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Alternative lengthening of telomeres renders cancer cells hypersensitive to ATR inhibitors. Feng J, Funk WD, Wang SS, Weinrich SL, Avilion AA, Chiu CP, Adams RR, Chang E, Allsopp RC, Yu J, et al. This is recapitulated in prematurely aged telomerase mutants ( tert-/- ). The surviving BFB daughter cells accumulate cancer-relevant chromosomal alterations during crisis and ultimately activate telomerase to dampen DNA damage signaling and quell rampant chromosomal instability, enabling full malignant progression. (2014). Repair of critically short or telomere Schepers AG, Vries R, van den Born M, van de Wetering M, and Clevers H (2011). Telomere Telomeres: history, health, and hallmarks of aging The escalating social and economic burden of an aging world population has placed aging research at center stage. telomere 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). Telomere shortening is nearly universal in pancreatic intraepithelial neoplasia. Short telomeres reduce the risk of cancer early in life at the expense of impaired regeneration late in life. (2011). HHS Vulnerability Disclosure, Help 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 ). Further activation of telomerase leads to the progression to invasion and metastasis. In closing, the pursuit of the fundamental knowledge of chromosome structure and cell biology has illuminated mechanisms central to many major human diseases and aging itself. (1995). Here, through the lens of telomere biology, we examine how telomere dysfunction may amplify or drive molecular biological processes underlying each hallmark of aging and contribute to the development of age-related diseases such as neurodegeneration and cancer. 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. Shortened telomeres also lead to telomeric fusion and cycles of break-fusion-bridges. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. Schaetzlein S, Kodandaramireddy NR, Ju Z, Lechel A, Stepczynska A, Lilli DR, Clark AB, Rudolph C, Kuhnel F, Wei K Loss of telomeric DNA during aging of normal and trisomy 21 human lymphocytes. These murine models revealed the complex role of telomeres in the evolution of cancer, specifically, how telomere dysfunction enhances tumor initiation while restricting full malignant progression (Chin et al., 1999; Rudolph et al., 2001). Analyses of non-coding somatic drivers in 2,658 cancer whole genomes. Both killifish (Harel et al., 2015) and zebrafish (Carneiro et al., 2016) serve as models for telomere biology studies; their telomere length is similar to that of humans, while their telomere dysfunction phenotypes mirror those in murine models. 13:931785. doi: 10.3389/fgene.2022.931785. the contents by NLM or the National Institutes of Health. 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. Calado RT, Yewdell WT, Wilkerson KL, Regal JA, Kajigaya S, Stratakis CA, and Young NS (2009). This review provides an overview of the history and current state of telomere research, highlights mechanistic connections between telomere dysfunction and aging (2002). This review provides an overview of the history and current state of telomere research, highlights mechanistic connections between telomere dysfunction and aging hallmarks, and examines the seemingly pervasive roles of telomeres and telomerase in driving hallmarks of aging, progeria syndromes, and common age-associated diseases Deregulated protein folding occurs in several neurological diseases of aging, such as Alzheimers disease and Parkinsons disease, which exhibit misfolded -amyloid peptide and -synuclein, respectively. That telomere dysfunction can drive inflammatory diseases in human aging is evident from the study of telomeropathy. Additionally, DNA damage signaling and PARP activation, as a consequence of telomere dysfunction, reduce NAD pools and impair sirtuin function. Nassour J, Radford R, Correia A, Fuste JM, Schoell B, Jauch A, Shaw RJ, and Karlseder J (2019). Microglial activation and amyloid-beta clearance induced by exogenous heat-shock proteins. Telomere dysfunction induces metabolic and mitochondrial compromise. A Big Bang model of human colorectal tumor growth. WebRecent findings. Telomere dysfunction in ageing and age-related diseases Defects in telomere maintenance molecules impair osteoblast differentiation and promote osteoporosis. Accessibility Similarly, transient induction of telomere uncapping in telomerase wildtype mice (by mutant TRF2 protein and disruption of the shelterin complex) increases initiation and progression of hepatocellular carcinoma in carcinogen-treated mice (Begus-Nahrmann et al., 2012). On the current trajectory, 2.1 billion individuals will be older than age 60 by 2050 (United Nations, 2017). Puente BN, Kimura W, Muralidhar SA, Moon J, Amatruda JF, Phelps KL, Grinsfelder D, Rothermel BA, Chen R, Garcia JA, et al. (2004). Bai P, Canto C, Oudart H, Brunyanszki A, Cen Y, Thomas C, Yamamoto H, Huber A, Kiss B, Houtkooper RH, et al. The TEDS theory of aging proposes that telomere erosion allowed lifespan to increase by suppressing the growth of malignant tumors before reproduction. Rudolph KL, Chang S, Millard M, Schreiber-Agus N, and DePinho RA (2000). This interconnectedness of telomeres virtually all the hallmarks of aging serves to both initiate and escalate the aging process. Laish I, Mannasse-Green B, Hadary R, Biron-Shental T, Konikoff FM, Amiel A, and Kitay-Cohen Y (2016). Telomere dysfunction and resultant p53-mediated repression of SIRT1 expression is also relevant to the aging hallmark of altered proteostasis. We describe how the intimate link of telomeres and aging mechanisms informs the development of anti-aging and disease preventive strategies. Accordingly, in this disease, there is reduced expression of shelterin proteins including TRF1, RAP1, and POT1as well as TIN2 and TPP1. PARP-1 inhibition increases mitochondrial metabolism through SIRT1 activation. O'Hagan RC, Chang S, Maser RS, Mohan R, Artandi SE, Chin L, and DePinho RA (2002). The ALT pathway can also serve as a resistance mechanism for telomerase inhibitor therapies. Strikingly, these TERC/p53-null mice not only show increased cancer initiation but also a humanized tumor spectrum possessing complex karyotypes. Telomeres , aging and reproduction - LWW Uncontrolled ROS are also known to impact gluconeogenesis, fatty acid metabolism, and -oxidation, which can drive age-related metabolic diseases including diabetes, cancer (see Telomere dysfunction, telomerase and cancer), inflammatory conditions, sarcopenia, and neurodegenerative diseases like Alzheimers disease, Parkinsons disease, multiple sclerosis, and amyotrophic lateral sclerosis, as well as overall frailty. Given the association between short telomeres and genetic and environmental factors, their role in pregnancy has become an intriguing area of research. Anderson R, Lagnado A, Maggiorani D, Walaszczyk A, Dookun E, Chapman J, Birch J, Salmonowicz H, Ogrodnik M, Jurk D, et al. Telomere 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. Front. Furthermore, transcriptomic analysis of diverse tissues in the late-generation TERC/ mouse revealed prominent representation of p53 and PGC1/ target genes, enabling us to identify a common pathway integrating three competing theories of agingaccumulating genotoxic stress, declining mitochondrial function, and increasing oxidative damage. p53 deficiency rescues the adverse effects of telomere loss and cooperates with telomere dysfunction to accelerate carcinogenesis. Reverse transcriptase motifs in the catalytic subunit of telomerase, POT1 as a terminal transducer of TRF1 telomere length control. Telomere Dysfunction in Nonalcoholic Fatty Liver Disease and Cryptogenic Cirrhosis. In a press release from The Sagol Center for Hyperbaric Medicine and Research, Efrati says understanding telomere shortening is "considered the 'Holy Grail' of the biology of aging". Additionally, human tumor tissues show elevated TERT and TERC expression compared to matched normal tissues (Meyerson et al., 1997), and malignant transformation of cultured human primary cells requires enforced TERT expression, indicating that telomere maintenance is essential for full malignant transformation (Hahn et al., 1999). While such RNAs are encoded within introns of other genes, TERC is a prototypical gene with its own promoter (Feng et al., 1995). Such inflammatory diseases include inflammatory bowel disease (Risques et al., 2008; Risques et al., 2011), pancreatitis (van Heek et al., 2002), non-alcoholic fatty liver disease (Laish et al., 2016), chronic obstructive pulmonary disease (Birch et al., 2016), and liver cirrhosis as a consequence of chronic liver disease (Wiemann et al., 2002) among others. Essential role of mouse telomerase in highly proliferative organs. The evolutionarily conserved function of telomere end protection spans from lower multicellular organisms such as T. thermophila to higher-order organisms including Homo sapiens (Roake and Artandi, 2020). Whether telomere length is a marker of biological aging or a cause of it remains to be seen. Med. In the absence of a p53 checkpoint, these events lead to tumorigenesis. The Nobel Laureates have shown that the Telomere The precise conceptualization of aging as it relates to health is still being refined, with the ultimate goal of defining young or old by biomarkers reflecting cellular age. These processes lead to aging and other degenerative and inflammatory diseases. The developmental program encoded in DNA is the primary determinant of lifespan. Telomere-based crisis: functional differences between telomerase activation and ALT in tumor progression. 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. Specifically, a recent study highlighted the role of senescent cells in driving Alzheimers disease (Bussian et al., 2018). Along these lines, it was shown that the selective inhibition of p21-dependent cell cycle arrest (Choudhury et al., 2007) or Puma-mediated apoptosis (Sperka et al., 2011) could prolong the maintenance of tissue integrity and lifespan in telomere-dysfunctional mice without increasing cancer development. It may cause telomere attrition which can lead to oncogenic incidence in These pleiotropic actions can drive atherosclerosis, type II diabetes, osteoarthritis, and Parkinsons and Alzheimers diseases. Choi J, Southworth LK, Sarin KY, Venteicher AS, Ma W, Chang W, Cheung P, Jun S, Artandi MK, Shah N, et al. We propose a telomere theory of reproductive aging that posits telomere shortening in the female germ line as the primary driver of reproductive aging in women. ScienceDaily Furthermore, adenoviral delivery of telomerase in aged mice improves cardiac function following acute myocardial infarction, enhances muscle coordination and kidney and liver function, reduces insulin resistance and subcutaneous fat depletion, increases bone mineral density, and extends life expectancy without causing an increase in cancer incidence (Hong and Yun, 2019). Historically, while telomerase was known to be consistently upregulated in cancer, its role in cellular transformation was documented in 1999 when enforced TERT expression, together with classical oncogenes, promoted full malignant transformation of primary human cells (Hahn et al., 1999). Finally, do your best to exercise when you caneven if you have time for just a quick walk. Telomere shortening, as seen with aging, can cause chromosomal instability and promote cancer progression. (2002). Mar 28, 2022--Listen. Physicists Breakthrough Discovery in Genetic Protective Layer. Christina Camell. 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). The developmental program encoded in DNA is Telomeres Notably, the premature aging phenotypes associated with mitochondrial dysfunction mirror those of telomerase-deficient mice, p53-hyperactivated mice (Tyner et al., 2002), and PGC1/-null mice (Lai et al., 2008). Telomeres Antitelomerase therapy provokes ALT and mitochondrial adaptive mechanisms in cancer. Killela PJ, Reitman ZJ, Jiao Y, Bettegowda C, Agrawal N, Diaz LA Jr., Friedman AH, Friedman H, Gallia GL, Giovanella BC, et al. Ablation of telomerase and telomere loss leads to cardiac dilatation and heart failure associated with p53 upregulation. 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). Cellular senescence is an irreversible cell arrest process, which is determined by a variety of complicated mechanisms, including telomere attrition, mitochondrial dysfunction, metabolic disorders, loss of protein homeostasis, epigenetic changes, etc. Telomere shortening and tumor formation by mouse cells lacking telomerase RNA. The link between telomere dysfunction and the hallmarks of aging, the incidence of age-associated diseases, and the development of inherited and acquired degenerative conditions has catalyzed interest in telomerase restoration therapy as a potential antiaging strategy (Figure 6). Now, Salk scientists have discovered that when telomeres become very short, they communicate with mitochondria, the cell's powerhouses. In summary, the structure of telomeres, coupled with the highly regulated activity and recruitment of telomerase, ensures proper telomere maintenance in normal cells. Telomere shortening is one of the main hallmarks of aging and is commonly observed in most cell types . 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). Gonzalez-Guardia L, Yubero-Serrano EM, Rangel-Zuniga O, Marin C, Camargo A, Perez-Martinez P, Delgado-Lista J, Gomez-Delgado F, Garcia-Rios A, Tinahones FJ, et al. Telomeres, aging, and cancer: the big picture - PMC telomere Systematic analysis of noncoding somatic mutations and gene expression alterations across 14 tumor types. Jonassaint NL, Guo N, Califano JA, Montgomery EA, and Armanios M (2013). AMPK is a central sensor of nutrients that modulates mTOR signaling and transcriptionally activates FOXO transcription factors and SIRT1 (Saxton and Sabatini, 2017). The accumulation leads to gradual neuronal death and cognitive impairment. Harley CB, Liu W, Blasco M, Vera E, Andrews WH, Briggs LA, and Raffaele JM (2011). Nature Reviews Immunology (2022) Telomeres are a life-extending gift Telomeres Here, we show that gut-specific telomerase activity in tert-/- We would like to thank Denise J. The following subsections outline how telomere dysfunction links to the mechanisms underlying each hallmark of aging. The role of telomere attrition and damage in inducing a permanent cell cycle arrest was further demonstrated using human fibroblasts overexpressing a mutant form of TRF2 (TRF2BM) through activation of DNA damage check-points (d'Adda di Fagagna et al., 2003). Barnes RP, Fouquerel E, and Opresko PL (2019). A mammalian telomerase-associated protein. Web2022 Jan;73:101507. doi: 10.1016/j.arr.2021.101507. Telomeres Lopez-Otin C, Blasco MA, Partridge L, Serrano M, and Kroemer G (2013). (2011). 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). Direct evidence of a role for mitochondrial decline in driving processes of aging derives from mice harboring mutations in the mitochondrial polymerase POLG. Pech MF, Garbuzov A, Hasegawa K, Sukhwani M, Zhang RJ, Benayoun BA, Brockman SA, Lin S, Brunet A, Orwig KE, et al. Begus-Nahrmann Y, Hartmann D, Kraus J, Eshraghi P, Scheffold A, Grieb M, Rasche V, Schirmacher P, Lee HW, Kestler HA, et al. Blasco MA, Lee HW, Hande MP, Samper E, Lansdorp PM, DePinho RA, and Greider CW (1997). Thus, it is plausible that telomere dysfunction-induced repression of SIRT1 and resultant decreased HSP70 levels impair protein homeostasis and heat shock responses during stress (Westerheide et al., 2009). Most importantly, a deeper understanding of the regulation of telomerase expression and function is needed to define the contributions of telomerase to normal aging as well as inherited and somatic degenerative disease pathogenesis in humans. Short telomeres reduce the risk of cancer early in life at the expense of impaired regeneration late in life. Chakravarti D, H.B., Mao X, Rashid A, Li J, Liao w., Whitley EM, Dey P, Hou P, LaBella KA, Chang A, Wang G, Spring DJ, Deng P, Zhao D, Liang X, Lan Z, Lin Y, Sarkar S, Terranova C, Deribe YL, Blutt SE, Okhuysen P, Zhang J, Sanchez V, Nielsen ON, Dupont A, Younes M, Patel KR, Shroyer N, Rai K, Estes M, Alan W, Bertuch A, DePinho RA (2020). As a library, NLM provides access to scientific literature. TERC contains an H/ACA domain consisting of a three-nucleotide sequence, termed the CAB box, that is essential for binding to telomerase Cajal body protein 1 (TCAB1). The following are the two most well-studied ones: the first involves impeding the replicative potential of tissue stem cells (another hallmark of aging: stem cell exhaustion) immune cells (so-called immunosenescence) and stromal cells; the second stems from disrupting organ function through release of pro-inflammatory factors including but not limited to interleukin 6 (IL-6) and tumor necrosis factor alpha (TNF) (Coppe et al., 2010) by senescent cells. A new procedure can quickly and efficiently increase the length of human telomeres, the protective caps on the ends of chromosomes that are linked to aging and disease, according to scientists at the Stanford University School of Medicine.. Flynn RL, Cox KE, Jeitany M, Wakimoto H, Bryll AR, Ganem NJ, Bersani F, Pineda JR, Suva ML, Benes CH, et al. This crisis-reactivation sequence generates more aggressive tumors, establishing that crisis enables acquisition of genomic events that endow a more aggressive malignant phenotype (Ding et al., 2012; Hu et al., 2012). For example, melanoma shows highly recurrent TERT promoter mutations, with an average 4-fold increase in TERT expression (Horn et al., 2013), and primary glioblastoma shows TERT promoter mutations in over 80% of cases (Killela et al., 2013). Deregulated nutrient sensing in aging relates to a highly conserved network consisting of IGF-1 and mTOR-S6 signaling pathways and members of the FOXO and AMPK families of proteins. Age-dependent changes in the epigenetic landscape include increased local methylation and decreased global methylation, increased H4K16 acetylation, H3K4 trimethylation, and H4K20 trimethylation, and decreased H3K9 monomethylation and H3K27 trimethylation (Barnes et al., 2019). Wright WE, Piatyszek MA, Rainey WE, Byrd W, and Shay JW (1996). It also maintains the genomic integrity and chromosomal stability. Similarly, overexpression of TRF1 or deregulation of POT1 impairs telomerase binding to telomere ends, causing telomere shortening (Loayza and De Lange, 2003; Smogorzewska et al., 2000). Telomerase modulates Wnt signalling by association with target gene chromatin. An official website of the United States government. Short telomeres result in chromosomal instability in hematopoietic cells and precede malignant evolution in human aplastic anemia. telomere This constrained malignant progression relates prominently to the activation of p53 in aspiring cancer cells experiencing telomere dysfunction. (2020). Short telomeres are associated with an increased risk of neurological and psychiatric disorders including dementia. Sahin E, Colla S, Liesa M, Moslehi J, Muller FL, Guo M, Cooper M, Kotton D, Fabian AJ, Walkey C, et al. Telomere dysfunction promotes non-reciprocal translocations and epithelial cancers in mice. Moreover, epithelial cancers are the predominant cancer types of the aged; these cancers are typically aneuploid and possess many chromosome structural alterations. Altered telomeres in tumors with ATRX and DAXX mutations. The increased cell proliferation and resistance to cell death upon ectopic TERT and TERC expression are attenuated through repression of p65.