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Telomere shortening to a critical length can trigger aging and shorter life spans in mice and humans by a mechanism that involves induction of a persistent DNA damage response at chromosome ends and loss of cellular viability. However, whether telomere length is a universal determinant of species longevity is not known. To determine whether telomere shortening can be a single parameter to predict species longevities, here we measured in parallel the telomere length of a wide variety of species (birds and mammals) with very different life spans and body sizes, including mouse (Mus musculus), goat (Capra hircus), Audouin's gull (Larus audouinii), reindeer (Rangifer tarandus), griffon vulture (Gyps fulvus), bottlenose dolphin (Tursiops truncatus), American flamingo (Phoenicopterus ruber), and Sumatran elephant (Elephas maximus sumatranus). We found that the telomere shortening rate, but not the initial telomere length alone, is a powerful predictor of species life span. These results support the notion that critical telomere shortening and the consequent onset of telomeric DNA damage and cellular senescence are a general determinant of species life span.

Key Points Mammalian telomeres are formed by tandem repeats of the TTAGGG sequence bound by a specialized six-protein complex known as shelterin, which has fundamental roles in the protection of chromosomes and the regulation of telomerase activity at chromosome ends. Excessive telomere shortening and severe telomere uncapping trigger a DNA damage response at chromosome ends, which are then recognized as double-strand breaks. Dysfunctional telomeres can lead to either cancer or ageing pathologies depending on the integrity of the DNA damage response. Studies with mouse models that support a role for these proteins in cancer susceptibility and ageing-related pathologies are discussed in this Review. Telomere dysfunction causes ageing and also constitutes a driving force for cellular transformation by causing genome instability. Molecular mechanisms underlying telomere-induced genomic instability are described. Anti-ageing activity of telomerase has been demonstrated in mice overexpressing TERT genetically engineered to be cancer-resistant by means of enhanced expression of the p53, p16 and ARF tumour suppressors. Telomere-maintenance is the main mechanism underlying the anti-ageing phenotype of TERT-transgenic mice. Telomere-independent functions of TERT have recently been described. Overexpression of TERT is a transcriptional modulator of the Wnt–β-catenin signalling pathway and has RNA-dependent RNA polymerase activity when in a complex with the RNA component of mitochondrial RNA processing endoribonuclease (RMRP). Roles for the shelterin component RAP1 beyond its roles in telomeres have been uncovered. Mammalian RAP1 is involved in subtelomeric gene silencing and transcriptional regulation, and it also acts as a essential modulator of the nuclear factor-κB (NF-κB)-mediated pathway. Telomerase and factors that influence its activity are very attractive targets for the treatment of degenerative diseases and cancer. TPP1 is involved in telomerase recruitment to telomeres. Drugs targeting TPP1 could certainly be a novel strategy for blocking the ultimate goal of telomerase, the lengthening of telomeres. Telomeres protect chromosomes from degradation and are therefore essential for ensuring genomic stability. These heterochromatic structures are bound by the shelterin complex, which regulates the activity of telomerase at the ends of chromosomes. This Review analyses the role of these telomeric proteins in cancer and ageing through modulating telomere length and protection, as well as through their 'extracurriculum' activities as gene expression regulators by binding to non-telomeric sites. Mammalian telomeres are formed by tandem repeats of the TTAGGG sequence, which are progressively lost with each round of cell division. Telomere protection requires a minimal length of TTAGGG repeats to allow the binding of shelterin, which prevents the activation of a DNA damage response (DDR) at chromosome ends. Telomere elongation is carried out by telomerase. Telomerase can also act as a transcriptional modulator of the Wnt–β-catenin signalling pathway and has RNA-dependent RNA polymerase activity. Dysfunctional telomeres can lead to either cancer or ageing pathologies depending on the integrity of the DDR. This Review discusses the role of telomeric proteins in cancer and ageing through modulating telomere length and protection, as well as regulating gene expression by binding to non-telomeric sites.

Key Points Telomeres are specialized chromatin structures located at the ends of chromosomes that protect chromosome ends from repair and degradation activities. Telomeres consist of G-rich repeats, which are bound by telomere-repeat-binding factors. Telomerase is a cellular reverse transcriptase that synthesizes telomeric repeats de novo at chromosome ends. Recombination between telomeric sequences can also lead to telomere elongation independently of telomerase. Telomeres and subtelomeres contain histone and DNA modifications that are also enriched at constitutive heterochromatin domains, such as those of pericentric heterochromatin. From yeast to mammals, loss of heterochromatic marks at telomeres and subtelomeres results in telomere-length deregulation and disruption of telomeric silencing, or TPE (the transcriptional repression of genes located near the telomeres). Loss of either histone methylation or DNA methylation at mammalian telomeres or subtelomeres also leads to de-repression of telomere recombination. Histone- and DNA-methylation defects are associated with several human diseases, including cancer. These defects could have an impact on telomere-length regulation, and therefore contribute to disease phenotypes. Telomere shortening to a critically short length leads to epigenetic defects at mammalian telomeres and subtelomeres, characterized by decreased histone and DNA methylation and increased histone acetylation. Histone and DNA modifications provide a mechanism by which telomere repeats are counted and autoregulated. Various diseases associated with ageing, including cancer and a number of premature ageing syndromes, are characterized by critically short telomeres, which in turn could affect the epigenetic status of telomeres and subtelomeres. Epigenetic modifications are key players in the regulation of fly and yeast telomeres, and recent studies indicate that the same applies in mammalian cells. These findings have implications for our understanding of the roles of telomeres in ageing and cancer. Increasing evidence indicates that chromatin modifications are important regulators of mammalian telomeres. Telomeres provide well studied paradigms of heterochromatin formation in yeast and flies, and recent studies have shown that mammalian telomeres and subtelomeric regions are also enriched in epigenetic marks that are characteristic of heterochromatin. Furthermore, the abrogation of master epigenetic regulators, such as histone methyltransferases and DNA methyltransferases, correlates with loss of telomere-length control, and telomere shortening to a critical length affects the epigenetic status of telomeres and subtelomeres. These links between epigenetic status and telomere-length regulation provide important new avenues for understanding processes such as cancer development and ageing, which are characterized by telomere-length defects.

A key process in organ homeostasis is the mobilization of stem cells out of their niches. We show through analysis of mouse models that telomere length, as well as the catalytic component of telomerase, Tert, are critical determinants in the mobilization of epidermal stem cells. Telomere shortening inhibited mobilization of stem cells out of their niche, impaired hair growth, and resulted in suppression of stem cell proliferative capacity in vitro. In contrast, Tert overexpression in the absence of changes in telomere length promoted stem cell mobilization, hair growth, and stem cell proliferation in vitro. The effects of telomeres and telomerase on stem cell biology anticipate their role in cancer and aging.

Short telomeres trigger age-related pathologies and shorter lifespans in mice and humans. In the past, we generated mouse embryonic (ES) cells with longer telomeres than normal (hyper-long telomeres) in the absence of genetic manipulations, which contributed to all mouse tissues. To address whether hyper-long telomeres have deleterious effects, we generated mice in which 100% of their cells are derived from hyper-long telomere ES cells. We observe that these mice have longer telomeres and less DNA damage with aging. Hyper-long telomere mice are lean and show low cholesterol and LDL levels, as well as improved glucose and insulin tolerance. Hyper-long telomere mice also have less incidence of cancer and an increased longevity. These findings demonstrate that longer telomeres than normal in a given species are not deleterious but instead, show beneficial effects. Telomere shortening is associated with aging. Here the authors analyze mice with hyperlong telomeres and demonstrate that longer telomeres than normal have beneficial effects such as delayed metabolic aging, increased longevity and less incidence of cancer.

Carlos López-Otín and colleagues report recurrent mutations in POT1 in chronic lymphocytic leukemia. This is the first member of the telomeric shelterin complex reported to be mutated in human cancer. Chronic lymphocytic leukemia (CLL) is the most frequent leukemia in adults 1 , 2 , 3 . We have analyzed exome sequencing data from 127 individuals with CLL and Sanger sequencing data from 214 additional affected individuals, identifying recurrent somatic mutations in POT1 (encoding protection of telomeres 1) in 3.5% of the cases, with the frequency reaching 9% when only individuals without IGHV @ mutations were considered. POT1 encodes a component of the shelterin complex and is the first member of this telomeric structure found to be mutated in human cancer. Somatic mutation of POT1 primarily occurs in gene regions encoding the two oligonucleotide-/oligosaccharide-binding (OB) folds and affects key residues required to bind telomeric DNA. POT1 -mutated CLL cells have numerous telomeric and chromosomal abnormalities that suggest that POT1 mutations favor the acquisition of the malignant features of CLL cells. The identification of POT1 as a new frequently mutated gene in CLL may facilitate novel approaches for the clinical management of this disease.

Key Points Telomeres are specialized chromatin structures at the ends of chromosomes, which consist of tandem DNA repeats (of TTAGGG) and associated proteins. Telomeres are also bound by nucleosome arrays, which contain epigenetic modifications that are characteristic of constitutive heterochromatin. Telomeres protect chromosome ends from repair and degradation activities. This function is impaired by both the shortening of TTAGGG repeats to below a critical length, and the loss of telomere-binding proteins. Dysfunctional telomeres trigger a DNA damage response, which results in cell-cycle arrest or apoptosis. Telomere dysfunction can also lead to end-to-end chromosome fusions, and can interfere with the repair of DNA lesions in non-telomeric regions, resulting in hypersensitivity to various genotoxic agents. Telomerase is a cellular reverse transcriptase that synthesizes de novo telomeric repeats at chromosome ends. Most somatic tissues lack telomerase activity and show progressive telomere shortening coupled to cell division. Various diseases associated with ageing, including cancer, as well as a number of premature ageing syndromes, are characterized by critically short telomeres. Telomere shortening and the absence of telomerase in normal tissues is a tumour-suppression mechanism. By contrast, tumours aberrantly upregulate telomerase, which elongates short telomeres and allows continuous growth. Mice that lack telomerase activity age prematurely and are more resistant to cancer. Human premature ageing syndromes that are characterized by short telomeres are recapitulated in the mouse only when in the context of telomerase-deficiency and short telomeres. The telomerase core components telomerase reverse transcriptase (TERT) and telomerase RNA component (TERC), as well as telomerase-interacting protein dyskeratosis congenita 1, dyskerin (DKC1), are mutated in the premature ageing human diseases dyskeratosis congenita and aplastic anaemia. Several telomere-binding proteins are altered in human cancer and premature ageing syndromes that are characterized by chromosomal instability. Telomerase and telomere-binding proteins are new potential targets for anti-cancer and anti-ageing therapies. Telomere length and telomerase activity are important factors in the pathobiology of human disease. Age-related diseases and premature ageing syndromes are characterized by short telomeres, which can compromise cell viability, whereas tumour cells can prevent telomere loss by aberrantly upregulating telomerase. Altered functioning of both telomerase and telomere-interacting proteins is present in some human premature ageing syndromes and in cancer, and recent findings indicate that alterations that affect telomeres at the level of chromatin structure might also have a role in human disease. These findings have inspired a number of potential therapeutic strategies that are based on telomerase and telomeres.

Here, we describe a role for mammalian DNA methyltransferases (DNMTs) in telomere length control. Mouse embryonic stem (ES) cells genetically deficient for DNMT1 , or both DNMT3a and DNMT3b have dramatically elongated telomeres compared with wild-type controls. Mammalian telomere repeats (TTAGGG) lack the canonical CpG methylation site. However, we demonstrate that mouse subtelomeric regions are heavily methylated, and that this modification is decreased in DNMT-deficient cells. We show that other heterochromatic marks, such as histone 3 Lys 9 (H3K9) and histone 4 Lys 20 (H4K20) trimethylation, remain at both subtelomeric and telomeric regions in these cells. Lack of DNMTs also resulted in increased telomeric recombination as indicated by sister-chromatid exchanges involving telomeric sequences, and by the presence of 'alternative lengthening of telomeres' (ALT)-associated promyelocytic leukaemia (PML) bodies (APBs). This increased telomeric recombination may lead to telomere-length changes, although our results do not exclude a potential involvement of telomerase and telomere-binding proteins in the aberrant telomere elongation observed in DNMT-deficient cells. Together, these results demonstrate a previously unappreciated role for DNA methylation in maintaining telomere integrity.

Differentiated cells in a culture dish can assume a new identity when manipulated to express four transcription factors. This “reprogramming” process has sparked interest because conceivably it could be harnessed as a therapeutic strategy for tissue regeneration. Mosteiro et al. used a mouse model to study the signals that promote cell reprogramming in vivo. They found that the factors that trigger reprogramming in vitro do the same in vivo; however, they also inflict cell damage. The damaged cells enter a state of senescence and begin secreting certain factors that promote reprogramming, including an inflammatory cytokine called interleukin-6. Thus, in the physiological setting, cell senescence may create a tissue context that favors reprogramming of neighboring cells. Science , this issue p. 10.1126/science.aaf4445 In mice, senescent cells created by tissue damage induce reprogramming of neighboring cells, enhancing tissue repair. Reprogramming of differentiated cells into pluripotent cells can occur in vivo, but the mechanisms involved remain to be elucidated. Senescence is a cellular response to damage, characterized by abundant production of cytokines and other secreted factors that, together with the recruitment of inflammatory cells, result in tissue remodeling. Here, we show that in vivo expression of the reprogramming factors OCT4, SOX2, KLF4, and cMYC (OSKM) in mice leads to senescence and reprogramming, both coexisting in close proximity. Genetic and pharmacological analyses indicate that OSKM-induced senescence requires the Ink4a/Arf locus and, through the production of the cytokine interleukin-6, creates a permissive tissue environment for in vivo reprogramming. Biological conditions linked to senescence, such as tissue injury or aging, favor in vivo reprogramming by OSKM. These observations may be relevant for tissue repair.

A major limitation of studies of the relevance of telomere length to cancer and age-related diseases in human populations and to the development of telomere-based therapies has been the lack of suitable high-throughput (HT) assays to measure telomere length. We have developed an automated HT quantitative telomere FISH platform, HT quantitative FISH (Q-FISH), which allows the quantification of telomere length as well as percentage of short telomeres in large human sample sets. We show here that this technique provides the accuracy and sensitivity to uncover associations between telomere length and human disease.