Telomere length has emerged as a promising biomarker in studies that test the hypothesis that internalizing psychiatric disorders are associated with accumulating cellular damage. We tested the association between the persistence of internalizing disorders (depression, generalized anxiety disorder and post-traumatic stress disorder) and leukocyte telomere length (LTL) in the prospective...

In recent years there has been a large expansion in our understanding of SIRT6 biology including its structure, regulation, biochemical activity, and biological roles. SIRT6 functions as an ADP-ribosylase and NAD(+)-dependent deacylase of both acetyl groups and long-chain fatty-acyl groups. Through these functions SIRT6 impacts upon cellular homeostasis by regulating DNA repair, telomere maintenance, and glucose and lipid metabolism, thus affecting diseases such diabetes, obesity, heart disease,...

Human leukocyte telomere length (LTL) decreases with age and shorter LTL has previously been associated with increased prospective mortality. However, it is not clear whether LTL merely marks the health status of an individual by its association with parameters of immune function, for example, or whether telomere shortening also contributes causally to lifespan variation in humans....

Aging phenotypes are dictated by myriad cellular changes including telomere shortening. In most tissues, telomere shortening is accelerated during replication if unrepaired oxidative damage to telomere sequences is present. However, the effect of reactive oxygen species exposure on skeletal muscle telomeres is unknown. We sought to determine if oxidative stress shortens telomeres in isolated adult rodent skeletal muscle fibers. Flexor digitorum brevis muscles were dissected from male mice...

Epidemiological studies, including those in identical twins, and in individuals in utero during periods of famine have provided robust evidence of strong correlations between low birth-weight and subsequent risk of disease in later life, including type 2 diabetes (T2D), CVD, and metabolic syndrome. These and studies in animal models have suggested that the early environment, especially early nutrition, plays an important role in mediating these associations. The concept of early life programming...

Maintenance of telomere length and structure is essential for cell survival. Telomere synthesis is mediated by the ribonucleoprotein telomerase in 90% of cancer cells, and is regulated mainly by transcription of the human telomerase reverse transcriptase subunit, hTERT. However, transcriptome analysis reveals complex splicing patterns and to date, twenty-two alternatively-spliced hTERT mRNAs have been reported, yet their functions have not been fully elucidated. The best characterized hTERT...

Recent research suggests pessimistic orientation is associated with shorter leukocyte telomere length (LTL). However, this is the first study to look not only at effects of pessimistic orientation on average LTL at multiple time points, but also at effects on the rate of change in LTL over time....

Chiral recognition of DNA molecules is important because DNA chiral transition and its different conformations are involved in a series of important life events. Among them, polymorphic human telomere DNA has attracted great interests in recent years because of its important roles in chromosome structural integrity. In this report, we examine the short-term effect of chiral metallo-supramolecular complex enantiomers treatment on tumor cells, and find that a zinc-finger-like alpha helical chiral...

Sirtuin 1 (SIRT1) is a nicotinamide adenine dinucleotide (NAD)-dependent deacetylase that is implicated in plethora of biological processes, including metabolism, aging, stress response, and tumorigenesis. Telomerase (TERT) is essential for telomere maintenance. Activation of TERT is considered a crucial step in tumorigenesis, and therefore it is a potential therapeutic target against cancer. We have recently found that SIRT1 expression is highly elevated in hepatocellular carcinoma, and the...

Senescence of vascular endothelial cells leads to endothelial dysfunction and contributes to the progression of atherosclerosis. Liver X receptors (LXRs) are nuclear receptors whose activation protects against atherosclerosis by transcriptional regulation of genes important in promoting cholesterol efflux and inhibiting inflammation. Here we found that LXR activation with specific ligands reduced the increase in senescence-associated (SA) β-gal activity, a senescence marker, and reversed the...

Telomerase is required for the unlimited lifespan of cancer cells. The vast majority of pancreatic adenocarcinomas overexpress telomerase activity and blocking telomerase could limit their lifespan. GRN163L (Imetelstat) is a lipid-conjugated N3'→P5' thio-phosphoramidate oligonucleotide that blocks the template region of telomerase. The aim of this study was to define the effects of long-term GRN163L exposure on the maintenance of telomeres and lifespan of pancreatic cancer cells. Telomere...

In the absence of telomerase, telomeres progressively shorten with every round of DNA replication, leading to replicative senescence. In telomerase-deficient Saccharomyces cerevisiae, the shortest telomere triggers the onset of senescence by activating the DNA damage checkpoint and recruiting homologous recombination (HR) factors. Yet, the molecular structures that trigger this checkpoint and the mechanisms of repair have remained elusive. By tracking individual telomeres, we show that telomeres...

The shortening of telomeres as a causative factor in ageing is a widely discussed hypothesis in ageing research. The study of telomere length and its regenerating enzyme telomerase in the longest-lived non-colonial animal on earth, Arctica islandica, should inform whether the maintenance of telomere length plays a role in reaching the extreme maximum lifespan (MLSP) of >500years in this species. Since longitudinal measurements on living animals cannot be achieved, a cross-sectional analysis of a...

Telomere length provides an estimate of cellular aging and is influenced by oxidative stress and health behaviors such as diet and exercise. This article describes relationships between telomere length and sleep parameters that included total sleep time (TST), wake after sleep onset (WASO), and self-reported sleep quality in a sample of adults with chronic illness....

To examine whether subjective sleep quality and sleep duration moderate the association between age and telomere length (TL)....

Leukemia stem cells (LSCs) play important roles in leukemia initiation, progression and relapse, and thus represent a critical target for therapeutic intervention. Hence, it is extremely urgent to explore new therapeutic strategies directly targeting LSCs for acute myelogenous leukemia (AML) therapy. We show here that Angelica sinensis polysaccharide (ASP), a major active component in Dong quai (Chinese Angelica sinensis), effectively inhibited human AML CD34+CD38? cell proliferation in vitro...

Telomeres, DNA-protein structures at chromosome ends, shorten with age, and telomere length has been linked to age-related diseases and survival. In vitro studies revealed that the shortest telomeres trigger cell senescence, but whether the shortest telomeres are also the best biomarker of ageing is not known. We measured telomeres in erythrocytes of wild common terns Sterna hirundo using terminal restriction fragment analysis. This yields a distribution of telomere lengths for each sample, and...

Chromosomal instability in peripheral blood mononuclear cells has a role in the onset of primary biliary cirrhosis. We hypothesized that patients with primary biliary cirrhosis may harbour telomere dysfunction, with consequent chromosomal instability and cellular senescence....

Exposure to chronic stressors is associated with accelerated biological aging as indicated by reduced leukocyte telomere length (LTL). This impact could be because of chronic overactivation of the body's physiological stress systems. This study examined the associations between LTL and the immune system, hypothalamic-pituitary-adrenal axis and autonomic nervous system. LTL was assessed in 2936 adults from the Netherlands Study of Depression and Anxiety. Inflammation markers (interleukin-6,...

Telomeres comprise the protective caps of natural chromosome ends and function in the suppression of DNA damage signaling and cellular senescence. Therefore, techniques used to determine telomere length are important in a number of studies, ranging from those investigating telomeric structure to effects on human disease. Terminal restriction fragment (TRF) analysis has for a long time shown to be one of the most accurate methods for quantification of absolute telomere length and range from a...

It is widely believed that females have longer telomeres than males, although results from studies have been contradictory....

Most organisms, including ourselves, are exposed to environmental stressors at various points during life, and responses to such stressors have been optimised by evolution to give the best fitness outcomes. It is expected that environmental change will substantially increase long-term stress exposure in many animal groups in the coming decades. A major challenge for biologists is to understand and predict how this will influence individuals, populations and ecosystems, and over what time scale...

Oligonucleotides homologous to 3'-telomere overhang (T-oligos) trigger inherent telomere-based DNA damage responses mediated by p53 and/or ATM and induce senescence or apoptosis in various cancerous cells. However, T-oligo has limited stability in vivo due to serum and intracellular nucleases. To develop T-oligo as an innovative, effective therapeutic drug and to understand its mechanism of action, we investigated the antitumor effects of T-oligo or T-oligo complexed with a novel cationic alpha...

This perspective review focused on the Werner syndrome (WS) by addressing the issue of how a single mutation in a WRN gene encoding WRN DNA helicase induces a wide range of premature aging phenotypes accompanied by an abnormal pattern of tumors. The key event caused by WRN gene mutation is the dysfunction of telomeres. Studies on normal aging have identified a molecular circuit in which the dysfunction of telomeres caused by cellular aging activates the TP53 gene. The resultant p53 suppresses...

Although telomere shortening occurs as a natural part of aging, there is now a robust body of research that suggests that there is a relationship between psychosocial, environmental, and behavioral factors and changes in telomere length. These factors need to be considered when integrating telomere measurement in biobehavioral research studies....

The intersection of aging and HIV/AIDS is a looming 'epidemic within an epidemic.' This paper reviews how HIV/AIDS and its therapy cause premature aging or contribute mechanistically to HIV-associated non-AIDS illnesses (HANA). Survival with HIV/AIDS has markedly improved by therapy combinations containing nucleoside reverse transcriptase inhibitors (NRTIs), non-nucleoside reverse transcriptase inhibitors, and protease inhibitors (PIs) called HAART (highly active antiretroviral therapy). Because...

Telomerase reverse transcriptase (TERT) is the protein component of telomerase and combined with an RNA molecule, telomerase RNA component, forms the telomerase enzyme responsible for telomere elongation. Telomerase is essential for maintaining telomere length from replicative attrition and thus contributes to the preservation of genome integrity. Although diverse mouse models have been developed and studied to prove the physiological roles of telomerase as a telomere- elongating enzyme, recent...

Our previous in vivo study demonstrated that human nucleus pulposus chondrocytes (NPCs) in aging discs exhibited characteristic senescent features such as an increased senescence-associated β-galactosidase (SA-β-gal) expression, shortened telomere, and decreased telomerase activity. The replicative p53-p21-pRB pathway, rather than the stress-induced p16-pRB pathway, played a more important role in the senescence of NPCs in an in vivo condition, although there is a situation in which both the...

Fine structural details of glycans attached to the conserved N-glycosylation site significantly not only affect function of individual immunoglobulin G (IgG) molecules but also mediate inflammation at the systemic level. By analyzing IgG glycosylation in 5,117 individuals from four European populations, we have revealed very complex patterns of changes in IgG glycosylation with age. Several IgG glycans (including FA2B, FA2G2, and FA2BG2) changed considerably with age and the combination of these...

Several clinical studies suggest the involvement of premature ageing processes in chronic obstructive pulmonary disease (COPD). Using an epidemiological approach, we studied whether accelerated ageing indicated by telomere length, a marker of biological age, is associated with COPD and asthma, and whether intrinsic age-related processes contribute to the interindividual variability of lung function. Our meta-analysis of 14 studies included 934 COPD cases with 15 846 controls defined according to...

Telomere length is a marker of cellular aging that varies with the individual, is inherited, and is highly correlated across somatic cell types within persons. Interindividual variability of telomere length may partly explain differences in reproductive aging rates. We examined whether leukocyte telomere length was associated with menopausal age....

Telomeres are specialized chromatin structures located at the ends of eukaryotic chromosomes, and telomere length plays a clear role in various diseases. However, it is not known whether telomere length is related to polycystic ovary syndrome (PCOS)....

Sleep apnea poses an elevated risk for chronic age-related diseases. Leukocyte telomere length (LTL), a biomarker and factor associated with accelerated cellular aging processes, may serve as a novel mechanism underlying these disease risks. We investigated if a history of clinician-diagnosed sleep apnea or primary snoring was associated with LTL in later adulthood....

The aged liver is more sensitive to the drug treatments and has a high probability of developing liver disorders such as fibrosis, cirrhosis, and cancer. Here we present mechanisms underlying age-associated severe liver injury and acceleration of liver proliferation after CCl4 treatments. We have examined liver response to CCl4 treatments using old WT mice and young C/EBPα-S193D knockin mice, which express an aged-like isoform of C/EBPα. Both animal models have altered chromatin structure as...

Although somatic cell nuclear transfer (SCNT) and induction of pluripotency (to form iPSCs) are both recognized reprogramming methods, there has been relatively little comparative analysis of the resulting pluripotent cells. Here, we examine the capacity of these two reprogramming approaches to rejuvenate telomeres using late-generation telomerase-deficient (Terc(-/-)) mice that exhibit telomere dysfunction and premature aging. We found that embryonic stem cells established from Terc(-/-) SCNT...

Although HIV-associated neurocognitive disorders (HAND) result from injury and loss of neurons, productive infection routinely takes place in cells of macrophage lineage. In such a complex context, astrocytosis induced by local chemokines/cytokines is one of the hallmarks of HIV neuropathology. Whether this sustained astrocyte activation is able to alter telomere-aging process is unknown. We hypothesized that interaction of HIV with astrocytes may impact astrocyte telomerase activity (TA) and...

Despite public health campaigns discouraging smoking, 1,000 American children every day become smokers, ensuring that tobacco-related health complications will be with us for decades to come. Smoking is the greatest risk factor for both chronic obstructive lung disease and interstitial lung disease. The facts that not every smoker develops chronic lung disease and that lung pathology differs markedly among smokers indicate that individual susceptibility must be a central determinant of lung...

Senescence of vascular smooth muscle cells (VSMCs) contributes to aging as well as age-related diseases of the cardiovascular system. Senescent VSMCs have been shown to be present in atherosclerotic plaques. Both replicative (RS) and stress-induced premature senescence (SIPS) accompany cardiovascular diseases. We aimed to establish the signature of RS and SIPS of VSMCs, induced by a common anticancer drug, doxorubicin, and to discover the so far undisclosed features of senescent cells that are...

leukocyte telomere length (TL) is considered a marker of biological aging. Several studies have investigated the link between leukocyte TL and aging-associated functional attributes of the brain, but no prior study has investigated whether TL can be linked to brain atrophy and white matter hyperintensities (WMHs); two prominent structural manifestations of brain aging....

Patients with major depressive disorder (MDD) have an increased onset risk of aging-related somatic diseases such as heart disease, diabetes, obesity and cancer. This suggests mechanisms of accelerated biological aging among the depressed, which can be indicated by a shorter length of telomeres. We examine whether MDD is associated with accelerated biological aging, and whether depression characteristics such as severity, duration, and psychoactive medication do further impact on biological...

Telomere length is related to cellular aging and cardiovascular disease. Nevertheless, the specific role of cellular aging in this process is still unclear. The aim of this report was to analyze the prognostic value of telomere length in men admitted for acute coronary syndrome. Telomere length was measured by quantitative polymerase chain reaction in peripheral blood leukocytes of 203 men classified into 2 groups: those aged 50 to 75 years and those >75 years. Clinical follow-up had been done...

Human 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....

Telomeres use distinct mechanisms (not used by arms or centromeres) to mediate cohesion between sister chromatids. However, the motivation for a specialized mechanism at telomeres is not well understood. Here we show, using fluorescence in situ hybridization and live-cell imaging, that persistent sister chromatid cohesion at telomeres triggers a prolonged anaphase in normal human cells and cancer cells. Excess cohesion at telomeres can be induced by inhibition of tankyrase 1, a poly(ADP-ribose)...

Hypoxia favors stem cell quiescence, whereas normoxia is required for stem cell activation, but whether cardiac stem cell (CSC) function is regulated by the hypoxic/normoxic state of the cell is currently unknown....

Cell therapies utilizing mesenchymal stem cells (MSCs) could overcome limitations of traditional treatments for reconstructing craniofacial tissues. This large-scale study explored a standardized methodology for the isolation and clinical-scale expansion of alveolar bone marrow-derived MSCs (aBMSCs). We harvested 103 alveolar bone marrow samples from 45 patients using 1 of 3 standardized methodologies. Following aBMSC isolation, cells were characterized through cell-surface marker expression and...

The objective of this study was to provide a systematic review and meta-analysis of studies on the relationship between body mass index (BMI) and leukocyte telomere length (LTL). Relevant studies were identified by a systematic search of MEDLINE, Embase and Web of Knowledge databases. Pooled correlation and regression coefficients were calculated using meta-analysis methods for both cross-sectional and longitudinal studies. Studies without suitable data for meta-analysis were summarized...

Telomerase contributes to cell proliferation and survival through both telomere-dependent and telomere-independent mechanisms. In this report, we discovered that endoplasmic reticulum (ER) stress transiently activates the catalytic components of telomerase (TERT) expression in human cancer cell lines and murine primary neural cells. Importantly, we show that depletion of hTERT sensitizes cells to undergo apoptosis under ER stress, whereas increased hTERT expression reduces ER stress-induced cell...

Leukocyte telomere length (LTL) ostensibly shortens with age and has been moderately associated with mortality. In humans, these findings have come almost solely from cross-sectional studies. Only recently has LTL shortening within individuals been analyzed in longitudinal studies. Such studies are relevant to establish LTL dynamics as biomarkers of mortality as well as to disentangle the causality of telomeres on aging....

Bovine papillomavirus 1 (BPV-1) is a well recognized etiopathogenetic factor in a cancer-like state in horses, namely equine sarcoid disease. Nevertheless, little is known about BPV-1-mediated cell transforming effects. It was shown that BPV-1 triggers genomic instability through DNA hypomethylation and oxidative stress. In the present study, we further characterized BPV-1-positive fibroblasts derived from sarcoid tumors. The focus was on cancer-like features of sarcoid-derived fibroblasts,...

Chromosomal and genomic instability due to telomere dysfunction is known to play an important role in carcinogenesis. To study telomere shortening in the epidermis surrounding actinic keratosis, we measured telomere lengths of basal, parabasal, and suprabasal cells in epidermis with actinic keratosis (actinic keratosis group, n = 18) and without actinic keratosis (sun-protected, n = 15, and sun-exposed, n = 13 groups) and in actinic keratosis itself as well as in dermal fibroblasts in the 3...

Most human populations are undergoing a demographic transition regarding their age structure. This transition is reflected in chronic non-communicable diseases featuring among the main contributors to burden of disease. Considering that the aging process is a major risk factor for such conditions, understanding the mechanisms underlying aging and age-related diseases is critical to develop strategies to impact human health at population and/or individual-levels. Two different aspects of aging...

Telomere length and the rate of telomere attrition vary between individuals and have been interpreted as the rate at which individuals have aged. The biology of telomeres dictates shortening with age, although telomere elongation with age has repeatedly been observed within a minority of individuals in several populations. These findings have been attributed to error, rather than actual telomere elongation, restricting our understanding of its possible biological significance. Here we present a...

Excessive shortening of the telomeric ends of chromosomes is a marker of accelerated aging. Oxidative stress and nutritional deficiency may influence this process. The aim of this study was to investigate the effect of ω-3 polyunsaturated fatty acid (ω-3 PUFA) supplementation on telomeric shortening in elderly individuals with mild cognitive impairment (MCI)....

To explore the usefulness of carotid ultrasound examination as a marker of aging and predictor of disability among older people....

Aging of an individual entails a progressive decline of functional reserves and loss of homeostasis that eventually lead to mortality. This process is highly individualized and is influenced by multiple genetic, epigenetic and environmental factors. This individualization and the diversity of factors influencing aging result in a significant heterogeneity among people with the same chronological age, representing a major challenge in daily oncology practice. Thus, many factors other than mere...

Dyskeratosis congenita (DC) is a rare inherited bone marrow failure syndrome with high clinical heterogeneity. Various mutations have been reported in DC patients, affecting genes that code for components of H/ACA ribonucleoproteins, proteins of the telomerase complex and components of the shelterin complex....