Telomere in Aging and Age-Related Diseases

Anna Meiliana, Nurrani Mustika Dewi, Andi Wijaya


BACKGROUND: The number of elderly population in the world keep increasing. In their advanced ages, many elderly face years of disability because of multiple chronic diseases, frailty, making them lost their independence. Consequently, this could have impacts on social and economic stability. A huge challenge has been sent for biomedical researchers to compress or at least eliminate this period of disability and increase the health span.

CONTENT: Over the past decades, many studies of telomere biology have demonstrated that telomeres and telomere-associated proteins are implicated in human diseases. Accelerated telomere erosion was clearly correlated with a pack of metabolic and inflammatory diseases. Critically short telomeres or the unprotected end, are likely to form telomeric fusion, generating genomic instability, the cornerstone for carcinogenesis. Enlightening how telomeres involved in the mechanisms underlying the diseases’ pathogenesis was expected to uncover new molecular targets for any important diagnosis or therapeutic implications.

SUMMARY: Telomere shortening was foreseen as an imporant mechanism to supress tumor by limiting cellular proliferative capacity by regulating senescence check point activation. Many human diseases and carcinogenesis are causally related to defective telomeres, asserting the importance of telomeres sustainment. Thus, telomere length assessment might serve as an important tool for clinical prognostic, diagnostic, monitoring and management.

KEYWORDS: telomerase, cellular senescence, aging, cancer

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Tlsty TD. Genomic instability and its role in neoplasia. Curr Top Microbiol Immunol. 1997; 221: 37-46, CrossRef.

Lengauer C, Kinzler KW, Vogelstein B. Genetic instabilities in human cancers. Nature. 1998; 396: 643-9, CrossRef.

Taylor AM. Chromosome instability syndromes. Best Pract Res Clin Haematol. 2001; 14: 631-44, CrossRef.

Murnane JP. Telomeres and chromosome Instability. DNA Repair. 2006; 5: 1082-92, CrossRef.

de Lange T. How telomere solve the end-protection problem. Science. 2009; 326: 948-52, CrossRef.

de Lange T, Lundblad V, Blackburn EH. Telomeres. New York: Cold Spring Harbor Laboratory Press; 2006, CrossRef.

O'Sullivan RJ, Karlseder J. Telomeres: protecting chromosomes against genome instability. Nat Rev Mol Cell Biol. 2010; 11: 171-81, CrossRef.

Gilson E, Geli V. How telomeres are replicated. Nat Rev Mol Cell Biol. 2007; 8: 825-38, CrossRef.

Verdun RE, Karlseder J. Replication and protection of telomeres. Nature. 2007; 447: 924-31, CrossRef.

d'Adda di Fagagna F, Reaper PM, Clay-Farrace L, Fiegler H, Carr P, Von Zglinicki T, et al. A DNA damage checkpoint response in telomere-initiated senescence. Nature. 2003; 426: 194-8, CrossRef.

Artandi SE, DePinho RA. Telomeres and telomerase in cancer. Carcinogenesis. 2010; 31: 9-18, CrossRef.

Lansdorp PM. Telomeres and disease. EMBO J. 2009; 28: 2532-40, CrossRef.

Sandin S, Rhodes D. Telomerase structure. Curr Opin Struc Biol. 2014; 25: 104-10, CrossRef.

Gunes C, Rudolph KL. The role of telomeres in stem cells and cancer. Cell. 2013; 152: 390-3, CrossRef.

Armanios M. Syndromes of telomere shortening. Annu Rev Genomics Hum Genet. 2009; 10: 45-61, CrossRef.

Armanios M. Telomerase and idiopathic pulmonary fibrosis. Mutat Res. 2012; 730: 52-8, CrossRef.

Nelson ND, Bertuch A. Dyskeratosis congenita as a disease of telomere maintenance. Mutat Res. 2012; 730: 43-51, CrossRef.

Buseman CM, Wright WE, Shay JW. Is telomerase a viable target in cancer. Mutat Res. 2012; 730: 90-7, CrossRef.

Stewart JA, Chaiken MF, Wang F, Price CM. Maintaining the end: roles of telomere proteins in end-protection, telomere replication and length regulation. Mutat Res. 2012; 730: 12-9, CrossRef.

Blackburn EH, Epel ES, Lin J. Human telomere biology: A contributory and interactive factor in aging, disease risks, and protection. Science. 2015; 350: 1193-8, CrossRef.

Doksani Y, de Lange T. The role of double-strand break repair pathways at functional and dysfunctional telomeres. Cold Spring Harb Perspect Biol. 2014; 6: a016576, CrossRef.

Hug N, Lingner J. Telomere length homeostasis. Chromosoma. 2006; 115: 413-25, CrossRef.

De Lange. Shelterin: the protein complex that shapes and safeguards human telomeres. Genes Dev. 2005; 19: 2100-10, CrossRef.

De Boer R, van der Harst P, Van Gilst WH. Telomere biology in healthy aging and disease. Eur J Physiol 2010; 459: 259-68, CrossRef.

Xie Z, Jay KA, Smith DL, Zhang Y, Liu Z, Zheng J, et al. Early telomerase inactivation accelerates aging independently of telomere length. Cell. 2015; 160: 928-39, CrossRef.

Greider CW. Regulating telomere length from the inside out: the replication fork model. Genes Dev. 2016; 30: 1483-91, CrossRef.

Blackburn EH, Collins K. Telomerase: an RNP enzyme synthesizes DNA. Cold Spring Harb Perspect Biol. 2011; 3: a003558, CrossRef.

Levy MZ, Allsopp RC, Futcher AB, Greider CW, Harley CB. Telomere end-replication problem and cell aging. J Mol Biol. 1992; 225: 951-60, CrossRef.

Stewart SA, Weinberg RA. Telomeres: cancer to human aging. Annu Rev Cell Dev Biol. 2006; 22: 531-57, CrossRef.

Shay JW, Wright WE. Role of telomeres and telomerase in cancer. Semin Cancer Biol. 2011; 21: 349-53, CrossRef.

Podlevsky JD, Chen JL. It all comes together at the ends: Telomerase structure, function, and biogenesis. Mutat Res. 2012; 730: 3-11, CrossRef.

Schmidt JC, Cech TR. Human telomerase: biogenesis, trafficking, recruitment, and activation. Genes Dev. 2015; 29: 1095-105, CrossRef.

Greider CW, Blackburn EH. A telomeric sequence in the RNA of Tetrahymena telomerase required for telomere repeat synthesis. Nature. 1989; 337: 331-7, CrossRef.

Shippen-Lentz D, Blackburn EH. Functional evidence for an RNA template in telomerase. Science. 1990; 247: 546-52, CrossRef.

Yu GL, Bradley JD, Attardi LD, Blackburn EH. In vivo alteration of telomere sequences and senescence caused by mutated Tetrahymena telomerase RNAs. Nature. 1990; 344: 126-32, CrossRef.

Fu D, Collins K. Distinct biogenesis pathways for human telomerase RNA and H/ACA small nucleolar RNAs. Mol Cell. 2003; 11: 1361-72, CrossRef.

Kiss T, Fayet-Lebaron E, Jády BE. Box H/ACA small ribonucleoproteins. Mol Cell. 2010; 37: 597-606, CrossRef.

Egan ED, Collins K. Specificity and stoichiometry of subunit interactions in the human telomerase holoenzyme assembled In Vivo. Mol Cell Biol. 2010; 30: 2775-86, CrossRef.

Venteicher AS, Abreu EB, Meng Z, McCann KE, Terns RM, Veenstra TD, et al. A human telomerase holoenzyme protein required for Cajal body localization and telomere synthesis. Science. 2009; 323: 644-8, CrossRef.

Buckingham EM, Klingelhutz AJ. The role of telomeres in the ageing of human skin. Exp Dermatol 2011; 20:297-302, CrossRef.

O’Connor CM, Lai CK, Collins K. Two purified domains of telomerase reverse transcriptase reconstitute sequence-specific interactions with RNA. J Biol Chem. 2005 280: 17533-9, CrossRef.

Jacobs SA, Podell ER, Cech TR. Crystal structure of the essential N-terminal domain of telomerase reverse transcriptase. Nat Struct Mol Biol. 2006; 13: 218-25, CrossRef.

Robart AR, Collins K. Human telomerase domain interactions capture DNA for TEN domain-dependent processive elongation. Mol Cell. 2011; 42: 308-18, CrossRef.

Collins K. Single-stranded DNA repeat synthesis by telomerase. Curr Opin Chem Biol. 2011; 15: 643-8,

Lai CK, Mitchell JR, Collins K. RNA binding domain of telomerase reverse transcriptase. Mol Cell Biol. 2001; 21: 990-1000, CrossRef.

Belfort M, Curcio MJ, Lue NF. Telomerase and retrotransposons: Reverse transcriptases that shaped genomes. Proc Natl Acad Sci. 2011; 108: 20304-10, CrossRef.

Xie M, Podlevsky JD, Qi X, Bley CJ, Chen JJ. A novel motif in telomerase reverse transcriptase regulates telomere repeat addition rate and processivity. Nucleic Acids Res. 2010; 38: 1982-96, CrossRef.

Qi X, Xie M, Brown AF, Bley CJ, Podlevsky JD, Chen JJ. RNA/ DNA hybrid binding affinity determines telomerase template- translocation efficiency. EMBO J. 2012; 31: 150-61, CrossRef.

Autexier C, Lue NF. The structure and function of telomerase reverse transcriptase. Annu Rev Biochem. 2006; 75: 493-517, CrossRef.

Wyatt HD, West SC, Beattie TL. InTERTpreting telomerase structure and function. Nucleic Acids Res. 2010; 38: 5609-22, CrossRef.

Kirwan M, Dokal I. Dyskeratosis congenita, stem cells and telomeres. Biochim Biophys Acta. 2009; 1792: 371-9, CrossRef.

Kim NW, Piatyszek MA, Prowse KR, Harley CB, West MD, Ho PL, et al. Specific association of human telomerase activity with immortal cells and cancer. Science. 1994; 266: 2011-5, CrossRef.

Horn S, Figl A, Rachakonda PS, Fischer C, Sucker A, Gast A, et al. TERT promoter mutations in familial and sporadic melanoma. Science. 2013; 339: 959-61, CrossRef.

Huang FW, Hodis E, Xu MJ, Kryukov GV, Chin L, Garraway LA. Highly recurrent TERT promoter mutations in human melanoma. Science. 2013; 339: 957-9, CrossRef.

Heidenreich B, Rachakonda PS, Hemminki K, Kumar R. TERT promoter mutations in cancer development. Curr Opin Genet Dev. 2014; 24: 30-7, CrossRef.

Borah S, Xi L, Zaug AJ, Powell NM, Dancik GM, Cohen SB, et al. Cancer. TERT pro moter mutations and telomerase reactivation in urothelial cancer. Science. 2015; 347: 1006-10, CrossRef.

Armanios M, Blackburn EH. The telomere syndromes. Nat Rev Genet. 2012; 13: 693-704, CrossRef.

Campisi J, di Fagagna F. Cellular senescence: when bad things happen to good cells. Nat Rev Mol Cell Biol. 2007; 8: 729-40, CrossRef.

Collado M, Biasco MA, Serrano M. Cellular senescence in cancer and aging. Cell. 2007; 130: 223-33, CrossRef.

Hayflick L, Moorehead PS. The serial cultivation of human diploid cell strains. Exp. Cell Res. 1961; 25: 585-621, CrossRef.

Hayflick L. The illusion of cell immortality. Br J Cancer. 2000; 83: 841-6, CrossRef.

Boukamp P. Biological clocks in the ageing cell. In: Von Zglinicki T, editor. Aging at the Molecular Level. Dordrecht; Kluwer Academic: 2003, NLMID.

Blackburn EH. Telomere states and cell fates. Nature. 2000; 408: 53-6, CrossRef.

Von Zglinicki T, Saretzki G, Ladhoff J, di Fagagna Fd, Jackson SP. Human cell senescence as a DNA damage response. Mech Ageing Dev. 2005; 126: 111-7, CrossRef.

Burton DGA. Cellular senescence, ageing and disease. Age. 2009; 31: 1-9, CrossRef.

Joosten SA, van Ham V, Nolan CE, Borrias MC, Jardine AG, Shiels PG, et al. Telomere shortening and cellular senescence in a model of chronic renal allograft rejection. Am J Pathol. 2003; 162: 1305-12, CrossRef.

von Zglinicki T, Pilger R, Sitte N. Accumulation of single-strand breaks is the major cause of telomere shortening in human fibroblasts. Free Radic Biol Med. 2000; 28: 64-74, CrossRef.

Di Micco R, Fumagalli M, Cicalese A, Piccinin S, Gasparini P, Luise C, et al. Oncogene-induced senescence is a DNA damage response triggered by DNA hyper-replication. Nature. 2006; 444: 638-42, CrossRef.

von Zglinicki T, Martin-Ruiz CM. Telomeres as biomarkers for ageing and age-related diseases. Curr Mol Med. 2005; 5: 197-203, CrossRef.

Burton DG, Allen MC, Bird JL, Faragher RG. Bridging the gap: ageing, pharmacokinetics and pharmacodynamics. J Pharm Pharmacol. 2005; 57: 671-9, CrossRef.

Burton DG, Sheerin A, Ostler EL, Smith K, Giles PJ, Lowe J, et al. Cyclin D1 over-expression permits the reproducible detection of senescent human vascular smooth muscle cells. Ann NY Acad Sci. 2007; 1119: 20-31, CrossRef.

Campisi J. Aging and cancer: the double-edged sword of replicative senescence. J Am Geriatr Soc. 1997; 45: 482-8, CrossRef.

Campisi J. The biology of replicative senescence. Eur J Cancer. 1997; 33: 703-9, CrossRef.

Gil J, Peters G. Regulation of the INK4b-ARF-INK4a tumour suppressor locus: all for one or one for all. Nat Rev Mol Cell Biol. 2006; 7: 667-77, CrossRef.

Kim WY, Sharpless NE. The regulation of INK4/ARF in cancer and aging. Cell. 2006; 127: 265-75, CrossRef.

Serrano M, Lin AW, McCurrach ME, Beach D, Lowe SW. Oncogenic ras provokes premature cell senescence associated with accumulation of p53 and p16INK4a. Cell. 1997; 88: 593-602, CrossRef.

Hahn WC, Weinberg RA. Rules for making human tumor cells. N Engl J Med. 2008; 347: 1593-603, CrossRef.

Blagosklonny MV. Cell cycle arrest is not senescence. Aging. 2011; 3: 94-101, CrossRef.

Acosta JC, O'Loghlen A, Banito A, Guijarro MV, Augert A, Raguz S, et al. Chemokine signaling via the CXCR2 receptor reinforces senescence. Cell. 2008; 133: 1006-18, CrossRef.

Bavik C, Coleman I, Dean JP, Knudsen B, Plymate S, Nelson PS. The gene expression program of prostate fibroblast senescence modulates neoplastic epithelial cell proliferation through paracrine mechanisms. Cancer Res. 2006; 66: 794-802, CrossRef.

Coppe JP, Patil CK, Rodier F, Sun Y, Munoz D, Goldstein J, et al. Senescence-associated secretory phenotypes reveal cell non-automous functions of oncogenic RAS and the p53 tumor suppressor. PLoS Biol. 2008; 6: 2853-68, CrossRef.

Kortlever RM, Higgins PJ, Bernards R. Plasminogen activator inhibitor-1 is a critical downstream target of p53 in the induction of replicative senescence. Nature Cell Biol. 2006; 8: 877-84, CrossRef.

Kuilman T, Michaloglou C, Vredeveld LCW, Douma S, van Doorn R, Desmet CJ, et al. Oncogene-induced senescence relayed by an interleukin-dependent inflammatory network. Cell. 2008; 133: 1019-31, CrossRef.

Wajapeyee N, Serra RW, Zhu X, Mahalingam M, Green MR. Oncogenic BRAF induces senescence and apoptosis through pathways mediated by the secreted protein IGFBP7. Cell. 2008; 132: 363-74, CrossRef.

Campisi J, Andersen J, Kapahi P, Melov S. Cellular senescence: a link between cancer and age-related degenerative disease? Semin Cancer Biol. 2011; 21: 354-9, CrossRef.

Dimri GP, Lee X, Basile G, Acosta M, Scott G, Roskelley C, et al. 1995. A biomarker that identifies senescent human cells in culture and in aging skin in vivo. Proc Natl Acad Sci 92: 9363-7, CrossRef.

Debacq-Chainiaux F, Erusalimsky JD, Campisi J, Toussaint O. Protocols to detect senescence-associated -galactosidase (SA-gal) activity, a biomarker of senescent cells in culture and in vivo. Nat Protoc. 2009; 4: 1798-806, CrossRef.

Lee BY, Han JA, Im JS, Morrone A, Johung K, Goodwin EC, et al. Senescence-associated b-galactosidase is lysosomal b-galactosidase. Aging Cell. 2006; 5: 187-95, CrossRef.

Kurz DJ, Decary S, Hong Y, Erusalimsky JD. Senescence-associated b-galactosidase reflects an increase in lysosomal mass during replicative ageing of human endothelial cells. J Cell Sci. 2000; 113: 3613-622, PMID.

Yang NC, Hu ML. The limitations and validities of senescence associated-b-galactosidase activity as an aging marker for human foreskin fibroblast Hs68 cells. Exp Gerontol. 2005; 40: 813-9, CrossRef.

Kuilman T, Michaloglou C, Mooi WJ, Peeper DS. The essence of senescence. Genes Dev 2016; 24: 2463-79, CrossRef.

Kirkwood TB, Holliday R. The evolution of ageing and longevity. Proc R Soc Lond B Biol Sci. 1979; 205: 531-46, CrossRef.

Kanapuru B, Ershler WB. Inflammation, coagulation, and the pathway to frailty. Am J Med. 2009; 122: 605-13, CrossRef.

Finkel T, Serrano M, Blasco MA. The common biology of cancer and ageing. Nature. 2007; 448: 767-74, CrossRef.

Kirkwood T.B. Understanding the odd science of aging. Cell. 2005; 120: 437-47, CrossRef.

Sahin E, DePinho R. Linking functional decline of telomeres, mitochondria and stem cells during ageing. Nature. 2010; 464: 520-8, CrossRef.

Aubert G, Lansdorp PM. Telomeres and aging. Physiol Rev. 2008; 88: 557-79, CrossRef.

Sharpless NE, DePinho RA. How stem cells age and why this makes us grow old. Nature Rev Mol Cell Biol. 2007; 8: 703-13, CrossRef.

Rossi D J, Jamieson CH, Weissman IL. Stems cells and the pathways to aging and cancer. Cell. 2008; 132: 681-96, CrossRef.

Maier B, Gluba W, Bernier B, Turner T, Mohammad K, Guise T, et al. Modulation of mammalian life span by the short isoform of p53. Genes Dev. 2004l; 18: 306-19, CrossRef.

Tyner SD, Venkatachalam S, Choi J, Jones S, Ghebranious N, Igelmann H, et al. p53 mutant mice that display early ageing-associated phenotypes. Nature. 2002; 415: 45-53, CrossRef.

Finkel T, Deng CX, Mostoslavsky R. Recent progress in the biology and physiology of sirtuins. Nature. 2009; 460: 587-91, CrossRef.

Bodnar AG, Ouellette M, Frolkis M, Holt SE, Chiu CP, Morin GB, et al. Extension of life-span by introduction of telomerase into normal human cells. Science. 1998; 279: 349-52, PMID.

Shay JW, Wright WE, Werbin H. Defining the molecular mechanism of human cell immortalization. Biochim Biophys Acta. 1991; 1072: 1-7, CrossRef.

Verfaillie CM, Pera MF, Lansdorp PM. Stem cells: hype and reality. Hematology. 2002; (n.v): 369-91, PMID.

De Lange T. Telomere dynamics and genome instability in human cancer. In: Blackburn EH, Greider CW, editors. Telomeres. Plainview: Cold Spring Harbor Laboratory; 1995. p.265-93, NLMID.

Sharpless NE, DePinho RA. Telomeres, stem cells, senescence, cancer. J Clin Invest. 2004; 113: 160-8, CrossRef.

Artandi SE, Chang S, Lee SL, Alson S, Gottlieb GJ, Chin L, et al. Telomere dysfunction promotes non-reciprocal translocations and epithelial cancers in mice. Nature. 2000; 406: 641-5, CrossRef.

Vousden KH, Lane DP. p53 in health and disease. Nat Rev Mol Cell Biol. 2007; 8: 275-83, CrossRef.

Maciejowski J, de Lange T. Telomeres in cancer: tumour suppression and genome instability. Nat Rev Mol Cell Biol. 2017; 18: 175-86, CrossRef.

Langford LA, Piatyszek MA, Xu RS, Schold SC, Wright WE, Shay JW. Telomerase activity in ordinary meningiomas predicts poor outcome. Human Pathol. 1997; 28: 416-20, CrossRef.

Roger L, Jones RE, Heppel NH, Williams GT, Sampson JR, Baird DM, et al. Extensive telomere erosion in the initiation of colorectal adenomas and its association with chromosomal instability. J Natl Cancer Inst. 2013; 105: 1202-11, CrossRef.

Riboni R, Casati A, Nardo T, Zaccaro E, Ferretti L, Nuzzo F, et al. Telomeric fusions in cultured human fibroblasts as a source of genomic instability. Cancer Genet Cytogenet. 1997; 95: 130-6, CrossRef.

Maciejowski J, Li Y, Bosco N, Campbell PJ, de Lange T. Chromothripsis and kataegis induced by telomere crisis. Cell. 2015; 163: 1641-54, CrossRef.

Davoli T, Denchi EL, de Lange T. Persistent telomere damage induces bypass of mitosis and tetraploidy. Cell. 2010; 141: 81-93, CrossRef.

Davoli T, de Lange T. Telomere-driven tetraploidization occurs in human cells undergoing crisis and promotes transformation of mouse cells. Cancer Cell. 2012; 21: 765-76, CrossRef.

Llorente B, Smith CE, Symington LS. Break-induced replication: what is it and what is it for? Cell Cycle. 2008; 7: 859-64, CrossRef.

Anand RP, Lovett ST, Haber JE. Break-induced DNA replication. Cold Spring Harb Perspect Biol. 2013; 5: a010397, CrossRef.

Shih IM, Zhou W, Goodman SN, Lengauer C, Kinzler KW, Vogelstein B. Evidence that genetic instability occurs at an early stage of colorectal tumorigenesis. Cancer Res. 2001; 61: 818-22, article.

Liddiard K, Ruis B, Takasugi T, Harvey A, Ashelford KE, Hendrickson EA, et al. Sister chromatid telomere fusions, but not NHEJ-mediated inter-chromosomal telomere fusions, occur independently of DNA ligases 3 and 4. Genome Res. 2016; 26: 588-600, CrossRef.

Shay JW, Bacchetti S. A survey of telomerase in human cancer. Eur J Cancer. 1997; 33: 787-91, CrossRef.

Shay JW. Role of Telomeres and Telomerase in Aging and Cancer. Cancer Discov. 2016; 6: 584-93, CrossRef.

Harley CB. Telomerase and cancer therapeutics. Nat Rev Cancer. 2008; 8: 167-79, CrossRef.

Hiyama E, Hiyama K. Telomerase as tumor marker. Cancer Lett. 2003; 194: 221-33, CrossRef.

Phatak P, Burger AM. Telomerase and its potential for therapeutic intervention. Br J Pharmacol. 2007; 152: 1003-11, CrossRef.

Armanios M, Greider CW. Telomerase and cancer stem cells. Cold Spring Harb Symp Quant Biol. 2005; 70: 205-8, CrossRef.

Ho MM, Ng AV, Lam S, Hung JY. Side population in human lung cancer cell lines and tumors is enriched with stem-like cancer cells. Cancer Res. 2007; 67: 4827-33, CrossRef.

Phatak P, Cookson JC, Dai F, Smith V, Gartenhaus RB, Stevens MF, et al. Telomere uncapping by the G-quadruplex ligand RHPS4 inhibits clonogenic tumour cell growth in vitro and in vivo consistent with a cancer stem cell targeting mechanism. Br J Cancer. 2007; 96: 1223-33, CrossRef.

Tchkonia T, Zhu Y, van Deursen J, Campisi J, Kirkland JL. Cellular senescence and the senescent secretory phenotype: therapeutic opportunities. J Clin Invest. 2013; 123: 966-72, CrossRef.

Suram A, Kaplunov J, Patel PL, Ruan H, Cerutti A, Boccardi V, et al. Oncogene-induced telomere dysfunction enforces cellular senescence in human cancer precursor lesions. EMBO J. 2012; 31: 2839-51, CrossRef.

Chen JH, Stoeber K, Kingsbury S, Ozanne SE, Williams GH, Hales CN. Loss of proliferative capacity and induction of senescence in oxidatively stressed human fibroblasts. J Biol Chem. 2004; 279: 49439-46, CrossRef.

Courtois-Cox S, Jones SL, Cichowski K. Many roads lead to oncogene-induced senescence. Oncogene. 2008; 27: 2801-9, CrossRef.

Braig M, Lee S, Loddenkemper C, Rudolph C, Peters AHFM, Schlegelberger B, et al. Oncogene-induced senescence as an initial barrier in lymphoma development. Nature. 2005; 436: 660-5, CrossRef.

Haigis KM, Sweet-Cordero A. New insights into oncogenic stress. Nat Genet. 2011; 43: 177-8, CrossRef.

Braig M, Schmitt CA. Oncogene-induced senescence: putting the brakes on tumor development. Cancer Res. 2006; 66: 2881-4, CrossRef.

Prieur A, Peeper DS. Cellular senescence in vivo: a barrier to tumorigenesis. Curr Opin Cell Biol. 2008; 20: 150-5, CrossRef.

Campisi J. Cellular senescence as a tumor-suppressor mechanism. Trends Cell Biol. 2001; 11: S27-31, CrossRef.

Guerra C, Collado M, Navas C, Schuhmacher AJ, Hernández-Porras I, Cañamero M, et al. Pancreatitis-induced inlammation contributes to pancreatic cancer by inhibiting oncogene-induced senescence. Cancer Cell. 2011; 19: 728-39, CrossRef.

Burton DG. Cellular senescence, ageing and disease. Age. 2009; 31: 1-9, CrossRef.

Campisi J. Senescent cells, tumor suppression, and organismal aging: good citizens, bad neighbors. Cell. 2005; 120: 513-22, CrossRef.

Jeyapalan JC, Sedivy JM. Cellular senescence and organismal aging. Mech Ageing Dev. 2008; 129: 467-74, CrossRef.

Baker DJ, Perez-Terzic C, Jin F, Pitel KS, Niederländer NJ, Jeganathan K, et al. Opposing roles for p16Ink4a and p19Arf in senescence and ageing caused by BubR1 insufficiency. Nat Cell Biol. 2008; 10: 825-36, CrossRef.

Krishnamurthy J, Torrice C, Ramsey MR, Kovalev GI, Al-Regaiey K, Su L, et al. Ink4a/Arf expression is a biomarker of aging. J Clin Invest. 2004; 114: 1299-307, CrossRef.

Jeyapalan JC, Ferreira M, Sedivy JM, Herbig U. Accumulation of senescent cells in mitotic tissue of aging primates. Mech Ageing Dev. 2007; 128: 36-44, CrossRef.

Waaijer ME, Parish WE, Strongitharm BH, van Heemst D, Slagboom PE, de Craen AJ, et al. The number of p16INK4a positive cells in human skin reflects biological age. Aging Cell. 2012; 11: 722-5, CrossRef.

Baker DJ, Wijshake T, Tchkonia T, LeBrasseur NK, Childs BG, van de Sluis B, et al. Clearance of p16Ink4a-positive senescent cells delays ageing-associated disorders. Nature. 2011; 479: 232-6, CrossRef.

Kannel WB, McGee DL. Diabetes and cardiovascular disease. The Framingham study. JAMA. 1979; 241: 2035-8, CrossRef.

Booth GL, Kapral MK, Fung K, Tu JV. Relation between age and cardio- vascular disease in men and women with diabetes compared with non-diabetic people: a population-based retrospective cohort study. Lancet. 2006; 368: 29-36, CrossRef.

D’Mello MJJ, Ross SA, Briel M, Anand SS, Gerstein H, Pare G. Association between shortened leukocyte telomere length and cardiometabolic outcomes: Systematic Review and Meta-Analysis. Circ Cardiovasc Genet. 2015; 8: 82-90, CrossRef.

Müezzinler A, Zaineddin AK, Brenner H. A systematic review of leukocyte telomere length and age in adults. Ageing Res Rev. 2013; 12: 509-19, CrossRef.

Cherkas LF, Hunkin JL, Kato BS, Richards JB, Gardner JP, Surdulescu GL, et al. The association between physical activity in leisure time and leukocyte telomere length. Arch Intern Med. 2008; 168: 154-8, CrossRef.

Song Z, von Figura G, Liu Y, Kraus JM, Torrice C, Dillon P, et al. Lifestyle impacts on the aging-associated expression of biomarkers of DNA damage and telomere dysfunction in human blood. Aging cell. 2010; 9: 607-15, CrossRef.

Njajou OT, Cawthon RM, Blackburn EH, Harris TB, Li R, Sanders JL, et al. Shorter telomeres are associated with obesity and weight gain in the elderly. Int J Obes (Lond). 2012; 36: 1176-9, CrossRef.

Tzanetakou IP, Katsilambros NL, Benetos A, Mikhailidis DP, Perrea DN, et al. “Is obesity linked to aging?”: adipose tissue and the role of telomeres. Ageing Res Rev. 2012; 11: 220-9,

Kong CM, Lee XW, Wang X. Telomere shortening in human diseases. FEBS J. 2013; 280: 3180-93, CrossRef.

Eitan E, Hutchison ER, Mattson MP. Telomere shortening in neurological disorders: an abundance of unanswered questions. Trends Neurosci. 2014; 37: 256-63, CrossRef.

von Zglinicki T. Oxidative stress shortens telomeres. Trends Biochem Sci. 2002; 27: 339-44, CrossRef.

Uziel Y, Chapnick G, Rothschild M, Tauber T, Press J, Harel L, et al. Nitrous oxide sedation for intra-articular injection in juvenile idiopathic arthritis. Pediatr Rheumatol Online J. 2008; 6: 1, CrossRef.

Pedersen-Lane JH, Zurier RB, Lawrence DA. Analysis of the thiol status of peripheral blood leukocytes in rheumatoid arthritis patients. J Leukoc Biol. 2007; 81: 934–41, CrossRef.

Sampson MJ, Winterbone MS, Hughes JC, Dozio N, Hughes DA. Monocyte telomere shortening and oxidative DNA damage in type 2 diabetes. Diabetes Care. 2006; 29: 283-9, CrossRef.

Fumagalli M, Rossiello F, Clerici M, Barozzi S, Cittaro D, Kaplunov JM, et al. Telomeric DNA damage is irreparable and causes persistent DNA-damage-response activation. Nat Cell Biol. 2012; 14: 355-65, CrossRef.

Morocz M, Kálmán J, Juhász A, Sinkó I, McGlynn AP, Downes CS, et al. Elevated levels of oxidative DNA damage in lymphocytes from patients with Alzheimer's disease. Neurobiol Aging. 2002; 23: 47-53, PMID.

Jaworska A, Dzbek J, Styczynska M, Kuznicki J. Analysis of calcium homeostasis in fresh lymphocytes from patients with sporadic Alzheimer’s disease or mild cognitive impairment. Biochim Biophys Acta. 2013; 1833: 1692-9, CrossRef.

Liu JP, Chen SM, Cong YS, Nicholls C, Zhou SF, Tao ZZ, et al. Regulation of telomerase activity by apparently opposing elements. Ageing Res Rev. 2010; 9: 245-56, CrossRef.

Bauer ME, Jeckel CM, Luz C. The role of stress factors during aging of the immune system. Ann N Y Acad Sci. 2009; 1153: 139-52, CrossRef.

Epel ES. Psychological and metabolic stress: a recipe for accelerated cellular aging? Hormones (Athens). 2009; 8: 7-22, CrossRef.

Price LH, Kao HT, Burgers DE, Carpenter LL, Tyrka AR. Telomeres and early-life stress: an overview. Biol Psychiatry. 2013; 73: 15-23, CrossRef.

Weng NP. Telomeres and immune competency. Curr Opin Immunol. 2012; 24: 47-5, CrossRef.

Rolyan H, Scheffold A, Heinrich A, Begus-Nahrmann Y, Langkopf BH, Hölter SM, et al. Telomere shortening reduces Alzheimer’s disease amyloid pathology in mice. Brain. 2011; 134: 2044-56, CrossRef.

Schwartz M, Shechter R. Systemic inflammatory cells fight off neurodegenerative disease. Nat Rev Neurol. 2010; 6: 405-10, CrossRef.

Jurk D, Wang C, Miwa S, Maddick M, Korolchuk V, Tsolou A, et al. Postmitotic neurons develop a p21-dependent senescence-like phenotype driven by a DNA damage response. Aging Cell. 2012; 11: 996-1004, CrossRef.

Hemann MT, Strong MA, Hao LY, Greider CW. The shortest telomere, not average telomere length, is critical for cell viability and chromosome stability. Cell. 2001; 107: 67-77, CrossRef.

Vera E, Bernardes de Jesus B, Foronda M, Flores JM, Blasco MA. The rate of increase of short telomeres predicts longevity in mammals. Cell Rep. 2012; 2: 732-7, CrossRef.

Shalev I, Moffitt TE, Sugden K, Williams B, Houts RM, Danese A, et al. Exposure to violence during childhood is associated with telomere erosion from 5 to 10 years of age: a longitudinal study. Mol Psychiatry. 2013; 18: 576-81, CrossRef.

Kiecolt-Glaser JK, Gouin JPP, Weng NPP, Malarkey WB, Beversdorf DQ, Glaser R. Childhood adversity heightens the impact of later-life caregiving stress on telomere length and inflammation. Psychosom Med 2011; 73: 16-22, CrossRef.

Drury SS, Theall K, Gleason MM, Smyke AT, De Vivo I, Wong JY, et al. Telomere length and early severe social deprivation: linking early adversity and cellular aging. Mol Psychiatry. 2012; 17: 719-27, CrossRef.

Entringer S, Epel ES, Kumsta R, Lin J, Hellhammer DH, Blackburn EH, et al. Stress exposure in intrauterine life is associated with shorter telomere length in young adulthood. Proc Natl Acad Sci USA. 2011; 108: E513-8, CrossRef.

Glass D, Parts L, Knowles D, Aviv A, Spector TD. No correlation between childhood maltreatment and telomere length. Biol Psychiatry. 2010; 68: e21-2, CrossRef.

Damjanovic AK1, Yang Y, Glaser R, Kiecolt-Glaser JK, Nguyen H, Laskowski B, et al. Accelerated telomere erosion is associated with a declining immune function of caregivers of Alzheimer's disease patients. J Immunol. 2007; 179: 4249-54, CrossRef.

Epel ES, Blackburn EH, Lin J, Dhabhar FS, Adler NE, Morrow JD, et al. Accelerated telomere shortening in response to life stress. Proc Natl Acad Sci USA. 2004; 101: 17312-5, CrossRef.

O’Donovan A, Tomiyama AJ, Lin J, Puterman E, Adler NE, Kemeny M, et al. Stress appraisals and cellular aging: a key role for anticipatory threat in the relationship between psychological stress and telomere length. Brain Behav Immun. 2012; 26: 573-9, CrossRef.

Puterman E, Lin J, Blackburn E, O'Donovan A, Adler N, Epel E. The power of exercise: buffering the effect of chronic stress on telomere length. PLoS One. 2010; 5: e10837, CrossRef.

Humphreys J, Epel ES, Cooper BA, Lin J, Blackburn EH, Lee KA. Telomere shortening in formerly abused and never abused women. Biol Res Nurs. 2012; 14: 115-23, CrossRef.

Hoen PW, de Jonge P, Na BY, Farzaneh-Far R, Epel E, Lin J, et al. Depression and leukocyte telomere length in patients with coronary heart disease: data from the Heart and Soul Study. Psychosom Med. 2011; 73: 541-7, CrossRef.

Verhoeven JE, Révész D, Epel ES, Lin J, Wolkowitz OM, Penninx BW. Major depressive disorder and accelerated cellular aging: results from a large psychiatric cohort study. Mol Psychiatry. 2014; 19: 895-901, CrossRef.

Wolkowitz OM, Mellon SH, Epel ES, Lin J, Dhabhar FS, Su Y, et al. Leukocyte telomere length in major depression: correlations with chronicity, inflammation and oxidative stress--preliminary findings. PLoS One. 2011; 6: e17837, CrossRef.

Puterman E, Lin J, Krauss J, Blackburn EH, Epel ES. Determinants of telomere attrition over 1 year in healthy older women: stress and health behaviors matter. Mol Psychiatry. 2015; 20: 529-35, CrossRef.

Holohan B, Wright WE, Shay JW. Cell biology of disease: Telomeropathies: an emerging spectrum disorder. J Cell Biol. 2014; 205: 289-99, CrossRef.

Kirwan M, Dokal I. Dyskeratosis congenita: a genetic disorder of many faces. Clin Genet. 2008; 73: 103-12, CrossRef.

Heiss NS, Knight SW, Vulliamy TJ, Klauck SM, Wiemann S, Mason PJ, et al. X-linked dyskeratosis congenita is caused by mutations in a highly conserved gene with putative nucleolar functions. Nat Genet, CrossRef.

Tsangaris E, Adams SL, Yoon G, Chitayat D, Lansdorp P, Dokal I. Ataxia and pancytopenia caused by a mutation in TINF2. Hum Genet. 2008; 124: 507-13, CrossRef.

Mitchell JR, Wood E, Collins K. A telomerase component is defective in the human disease dyskeratosis congenita. Nature. 1999; 402: 551-5, CrossRef.

Dokal I. Dyskeratosis congenita. Hematology Am Soc Hematol Educ Program. 2011; 2011: 480-6, CrossRef.

Young NS. Bone marrow failure and the new telomere diseases: practice and research. Hematology. 2012; 17 (Suppl 1): S18-21, CrossRef.

Armanios MY, Chen JJ, Cogan JD, Alder JK, Ingersoll RG, Markin C, et al. Telomerase mutations in families with idiopathic pulmonary fibrosis. N Engl J Med. 2007. 356: 1317-26, CrossRef.

Tsakiri KD, Cronkhite JT, Kuan PJ, Xing C, Raghu G, Weissler JC, et al. Adult-onset pulmonary fibrosis caused by mutations in telomerase. Proc Natl Acad Sci USA. 2007; 104: 7552-7, CrossRef.

Cronkhite JT, Xing C, Raghu G, Chin KM, Torres F, Rosenblatt RL, et al. Telomere shortening in familial and sporadic pulmonary fibrosis. Am J Respir Crit Care Med. 2008; 178: 729-37, CrossRef.

Calado RT, Regal JA, Kleiner DE, Schrump DS, Peterson NR, Pons V, et al. A spectrum of severe familial liver disorders associate with telomerase mutations. PLoS ONE. 2009; 4: e7926, CrossRef.

Fogarty PF, Yamaguchi H, Wiestner A, Baerlocher GM, Sloand E, Zeng WS, et al. Late presentation of dyskeratosis congenita as apparently acquired aplastic anaemia due to mutations in telomerase RNA. Lancet. 2003; 362: 1628-30, CrossRef.

Calado RT, Regal JA, Hills M, Yewdell WT, Dalmazzo LF, Zago MA, et al. Constitutional hypomorphic telomerase mutations in patients with acute myeloid leukemia. Proc Natl Acad Sci USA. 2009; 106: 1187-92, CrossRef.

Ludwig FC, Smoke ME. The measurement of biological age. Exp Aging Res. 1980; 6: 497-522, CrossRef.

Schneider EL, Reff ME. Biological Markers of Aging. Bethesda: U.S. Dept. of Health and Human Services, National Institutes of Health, Public Health Service; 1982, NLMID.

Sprott RL, Schneider EL. Biomarkers of aging. In: Hart S, Editor. Proceedings of the International Conference on Nutrition and Aging. New York: A.R. Liss; 1985. p.43-52.

Sprott RL. Biomarkers of aging and disease: Introduction and definitions. Exp Gerontol. 2010; 45: 2-4, CrossRef.

Butler RN, Sprott R, Warner H, Bland J, Feuers R, Forster M, et al. Biomarkers of aging: from primitive organisms to humans. J Gerontol A Biol Sci Med Sci. 2004; 59: B560-7, CrossRef.

Blasco MA. Telomeres and human disease: Ageing, cancer and beyond. Nat Rev Genet. 2005; 6: 611-22, CrossRef.

Jaskelioff M, Muller FL, Paik JH, Thomas E, Jiang S, Adams AC, et al. Telomerase reactivation reverses tissue degeneration in aged telomerase-deficient mice. Nature. 2011; 469: 102-6, CrossRef.

Rudolph KL, Chang S, Millard M, Schreiber-Agus N, DePinho RA. Inhibition of experimental liver cirrhosis in mice by telomerase gene delivery. Science. 2000; 287: 1253-8, CrossRef.

Honig LS, Schupf N, Lee JH, Tang MX, Mayeux R. Shorter telomeres are associated with mortality in those with APOE epsilon4 and dementia. Ann Neurol. 2006; 60: 181-7, CrossRef.

Fauce SR, Jamieson BD, Chin AC, Mitsuyasu RT, Parish ST, Ng HL, et al. Telomerase-based pharmacologic enhancement of antiviral function of human CD8+ T lymphocytes. J Immunol. 2008; 181: 7400-6, CrossRef.

Harley CB, Liu W, Blasco M, Vera E, Andrews WH, Briggs LA, Raffaele JM. A natural product telomerase activator as part of a health maintenance program. Rejuvenation Res. 2011; 14: 45-56, CrossRef.

Dagarag M, Evazyan T, Rao N, Effros RB. Genetic manipulation of telomerase in HIV-specific CD8+ T cells: Enhanced antiviral functions accompany the increased proliferative potential and telomere length stabilization. J Immunol. 2004; 173: 6303-11, CrossRef.

Itahana K, Campisi J, Dimri GP. Methods to detect biomarkers of cellular senescence: the senescence-associated beta-galactosidase assay. Methods Mol Biol. 2007; 371: 21-31, CrossRef.

Collado M, Gil J, Efeyan A, Guerra C, Schuhmacher AJ, Barradas M, et al. Tumour biology: Senescence in premalignant tumours. Nature. 2005; 436: 642, CrossRef.

Cao L, Li W, Kim S, Brodie SG, Deng CX. Senescence, aging, and malignant transformation mediated by p53 in mice lacking the Brca1 full-length isoform. Genes Dev. 2003; 17: 201-13, CrossRef.

Sun LQ, Lee DW, Zhang Q, Xiao W, Raabe EH, Meeker A, et al. Growth retardation and premature aging phenotypes in mice with disruption of the SNF2-like gene, PASG. Genes Dev. 2004; 18: 1035-46, CrossRef.

Castro P, Giri D, Lamb D, Ittmann M. Cellular senescence in the pathogenesis of benign prostatic hyperplasia. Prostate. 2003; 55: 30-8, CrossRef.

Mishima K, Handa JT, Aotaki-Keen A, Lutty GA, Morse LS, Hjelmeland LM. Senescence-associated beta-galactosidase histochemistry for the primate eye. Invest Ophthalmol Vis Sci. 1999; 40: 1590-3, PMID.

Melk A, Schmidt BM, Takeuchi O, Sawitzki B, Rayner DC, Halloran PF. Expression of p16INK4a and other cell cycle regulator and senescence associated genes in aging human kidney. Kidney Int. 2004; 65: 510-20, CrossRef.

Collado M, Serrano M. Senescence in tumours: Evidence from mice and humans. Nat Rev Cancer. 2010; 10: 51-7, CrossRef.

Narita M, Nũnez S, Heard E, Narita M, Lin AW, Hearn SA, et al. Rb-mediated heterochromatin formation and silencing of E2F target genes during cellular senescence. Cell. 2003; 113: 703-16, CrossRef.

Zhang R, Chen W, Adams PD. Molecular dissection of formation of senescence-associated heterochromatin foci. Mol Cell Biol. 2007; 27: 2343-58, CrossRef.

Funayama R, Ishikawa F. Cellular senescence and chromatin structure. Chromosoma. 2007; 116: 431-40, CrossRef.

Bernardes de Jesus B, Blasco MA. Assesing cell and organ senescence biomarkers. Circ Res. 2012; 111: 97-109, CrossRef.

Takai H, Smogorzewska A, de Lange T. DNA damage foci at dysfunctional telomeres. Curr Biol. 2003; 13: 1549-56, CrossRef.

Zhu H, Belcher M, van der Harst P. Healthy aging and disease: Role for telomere biology? Clin Sci (Lond). 2011; 120: 427-40, CrossRef.

Sarin KY, Cheung P, Gilison D, Lee E, Tennen RI, Wang E, et al. Conditional telomerase induction causes proliferation of hair follicle stem cells. Nature. 2005; 436: 1048-52, CrossRef.

Park JI, Venteicher AS, Hong JY, Choi J, Jun S, Shkreli M, et al. Telomerase modulates Wnt signalling by association with target gene chromatin. Nature. 2009; 460: 66-72, CrossRef.

Rao TP, Kühl M. An updated overview on Wnt signaling pathways: A prelude for more. Circ Res. 2010; 106: 1798-806, CrossRef.

Jager K, Walter M. Therapeutic targeting of telomerase. Genes (Basel). 2016; 7: E39, CrossRef.

Dock JN, Effros RB. Role of CD8 T cell replicative senescence in human aging and in HIV-mediated immunosenescence. Aging Dis. 2011; 2: 382-97, PMID.

Harley CB, Liu W, Blasco M, Vera E, Andrews WH, Briggs LA, et al. A natural product telomerase activator as part of a health maintenance program. Rejuvenation Res. 2011; 14: 45-56, CrossRef.

Bernardes de Jesus B, Schneeberger K, Vera E, Tejera A, Harley CB, Blasco MA. The telomerase activator TA-65 elongates short telomeres and increases health span of adult/old mice without increasing cancer incidence. Aging Cell. 2011; 10: 604-21, CrossRef.

Pearce VP, Sherrell J, Lou Z, Kopelovich L, Wright WE, Shay JW. Immortalization of epithelial progenitor cells mediated by resveratrol. Oncogene. 2008; 27: 2365-74, CrossRef.

Xia L, Wang XX, Hu XS, Guo XG, Shang YP, Chen HJ, et al. Resveratrol reduces endothelial progenitor cells senescence through augmentation of telomerase activity by Akt-dependent mechanisms. Br J Pharmacol. 2008; 155: 387-94, CrossRef.

Sprouse AA, Steding CE, Herbert BS. Pharmaceutical regulation of telomerase and its clinical potential. J Cell Mol Med. 2012; 16: 1-7, CrossRef.

Babizhayev MA, Yegorov YE. Telomere attrition in lens epithelial cells - a target for N-acetylcarnosine therapy. Front Biosci (Landmark Ed). 2010; 15: 934-56, CrossRef.

Eitan E, Tichon A, Gazit A, Gitler D, Slavin S, Priel E. Novel telomerase-increasing compound in mouse brain delays the onset of amyotrophic lateral sclerosis. EMBO Mol Med. 2012; 4: 313-29, CrossRef.

Haendeler J, Hoffmann J, Diehl JF, Vasa M, Spyridopoulos I, Zeiher AM, et al. Antioxidants inhibit nuclear export of telomerase reverse transcriptase and delay replicative senescence of endothelial cells. Circ Res. 2004; 94: 768-75, CrossRef.

Tanaka Y, Moritoh Y, Miwa N. Age-dependent telomere-shortening is repressed by phosphorylated alpha-tocopherol together with cellular longevity and intracellular oxidative-stress reduction in human brain microvascular endotheliocytes. J Cell Biochem. 2007; 102: 689-703, CrossRef.

Passos JF, Saretzki G, Ahmed S, Nelson G, Richter T, Peters H, et al. Mitochondrial dysfunction accounts for the stochastic heterogeneity in telomere-dependent senescence. PLoS Biol. 2007; 5: e110, CrossRef.

Brouilette SW, Moore JS, McMahon AD, Thompson JR, Ford I, Shepherd J, et al. Telomere length, risk of coronary heart disease, and statin treatment in the West of Scotland Primary Prevention Study: A nested case-control study. Lancet. 2007; 369: 107-14, CrossRef.

Spyridopoulos I, Haendeler J, Urbich C, Brummendorf TH, Oh H, Schneider MD, Zeiher AM, et al. Statins enhance migratory capacity by upregulation of the telomere repeat binding factor TRF2 in endothelial progenitor cells. Circulation. 2004; 110: 3136-42, CrossRef.

Dong XX, Hui YJ, Xiang WX, Rong ZF, Jian S, Zhu CJ. GinkgoBiloba extract reduces endothelial progenitor-cell senescence trough augmentation of telomerase activity. J Cardiovasc Pharmacol. 2007; 49: 111-5, PMID.

Bar C, Thum T. Changing Direction: From Therapeutic Telomerase Inhibition to Activation? Circ Res. 2017; 120: 1393-5, CrossRef.

Hahn WC, Counter CM, Lundberg AS, Beijersbergen RL, Brooks MW, Weinberg RA. Creation of human tumor cells with defined genetic elements. Nature. 1999; 400: 464-8, CrossRef.


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