Telomere and its role in the aging pathways: telomere shortening, cell senescence and mitochondria dysfunction

Abdallah P, Luciano P, Runge KW, Lisby M, Geli V, Gilson E, Teixeira MT (2009) A two-step model for senescence triggered by a single critically short telomere. Nat Cell Biol 11:988–993. https://doi.org/10.1038/ncb1911 Abreu E et al (2010) TIN2-tethered TPP1 recruits human telomerase to telomeres in vivo. Mol Cell Biol 30:2971–2982. https://doi.org/10.1128/MCB.00240-10 Acosta JC et al (2013) A complex secretory program orchestrated by the inflammasome controls paracrine senescence. Nat Cell Biol 15:978–990. https://doi.org/10.1038/ncb2784 Alder JK et al (2015) Telomere dysfunction causes alveolar stem cell failure. Proc Natl Acad Sci USA 112:5099–5104. https://doi.org/10.1073/pnas.1504780112 Allsopp RC et al (1992) Telomere length predicts replicative capacity of human fibroblasts. Proc Natl Acad Sci USA 89:10114–10118 Anso E et al (2017) The mitochondrial respiratory chain is essential for haematopoietic stem cell function. Nat Cell Biol. https://doi.org/10.1038/ncb3529 Armanios M, Alder JK, Parry EM, Karim B, Strong MA, Greider CW (2009) Short telomeres are sufficient to cause the degenerative defects associated with aging. Am J Hum Genet 85:823–832. https://doi.org/10.1016/j.ajhg.2009.10.028 Arnoult N, Karlseder J (2015) Complex interactions between the DNA-damage response and mammalian telomeres. Nat Struct Mol Biol 22:859–866. https://doi.org/10.1038/nsmb.3092 Azzalin CM, Lingner J (2015) Telomere functions grounding on TERRA firma. Trends Cell Biol 25:29–36. https://doi.org/10.1016/j.tcb.2014.08.007 Azzalin CM, Reichenbach P, Khoriauli L, Giulotto E, Lingner J (2007) Telomeric repeat containing RNA and RNA surveillance factors at mammalian chromosome ends. Science 318:798–801. https://doi.org/10.1126/science.1147182 Baker DJ et al (2011) Clearance of p16Ink4a-positive senescent cells delays ageing-associated disorders. Nature 479:232–236. https://doi.org/10.1038/nature10600 Baker DJ, Weaver RL, van Deursen JM (2013) p21 both attenuates and drives senescence and aging in BubR1 progeroid mice. Cell Rep 3:1164–1174. https://doi.org/10.1016/j.celrep.2013.03.028 Baker DJ et al (2016) Naturally occurring p16(Ink4a)-positive cells shorten healthy lifespan. Nature 530:184–189. https://doi.org/10.1038/nature16932 Balestro E et al (2016) Immune inflammation and disease progression in idiopathic pulmonary fibrosis. PLoS ONE 11:e0154516. https://doi.org/10.1371/journal.pone.0154516 Bandaria JN, Qin PW, Berk V, Chu S, Yildiz A (2016) Shelterin protects chromosome ends by compacting telomeric chromatin. Cell 164:735–746. https://doi.org/10.1016/j.cell.2016.01.036 Bar C, Blasco MA (2016) Telomeres and telomerase as therapeutic targets to prevent and treat age-related diseases. F1000Research. https://doi.org/10.12688/f1000research.7020.1 Bar C, Huber N, Beier F, Blasco MA (2015) Therapeutic effect of androgen therapy in a mouse model of aplastic anemia produced by short telomeres. Haematologica 100:1267–1274. https://doi.org/10.3324/haematol.2015.129239 Barzilai N, Crandall JP, Kritchevsky SB, Espeland MA (2016) Metformin as a tool to target aging. Cell Metab 23:1060–1065. https://doi.org/10.1016/j.cmet.2016.05.011 Beausejour CM, Krtolica A, Galimi F, Narita M, Lowe SW, Yaswen P, Campisi J (2003) Reversal of human cellular senescence: roles of the p53 and p16 pathways. EMBO J 22:4212–4222. https://doi.org/10.1093/Emboj/Cdg417 Bedrat A, Lacroix L, Mergny JL (2016) Re-evaluation of G-quadruplex propensity with G4Hunter. Nucleic Acids Res 44:1746–1759. https://doi.org/10.1093/nar/gkw006 Benarroch-Popivker D et al (2016) TRF2-mediated control of telomere DNA Topology as a mechanism for chromosome-end protection. Mol Cell 61:274–286. https://doi.org/10.1016/j.molcel.2015.12.009 Bernardes de Jesus B, Schneeberger K, Vera E, Tejera A, Harley CB, Blasco MA (2011) The telomerase activator TA-65 elongates short telomeres and increases health span of adult/old mice without increasing cancer incidence. Aging Cell 10:604–621. https://doi.org/10.1111/j.1474-9726.2011.00700.x Bernardes de Jesus B, Vera E, Schneeberger K, Tejera AM, Ayuso E, Bosch F, Blasco MA (2012) Telomerase gene therapy in adult and old mice delays aging and increases longevity without increasing cancer. EMBO Mol Med 4:691–704. https://doi.org/10.1002/emmm.201200245 Bernet JD, Doles JD, Hall JK, Kelly Tanaka K, Carter TA, Olwin BB (2014) p38 MAPK signaling underlies a cell-autonomous loss of stem cell self-renewal in skeletal muscle of aged mice. Nat Med 20:265–271. https://doi.org/10.1038/nm.3465 Birch J, Barnes PJ, Passos JF (2018) Mitochondria, telomeres and cell senescence: implications for lung ageing and disease. Pharmacol Ther 183:34–49. https://doi.org/10.1016/j.pharmthera.2017.10.005 Blackburn EH, Epel ES, Lin J (2015) Human telomere biology: a contributory and interactive factor in aging, disease risks, and protection. Science 350:1193–1198. https://doi.org/10.1126/science.aab3389 Borah S et al (2015) Cancer. TERT promoter mutations and telomerase reactivation in urothelial cancer. Science 347:1006–1010. https://doi.org/10.1126/science.1260200 Brack AS, Conboy MJ, Roy S, Lee M, Kuo CJ, Keller C, Rando TA (2007) Increased Wnt signaling during aging alters muscle stem cell fate and increases fibrosis. Science 317:807–810. https://doi.org/10.1126/science.1144090 Calado RT, Yewdell WT, Wilkerson KL, Regal JA, Kajigaya S, Stratakis CA, Young NS (2009) Sex hormones, acting on the TERT gene, increase telomerase activity in human primary hematopoietic cells. Blood 114:2236–2243. https://doi.org/10.1182/blood-2008-09-178871 Chambers VS, Marsico G, Boutell JM, Di Antonio M, Smith GP, Balasubramanian S (2015) High-throughput sequencing of DNA G-quadruplex structures in the human genome. Nat Biotechnol 33:877–881. https://doi.org/10.1038/nbt.3295 Chandel NS, Jasper H, Ho TT, Passegue E (2016) Metabolic regulation of stem cell function in tissue homeostasis and organismal ageing. Nat Cell Biol 18:823–832. https://doi.org/10.1038/ncb3385 Childs BG, Durik M, Baker DJ, van Deursen JM (2015) Cellular senescence in aging and age-related disease: from mechanisms to therapy. Nat Med 21:1424–1435. https://doi.org/10.1038/nm.4000 Chu HP et al (2017) TERRA RNA antagonizes ATRX and protects telomeres. Cell 170(86–101):e116. https://doi.org/10.1016/j.cell.2017.06.017 Cohen HY et al (2004) Calorie restriction promotes mammalian cell survival by inducing the SIRT1 deacetylase. Science 305:390–392. https://doi.org/10.1126/science.1099196 Colavitti R, Finkel T (2005) Reactive oxygen species as mediators of cellular senescence Iubmb. Life 57:277–281. https://doi.org/10.1080/15216540500091890 Conboy IM, Conboy MJ, Wagers AJ, Girma ER, Weissman IL, Rando TA (2005) Rejuvenation of aged progenitor cells by exposure to a young systemic environment. Nature 433:760–764. https://doi.org/10.1038/nature03260 Cooke HJ, Smith BA (1986) Variability at the telomeres of the human X/Y pseudoautosomal region. Cold Spring Harb Symp Quant Biol 51(Pt 1):213–219 Copelan EA (2006) Hematopoietic stem-cell transplantation. N Engl J Med 354:1813–1826. https://doi.org/10.1056/NEJMra052638 Coppe JP, Desprez PY, Krtolica A, Campisi J (2010) The senescence-associated secretory phenotype: the dark side of tumor suppression. Annu Rev Pathol 5:99–118. https://doi.org/10.1146/annurev-pathol-121808-102144 Correia-Melo C et al (2016) Mitochondria are required for pro-ageing features of the senescent phenotype. EMBO J 35:724–742. https://doi.org/10.15252/embj.201592862 Cosgrove BD et al (2014) Rejuvenation of the muscle stem cell population restores strength to injured aged muscles. Nat Med 20:255–264. https://doi.org/10.1038/nm.3464 Dabrowska A, Venero JL, Iwasawa R, Hankir MK, Rahman S, Boobis A, Hajji N (2015) PGC-1alpha controls mitochondrial biogenesis and dynamics in lead-induced neurotoxicity. Aging 7:629–647. https://doi.org/10.18632/aging.100790 d’Adda di Fagagna F (2008) Living on a break: cellular senescence as a DNA-damage response. Nat Rev Cancer 8:512–522. https://doi.org/10.1038/nrc2440 Davalos AR et al (2013) p53-dependent release of Alarmin HMGB1 is a central mediator of senescent phenotypes. J Cell Biol 201:613–629. https://doi.org/10.1083/jcb.201206006 de Lange T (2005) Shelterin: the protein complex that shapes and safeguards human telomeres. Genes Dev 19:2100–2110. https://doi.org/10.1101/gad.1346005 de Lange T (2009) How telomeres solve the end-protection problem. Science 326:948–952. https://doi.org/10.1126/science.1170633 de Magalhaes JP, Passos JF (2018) Stress, cell senescence and organismal ageing. Mech Ageing Dev 170:2–9. https://doi.org/10.1016/j.mad.2017.07.001 Deng Z, Norseen J, Wiedmer A, Riethman H, Lieberman PM (2009) TERRA RNA binding to TRF2 facilitates heterochromatin formation and ORC recruitment at telomeres. Mol Cell 35:403–413. https://doi.org/10.1016/j.molcel.2009.06.025 Derevyanko A, Whittemore K, Schneider RP, Jimenez V, Bosch F, Blasco MA (2017) Gene therapy with the TRF1 telomere gene rescues decreased TRF1 levels with aging and prolongs mouse health span. Aging Cell 16:1353–1368. https://doi.org/10.1111/acel.12677 Doksani Y, Wu JY, de Lange T, Zhuang X (2013) Super-resolution fluorescence imaging of telomeres reveals TRF2-dependent T-loop formation. Cell 155:345–356. https://doi.org/10.1016/j.cell.2013.09.048 Erdel F, Kratz K, Willcox S, Griffith JD, Greene EC, de Lange T (2017) Telomere recognition and assembly mechanism of mammalian shelterin. Cell Rep 18:41–53. https://doi.org/10.1016/j.celrep.2016.12.005 Fallet E, Jolivet P, Soudet J, Lisby M, Gilson E, Teixeira MT (2014) Length-dependent processing of telomeres in the absence of telomerase. Nucleic Acids Res 42:3648–3665. https://doi.org/10.1093/nar/gkt1328 Fang EF et al (2014) Defective mytophagy in XPA via PARP-1 hyperactivation and NAD(+)/SIRT1 reduction. Cell 157:882–896. https://doi.org/10.1016/j.cell.2014.03.026 Fang EF, Scheibye-Knudsen M, Chua KF, Mattson MP, Croteau DL, Bohr VA (2016) Nuclear DNA damage signalling to mitochondria in ageing. Nat Rev Mol Cell Biol 17:308–321. https://doi.org/10.1038/nrm.2016.14 Flores I, Cayuela ML, Blasco MA (2005) Effects of telomerase and telomere length on epidermal stem cell behavior. Science 309:1253–1256. https://doi.org/10.1126/science.1115025 Franceschi C, Campisi J (2014) Chronic inflammation (inflammaging) and its potential contribution to age-associated diseases. J Gerontol Ser A Biol Sci Med Sci 69(Suppl 1):S4–S9. https://doi.org/10.1093/gerona/glu057 Frank AK, Tran DC, Qu RW, Stohr BA, Segal DJ, Xu L (2015) The shelterin TIN2 subunit mediates recruitment of telomerase to telomeres. PLoS Genet 11:e1005410. https://doi.org/10.1371/journal.pgen.1005410 Frankel LK, Sallans L, Limbach PA, Bricker TM (2013) Oxidized amino acid residues in the vicinity of Q(A) and Pheo(D1) of the photosystem II reaction center: putative generation sites of reducing-side reactive oxygen species. PLoS ONE 8:e58042. https://doi.org/10.1371/journal.pone.0058042 Frescas D, de Lange T (2014) TRF2-tethered TIN2 can mediate telomere protection by TPP1/POT1. Mol Cell Biol 34:1349–1362. https://doi.org/10.1128/MCB.01052-13 Garcia S et al (2018) Overexpression of PGC-1 alpha in aging muscle enhances a subset of young-like molecular patterns. Aging Cell. https://doi.org/10.1111/acel.12707 Gaullier G et al (2016) A higher-order entity formed by the flexible assembly of RAP1 with TRF2. Nucleic Acids Res 44:1962–1976. https://doi.org/10.1093/nar/gkv1531 Gibson BA, Kraus WL (2012) New insights into the molecular and cellular functions of poly(ADP-ribose) and PARPs. Nat Rev Mol Cell Biol 13:411–424. https://doi.org/10.1038/nrm3376 Gomes AP et al (2013) Declining NAD(+) induces a pseudohypoxic state disrupting nuclear-mitochondrial communication during. Aging Cell 155:1624–1638. https://doi.org/10.1016/j.cell.2013.11.037 Grabowska W, Sikora E, Bielak-Zmijewska A (2017) Sirtuins, a promising target in slowing down the ageing process. Biogerontology 18:447–476. https://doi.org/10.1007/s10522-017-9685-9 Graf M et al (2017) Telomere length determines TERRA and R-loop regulation through the cell cycle. Cell 170(72–85):e14. https://doi.org/10.1016/j.cell.2017.06.006 Greider CW, Blackburn EH (1989) A telomeric sequence in the RNA of tetrahymena telomerase required for telomere repeat synthesis. Nature 337:331–337. https://doi.org/10.1038/337331a0 Griffith JD, Comeau L, Rosenfield S, Stansel RM, Bianchi A, Moss H, de Lange T (1999) Mammalian telomeres end in a large duplex loop. Cell 97:503–514 Hansel-Hertsch R, Di Antonio M, Balasubramanian S (2017) DNA G-quadruplexes in the human genome: detection, functions and therapeutic potential. Nat Rev Mol Cell Biol 18:279–284. https://doi.org/10.1038/nrm.2017.3 Harley CB, Futcher AB, Greider CW (1990) Telomeres shorten during ageing of human fibroblasts. Nature 345:458–460. https://doi.org/10.1038/345458a0 Harley CB, Vaziri H, Counter CM, Allsopp RC (1992) The telomere hypothesis of cellular aging. Exp Gerontol 27:375–382 Harper JW, Adami GR, Wei N, Keyomarsi K, Elledge SJ (1993) The p21 Cdk-interacting protein Cip1 is a potent inhibitor of G1 cyclin-dependent kinases. Cell 75:805–816 He S, Sharpless NE (2017) Senescence in health and disease. Cell 169:1000–1011. https://doi.org/10.1016/j.cell.2017.05.015 Herbert KE, Mistry Y, Hastings R, Poolman T, Niklason L, Williams B (2008) Angiotensin II-mediated oxidative DNA damage accelerates cellular senescence in cultured human vascular smooth muscle cells via telomere-dependent and independent pathways. Circ Res 102:201–208. https://doi.org/10.1161/Circresaha.107.158626 Hernandez-Segura A, Nehme J, Demaria M (2018) Hallmarks of cellular senescence. Trends Cell Biol 28:436–453. https://doi.org/10.1016/j.tcb.2018.02.001 Herranz N et al (2015) mTOR regulates MAPKAPK2 translation to control the senescence-associated secretory phenotype. Nat Cell Biol 17:1205–1217. https://doi.org/10.1038/ncb3225 Hitchings AW, Archer JR, Srivastava SA, Baker EH (2015) Safety of metformin in patients with chronic obstructive pulmonary disease and type 2 diabetes mellitus. COPD 12:126–131. https://doi.org/10.3109/15412555.2015.898052 Hu C et al (2017) Structural and functional analyses of the mammalian TIN2-TPP1-TRF2 telomeric complex. Cell Res 27:1485–1502. https://doi.org/10.1038/cr.2017.144 Huppert JL, Balasubramanian S (2005) Prevalence of quadruplexes in the human genome. Nucleic Acids Res 33:2908–2916. https://doi.org/10.1093/nar/gki609 Itahana K, Dimri G, Campisi J (2001) Regulation of cellular senescence by p53. Eur J Biochem 268:2784–2791 Ito K, Suda T (2014) Metabolic requirements for the maintenance of self-renewing stem cells. Nat Rev Mol Cell Biol 15:243–256. https://doi.org/10.1038/nrm3772 Jang YC, Sinha M, Cerletti M, Dall’Osso C, Wagers AJ (2011) Skeletal muscle stem cells: effects of aging and metabolism on muscle regenerative function. Cold Spring Harb Symp Quant Biol 76:101–111. https://doi.org/10.1101/sqb.2011.76.010652 Jeon OH et al (2017) Local clearance of senescent cells attenuates the development of post-traumatic osteoarthritis and creates a pro-regenerative environment. Nat Med 23:775–781. https://doi.org/10.1038/nm.4324 Jiang J, Wang Y, Susac L, Chan H, Basu R, Zhou ZH, Feigon J (2018) Structure of telomerase with telomeric DNA. Cell 173(1179–1190):e1113. https://doi.org/10.1016/j.cell.2018.04.038 Kang Y et al (2018) Telomere dysfunction disturbs macrophage mitochondrial metabolism and the NLRP3 inflammasome through the PGC-1alpha/TNFAIP3 axis. Cell Rep 22:3493–3506. https://doi.org/10.1016/j.celrep.2018.02.071 Kar A, Willcox S, Griffith JD (2016) Transcription of telomeric DNA leads to high levels of homologous recombination and t-loops. Nucleic Acids Res 44:9369–9380. https://doi.org/10.1093/nar/gkw779 Kauppila TES, Kauppila JHK, Larsson NG (2017) Mammalian mitochondria and aging: an update. Cell Metab 25:57–71. https://doi.org/10.1016/j.cmet.2016.09.017 Kelleher C, Kurth I, Lingner J (2005) Human protection of telomeres 1 (POT1) is a negative regulator of telomerase activity in vitro. Mol Cell Biol 25:808–818. https://doi.org/10.1128/MCB.25.2.808-818.2005 Kibe T, Zimmermann M, de Lange T (2016) TPP1 blocks an ATR-mediated resection mechanism at telomeres. Mol Cell 61:236–246. https://doi.org/10.1016/j.molcel.2015.12.016 Kim NW et al (1994) Specific association of human telomerase activity with immortal cells and cancer. Science 266:2011–2015 Kuilman T, Peeper DS (2009) Senescence-messaging secretome: SMS-ing cellular stress. Nat Rev Cancer 9:81–94. https://doi.org/10.1038/nrc2560 Laberge RM, Awad P, Campisi J, Desprez PY (2012) Epithelial–mesenchymal transition induced by senescent fibroblasts. Cancer Microenviron 5:39–44. https://doi.org/10.1007/s12307-011-0069-4 Laberge RM et al (2015) MTOR regulates the pro-tumorigenic senescence-associated secretory phenotype by promoting IL1A translation. Nat Cell Biol 17:1049–1061. https://doi.org/10.1038/ncb3195 Laplante M, Sabatini DM (2012) mTOR signaling in growth control and disease. Cell 149:274–293. https://doi.org/10.1016/j.cell.2012.03.017 Latrick CM, Cech TR (2010) POT1–TPP1 enhances telomerase processivity by slowing primer dissociation and aiding translocation. EMBO J 29:924–933. https://doi.org/10.1038/emboj.2009.409 Law MJ et al (2010) ATR-X syndrome protein targets tandem repeats and influences allele-specific expression in a size-dependent manner. Cell 143:367–378. https://doi.org/10.1016/j.cell.2010.09.023 Lawless C, Wang C, Jurk D, Merz A, Zglinicki T, Passos JF (2010) Quantitative assessment of markers for cell senescence. Exp Gerontol 45:772–778. https://doi.org/10.1016/j.exger.2010.01.018 Lazzerini-Denchi E, Sfeir A (2016) Stop pulling my strings—what telomeres taught us about the DNA damage response. Nat Rev Mol Cell Biol 17:364–378. https://doi.org/10.1038/nrm.2016.43 Lee YW, Arora R, Wischnewski H, Azzalin CM (2018) TRF1 participates in chromosome end protection by averting TRF2-dependent telomeric R loops. Nat Struct Mol Biol 25:147–153. https://doi.org/10.1038/s41594-017-0021-5 Lei M, Zaug AJ, Podell ER, Cech TR (2005) Switching human telomerase on and off with hPOT1 protein in vitro. J Biol Chem 280:20449–20456. https://doi.org/10.1074/jbc.M502212200 Loayza D (2003) POT1 as a terminal transducer of TRF1 telomere length control. Nature 445:1013–1018 Lopez-Otin C, Blasco MA, Partridge L, Serrano M, Kroemer G (2013) The hallmarks of aging. Cell 153:1194–1217. https://doi.org/10.1016/j.cell.2013.05.039 Lossaint G, Besnard E, Fisher D, Piette J, Dulic V (2011) Chk1 is dispensable for G2 arrest in response to sustained DNA damage when the ATM/p53/p21 pathway is functional. Oncogene 30:4261–4274. https://doi.org/10.1038/onc.2011.135 Makarov VL, Hirose Y, Langmore JP (1997) Long G tails at both ends of human chromosomes suggest a C strand degradation mechanism for telomere shortening. Cell 88:657–666 Maryanovich M et al (2015) An MTCH2 pathway repressing mitochondria metabolism regulates haematopoietic stem cell fate. Nat Commun 6:7901. https://doi.org/10.1038/ncomms8901 McClintock B (1941) The stability of broken ends of chromosomes in Zea mays. Genetics 26:234–282 McElligott R, Wellinger RJ (1997) The terminal DNA structure of mammalian chromosomes. EMBO J 16:3705–3714. https://doi.org/10.1093/emboj/16.12.3705 McHugh D, Gil J (2017) Senescence and aging: causes, consequences, and therapeutic avenues. J Cell Biol. https://doi.org/10.1083/jcb.201708092 McHugh D, Gil J (2018) Senescence and aging: causes, consequences, and therapeutic avenues. J Cell Biol 217:65–77. https://doi.org/10.1083/jcb.201708092 Mihaylova MM, Shaw RJ (2011) The AMPK signalling pathway coordinates cell growth, autophagy and metabolism. Nat Cell Biol 13:1016–1023. https://doi.org/10.1038/ncb2329 Montero JJ, Lopez de Silanes I, Grana O, Blasco MA (2016) Telomeric RNAs are essential to maintain telomeres. Nat Commun 7:12534. https://doi.org/10.1038/ncomms12534 Moravec M et al (2016) TERRA promotes telomerase-mediated telomere elongation in Schizosaccharomyces pombe. EMBO Rep 17:999–1012. https://doi.org/10.15252/embr.201541708 Morgan RG, Donato AJ, Walker AE (2018) Telomere uncapping and vascular aging. Am J Physiol Heart Circ Physiol. https://doi.org/10.1152/ajpheart.00008.2018 Morin GB (1989) The human telomere terminal transferase enzyme is a ribonucleoprotein that synthesizes TTAGGG repeats. Cell 59:521–529 Moyzis RK et al (1988) A highly conserved repetitive DNA sequence, (TTAGGG)n, present at the telomeres of human chromosomes. Proc Natl Acad Sci USA 85:6622–6626 Muezzinler A, Zaineddin AK, Brenner H (2013) A systematic review of leukocyte telomere length and age in adults. Ageing Res Rev 12:509–519. https://doi.org/10.1016/j.arr.2013.01.003 Muller HJ (1938) The remaking of chromosomes. Collect Net-Woods Hole 13:181–195 Munoz-Espin D, Serrano M (2014) Cellular senescence: from physiology to pathology. Nat Rev Mol Cell Biol 15:482–496. https://doi.org/10.1038/nrm3823 Nakamaru Y et al (2009) A protein deacetylase SIRT1 is a negative regulator of metalloproteinase-9. FASEB J 23:2810–2819. https://doi.org/10.1096/fj.08-125468 Nandakumar J, Bell CF, Weidenfeld I, Zaug AJ, Leinwand LA, Cech TR (2012) The TEL patch of telomere protein TPP1 mediates telomerase recruitment and processivity. Nature 492:285–289. https://doi.org/10.1038/nature11648 Nelson G, Wordsworth J, Wang C, Jurk D, Lawless C, Martin-Ruiz C, von Zglinicki T (2012) A senescent cell bystander effect: senescence-induced senescence. Aging Cell 11:345–349. https://doi.org/10.1111/j.1474-9726.2012.00795.x Nikolich-Zugich J (2018) The twilight of immunity: emerging concepts in aging of the immune system. Nat Immunol 19:10–19. https://doi.org/10.1038/s41590-017-0006-x Oganesian L, Moon IK, Bryan TM, Jarstfer MB (2006) Extension of G-quadruplex DNA by ciliate telomerase. EMBO J 25:1148–1159. https://doi.org/10.1038/sj.emboj.7601006 Olovnikov AM (1973) A theory of marginotomy. The incomplete copying of template margin in enzymic synthesis of polynucleotides and biological significance of the phenomenon. J Theor Biol 41:181–190 Parrinello S, Coppe JP, Krtolica A, Campisi J (2005) Stromal-epithelial interactions in aging and cancer: senescent fibroblasts alter epithelial cell differentiation. J Cell Sci 118:485–496. https://doi.org/10.1242/jcs.01635 Pricola KL, Kuhn NZ, Haleem-Smith H, Song Y, Tuan RS (2009) Interleukin-6 maintains bone marrow-derived mesenchymal stem cell stemness by an ERK1/2-dependent mechanism. J Cell Biochem 108:577–588. https://doi.org/10.1002/jcb.22289 Prolla TA, Denu JM (2014) NAD + deficiency in age-related mitochondrial dysfunction. Cell Metab 19:178–180. https://doi.org/10.1016/j.cmet.2014.01.005 Rai R, Chen Y, Lei M, Chang S (2016) TRF2-RAP1 is required to protect telomeres from engaging in homologous recombination-mediated deletions and fusions. Nat Commun 7:10881 Ray S, Bandaria JN, Qureshi MH, Yildiz A, Balci H (2014) G-quadruplex formation in telomeres enhances POT1/TPP1 protection against RPA binding. Proc Natl Acad Sci USA 111:2990–2995. https://doi.org/10.1073/pnas.1321436111 Redon S, Reichenbach P, Lingner J (2010) The non-coding RNA TERRA is a natural ligand and direct inhibitor of human telomerase. Nucleic Acids Res 38:5797–5806. https://doi.org/10.1093/nar/gkq296 Rera M et al (2011) Modulation of longevity and tissue homeostasis by the Drosophila PGC-1 homolog. Cell Metab 14:623–634. https://doi.org/10.1016/j.cmet.2011.09.013 Rhodes D, Lipps HJ (2015) G-quadruplexes and their regulatory roles in biology. Nucleic Acids Res 43:8627–8637. https://doi.org/10.1093/nar/gkv862 Rippe K, Luke B (2015) TERRA and the state of the telomere. Nat Struct Mol Biol 22:853–858. https://doi.org/10.1038/nsmb.3078 Roake CM, Artandi SE (2017) Control of cellular aging, tissue function, and cancer by p53 downstream of telomeres. Cold Spring Harb Perspect Med. https://doi.org/10.1101/cshperspect.a026088 Rocheteau P et al (2015) Sepsis induces long-term metabolic and mitochondrial muscle stem cell dysfunction amenable by mesenchymal stem cell therapy. Nat Commun 6:10145. https://doi.org/10.1038/ncomms10145 Rodgers JT, Lerin C, Haas W, Gygi SP, Spiegelman BM, Puigserver P (2005) Nutrient control of glucose homeostasis through a complex of PGC-1alpha and SIRT1. Nature 434:113–118. https://doi.org/10.1038/nature03354 Sagie S et al (2017) Telomeres in ICF syndrome cells are vulnerable to DNA damage due to elevated DNA:RNA hybrids. Nat Commun 8:14015. https://doi.org/10.1038/ncomms14015 Sahin E et al (2011) Telomere dysfunction induces metabolic and mitochondrial compromise. Nature 470:359–365. https://doi.org/10.1038/nature09787 Sarek G, Vannier JB, Panier S, Petrini JHJ, Boulton SJ (2016) TRF2 recruits RTEL1 to telomeres in S phase to promote T-loop unwinding. Mol Cell 61:788–789. https://doi.org/10.1016/j.molcel.2016.02.016 Schaffitzel C, Berger I, Postberg J, Hanes J, Lipps HJ, Pluckthun A (2001) In vitro generated antibodies specific for telomeric guanine-quadruplex DNA react with Stylonychia lemnae macronuclei. Proc Natl Acad Sci USA 98:8572–8577. https://doi.org/10.1073/pnas.141229498 Schoeftner S, Blasco MA (2008) Developmentally regulated transcription of mammalian telomeres by DNA-dependent RNA polymerase II. Nat Cell Biol 10:228–236. https://doi.org/10.1038/ncb1685 Sfeir A, Kosiyatrakul ST, Hockemeyer D, MacRae SL, Karlseder J, Schildkraut CL, de Lange T (2009) Mammalian telomeres resemble fragile sites and require TRF1 for efficient replication. Cell 138:90–103. https://doi.org/10.1016/j.cell.2009.06.021 Sharpless NE, Depinho RA (2007) How stem cells age and why this makes us grow old. Nat Rev Mol Cell Biol 8:703–713. https://doi.org/10.1038/nrm2241 Shay JW, Pereira-Smith OM, Wright WE (1991) A role for both RB and p53 in the regulation of human cellular senescence. Exp Cell Res 196:33–39 Smith JS et al (2011) Rudimentary G-quadruplex-based telomere capping in Saccharomyces cerevisiae. Nat Struct Mol Biol 18:478–485. https://doi.org/10.1038/nsmb.2033 Smogorzewska A, van Steensel B, Bianchi A, Oelmann S, Schaefer MR, Schnapp G, de Lange T (2000) Control of human telomere length by TRF1 and TRF2. Mol Cell Biol 20:1659–1668 Son MJ, Kwon Y, Son T, Cho YS (2016) Restoration of mitochondrial NAD(+) levels delays stem cell senescence and facilitates reprogramming of aged somatic cells. Stem Cells 34:2840–2851. https://doi.org/10.1002/stem.2460 Sousa-Victor P et al (2014) Geriatric muscle stem cells switch reversible quiescence into senescence. Nature 506:316–321. https://doi.org/10.1038/nature13013 Soysal P et al (2016) Inflammation and frailty in the elderly: a systematic review and meta-analysis. Ageing Res Rev 31:1–8. https://doi.org/10.1016/j.arr.2016.08.006 Steenstrup T et al (2017) Telomeres and the natural lifespan limit in humans. Aging 9:1130–1142. https://doi.org/10.18632/aging.101216 Sugino A, Hirose S, Okazaki R (1972) RNA-linked nascent DNA fragments in Escherichia coli. Proc Natl Acad Sci USA 69:1863–1867 Sui B, Hu C, Jin Y (2016) Mitochondrial metabolic failure in telomere attrition-provoked aging of bone marrow mesenchymal stem cells. Biogerontology 17:267–279. https://doi.org/10.1007/s10522-015-9609-5 Sun N, Youle RJ, Finkel T (2016) The mitochondrial basis of aging. Mol Cell 61:654–666. https://doi.org/10.1016/j.molcel.2016.01.028 Takai KK, Kibe T, Donigian JR, Frescas D, de Lange T (2011) Telomere protection by TPP1/POT1 requires tethering to TIN2. Mol Cell 44:647–659. https://doi.org/10.1016/j.molcel.2011.08.043 Takai KK, Kibe T, Donigian JR, Frescas D, de Lange T (2017) Telomere protection by TPP1/POT1 requires tethering to TIN2. Mol Cell 67:162. https://doi.org/10.1016/j.molcel.2017.05.033 Takubo K et al (2013) Regulation of glycolysis by Pdk functions as a metabolic checkpoint for cell cycle quiescence in hematopoietic stem cells. Cell Stem Cell 12:49–61. https://doi.org/10.1016/j.stem.2012.10.011 van Deursen JM (2014) The role of senescent cells in ageing. Nature 509:439–446. https://doi.org/10.1038/nature13193 Verdin E (2015) NAD(+) in aging, metabolism, and neurodegeneration. Science 350:1208–1213. https://doi.org/10.1126/science.aac4854 Wahlestedt M et al (2013) An epigenetic component of hematopoietic stem cell aging amenable to reprogramming into a young state. Blood 121:4257–4264. https://doi.org/10.1182/blood-2012-11-469080 Wang F, Podell ER, Zaug AJ, Yang Y, Baciu P, Cech TR, Lei M (2007) The POT1–TPP1 telomere complex is a telomerase processivity factor. Nature 445:506–510. https://doi.org/10.1038/nature05454 Wang X et al (2011) A positive role for c-Abl in Atm and Atr activation in DNA damage response. Cell Death Differ 18:5–15. https://doi.org/10.1038/cdd.2010.106 Wang Y, Wang XW, Flores ER, Yu J, Chang S (2016) Dysfunctional telomeres induce p53-dependent and independent apoptosis to compromise cellular proliferation and inhibit tumor formation. Aging Cell 15:646–660. https://doi.org/10.1111/acel.12476 Watson JD (1972) Origin of concatemeric T7 DNA. Nat New biol 239:197–201 Webb CJ, Zakian VA (2016) Telomerase RNA is more than a DNA template. RNA Biol 13:683–689. https://doi.org/10.1080/15476286.2016.1191725 Wiley CD, Campisi J (2016) From ancient pathways to aging cells-connecting metabolism and cellular senescence. Cell Metab 23:1013–1021. https://doi.org/10.1016/j.cmet.2016.05.010 Wiley CD et al (2016) Mitochondrial dysfunction induces senescence with a distinct secretory phenotype. Cell Metab 23:303–314. https://doi.org/10.1016/j.cmet.2015.11.011 Wu P, Takai H, de Lange T (2012) Telomeric 3′ overhangs derive from resection by Exo1 and Apollo and fill-in by POT1b-associated CST. Cell 150:39–52. https://doi.org/10.1016/j.cell.2012.05.026 Wu RA, Upton HE, Vogan JM, Collins K (2017) Telomerase mechanism of telomere synthesis. Annu Rev Biochem 86:439–460. https://doi.org/10.1146/annurev-biochem-061516-045019 Xin H et al. (2007) TPP1 is a homologue of ciliate TEBP-beta and interacts with POT1 to recruit telomerase Nature 445:559-562 https://doi.org/10.1038/nature05469 Xiong Y, Hannon GJ, Zhang H, Casso D, Kobayashi R, Beach D (1993) p21 is a universal inhibitor of cyclin kinases. Nature 366:701–704. https://doi.org/10.1038/366701a0 Xu L, Li S, Stohr BA (2013) The role of telomere biology in cancer. Annu Rev Pathol 8:49–78. https://doi.org/10.1146/annurev-pathol-020712-164030 Yu TY, Kao YW, Lin JJ (2014) Telomeric transcripts stimulate telomere recombination to suppress senescence in cells lacking telomerase. Proc Natl Acad Sci USA 111:3377–3382. https://doi.org/10.1073/pnas.1307415111 Zahler AM, Williamson JR, Cech TR, Prescott DM (1991) Inhibition of telomerase by G-quartet DNA structures. Nature 350:718–720. https://doi.org/10.1038/350718a0 Zhang R, Chen W, Adams PD (2007) Molecular dissection of formation of senescence-associated heterochromatin foci. Mol Cell Biol 27:2343–2358. https://doi.org/10.1128/MCB.02019-06 Zhang H et al (2016) NAD(+) repletion improves mitochondrial and stem cell function and enhances life span in mice. Science 352:1436–1443. https://doi.org/10.1126/science.aaf2693 Zhu Y et al (2015) The Achilles’ heel of senescent cells: from transcriptome to senolytic drugs. Aging Cell 14:644–658. https://doi.org/10.1111/acel.12344 Zole E, Ranka R (2018) Mitochondria, its DNA and telomeres in ageing and human population. Biogerontology 19:189–208. https://doi.org/10.1007/s10522-018-9748-6 Zou L, Elledge SJ (2003) Sensing DNA damage through ATRIP recognition of RPA-ssDNA complexes. Science 300:1542–1548. https://doi.org/10.1126/science.1083430 Zwerschke W, Mazurek S, Stockl P, Hutter E, Eigenbrodt E, Jansen-Durr P (2003) Metabolic analysis of senescent human fibroblasts reveals a role for AMP in cellular senescence. Biochem J 376:403–411. https://doi.org/10.1042/BJ20030816