Somatic mutations in POT1 or RAP1 can occur in familial glioma, familial melanoma, Li-Fraumenilike syndrome, parathyroid adenoma, cardiac angiosarcomas, mantle cell lymphoma, and hepatocellular carcinoma (Fernandes et al., 2020). It will accelerate the homeostatic destruction of CD8 + memory T cells, and leads to cellular senescence. Short telomeres result in chromosomal instability in hematopoietic cells and precede malignant evolution in human aplastic anemia. These precursors are de-adenylated by the disease-associated poly (A)-specific ribonuclease (PARN), which promotes TERC maturation and accumulation (Roake and Artandi, 2020). We would also like to acknowledge David Aten for his help with the illustrations and the Department of Medical Illustration at MD Anderson Cancer Center. Recent studies have shown that overexpression of HSP70 is neuroprotective in Drosophila and in mouse and rat models of both Alzheimers disease and Parkinsons disease (Auluck et al., 2002; Kakimura et al., 2002; Klucken et al., 2004). Ablation of telomerase and telomere loss leads to cardiac dilatation and heart failure associated with p53 upregulation. Telomere dysfunction and Atm deficiency compromises organ homeostasis and accelerates ageing. Telomeres in aging and stem cells. Autophagic cell death restricts chromosomal instability during replicative crisis. et al. In 2000, further analysis of late-generation mTERC/;p53+/ mice (Artandi et al., 2000) revealed a humanized tumor spectrum of epithelial cancers possessing chromosomal rearrangements and nonreciprocal translocations typical of human cancer genomes. 13:931785. doi: 10.3389/fgene.2022.931785. Defects in telomere maintenance molecules impair osteoblast differentiation and promote osteoporosis. In the early 1970s, Olovnikov and Watson introduced the end replication problem by observing the asymmetry in linear DNA replication and predicting that each cell division would incur a loss of chromosomal DNA from the termini of the lagging strand due to removal of the terminal RNA primer, thereby leading to progressive chromosomal shortening (Olovnikov, 1973; Watson, 1972 ). (2002). This section summarizes mounting evidence linking telomere functionality to aging processes such as frailty as well as age-related diseases including cardiovascular diseases (atherosclerosis, vascular dementia, coronary artery disease), metabolic disease (type II diabetes), neurological disease (Parkinsons disease) and cancer. Muller coined the term telomere from the Greek telos meaning end and meros meaning part, hence end-part (Figure 1). WebTelomeres are deoxynucleic acid caps at the ends of chromosomes that naturally shorten over one's lifespan; because of this, short telomeres have been studied as a marker of This was followed by the cloning of human telomerase reverse transcriptase (hTERT) (Harrington et al., 1997) and the telomerase RNA component (hTERC) (Feng et al., 1995). Telomere dysfunction-induced mitochondrial impairment increases the dependency of tissues on glucose metabolism (Missios et al., 2014). Structurally, telomeres consist of tandem repeat sequences of TTAGGG measuring from several to tens of kilobases and terminating at the 3 end in a single-stranded 75-to-300nucleotide overhang enriched in guanine nucleotides (Figure 2B). Stated differently, the absence of this mutational mechanism in the mouse (long telomeres and promiscuous telomerase expression) protects mice from developing epithelial cancers. (2017). ALT lengthens telomeres using DNA homologydirected repair mechanisms in which telomeric DNA templates are copied from sister chromatids or non-homologous chromosomes. The intimate link of telomeres to aging hallmarks informs preventive and therapeutic interventions designed to attenuate aging itself and reduce the incidence of age-associated diseases. Telomere Dysfunction and Senescence-associated Pathways in Bronchiectasis. Short telomeres are associated with an increased risk of neurological and psychiatric disorders including dementia. Direct telomere and epigenetic interaction is reflected in the regulation of sirtuins, a family of seven (SIRT1-7) NAD+ dependent deacetylases regulating life- and health-span (Amano and Sahin, 2019). Finally, cancer-prone mice engineered with an inducible TERT allele first experience telomere-based crisis followed by subsequent telomerase reactivation. First, these models established that telomere dysfunction accelerates signs and symptoms of aging characterized by shortened life expectancy, an aged appearance, declining tissue stem cell reserves, organ atrophy, and diminished capacity to cope with stress, injury, and regenerative demands (Lee et al., 1998; Rudolph et al., 1999). Meyerson M, Counter CM, Eaton EN, Ellisen LW, Steiner P, Caddle SD, Ziaugra L, Beijersbergen RL, Davidoff MJ, Liu Q, et al. Tumour evolution inferred by single-cell sequencing. ALT occurs in 5% to 15% of human cancers, particularly in osteosarcoma and glioblastoma, and is typically associated with poor prognosis (Heaphy et al., 2011). Additional mechanisms driving increased TERT expression in cancer also result from crisis-induced chromosomal alterations (Artandi et al., 2000), which produce focal amplifications of the TERT locus in hepatocellular carcinoma (Totoki et al., 2014). Timeline of discoveries in the human telomere field. Houtkooper RH, Pirinen E, and Auwerx J (2012). Ageing Res Rev. The hallmarks of aging comprise diverse molecular mechanisms and cellular systems that are interrelated and act in concert to drive the aging process. (2012). On the cellular level, telomeropathy is characterized by (i) hematopoietic stem cell depletion leading to bone marrow failure, (ii) immunosenescence of lymphocytes and (iii) intestinal stem cell loss resulting in intestinal villous atrophy associated with crypt cell apoptosis, villous blunting, basal plasmacytosis, and intraepithelial lymphocytosis (Jonassaint et al., 2013). (2008). The laboratory mouse, Mus musculus, possesses telomeres up to ten times longer than those of humans (30-150 kb in mice versus 10-15 kb in humans) (Kipling and Cooke, 1990 ). Navin N, Kendall J, Troge J, Andrews P, Rodgers L, McIndoo J, Cook K, Stepansky A, Levy D, Esposito D, et al. Therefore, telomere length (TL) has been recognized for a long time as one of the best biomarkers of aging. In 1990, this journey of discovery culminated in evidence that telomere attrition occurs in parallel with the replicative lifespan of human primary cells in culture, establishing that short telomeres trigger the Hayflick limit (Harley et al., 1990). Moreover, the loss of p53 enables cells to survive these DNA double-strand breakage events to produce aberrant chromosomal imbalances and nonreciprocal translocations that drive cancer initiation (see TELOMERES AND TELOMERASE IN AGE-RELATED DISEASES AND CANCER). Short telomeres reduce the risk of cancer early in life at the expense of impaired regeneration late in life. Telomeres mediate biologic aging in organisms as diverse as plants, yeast, and mammals. A particularly intriguing application of pulsatile telomerase activation therapy would be the treatment of progeroid diseases such as Werner and Bloom syndromes. In normal tissues, telomerase expression is abundant in germ cells (Lee et al., 1998) and present in undifferentiated stem and progenitor cells of the skin (Lee et al., 1998; Rudolph et al., 1999), intestine (Schepers et al., 2011), hematopoietic system (Colla et al., 2015), hair bulge (Sarin et al., 2005), and testes (Rudolph et al., 1999 ). Aging processes encompass inflammatory signaling from genomically damaged or senescent cells. Analyses of non-coding somatic drivers in 2,658 cancer whole genomes. A mammalian telomerase-associated protein. A TERT-inducible model of prostate cancer has experimentally validated this cancer genome evolution concept. A Big Bang model of human colorectal tumor growth. In contrast, telomere intact controls (which did not experience crisis followed by telomerase reactivation) exhibited only local invasion (Ding et al., 2012). (2011). Kamijo T, Zindy F, Roussel MF, Quelle DE, Downing JR, Ashmun RA, Grosveld G, and Sherr CJ (1997). And that in turn will ultimately help us study aging and diseases such as cancer and develop drugs to fight them. While such RNAs are encoded within introns of other genes, TERC is a prototypical gene with its own promoter (Feng et al., 1995). NOP10, nucleolar protein family A, member 3; NHP2, nucleolar protein family A, member 2; TIN2, TERF1-interacting nuclear factor 2; TPP1, telomere protection protein 1; TRF1, telomeric repeat binding factor 1; TRF2, telomeric repeat binding factor 2, POT1, protection of telomeres 1; RAP1, TERF2-interacting protein; TCAB1, telomerase Cajal body protein 1; GAR1, nucleolar protein family A. member 1. These species differences enabled elucidation of the function of telomeres and telomerase in genome stability, aging, and cancer through the engineering and characterization of mice with shorter, human-like telomere lengths. Finally, do your best to exercise when you caneven if you have time for just a quick walk. Cancer is a disease of aging, with 1 in 2 men and 1 in 3 women in the US receiving a cancer diagnosis by age 80 (National Cancer Institute). Given the centrality of mitochondria in aging, the overlapping phenotypes of TERC-, PGC1/-, and POLG-null mice enabled us to link telomeres, mitochondria, and oxidative defense mechanisms in driving aging. Whether and how telomere dysfunction activates the senescence program in low-proliferative stroma tissues during normal aging requires further investigation, although it is tempting to speculate that reactive oxygen species (ROS)-induced damage of telomeres leads to TIF generation and induction of senescence. This is evident from pioneering studies from the de Lange laboratory demonstrating that perturbations in shelterin components, such as dominant-negative mutant forms of TRF2, can induce TIFs without changes in telomere length (van Steensel et al., 1998). This demographic milestone will be accompanied by major increases in age-associated diseases, such as Alzheimers disease, cardiovascular disease, and cancer (Melzer et al., 2020), which essentially double in incidence every 5 years after age 60. Horn S, Figl A, Rachakonda PS, Fischer C, Sucker A, Gast A, Kadel S, Moll I, Nagore E, Hemminki K, et al. Farazi PA, Glickman J, Jiang S, Yu A, Rudolph KL, and DePinho RA (2003). Fredriksson NJ, Ny L, Nilsson JA, and Larsson E (2014). In these chromosomally unstable high-grade prostate intraepithelial neoplasias, experimental reactivation of telomerase results in malignant progression including the acquisition of new phenotypes such as bone metastasis. Activation of telomerase in TERT-overexpression mouse models showed proliferation of quiescent hair follicle stem cells and kidney podocytes can occur independent of telomere length, TERC function or TERT reverse transcriptase function (Flores et al., 2005; Sarin et al., 2005). Enforced expression of mTERT or PGC1 or genetic ablation of p53 elevates expression of PGC1/, GLC-6-P and PEPCK and restores gluconeogenesis (Sahin et al., 2011). Pech MF, Garbuzov A, Hasegawa K, Sukhwani M, Zhang RJ, Benayoun BA, Brockman SA, Lin S, Brunet A, Orwig KE, et al. Shorter maternal telomeres, which could be aggravated by external factors, underly premature ovarian aging and other complications including preeclampsia, preterm birth and idiopathic pregnancy loss. Such an elemental role encourages the development and rigorous testing of telomerase activators for the treatment of aging and age-associated diseases as well as the assessment of efficient telomerase inhibitors for the treatment of advanced cancers. et al. Microglial activation and amyloid-beta clearance induced by exogenous heat-shock proteins. 88 Cdkn1a deletion improves stem cell function and lifespan of mice with dysfunctional telomeres without accelerating cancer formation. In the subset of cancers that are ALT-positive, targeting relevant immune circuits may also enhance response rates and outcomes. The Nobel Laureates have shown that the Colla S, Ong DS, Ogoti Y, Marchesini M, Mistry NA, Clise-Dwyer K, Ang SA, Storti P, Viale A, Giuliani N, et al. As noted, loss of telomere function leads to end-to-end fusion. Puente BN, Kimura W, Muralidhar SA, Moon J, Amatruda JF, Phelps KL, Grinsfelder D, Rothermel BA, Chen R, Garcia JA, et al. Specifically, in mice null for TERT or TERC, successive intergenerational crosses progressively shorten telomeres, culminating in telomere dysfunction (end-to-end fusions) by generation 3 (G3) (Artandi et al., 2000; Blasco et al., 1997). Telomere dysfunction drives tissue inflammation through activation of the ATM/cABL/YAP1 axis and driving secretion of mature IL18 to recruit and potentiate T cells and macrophages. In addition, alternative strategies to inhibit telomerase could generate a more meaningful impact in the clinic. Extension of life-span by introduction of telomerase into normal human cells. Auluck PK, Chan HY, Trojanowski JQ, Lee VM, and Bonini NM (2002). et al. Researchers have discovered a new structure of telomeric DNA, which could be key to living longer. The entwined processes of senescence and inflammation may be particularly relevant to the telomere-aging connection. p53 mutant mice that display early ageing-associated phenotypes. Telomeres are DNA-protein complexes that protect the ends of chromosomes. Attempts to change telomere length through lifestyle or behavioural Wright WE, Piatyszek MA, Rainey WE, Byrd W, and Shay JW (1996). Ghosh A, Saginc G, Leow SC, Khattar E, Shin EM, Yan TD, Wong M, Zhang Z, Li G, Sung WK, et al. In this video we cover how telomerase helps maintain telomere length in our cells, and how this influences how our bodies age, and why we develop diseases like cancer. In the ensuing years, mice null for TERC and TERT, alone or in combination with progeria or cancer-relevant alleles, established that telomere dysfunction can drive premature aging, cancer, and various degenerative diseases. (a, b) The average telomere length in T lymphocytes from males and females as reported in two independent studies (a) Quantitative fluorescence in situ hybridization was used to measure the ratio of fluorescence signals, expressed as T/C values, derived from Schepers AG, Vries R, van den Born M, van de Wetering M, and Clevers H (2011). These observations support the view that short dysfunctional telomeres as well as longer telomeres associated with DNA damage are likely to induce Sperka T, Song Z, Morita Y, Nalapareddy K, Guachalla LM, Lechel A, Begus-Nahrmann Y, Burkhalter MD, Mach M, Schlaudraff F ATM, Ataxia telangiectasia mutated; cABL, Abelson murine leukemia viral oncogene homolog 1; YAP1, Yes-associated protein1; IL 18, interleukin 18. The TEDS theory of aging proposes that telomere erosion allowed lifespan to increase by suppressing the growth of malignant tumors before reproduction. Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. Specifically, PAPD5 degrades TERC by 3 oligoadenylation, priming these transcripts for destruction by the RNA exosome. The upregulation telomerase activity is observed in over 85-90% of human cancers and provides an attractive target for cancer therapies. Mutations in and/or altered expression of shelterin proteins have been detected in cancer, although their precise roles in cancer initiation and progression are not yet determined. This limited efficacy may be attributable to the time required for telomeres to shorten to a length that can induce tumor shrinkage. Hahn WC, Counter CM, Lundberg AS, Beijersbergen RL, Brooks MW, and Weinberg RA (1999). Essential role of mouse telomerase in highly proliferative organs. TCAB1 is required for both catalytic activity and trafficking of telomerase to Cajal bodies, which aids in trafficking telomerase to telomere ends .Telomerase associates with TERC through its PK/T and CR4/5 domains. Authors Jue Lin 1 , Elissa Epel 2 Affiliations 1 UCSF Department of Biochemistry and Biophysics as hallmarks of aging where telomere maintenance is a key player interacting with mitochondria. Many age-related diseases were found to be associated with dysfunctional telomeres, which accelerate aging process due to the decrease in repair potential of With respect to the latter, the Hayflick limit triggers senescence and proliferative arrest via activation of the p53-p19ARF and p16Ink4a-Rb signaling pathways (Shay et al., 1991). The https:// ensures that you are connecting to the Sports Med Open. Differential impact of telomere dysfunction on initiation and progression of hepatocellular carcinoma, A genetic model for colorectal tumorigenesis. While telomerase extinction cured two-thirds of mice, the remaining mice developed recurrent tumors possessing hallmark features of ALT (Hu et al., 2012). Telomere dysfunction can drive the hallmarks of cellular aging. (2019). Clearance of p16Ink4a-positive senescent cells delays ageing-associated disorders. Along similar lines, in patients with germline mutations affecting telomere maintenance (e.g., DKC), telomerase activation therapy could alleviate progressive symptoms such as anemia, pulmonary fibrosis, and gastrointestinal dysfunction. This work also highlights the cooperation between cell-intrinsic telomere dysfunctiondriven molecular pathways and the microbiome in driving the inflammatory response. Telomeres play a role in innate immunity after virus infection. Sahin E, Colla S, Liesa M, Moslehi J, Muller FL, Guo M, Cooper M, Kotton D, Fabian AJ, Walkey C, et al. Interestingly, these recurrent tumors acquired amplifications and deletions in genes involved in homologous recombination that are known to play essential roles in ALT, as well as amplification of the PGc1 locus, which may signify ongoing mitochondrial stress in ALT-positive cells (Hu et al., 2012). In aging, mitochondrial function declines, leading to diminished energy (ATP) production as well as increased intracellular ROS. In contrast, telomere shortening in TERC-knockout mice increases tumor initiation but fails to induce tumor progression in a model of carcinogen-induced hepatocellular carcinoma (Farazi et al., 2003). Several small molecules have been identified that appear to activate TERT (Figure 6), including TA-65 (Harley et al., 2011) and histone deacetylase inhibitors (Won et al., 2004), although a clear understanding of their mechanisms of action is lacking. Evidence derives from a study where mouse mTerc/ Ink4a/Arf/ fibroblasts which were passaged extensively and showed development of ALT. Telomere shortening is a well-known hallmark of both cellular senescence and organismal aging. These studies catalyzed development of senolytic agents capable of clearing senescent cells in humans (Ellison-Hughes, 2020). Inactivation of the p53 tumor suppressor is one of the most frequent events in human epithelial cancers (Brosh and Rotter, 2009) and the status of p53 can dictate whether telomere dysfunction enhances or suppresses cancer development. Longevity, stress response, and cancer in aging telomerase-deficient mice. Telomere Stress Potentiates STING-Dependent Anti-tumor Immunity. Strikingly, when each of these alleles was crossed to the TERC-knockout mouse, the salient phenotypes of these syndromes surfaced as telomeres reached shorter, more human-like lengths (typically at G2-G3) (Chang et al., 2004; Du et al., 2004; Sacco et al., 2010; Wong et al., 2003). (2016). Harel I, Benayoun BA, Machado B, Singh PP, Hu CK, Pech MF, Valenzano DR, Zhang E, Sharp SC, Artandi SE, et al. Mar 28, 2022--Listen. Ageing reversal: scientists rejuvenate tissues in middle-aged mice. Diminished energy production causes overall frailty, while increased ROS causes cellular damage, including formation of 8-oxoguanine base lesions in DNA (note, telomeres are guanine-rich). Introduction. Published online 2022 Sep 4. doi: 10.1186/s40798-022-00503-1 PMCID: PMC9441412 PMID: 36057868 Physical Activity on Telomere Length as a Biomarker for Aging: A Systematic Review Marlies Schellnegger, 1,2,3 Alvin C. Lin, 3 Niels Hammer, 3 and Lars-Peter Kamolz 1,2 Moreover, murine somatic cells exhibit high levels of telomerase activity relative to the low activity found in human somatic cells (Kipling, 1997; Wright et al., 1996). (2015). Nuclear YAP1 upregulates inflammation and inflammasome genes such as pro-IL18, NLRC5, NLRP1b, and NLRP6. Wiemann SU, Satyanarayana A, Tsahuridu M, Tillmann HL, Zender L, Klempnauer J, Flemming P, Franco S, Blasco MA, Manns MP, et al. Flores I, Cayuela ML, and Blasco MA (2005). The publisher's final edited version of this article is available free at. We (2013). In this section, we detail the role of telomeres in processes of aging with an emphasis of how telomeres interrelate with the other hallmarks of aging, serving to drive or amplify these mechanisms (Figure 3). We regret being unable to cite the work of many of our colleagues due to limitations in space. The accumulation leads to gradual neuronal death and cognitive impairment. Telomerase inhibitors and senolytics inhibit processes that can thwart tumor progression, invasion and metastasis. Tissue stem cell exhaustion is a cardinal feature of aging. (2008). Mammalian telomeres end in a large duplex loop. 8600 Rockville Pike Shorter maternal telomeres, which could be aggravated by external factors, Here again, telomerase activation at very early stages of disease prior to entry into telomere-based crisis could prevent disease flares and carcinogenesis. d'Adda di Fagagna F, Reaper PM, Clay-Farrace L, Fiegler H, Carr P, Von Zglinicki T, Saretzki G, Carter NP, and Jackson SP (2003). Increases in glycolysis versus mitochondrial oxidative metabolism may also lead to changes in NAD/NADH pools, further impairing sirtuin activity. may contribute to aging independent of telomere length because DNA damage near telomeres may be irreparable and is capable of triggering senescence . Webon the knowledge acquired during the last 2 years about the telomere pathway and its influence on female fertility and the consequences for the newborn. Telomere dysfunction compromises mitochondrial function and oxidative defense, increasing ROS and creating a feed-forward loop involving p53/PGC-1/ signaling. Anderson R, Lagnado A, Maggiorani D, Walaszczyk A, Dookun E, Chapman J, Birch J, Salmonowicz H, Ogrodnik M, Jurk D, et al. Indeed, TERC-null mice were documented (Sahin et al., 2011) to have impaired mitochondrial function and diminished oxidative defense. Short dysfunctional telomeres impair tumorigenesis in the INK4a(delta2/3) cancer-prone mouse, Identification of a specific telomere terminal transferase activity in Tetrahymena extracts, A telomeric sequence in the RNA of Tetrahymena telomerase required for telomere repeat synthesis. Chin L, Artandi SE, Shen Q, Tam A, Lee SL, Gottlieb GJ, Greider CW, and DePinho RA (1999). et al. It remains to be determined whether the increased lifespan and disease-modifying activities of enforced TERT expression relate to TERTs actions on telomeres or to its activation of WNT, which may enhance stem cell reserves. (2013). Genetic variation in telomere length between humans is Influence of endothelial dysfunction on telomere length in subjects with metabolic syndrome: LIPGENE study. The most common recurrent single-nucleotide mutations in the TERT promoter occur at G228A and G250A, which generate de novo ETS consensus binding motifs to recruit GAPB, and potentially other ETS transcription factors, to elevate TERT expression (Bell et al., 2015). (B) Structure of tetomerase. Short telomeres are major drivers of the aging-dependent decline in organ function and increase in cancer risk (Hanahan, 2022; Lansdorp, 2022). Specifically, late-generation TERC/ mice null for p53 show an increase in cancer incidence and decreased survival (Artandi et al., 2000; Chin et al., 1999), whereas late-generation TERC/ mice null for Ink4a/Arf show a significant reduction in tumor incidence and increased survival (Greenberg et al., 1999). The telomere length (TL) has increasingly been used as a biomarker of human aging because it has been shown to predict the chances of survival and longevity. The link between aging and such diseases has motivated fundamental investigations into the mechanisms of aging and strategies to attenuate its impact. (2002). Sottoriva A, Kang H, Ma Z, Graham TA, Salomon MP, Zhao J, Marjoram P, Siegmund K, Press MF, Shibata D New research on telomere biology reaffirms the relationship of telomere attrition and female infertility. Bethesda, MD 20894, Web Policies Telomere shortening, as seen with aging, can cause chromosomal instability and promote cancer progression. Differentiated cells such as keratinocytes, fibroblasts, skeletal muscle myocytes, neurons, cardiac myocytes, and spermatids show modest or undetectable TERT levels (Artandi and DePinho, 2010; Pech et al., 2015). Telomere dysfunction at disease onset can drive tissue inflammation, which in turn can accelerate telomere shortening, creating a feed-forward loop that ultimately leads to disease recurrence and even cancer brought about by genomic instability, p53 loss, and telomerase reactivation. 2022 Dec; 8: 111. (2004). Genetic variation in telomere length between humans is shown in blue. Abstract Ageing organisms accumulate senescent cells that are thought to contribute to body dysfunction. BioViva CEO Liz Parrish believes we can extend lifespans by extending telomeres. Second, low-proliferative tissues such as heart, brain, and liver could experience ROS-induced damage of telomere sequences, causing attrition and uncapping over time. Second, these models highlighted the essentiality of telomere dysfunction in progeroid syndromes and Parkinsons disease (Chang et al., 2004; Lee et al., 1998; Rudolph et al., 1999; Wong et al., 2003). Correspondingly, mutations in the aforementioned components can disrupt the shelterin-telomere complex, causing end fusions and premature senescence (van Steensel et al., 1998). Genet. Telomeres play a central role in cell fate and aging by adjusting the cellular response to stress and growth stimulation on the basis of previous cell divisions and DNA Contrary to the potential applications of telomerase activation in antiaging therapy, the increased telomerase activity observed in most cancers has led to the development of antitelomerase therapeutics. In late generation TERT- or TERC-null mice, progressive telomere erosion leads to p53-dependent apoptotic elimination of tissue stem cells, which contributes to organ atrophy, particularly in highly proliferative tissues with high rates of self-renewal including the skin, intestine, testis, regenerating injured liver, and blood (Blasco et al., 1997; Chin et al., 1999; Colla et al., 2015; Jaskelioff et al., 2011; Lee et al., 1998; Rudolph et al., 1999; Rudolph et al., 2000; Sahin et al., 2011). In a lymphoma-prone ATM-mutant mouse model engineered with a tamoxifen-controlled TERT allele (TERT-ER) (Hu et al., 2012), extinction of telomerase activity resulted in re-entry of lymphoma cells into telomere-based crisis. Essential factors for ALT include MRE11, RAD50, NBS1, FEN1, MUS81, and FANCD2 (Cesare and Reddel, 2010). (2019). The average human telomere is 5000-15,000 (2007). In this review, we discuss our current understanding of the consequences of telomere instability in cancer and aging, and outline the opportunities and challenges that lie ahead in exploiting the reliance of cells on telomere maintenance for Short telomeres reduce the risk of cancer early in life at the expense of impaired regeneration late in life. Artandi SE, Chang S, Lee SL, Alson S, Gottlieb GJ, Chin L, and DePinho RA (2000). Telomere biology is one of the main pathways involved in organismal aging. Break-induced replication promotes fragile telomere formation, TELOMERES AND TELOMERASE IN AGE-RELATED DISEASES AND CANCER, Telomere dysfunction, telomerase and cancer, Icgc Tcga Pan-Cancer Analysis of Whole Genomes Consortium, 2020. Additionally, we summarize the role of genetic model systems in revealing the interconnectedness of telomeres with other mechanisms and pathways driving aging as well as premature aging syndromes. TERT promotes epithelial proliferation through transcriptional control of a Myc- and Wnt-related developmental program. Telomeres in aging and disease: lessons from zebrafish, Alternative lengthening of telomeres: models, mechanisms and implications. is co-Founder, Director and Advisor of Tvardi Therapeutics; co-Founder and Advisor of Asylia Therapeutics; co-Founder and Advisor of Nirogy Therapeutics; and co-Founder and Advisor of Stellanova Therapeutics. Beyond telomere maintenance, TERT may also impact stem cell biology via non-classical functions of TERT involving activation of the WNT pathway, a major regulator of stem cell homeostasis. In early-stage chronic lymphocytic leukemia, telomere dysfunction is linked to disease initiation and end-to-end fusions (Chang, 2013).

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