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 ). Wnt/beta-catenin signaling regulates telomerase in stem cells and cancer cells, Telomere Gene Therapy: Polarizing Therapeutic Goals for Treatment of Various Diseases. Med. (A) Structure of the D-loop and T-loop at the telomeric end. These cross-species differences enabled elucidation of a key mechanism driving the preponderance of epithelial cancers in aged humans, as well as the basis of genomic instability in these cancers. 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). This signaling circuit of telomerep53PGC1/mitochondria leads to escalating ROS levels and further ROS-mediated 8-hydroxydeoxyguanosine modification of guanosine bases at telomeres (Figure 4). 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). official website and that any information you provide is encrypted Telomere shortening, as seen with aging, can cause chromosomal instability and promote cancer progression. Telomeres are seen by many scientists as the key to living longer. 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). van Heek NT, Meeker AK, Kern SE, Yeo CJ, Lillemoe KD, Cameron JL, Offerhaus GJ, Hicks JL, Wilentz RE, Goggins MG, et al. may contribute to aging independent of telomere length because DNA damage near telomeres may be irreparable and is capable of triggering senescence . Cellular senescence is causally related to the occurrence and development of age-related Like the rest of a Thus, mice engineered to experience telomere-based crisis in the context of deactivated DNA damage signaling (p53 deficiency) illuminated a major mechanism driving the preponderance of epithelial cancers in aged humans and explained why such cancers develop radically altered cytogenetic profiles. Hastie ND, Dempster M, Dunlop MG, Thompson AM, Green DK, and Allshire RC (1990). These mutant mice show reduced mitochondrial abundance and abnormal mitochondrial morphology (e.g., fragmented cristae, disrupted external membrane) (Trifunovic et al., 2004) and exhibit premature aging (e.g., alopecia, kyphosis, reduced body weight, reduced subcutaneous fat, reduced bone mineral density consistent with osteoporosis, anemia, and cardiomyopathy). These pathways reciprocally regulate each other to maintain metabolic homeostasis. Choudhury AR, Ju Z, Djojosubroto MW, Schienke A, Lechel A, Schaetzlein S, Jiang H, Stepczynska A, Wang C, Buer J, et al. Flynn RL, Cox KE, Jeitany M, Wakimoto H, Bryll AR, Ganem NJ, Bersani F, Pineda JR, Suva ML, Benes CH, et al. Attempts to change telomere length through lifestyle or behavioural The length of telomeres is directly related to the number of times a cell can divide. 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). (2011). Telomere dysfunction can drive the hallmarks of cellular aging. Telomeropathy results from germline defects of telomere maintenance genes including TERT, TERC, DKC, PARN, RTEL1, TINF2, and POT1 as reviewed elsewhere (Opresko and Shay, 2017). (2011). These observations support the view that short dysfunctional telomeres as well as longer telomeres associated with DNA damage are likely to induce Kakimura J, Kitamura Y, Takata K, Umeki M, Suzuki S, Shibagaki K, Taniguchi T, Nomura Y, Gebicke-Haerter PJ, Smith MA, et al. Du X, Shen J, Kugan N, Furth EE, Lombard DB, Cheung C, Pak S, Luo G, Pignolo RJ, DePinho RA, et al. Finally, gene therapy studies have shown that CRISPR-mediated correction of the TERT promoter to wildtype sequences significantly prolongs the survival of glioma-bearing mice (Li et al., 2020). Blasco MA, Lee HW, Hande MP, Samper E, Lansdorp PM, DePinho RA, and Greider CW (1997). In such conditions, telomere dysfunction may serve to amplify and cooperate with the primary drivers of disease. Telomere dysfunction induces metabolic and mitochondrial compromise. WebAlthough several potentially modifiable traits and healthy behaviours have a quantifiable association with LTL, at least some of which are likely to be causal, these effects are not of a sufficient magnitude to substantially alter the association between LTL and various diseases or life expectancy. Indeed, telomere dysfunction has been described as one of the nine cellular and molecular hallmarks of aging (Lopez-Otin et al., 2013). Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. (2015). Essential factors for ALT include MRE11, RAD50, NBS1, FEN1, MUS81, and FANCD2 (Cesare and Reddel, 2010). Genetic variation in telomere length between humans is shown in blue. Mechanistically, eroded or uncapped telomeres undergo end-to-end fusion, forming dicentric chromosomes and resulting in breakage-fusion-bridge (BFB) cycles, aneuploidy and tetraploidization, translocations, amplifications, which create genomic instability through kataegis (localized hypermutations) and chromothripsis (clustered chromosomal rearrangements) during mitosis (Maciejowski and de Lange, 2017). 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. Cuttlefish remember details of their last meal, study finds. Telomere dysfunction compromises mitochondrial function and oxidative defense, increasing ROS and creating a feed-forward loop involving p53/PGC-1/ signaling. Over the last century, advances in public health and medicine have fueled a dramatic rise in life expectancy worldwide. Effects of telomerase and telomere length on epidermal stem cell behavior. In aging, mitochondrial function declines, leading to diminished energy (ATP) production as well as increased intracellular ROS. Shay JW, Pereira-Smith OM, and Wright WE (1991). 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. Specifically, telomere dysfunction activates ATM/cABL-induced phosphorylation of YAP1, resulting in its nuclear translocation. Meyerson M, Counter CM, Eaton EN, Ellisen LW, Steiner P, Caddle SD, Ziaugra L, Beijersbergen RL, Davidoff MJ, Liu Q, et al. Many knowledge gaps remain, such as elucidating the mechanisms governing telomerase expression and activity, the non-canonical functions of TERT, and the interplay between telomere dysfunction and pathological processes such as inflammatory, fibrotic, and degenerative diseases. WebAt this 2-day summit, youll learn how to: Understand the biology of telomeres: Discover how telomeres function in the body, the impact of shrinking telomeres on cells and Icgc Tcga Pan-Cancer Analysis of Whole Genomes Consortium (2020). 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. Chen C, Gu P, Wu J, Chen X, Niu S, Sun H, Wu L, Li N, Peng J, Shi S, et al. 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). Nevertheless, several questions remain regarding how the telomerase complex senses and is recruited to the shortest telomeres and the specific order in which the different components are assembled. That is, due to the persistent production of cytosolic DNA in ALT-positive cancer cells (Chen et al., 2017), it is tempting to speculate that these tumors may be more responsive to immunotherapy because cytosolic DNA upregulates interferon signaling via activation of cGAS-STING. 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 ). Elevated p53 expression is associated with dysregulation of the ubiquitin-proteasome system in dilated cardiomyopathy, A tandemly repeated sequence at the termini of the extrachromosomal ribosomal RNA genes in Tetrahymena. 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. PARP and sirtuins compete for the common pool of NAD+, such that inhibition of PARP or genetic ablation leads to increased sirtuin function in brown adipose tissue and muscle, as observed in PARP1 knockout mice (Bai et al., 2011). This review provides an overview of the history and current state of telomere research, highlights mechanistic connections between telomere dysfunction and aging Inclusion in an NLM database does not imply endorsement of, or agreement with, Repeated intermittent hyperoxic exposures, using certain hyperbaric oxygen therapy (HBOT) protocols, can induce regenerative effects which normally occur during hypoxia. WebTelomeres (yellow) sit at the ends of each chromosome. In addition, TERT interacts with the NF-B complex and binds IL-6 and TNF promoter elements, increasing cell proliferation and resistance to cell death (Ghosh et al., 2012). (2007). Bussian TJ, Aziz A, Meyer CF, Swenson BL, van Deursen JM, and Baker DJ (2018). Conditional telomerase induction causes proliferation of hair follicle stem cells, mTOR Signaling in Growth, Metabolism, and Disease. Three "drivers" of human aging can be identified. How telomeres contribute to aging and age-related diseases came to light through the study of mice and individuals harboring germline alterations in telomere maintenance genes. 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. In addition, hormonal agents such as danazol (an antiestrogenic and antiprogestogenic) and 5-dihydrotestosterone (an androgen), which can increase telomerase levels, are being tested in patients with telomeropathies (Calado et al., 2009; Townsley et al., 2016). Barnes RP, Fouquerel E, and Opresko PL (2019). Increases in glycolysis versus mitochondrial oxidative metabolism may also lead to changes in NAD/NADH pools, further impairing sirtuin activity. This shortening has been linked to aging, as it leads to cell death and tissue deterioration. Telomere shortening can occur through the wellknown endreplication problem or as a result of independent stochastic events. Citation: Son N, Cui Y and Xi W (2022) Association Between Telomere Length and Skin Cancer and Aging: A Mendelian Randomization Analysis. 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). 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 cellular aging. Researchers have discovered a new structure of telomeric DNA with the aid of physics and a tiny magnet. Lai L, Leone TC, Zechner C, Schaeffer PJ, Kelly SM, Flanagan DP, Medeiros DM, Kovacs A, and Kelly DP (2008). Epub 2022 Feb 14. Control of human telomere length by TRF1 and TRF2. Bodnar AG, Ouellette M, Frolkis M, Holt SE, Chiu CP, Morin GB, Harley CB, Shay JW, Lichtsteiner S, and Wright WE (1998). Schaetzlein S, Kodandaramireddy NR, Ju Z, Lechel A, Stepczynska A, Lilli DR, Clark AB, Rudolph C, Kuhnel F, Wei K This axis creates a feed-forward loop linking telomere dysfunction, mitochondria, and oxidative stress pathways, resulting in accelerated aging. et al. Shorter maternal telomeres, which could be aggravated by external factors, Role of Telomeres and Telomeric Proteins in Human Malignancies and Their Therapeutic Potential. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. A TERT-inducible model of prostate cancer has experimentally validated this cancer genome evolution concept. Treated cells behave as if they are much younger than untreated cells, multiplying with abandon in the In one 2022 study of more than 400,000 adults in the UK, researchers found that as little as 10 minutes of brisk walking per day was associated with longer telomeresenough that their biological age appeared 16 years younger by midlife 7. Longevity, stress response, and cancer in aging telomerase-deficient mice. The TEDS theory of aging proposes that telomere erosion allowed lifespan to increase by suppressing the growth of malignant tumors before reproduction. A platform for rapid exploration of aging and diseases in a naturally short-lived vertebrate. Laish I, Mannasse-Green B, Hadary R, Biron-Shental T, Konikoff FM, Amiel A, and Kitay-Cohen Y (2016). Further activation of telomerase leads to the progression to invasion and metastasis. On the tissue level, telomeropathy shows increased incidence of idiopathic pulmonary fibrosis, liver cirrhosis, and kidney diseases (Armanios and Blackburn, 2012), all of which are relate to increased inflammation. This work was also supported by NIH R01 CA084628 (to R.A.D.). In aging, the impact of telomere erosion on human and organismal Telomere biology is one of the main pathways involved in organismal aging. A PAPD5 small molecule inhibitor increased telomere length in induced pluripotent stem cells from dyskeratosis congenita patients and was well tolerated in mice over an extended period of time (Nagpal et al., 2020). et al. The entwined processes of senescence and inflammation may be particularly relevant to the telomere-aging connection. Sacco A, Mourkioti F, Tran R, Choi J, Llewellyn M, Kraft P, Shkreli M, Delp S, Pomerantz JH, Artandi SE, et al. Telomeres in aging and stem cells. Smogorzewska A, van Steensel B, Bianchi A, Oelmann S, Schaefer MR, Schnapp G, and de Lange T (2000). Telomere shortening is nearly universal in pancreatic intraepithelial neoplasia. A 2022 review found that regular moderate to vigorous physical activity appeared to help preserve telomere length. High telomerase is a hallmark of undifferentiated spermatogonia and is required for maintenance of male germline stem cells. The hallmarks delineated here outline a framework to stimulate further study of the role of telomeres and telomerases, which may help confront the lethal disease ultimately suffered by allaging. Genetic variation in telomere length between humans is Both TRF1 and TRF2 are upregulated in various tumor types, including cancers of the lung, breast, colon, stomach, and kidney suggestive of a supportive role for shelterin proteins in human cancer. Tumour evolution inferred by single-cell sequencing. 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). While telomerase is the most common telomere maintenance mechanism in cancer, cancer cells also utilize a telomerase-independent recombination-mediated mechanism, termed alternative lengthening of telomeres (ALT) (Henson et al., 2002). While ALT-positive cells maintained telomeres, they were unable to form lung metastases; however, upon mTERC transduction, telomerase-positive cancer cells acquired metastatic potential, establishing that ALT-positive and telomerase-positive cancers are not biologically equivalent (Chang et al., 2003). Westerheide SD, Anckar J, Stevens SM Jr., Sistonen L, and Morimoto RI (2009). Short telomeres are associated with an increased risk of neurological and psychiatric disorders including dementia. Telomere dysfunction promotes non-reciprocal translocations and epithelial cancers in mice. Tissue stem cell exhaustion is a cardinal feature of aging. At least a few hundred nucleotides of telomere repeats must cap each chromosome end to avoid activation of DNA repair pathways. 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. Griffith JD, Comeau L, Rosenfield S, Stansel RM, Bianchi A, Moss H, and de Lange T (1999). Telomerase inhibitors and senolytics inhibit processes that can thwart tumor progression, invasion and metastasis. Telomeres mediate biologic aging in organisms as diverse as plants, yeast, and mammals. Telomere Dysfunction and Senescence-associated Pathways in Bronchiectasis. Web2022 Jan;73:101507. doi: 10.1016/j.arr.2021.101507. Sci. Begus-Nahrmann Y, Hartmann D, Kraus J, Eshraghi P, Scheffold A, Grieb M, Rasche V, Schirmacher P, Lee HW, Kestler HA, et al. A Big Bang model of human colorectal tumor growth. This years Nobel Prize in Physiology or Medicine is awarded to three scientists who have solved a major problem in biology: how the chromosomes can be copied in a complete way during cell divisions and how they are protected against degradation. 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). Thus, the role of telomeres in tumor initiation depends on the integrity of p53-mediated DNA damage signaling and associated cellular checkpoint responses. 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). 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). Also, these murine malignancies exhibit minimal chromosome structural aberrations. Telomere shortening exposes functions for the mouse Werner and Bloom syndrome genes, First evidence that senolytics are effective at decreasing senescent cells in humans. 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 damage. Missios P, Zhou Y, Guachalla LM, von Figura G, Wegner A, Chakkarappan SR, Binz T, Gompf A, Hartleben G, Burkhalter MD, et al. TA-65 (cyclastragenol) is a natural compound isolated from various plant species in the genus of Astragalus. The TEDS theory of aging proposes that telomere erosion allowed lifespan to increase by suppressing the growth of malignant tumors before reproduction. Keywords: telomere length, skin cancer, skin aging, mendelian randomization, age. 2015;24:1916. (1997). Harrington L, McPhail T, Mar V, Zhou W, Oulton R, Bass MB, Arruda I, and Robinson MO (1997). 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. As a service to our customers we are providing this early version of the manuscript. Cdkn1a deletion improves stem cell function and lifespan of mice with dysfunctional telomeres without accelerating cancer formation. Lopez-Otin C, Blasco MA, Partridge L, Serrano M, and Kroemer G (2013). (2017). National Library of Medicine Telomere dysfunction drives aberrant hematopoietic differentiation and myelodysplastic syndrome. 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). Telomere dysfunction-induced mitochondrial impairment increases the dependency of tissues on glucose metabolism (Missios et al., 2014). Physicists Breakthrough Discovery in Genetic Protective Layer. Curiously, as mice age, the cancer spectrum consists primarily of hematopoietic (lymphoma) and mesenchymal (sarcoma) cancers, and few epithelial cancers (Brayton et al., 2012). Spring and Amy L. Ninetto for meticulously editing the document as well as Editing Services, Research Medical Library at MD Anderson Cancer Center. Additionally, while telomere shortening per se generates telomere dysfunction-induced foci (TIFs), ROS-induced guanine modification also produces TIFs, reflecting uncapping from shelterin disengagement (Anderson et al., 2019). (2014). Repair of critically short or There is a huge demand for novel treatment and/or prevention approaches for age-related diseases, which reduce life quality and one of the main reasons for death worldwide. Thus, combined telomerase and ALT pathwaysuppressing drugs (Flynn et al., 2015) could minimize emergence of resistance. Now, Salk scientists have discovered that when telomeres become very short, they communicate with mitochondria, the cell's powerhouses. On the current trajectory, 2.1 billion individuals will be older than age 60 by 2050 (United Nations, 2017). 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. In the subset of cancers that are ALT-positive, targeting relevant immune circuits may also enhance response rates and outcomes. Repair of critically short or Telomeres are the regions at the ends of linear chromosomes and in vertebrates are composed of large track of canonical TTAGGG Choi J, Southworth LK, Sarin KY, Venteicher AS, Ma W, Chang W, Cheung P, Jun S, Artandi MK, Shah N, et al. The oxygen-rich postnatal environment induces cardiomyocyte cell-cycle arrest through DNA damage response. (2015). Ding Z, Wu CJ, Jaskelioff M, Ivanova E, Kost-Alimova M, Protopopov A, Chu GC, Wang G, Lu X, Labrot ES, et al. 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. Melzer D, Pilling LC, and Ferrucci L (2020). A natural product telomerase activator as part of a health maintenance program. (2010). et al. (1995). Alternative lengthening of telomeres in mammalian cells. Also, deletion of Exo1 increases tissue maintenance and lifespan in telomere-dysfunctional mice by inhibiting the formation of chromosomal fusions and BFB cycles that drive the induction of DNA damage and the activation of p53-checkpoints in telomere-dysfunctional mice (Schaetzlein et al., 2007).
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