Bodnar AG, Ouellette M, Frolkis M, Holt SE, Chiu CP, Morin GB, et al. Are Telomeres the Key to Aging and Cancer - University of Utah Telomere dysfunction in ageing and age-related diseases If one assume spontaneous mutations can occur approximately each 20 cell divisions (about 1 million cells), and assuming that mutations provide a premalignant cell with a slight growth advantage, then after 60100 doubling (at least in cell culture conditions) the cells would contain some very short telomeres that are uncapped and initiate DNA damage signaling. Structure of Tetrahymena telomerase reveals previously unknown subunits, functions and interactions. A new approach to targeting telomerase expressing cancer cells is to develop telomerase-mediated, telomere uncapping compounds (103). The reactivation of telomerase activity in cancer progression. These issues have important implications for the development of telomerase therapeutics (discussed in a later section). Carlund O, Norberg A, Osterman P, Landfors M, Degerman S, Hultdin M. Sci Rep. 2023 May 16;13(1):7955. doi: 10.1038/s41598-023-34922-1. These toxicities require patients going off the telomerase inhibitor and very quickly the telomeres regain their length. Lingner J, Hughes TR, Shevchenko A, Mann M, Lundblad V, Cech TR. FANCI is Associated with Poor Prognosis and Immune Infiltration in Liver Hepatocellular Carcinoma. Insights into the evolution of longevity from the bowhead whale genome. TERT promoter mutations in familial and sporadic melanoma. Dana-Farber provides personalized care for each patient based on their unique needs; their experiences and results will vary. The role of telomere maintenance in the spontaneous growth arrest of pediatric low-grade gliomas. It is now believed that it requires 815 key oncogenic changes for a normal cell to become a cancer cell, so senescence could have evolved in humans to prevent most cancer until later in life. Tefferi A, Lasho TL, Begna KH, Patnaik MM, Zblewski DL, Finke CM, et al. Drugs Targeting a Pathway in Glioblastoma Must Clear a High Bar, Study Suggests. Vinagre J, Almeida A, Ppulo H, Batista R, Lyra J, Pinto V, et al. Robin JD, Ludlow AT, Chen M, Magdinier F, Batten K, Holohan B, et al. Von Zglinicki T, Saretzki G, Ladhoff J, d'Adda di Fagagna F, Jackson SP. Griffith JD, Comeau L, Rosenfield S, Standel RM, Bianchi A, Moss H, et al. A randomized phase II study of the telomerase inhibitor imetelstat as maintenance therapy for advanced non-small-cell lung cancer. A gene called Myc (pronounced "mick") that is among the most important drivers of cancer in both mice and humans also plays a newly discovered crucial role in aging, according to a new Cell . less than 12 Kb). Without telomeres, the main part of the chromosome the part with genes essential for life would get shorter each time a cell divides. The comparative biology of mammalian telomeres: ancestral states and functional transitions. In human cells the bypass or escape from senescence can be experimentally demonstrated by abrogating important cell cycle checkpoint genes [such as p53 (TP53), p21 (CDKN1A), p16INK4a (CDKN2A) and pRb (RB1)], leading to increased numbers of cell divisions of potentially initiated premalignant cells (3134). In addition, humans have also dramatically changed their lifestyles from our ancestral hunter gatherer, low fat and active environment, to a more sedentary, high fat, smoking, sun exposed, polluted environment. This has also been termed the Hayflick limit. Main Telomeres are the genomic portions at the ends of linear chromosomes. Almost all pre-neoplastic lesions have critically shortened telomeres and this may be an initial protective mechanism limiting the maximum number of divisions human cells can undergo. Telomeres gradually shorten every time a cell divides, however, resulting in less protection for the chromosomes. Telomerase by necessity would have to be carefully regulated in large long-lived species to avoid the early onset of cancer while in smaller mammals, such as mice, telomerase is known to be more promiscuous and most inbred strains of mice have very long telomeres compared to humans but the reasons for this are not well understood. Many investigators also use mRNA for TERT as a surrogate for telomerase enzyme activity but since there is now evidence that mRNA for TERT does exist in normal cells, caution is needed in using indirect methods for assuming enzyme activity. Telomeres are sections of DNA that are found at the ends of chromosomes and seem to play a role in aging. sharing sensitive information, make sure youre on a federal Thus, inbred strains of mice in a normal lifespan probably do not use telomere-based replicative aging as an anti-cancer protection mechanism (53). Epub 2007 Sep 4. Telomeres and telomerase in aging and cancer - PubMed Repressed telomerase and short telomeres would thus diminish the maximal number of replication-mediated mutations that would occur prior to engaging telomere-based senescence. However, while highly active during development and in cancer cells, the enzyme is down-regulated in most human somatic cells with a few exceptions such as human lymphocytes. These are cell types that need to undergo many divisions, or, in the case of germ cells, give rise to a new organism with its telomeric "clock" reset 5 ^5 5 start . Telomere shortening associated with chromosome instability is arrested in immortal cells which express telomerase activity. Federal government websites often end in .gov or .mil. CKM and TERT dual promoters drive CRISPR-dCas9 to specifically inhibit the malignant behavior of osteosarcoma cells. This makes telomerase a promising target for cancer therapy [10 . See this image and copyright information in PMC. Hormones regulate and coordinate multiple physiologic functions. While the importance of telomeres has been recognized for a long time (1819), the DNA sequence of telomeres was somewhat more recent (2021). Implications of mapping the human telomerase genes (hTERT) as the most distal gene on chromosome 5p. These examples demonstrate that one does not need to have telomerase activity to develop cancer, but a mechanism to maintain telomeres is required for the continuous growth of the advanced tumor (4547). Issues to consider when conducting telomere testing for disease susceptibility and aging are provided in Table 2. As part of cancer progression, as telomeres shorten the chromatin silencing effects may become relaxed resulting in a permissive environment for telomerase promoter mutations and telomerase reactivation (Figure 4). Using 3D FISH with a subtelomeric probe and a distal gene of interest, one can observe adjacent probe signals in young cells and separated signals in old cells with short telomeres. Therefore, aging and cancer are two ends of the same spectrum. What do we know about the dynamics of telomere length changes in prospective human longitudinal studies? Faithful execution of the developmental program requires stability of the (epi-)genome which is c 2023 Jul 6;28(1):52. doi: 10.1186/s11658-023-00464-7. Keane M, Semeiks J, Webb AE, Li YI, Quesada V, Craig T, et al. Seluanov A, Chen Z, Hine C, Sasahara TH, Ribeiro AA, Catania KC, et al. Interestingly, TERT promoter mutations in telomerase expressing normal human embryonic stem cells (hESC) only modestly increase telomerase activity (39). While wild type hESCs silence telomerase activity when induced to differentiate, telomerase remains active in hESCs with TERT promoter mutations under differentiation conditions (39). Increasing evidence indicates that both telomeres and telomerase contribute to cell survival and cancer via . Role of Telomeres and Telomerase in Cancer and Aging - PMC In addition, it is likely that what is often being called replicative (telomere-based) senescence is in fact a DNA damage response that may not be due to terminally shortened telomeres but perhaps inadequate cell culture conditions (57). In addition, it requires very little telomerase to maintain the shortest telomeres. Alternative lengthening of telomeres: models, mechanisms and implications. Telomeres are found at the end of chromosomes and play an important role in the replication and stability of chromosomes. 2007 Aug;37(1):43-7. doi: 10.1016/j.transci.2007.04.006. Julin B, Shui I, Heaphy CM, Joshu CE, Meeker AK, Giovannucci E, et al. Cancer resistance due to repressed telomerase and short telomeres might limit regenerative capacity, thus increasing the likelihood of age-dependent degenerative diseases, particularly as animals get older and their telomeres undergo further shortening. The .gov means its official. While this is correlative, and certainly does not prove a cause and effect relationship, these findings suggest that individuals with inherently short telomeres should be at increased risk for cancer. In cells with defective check-point activation, aging-associated telomere shortening can promote genome instability and cancer formation. Telomerase* / genetics. White LK, Wright WE, Shay JW. Figure 1. Telomeres, Telomerase and Cancer - PubMed The problem in using this technique in cancer cells, as opposed to normal diploid cells, is the global aneuploidy that exists in cancers raising the very real possibility that the single copy reference gene may not be accurate and almost nothing is mentioned about this in published studies. Telomeres and telomerase in cancer - Oxford Academic Harley CB. All somatic normal human cells display progressive telomere shortening with increased cell divisions. Lynch SM, Major JM, Cawthon R, Weinstein SJ, Virtamo J, Lan Q, et al. All these methods for measuring telomere lengths have their strengths and limitations. Alternatively, if telomerase was not activated sufficiently, then telomeres would continue to shorten with continuing cell divisions and the cells would eventually stop dividing. Are telomere length tests validated as a biomarkers of aging in humans? In addition to the accumulation of several mutations in oncogenes and tumor suppressor genes, almost all advanced cancer cells are immortal and have overcome the normal cellular signals that prevent continued cell division. The molecular mechanisms to bypass crisis are not well understood and in some instances a DNA recombination mechanism is engaged instead of telomerase (48, 56). Cancer cells often avoid senescence or cell death by maintaining their telomeres despite repeated cell divisions. eCollection 2023. 2023 Jun 9;24 (12):9932. doi: 10.3390/ijms24129932. Hemann MT, Strong MA, Hao LY, Greider CW. Canela A, Vera E, Klatt P, Blasco MA. Telomerase and cancer therapeutics. Roles of telomeres and telomerase in cancer, and advances in telomerase Telomere Length Dynamics and the Evolution of Cancer Genome Architecture. Reversible cellular senescence: A two-stage model for the immortalization of normal human diploid fibroblasts. The average human telomere is 5000-15,000 nucleotides long. Human telomere biology: A contributory and interactive factor in aging, disease risks, and protection. Petos paradox: evolutions prescription for cancer prevention. Thus, quantitation of the very shortest telomeres require more sensitive assays. Telomerase activation by genomic rearrangements in high-risk neuroblastoma. Cancer and telomerase: An ALTernative to telomerase. Consistently, telomerase activity in most cancer cells is elevated whereas telomere length is shorter, relative to corresponding . Why are there not more successful telomerase targeting approaches in cancer? Gorbunova V, Seluanov A, Zhang Z, Gladyshev VN, Vijg J. The shortest telomere, not average telomere length, is critical for cell viability and chromosome stability. Shay, J. W. Role of telomeres and telomerase in aging and cancer. Greaves M. Evolutionary determinants of cancer. Telomere terminal transferase (telomerase) enzyme activity (not the identification of the genes involved in telomerase) was discovered in 1985 in the single cell organism, Tetrahymena (1). Alternative splicing regulation of telomerase: a new paradigm? Dysfunctional telomeres are largely devoid of telomeric DNA and telomere-binding proteins, thus inducing DDR, including DNA repair and checkpoint responses. The bottleneck at present is that additional validation studies and clinical trials will be required before knowledge of telomerase activity will be useful in a practical sense for decisions regarding patient management. These ideas are captured in the Telomere Erosion in Disposable Soma theory of aging proposed herein. While normal cells with or without telomerase activity are not transformed, in the background of additional oncogenic changes, normal cells not only upregulate or reactivate telomerase but can become fully malignant. Thus, when telomeres reach a certain initial length (~1520 kb) during human development, three-dimensional chromatin structures involving telomere position effects over long distances (TPE-OLD) (6364) may silence the TERT gene. What are Telomeres and How Do They Play a Role in Cancer? Hou Y, Li J, Yu A, Deng K, Chen J, Wang Z, Huang L, Ma S, Dai X. Int J Med Sci. On the current trajectory, 2.1 billion individuals will be older than age 60 by 2050 ( United Nations, 2017 ). Rufer N, Dragowska W, Thornbury G, Roosnek E, Lansdorp PM. The .gov means its official. One could speculate that if telomerase was expressed at very high levels, then telomeres might elongate greatly and this could have detrimental consequences. Special Issue "The Dual Roles of Telomeres and Telomerase in Aging and With increasing cell divisions, telomeres progressively shorten. Huang FW, Hodis E, Xu MJ, Kryukov GV, Chin L, Garraway LA. Recent evidence suggests telomere length can regulate genes over long distances. Stern JL, Theodorescu D, Vogelstein B, Papadopoulos N, Cech TR. Telomeres, telomerase and cancer. Careers, Unable to load your collection due to an error. Shorter telomeres associate with a reduced risk of melanoma development. Alternatively, imetelstat may block terminal maturation in megakaryocyte precursors by inhibiting telomerase. The ALT pathway is not common in carcinomas but does appears in soft tissue sarcomas and some other less common tumor types but at present there are no directed therapies to the ALT pathway (48). An official website of the United States government. We review the present knowledge of telomeres and telomerase with special attention to their role in cell proliferation, cellular senescence, and human aging. Perifosine as a potential novel anti-telomerase therapy. Telomere reduction in human colorectal carcinoma and with ageing. Wong MS, Shay JW, Wright WE. The Role of Telomeres in Stem Cells and Cancer - ScienceDirect Telomere shortening has been associated with cellular senescence and the aging process, as well as major diseases, such as atherosclerosis, obesity, and cardiovascular disease. Telomeres and telomerase in leukaemia and lymphoma. Thus, a short telomere senescence-based mechanism would be a potent initial tumor suppressor mechanism since a large number of genetic and epigenetic alterations are required for a normal cell to become malignant. So one could ask, why are humans are especially vulnerable to cancer? Shay JW, Wright WE. The length of telomeres is directly related to the number of times a cell can divide. The cells trigger a self-destruct program, known as apoptosis, ending the life of the cell. A tandemly repeated sequence at the termini of the extrachromosomal ribosomal RNA genes in Tetrahymena. 2016 AACR. Autexier C, Greider CW. Tabori U, Vukovic B, Zielenska M, Hawkins C, Braude I, Rutka J, et al. While some anti-cancer mechanisms may have evolved in evolutionary terms such as dark pigmented skin to protect against UVB-induced cancers, humans in the modern era get a reasonably large tumor incidence [some estimate close to 50% in more developed, Western societies (8283)]. With the re Unraveling the potential of senescence-related genes in guiding clinical therapy of lung adenocarcinoma patients. If whales and elephants have evolved anti-cancer protection mechanisms what occurs in humans? A gene called Myc (pronounced "mick") that is among the most important drivers of cancer in both mice and humans also plays a newly discovered crucial role in aging, according to a new . The site is secure. Wright WE, Pereira-Smith OM, Shay JW. Eventually cells enter a state termed crisis, which is a period where cell division and death are in balance. Generally there are no or a very small percent (<10%) of promoter mutations in these cancer types. The following topics and questions in this review will be discussed (Table 1). The current review focuses on the connection of telomerase and telomeres with aging. As a library, NLM provides access to scientific literature. For this reason, some have called telomerase the immortality enzyme.Nevertheless, the telomeres in cancer cells are generally shorter than telomeres in normal cells. Despite many recent advances, telomerase remains a challenging target for cancer therapy. Why do TERT promoter mutations occur in a tissue-specific manner? With increasing cell divisions, telomeres progressively shorten. This has also been termed the Hayflick limit. 2019;2045:217-224. doi: 10.1007/7651_2018_120. However, there are exceptions such as the small long-lived mole rat (77) which show increases in tumor suppressor p15/p16 variants, decreased inflammation, and increases in highmolecular-mass hyaluronan, perhaps influencing cell adhesion. Similar to elephants, whales are rarely found to develop cancer. It is a common misconception that normal senescent cells undergo apoptosis and die. Telomeres: What are they, and how do they impact aging? Bilirubin and Redox Stress in Age-Related Brain Diseases - MDPI MeditationReduces the pace . Perhaps even more importantly, it is not certain what average telomere length actually means when it is well established that the shortest telomeres lead to senescence and genomic instability (93). While p53 protein is generally thought of as a tumor suppressor pathway, it is more difficult to understand in evolutionary terms how these extra copies could have been selected for to protect against cancer. Because the cancer cells will continue to proliferate before signals to initiate growth arrest or die is sensed by the cell, they are less likely to be as effective in first-line therapy but more likely to play a supportive role to control residual disease (maintenance therapy) after initial control is accomplished through conventional surgery, radiotherapy, general chemotherapy, and even targeted therapy. Why do chromosomes have telomeres? This may be particularly important in specific age-related diseases in which increased cell turnover due to the pathologic processes results in replicative senescence and a failure to maintain physiologic function (104). In the large majority of cancer cells, telomere length is maintained by telomerase. Bookshelf Funct Integr Genomics. Thus, with increased age it is believed that there is a gradual accumulation of senescent cells that may affect some aspects of aging. Shay JW, Wright WE. At present, there are no clinically approved strategies exploiting telomerase as a cancer therapy target. Estimating telomere length from whole genome sequence data. Telomeres and aging - PubMed Nan H, Du M, De Vivo I, Manson JE, Liu S, McTiernan A, Curb J, et al. There are few telomerase directed therapies and many of the assays used to measure telomeres and telomerase have serious limitations. ObesityReducing BMI by 10 units increased epigenetic age by one to three years. Mutation of the TERT promoter switch to active chromatin, and monoallelic TERT expression in multiple cancers. The telomerase gene will likely have many important applications in the future of medicine and cellular engineering. post reproduction), evolutionary adaptations have yet to occur in humans to the extent they have occurred in elephants and whales even though humans have shorter telomeres and repress telomerase in somatic tissues similarly to elephants and whales. Somatic mutations in the proximal promoter of the human telomerase reverse transcriptase gene (TERT) is now considered the most common noncoding mutation in cancer. C06 RR030414/RR/NCRR NIH HHS/United States, P50 CA070907/CA/NCI NIH HHS/United States, R01 AG001228/AG/NIA NIH HHS/United States. Biosciences Institute, Campus for Ageing and Vitality, Newcastle University, Newcastle upon Tyne NE4 5PL, UK. Main The ends of chromosomes are formed by telomeres special chromatin structures that are essential to protect these regions from recombination and degradation activities 1. In crisis there is a balance between cell growth and apoptosis and the vast majority of the cell population dies. Telomeres and telomerase play a crucial role in human aging and cancer. Senescence and immortalization: role of telomeres and telomerase Thus, while humans may have evolutionarily evolved more efficient DNA repair or other mechanisms to reduce cancer incidence, humans still appear to be less protected from developing cancer when compared to other large long-lived mammalian species. Keywords: aging, cancer, lifestyle, oxidative stress, telomere. Conflict of Interest: Life Length, Inc (Madrid) consultant and scientific advisor; Elizabeth Therapeutics, Inc, Founding Scientist. Greaves M, Ermini L. Evolutionary adaptation to risk of cancer: evidence from cancer resistance in elephants. Counter CM. It is known that telomerase is active during early human fetal development, then becomes silenced in most tissues at approximately 34 months gestation (62). A hallmark of advanced malignancies is the ability for continuous cell divisions that almost universally correlates with the stabilization of telomere length by the reactivation of telomerase. However, recent studies have shown that in the general population individuals with inherently long telomeres are also at a higher risk for major cancers (6771). Role of Telomeres and Telomerase in Aging and Cancer Regulation of hTERT (telomerase) alternative splicing: a new target for chemotherapy. Nakamura TM, Morin GB, Chapman KB, Weinrich SL, Andrews WH, Lingner J, et al. There are genes several megabases from a telomere that are silenced in young cells, expressed in old cells and repressed again when TERT is introduced into old cells. However, telomerase appears to be reactivated in essentially all human cancers. Thus it is entirely possible that TERT is regulated at multiple levels including long-distance telomere looping and chromatin modifications. In summary, telomerase activity is detected in the vast majority of human cancers. 2023 May 12;20(7):918-932. doi: 10.7150/ijms.83760. Genes (X and Y in the illustration) although closer to the telomere are not regulated by this mechanism (TPE-OLD). Chromosomes are the rod-like structures that contain the genes and other DNA in cells. Finally, if one deletes TERT or TERC (functional RNA template component of telomerase) from inbred strains of mice (81), telomeres do progressively shorten and in later generations mice develop aging phenotypes (stem cell dysfunction, cardiomyopathies, insulin resistance, diminished stress responses and only a modest increase in cancer) similar to humans (81). Unauthorized use of these marks is strictly prohibited. In two recent papers on the elephant (78) and the bowhead whale (79) there are emerging findings that mechanisms to reduce cancer risk in large mammals may have evolved. Why have current approaches not progressed? Another possibility is that the human TERT gene may autoregulate itself since it is located very close to the telomere end of chromosome 5 (61). What are the mechanisms for telomerase activation in common tumor types that do not have TERT promoter mutations? It is well recognized that telomeres progressively shorten with increased age in vitro and in vivo, ( 7 - 14) and, in combination with a series of oncogenic changes, cells with short telomeres escape senescence and become immortal ( Figure 1 ), generally by activating or upregulating telomerase. Is the telomere length test accurate within ~5% upon multiple biological replicates from the same individual? All somatic normal human cells display progressive telomere shortening with increased cell divisions. In contrast, many common solid tumor types do not have frequent TERT promoter mutations and very little is presently known why there is such large variations in frequencies of promoter mutations or if TERT promoter mutations are sufficient for the formation of tumors. The hallmark of cells escaping crisis is almost universally, stable but short telomere lengths and telomerase activity. Olovnikov AM. McClintock B. Telomere length dynamics in human lymphocytes subpopulations measured by flow cytometry. Cell division is necessary for growing new skin, blood, bone, and other cells. Comments (0) (Image credit: Getty Images) Jump to: Function Aging Cancer Telomeres. In summary, telomerase and its regulation of telomere length is both an important target for cancer therapy and for the treatment of age-related disease. Buseman CM, Wright WE, Shay JW. Telomerase in cancer and aging - PubMed Telomerase is a cellular reverse transcriptase (molecular motor) that adds new DNA onto the telomeres that are located at the ends of chromosomes (1, 1517).

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