Telomeres and Cell Senescence - Size Matters Not

EBioMedicine

Volumn 21, Issue , 2017, Pages 14-20

  Victorelli, Stella ^a   Passos, João F ^a  

^a NEWCASTLE UNIVERSITY   (United Kingdom)

Author keywords

Ageing; DNA damage; Senescence; Stress; Telomeres

Indexed keywords

TELOMERIC REPEAT BINDING FACTOR 2;

APOPTOSIS; CANCER GROWTH; CELL AGING; CELL CYCLE ARREST; CELL DIVISION; CELL STRESS; CELLULAR, SUBCELLULAR AND MOLECULAR BIOLOGICAL PHENOMENA AND FUNCTIONS; CRISPR CAS SYSTEM; DNA DAMAGE RESPONSE; DOUBLE STRANDED DNA BREAK; HUMAN; NONHUMAN; OXIDATIVE STRESS; PRIORITY JOURNAL; PROTEIN PHOSPHORYLATION; REVIEW; TELOMERE; TELOMERE DYSFUNCTION; TELOMERE HOMEOSTASIS; TELOMERE LENGTH; TELOMERE SHORTENING; AGING; ANIMAL; DNA DAMAGE; GENETICS; METABOLISM; PHYSIOLOGICAL STRESS; SIGNAL TRANSDUCTION;

AGING; ANIMALS; CELLULAR SENESCENCE; DNA DAMAGE; HUMANS; SIGNAL TRANSDUCTION; STRESS, PHYSIOLOGICAL; TELOMERE; TELOMERE HOMEOSTASIS; TELOMERE SHORTENING;

EID: 85017184675     PISSN: None     EISSN: 23523964     Source Type: Journal    
DOI: 10.1016/j.ebiom.2017.03.027     Document Type: Review

References (75)

1. Acosta, J.C., Banito, A., Wuestefeld, T., Georgilis, A., Janich, P., Morton, J.P., Athineos, D., Kang, T.-W., Lasitschka, F., Andrulis, M., Pascual, G., Morris, K.J., Khan, S., Jin, H., Dharmalingam, G., Snijders, A.P., Carroll, T., Capper, D., Pritchard, C., Inman, G.J., Longerich, T., Sansom, O.J., Benitah, S.A., Zender, L., Gil, J.s., A complex secretory program orchestrated by the inflammasome controls paracrine senescence. Nat. Cell Biol. 15:8 (2013), 978–990.
2. Baker, D.J., Childs, B.G., Durik, M., Wijers, M.E., Sieben, C.J., Zhong, J., Saltness, R.A., Jeganathan, K.B., Verzosa, G.C., Pezeshki, A., Khazaie, K., Miller, J.D., van Deursen, J.M., Naturally occurring p16Ink4a-positive cells shorten healthy lifespan. Nature 530:7589 (2016), 184–189.
3. Baker, D.J., Wijshake, T., Tchkonia, T., LeBrasseur, N.K., Childs, B.G., van de Sluis, B., Kirkland, J.L., van Deursen, J.M., Clearance of p16Ink4a-positive senescent cells delays ageing-associated disorders. Nature 479:7372 (2011), 232–236.
4. Baumann, P., Cech, T.R., Pot1, the putative telomere end-binding protein in fission yeast and humans. Science 292:5519 (2001), 1171–1175.
5. Beausejour, C.M., Krtolica, A., Galimi, F., Narita, M., Lowe, S.W., Yaswen, P., Campisi, J., Reversal of human cellular senescence: roles of the p53 and p16 pathways. EMBO J. 22:16 (2003), 4212–4222.
6. Bianchi, A., Smith, S., Chong, L., Elias, P., de Lange, T., TRF1 is a dimer and bends telomeric DNA. EMBO J. 16:7 (1997), 1785–1794.
7. Bilaud, T., Brun, C., Ancelin, K., Koering, C.E., Laroche, T., Gilson, E., Telomeric localization of TRF2, a novel human telobox protein. Nat. Genet. 17:2 (1997), 236–239.
8. Birch, J., Anderson, R.K., Correia-Melo, C., Jurk, D., Hewitt, G., Marques, F.M., Green, N.J., Moisey, E., Birrell, M.A., Belvisi, M.G., Black, F., Taylor, J.J., Fisher, A.J., De Soyza, A., Passos, J.F., DNA damage response at telomeres contributes to lung aging and chronic obstructive pulmonary disease. Am. J. Phys. Lung Cell. Mol. Phys. 309:10 (2015), L1124–L1137.
9. Blasco, M.A., Lee, H.W., Hande, M.P., Samper, E., Lansdorp, P.M., DePinho, R.A., Greider, C.W., Telomere shortening and tumor formation by mouse cells lacking telomerase RNA. Cell 91:1 (1997), 25–34.
10. Bodnar, A.G., Ouellette, M., Frolkis, M., Holt, S.E., Chiu, C.P., Morin, G.B., Harley, C.B., Shay, J.W., Lichtsteiner, S., Wright, W.E., Extension of life-span by introduction of telomerase into normal human cells. Science 279:5349 (1998), 349–352.
11. Bombarde, O., Boby, C., Gomez, D., Frit, P., Giraud-Panis, M.J., Gilson, E., Salles, B., Calsou, P., TRF2/RAP1 and DNA-PK mediate a double protection against joining at telomeric ends. EMBO J. 29:9 (2010), 1573–1584.
12. Cai, Z., Yan, L.J., Ratka, A., Telomere shortening and Alzheimer's disease. NeuroMolecular Med. 15:1 (2013), 25–48.
13. Cesare, A.J., Kaul, Z., Cohen, S.B., Napier, C.E., Pickett, H.A., Neumann, A.A., Reddel, R.R., Spontaneous occurrence of telomeric DNA damage response in the absence of chromosome fusions. Nat. Struct. Mol. Biol. 16:12 (2009), 1244–1251.
14. Chang, J., Wang, Y., Shao, L., Laberge, R.-M., Demaria, M., Campisi, J., Janakiraman, K., Sharpless, N.E., Ding, S., Feng, W., Luo, Y., Wang, X., Aykin-Burns, N., Krager, K., Ponnappan, U., Hauer-Jensen, M., Meng, A., Zhou, D., Clearance of senescent cells by ABT263 rejuvenates aged hematopoietic stem cells in mice. Nat. Med. 22:1 (2016), 78–83.
15. Choudhury, A.R., Ju, Z., Djojosubroto, M.W., Schienke, A., Lechel, A., Schaetzlein, S., Jiang, H., Stepczynska, A., Wang, C., Buer, J., Lee, H.-W., von Zglinicki, T., Ganser, A., Schirmacher, P., Nakauchi, H., Rudolph, K.L., Cdkn1a deletion improves stem cell function and lifespan of mice with dysfunctional telomeres without accelerating cancer formation. Nat. Genet. 39:1 (2007), 99–105.
16. Coppé, J.P., Patil, C.K., Rodier, F., Sun, Y., Muñoz, D.P., Goldstein, J., Nelson, P.S., Desprez, P.-Y., Campisi, J., Senescence-associated secretory phenotypes reveal cell-nonautonomous functions of oncogenic RAS and the p53 tumor suppressor. PLoS Biol., 6(12), 2008, e301.
17. Correia-Melo, C., Marques, F.D.M., Anderson, R., Hewitt, G., Hewitt, R., Cole, J., Carroll, B.M., Miwa, S., Birch, J., Merz, A., Rushton, M.D., Charles, M., Jurk, D., Tait, S.W.G., Czapiewski, R., Greaves, L., Nelson, G., Bohlooly-Y, M., Rodriguez-Cuenca, S., Vidal-Puig, A., Mann, D., Saretzki, G., Quarato, G., Green, D.R., Adams, P.D., von Zglinicki, T., Korolchuk, V.I., Passos, J.F., Mitochondria are required for pro-ageing features of the senescent phenotype. EMBO J. 35 (2016), 724–742.
18. d'Adda di Fagagna, F., Reaper, P.M., Clay-Farrace, L., Fiegler, H., Carr, P., von Zglinicki, T., Saretzki, G., Carter, N.P., Jackson, S.P., A DNA damage checkpoint response in telomere-initiated senescence. Nature 426:6963 (2003), 194–198.
19. Dai, D.F., Chiao, Y.A., Marcinek, D.J., Szeto, H.H., Rabinovitch, P.S., Mitochondrial oxidative stress in aging and healthspan. Longev Healthspan, 3, 2014, 6.
20. de Lange, T., Shelterin: the protein complex that shapes and safeguards human telomeres. Genes Dev. 19:18 (2005), 2100–2110.
21. Demaria, M., O'Leary, M.N., Chang, J., Shao, L., Liu, S., Alimirah, F., Koenig, K., Le, C., Mitin, N., Deal, A.M., Alston, S., Academia, E.C., Kilmarx, S., Valdovinos, A., Wang, B., de Bruin, A., Kennedy, B.K., Melov, S., Zhou, D., Sharpless, N.E., Muss, H., Campisi, J., Cellular senescence promotes adverse effects of chemotherapy and cancer relapse. Cancer Discov. 7:2 (2017), 165–176.
22. Demaria, M., Ohtani, N., Youssef, Sameh A., Rodier, F., Toussaint, W., Mitchell, James R., Laberge, R.-M., Vijg, J., Van Steeg, H., Martijn, E.T. Dollé, Hoeijmakers, Jan H.J., de Bruin, A., Hara, E., Campisi, J., An essential role for senescent cells in optimal wound healing through secretion of PDGF-AA. Dev. Cell 31:6 (2014), 722–733.
23. Doksani, Y., de Lange, T., Telomere-internal double-strand breaks are repaired by homologous recombination and PARP1/Lig3-dependent end-joining. Cell Rep. 17:6 (2016), 1646–1656.
24. Fairlie, J., Harrington, L., Enforced telomere elongation increases the sensitivity of human tumour cells to ionizing radiation. DNA Repair (Amst) 25 (2015), 54–59.
25. Fumagalli, M., Rossiello, F., Clerici, M., Barozzi, S., Cittaro, D., Kaplunov, J.M., Bucci, G., Dobreva, M., Matti, V., Beausejour, C.M., Herbig, U., Longhese, M.P., d'Adda di Fagagna, F., Telomeric DNA damage is irreparable and causes persistent DNA-damage-response activation. Nat. Cell Biol. 14:4 (2012), 355–365.
26. Fyhrquist, F., Saijonmaa, O., Telomere length and cardiovascular aging. Ann. Med. 44:Suppl. 1 (2012), S138–S142.
27. Galbiati, A., Beausejour, C., d'Adda di Fagagna, F., A novel single-cell method provides direct evidence of persistent DNA damage in senescent cells and aged mammalian tissues. Aging Cell 16:2 (2017), 422–427.
28. Gilgun-Sherki, Y., Melamed, E., Offen, D., The role of oxidative stress in the pathogenesis of multiple sclerosis: the need for effective antioxidant therapy. J. Neurol. 251:3 (2004), 261–268.
29. Griffith, J.D., Comeau, L., Rosenfield, S., Stansel, R.M., Bianchi, A., Moss, H., de Lange, T., Mammalian telomeres end in a large duplex loop. Cell 97:4 (1999), 503–514.
30. Guan, J.Z., Guan, W.P., Maeda, T., Guoqing, X., Guang Zhi, W., Makino, N., Patients with multiple sclerosis show increased oxidative stress markers and somatic telomere length shortening. Mol. Cell. Biochem. 400:1–2 (2015), 183–187.
31. Harley, C.B., Futcher, A.B., Greider, C.W., Telomeres shorten during ageing of human fibroblasts. Nature 345:6274 (1990), 458–460.
32. Haycock, P.C., Burgess, S., Nounu, A., Zheng, J., Okoli, G.N., Bowden, J., Wade, K.H., Timpson, N.J., Evans, D.M., Willeit, P., Aviv, A., Gaunt, T.R., Hemani, G., Mangino, M., Ellis, H.P., Kurian, K.M., Pooley, K.A., Eeles, R.A., Lee, J.E., Fang, S., Chen, W.V., Law, M.H., Bowdler, L.M., Iles, M.M., Yang, Q., Worrall, B.B., Markus, H.S., Hung, R.J., Amos, C.I., Spurdle, A.B., Thompson, D.J., O'Mara, T.A., Wolpin, B., Amundadottir, L., Stolzenberg-Solomon, R., Trichopoulou, A., Onland-Moret, N.C., Lund, E., Duell, E.J., Canzian, F., Severi, G., Overvad, K., Gunter, M.J., Tumino, R., Svenson, U., van Rij, A., Baas, A.F., Bown, M.J., Samani, N.J., van t'Hof, F.N., Tromp, G., Jones, G.T., Kuivaniemi, H., Elmore, J.R., Johansson, M., McKay, J., Scelo, G., Carreras-Torres, R., Gaborieau, V., Brennan, P., Bracci, P.M., Neale, R.E., Olson, S.H., Gallinger, S., Li, D., Petersen, G.M., Risch, H.A., Klein, A.P., Han, J., Abnet, C.C., Freedman, N.D., Taylor, P.R., Maris, J.M., Aben, K.K., Kiemeney, L.A., Vermeulen, S.H., Wiencke, J.K., Walsh, K.M., Wrensch, M., Rice, T., Turnbull, C., Litchfield, K., Paternoster, L., Standl, M., Abecasis, G.R., SanGiovanni, J.P., Li, Y., Mijatovic, V., Sapkota, Y., Low, S.K., Zondervan, K.T., Montgomery, G.W., Nyholt, D.R., van Heel, D.A., Hunt, K., Arking, D.E., Ashar, F.N., Sotoodehnia, N., Woo, D., Rosand, J., et al. Association between telomere length and risk of cancer and non-neoplastic diseases: a mendelian randomization study. JAMA Oncol., 2017.
33. Hayflick, L., Moorhead, P.S., The serial cultivation of human diploid cell strains. Exp. Cell Res. 25 (1961), 585–621.
34. Herbig, U., Ferreira, M., Condel, L., Carey, D., Sedivy, J.M., Cellular senescence in aging primates. Science, 311(5765), 2006, 1257.
35. Herbig, U., Jobling, W.A., Chen, B.P., Chen, D.J., Sedivy, J.M., Telomere shortening triggers senescence of human cells through a pathway involving ATM, p53, and p21(CIP1), but not p16(INK4a). Mol. Cell 14:4 (2004), 501–513.
36. Hewitt, G., Jurk, D., Marques, F.D., Correia-Melo, C., Hardy, T., Gackowska, A., Anderson, R., Taschuk, M., Mann, J., Passos, J.F., Telomeres are favoured targets of a persistent DNA damage response in ageing and stress-induced senescence. Nat. Commun., 3, 2012, 708.
37. Jacobs, J.J., de Lange, T., Significant role for p16INK4a in p53-independent telomere-directed senescence. Curr. Biol. 14:24 (2004), 2302–2308.
38. Jaskelioff, M., Muller, F.L., Paik, J.H., Thomas, E., Jiang, S., Adams, A.C., Sahin, E., Kost-Alimova, M., Protopopov, A., Cadinanos, J., Horner, J.W., Maratos-Flier, E., Depinho, R.A., Telomerase reactivation reverses tissue degeneration in aged telomerase-deficient mice. Nature 469:7328 (2011), 102–106.
39. Jurk, D., Wilson, C., Passos, J.F., Oakley, F., Correia-Melo, C., Greaves, L., Saretzki, G., Fox, C., Lawless, C., Anderson, R., Hewitt, G., Pender, S.L., Fullard, N., Nelson, G., Mann, J., van de Sluis, B., Mann, D.A., von Zglinicki, T., Chronic inflammation induces telomere dysfunction and accelerates ageing in mice. Nat. Commun., 2, 2014, 4172.
40. Kaul, Z., Cesare, A.J., Huschtscha, L.I., Neumann, A.A., Reddel, R.R., Five dysfunctional telomeres predict onset of senescence in human cells. EMBO Rep. 13:1 (2012), 52–59.
41. Krizhanovsky, V., Yon, M., Dickins, R.A., Hearn, S., Simon, J., Miething, C., Yee, H., Zender, L., Lowe, S.W., Senescence of activated stellate cells limits liver fibrosis. Cell 134:4 (2008), 657–667.
42. Kruk, P.A., Rampino, N.J., Bohr, V.A., DNA damage and repair in telomeres: relation to aging. Proc. Natl. Acad. Sci. U. S. A. 92:1 (1995), 258–262.
43. Lee, H.W., Blasco, M.A., Gottlieb, G.J., Horner, J.W. 2nd, Greider, C.W., DePinho, R.A., Essential role of mouse telomerase in highly proliferative organs. Nature 392:6676 (1998), 569–574.
44. Liu, L., Trimarchi, J.R., Smith, P.J., Keefe, D.L., Mitochondrial dysfunction leads to telomere attrition and genomic instability. Aging Cell 1:1 (2002), 40–46.
45. Mao, P., Liu, J., Zhang, Z., Zhang, H., Liu, H., Gao, S., Rong, Y.S., Zhao, Y., Homologous recombination-dependent repair of telomeric DSBs in proliferating human cells. Nat. Commun., 7, 2016, 12154.
46. Meena, J.K., Cerutti, A., Beichler, C., Morita, Y., Bruhn, C., Kumar, M., Kraus, J.M., Speicher, M.R., Wang, Z.Q., Kestler, H.A., d'Adda di Fagagna, F., Gunes, C., Rudolph, K.L., Telomerase abrogates aneuploidy-induced telomere replication stress, senescence and cell depletion. EMBO J. 34:10 (2015), 1371–1384.
47. Muñoz-Espín, D., Cañamero, M., Maraver, A., Gómez-López, G., Contreras, J., Murillo-Cuesta, S., Rodríguez-Baeza, A., Varela-Nieto, I., Ruberte, J., Collado, M., Serrano, M., Programmed cell senescence during mammalian embryonic development. Cell 155:5 (2013), 1104–1118.
48. Narita, M., Nunez, S., Heard, E., Narita, M., Lin, A.W., Hearn, S.A., Spector, D.L., Hannon, G.J., Lowe, S.W., Rb-mediated heterochromatin formation and silencing of E2F target genes during cellular senescence. Cell 113:6 (2003), 703–716.
49. Oexle, K., Zwirner, A., Advanced telomere shortening in respiratory chain disorders. Hum. Mol. Genet. 6:6 (1997), 905–908.
50. Oikawa, S., Kawanishi, S., Site-specific DNA damage at GGG sequence by oxidative stress may accelerate telomere shortening. FEBS Lett. 453:3 (1999), 365–368.
51. Olovnikov, A.M., Principle of marginotomy in template synthesis of polynucleotides. Dokl. Akad. Nauk SSSR 201:6 (1971), 1496–1499.
52. Opresko, P.L., Fan, J., Danzy, S., Wilson, D.M. 3rd, Bohr, V.A., Oxidative damage in telomeric DNA disrupts recognition by TRF1 and TRF2. Nucleic Acids Res. 33:4 (2005), 1230–1239.
53. Parrinello, S., Samper, E., Krtolica, A., Goldstein, J., Melov, S., Campisi, J., Oxygen sensitivity severely limits the replicative lifespan of murine fibroblasts. Nat. Cell Biol. 5:8 (2003), 741–747.
54. Passos, J.F., Nelson, G., Wang, C., Richter, T., Simillion, C., Proctor, C.J., Miwa, S., Olijslagers, S., Hallinan, J., Wipat, A., Saretzki, G., Rudolph, K.L., Kirkwood, T.B., von Zglinicki, T., Feedback between p21 and reactive oxygen production is necessary for cell senescence. Mol. Syst. Biol., 6, 2010, 347.
55. Passos, J.F., Saretzki, G., Ahmed, S., Nelson, G., Richter, T., Peters, H., Wappler, I., Birket, M.J., Harold, G., Schaeuble, K., Birch-Machin, M.A., Kirkwood, T.B., von Zglinicki, T., Mitochondrial dysfunction accounts for the stochastic heterogeneity in telomere-dependent senescence. PLoS Biol., 5(5), 2007, e110.
56. Patel, P.L., Suram, A., Mirani, N., Bischof, O., Herbig, U., Derepression of hTERT gene expression promotes escape from oncogene-induced cellular senescence. Proc. Natl. Acad. Sci. U. S. A. 113:34 (2016), E5024–E5033.
57. Petersen, S., Saretzki, G., von Zglinicki, T., Preferential accumulation of single-stranded regions in telomeres of human fibroblasts. Exp. Cell Res. 239:1 (1998), 152–160.
58. Richter, T., von Zglinicki, T., A continuous correlation between oxidative stress and telomere shortening in fibroblasts. Exp. Gerontol. 42:11 (2007), 1039–1042.
59. Ritschka, B., Storer, M., Mas, A., Heinzmann, F., Ortells, M.C., Morton, J.P., Sansom, O.J., Zender, L., Keyes, W.M., The senescence-associated secretory phenotype induces cellular plasticity and tissue regeneration. Genes Dev. 31:2 (2017), 172–183.
60. Sahin, E., Colla, S., Liesa, M., Moslehi, J., Muller, F.L., Guo, M., Cooper, M., Kotton, D., Fabian, A.J., Walkey, C., Maser, R.S., Tonon, G., Foerster, F., Xiong, R., Wang, Y.A., Shukla, S.A., Jaskelioff, M., Martin, E.S., Heffernan, T.P., Protopopov, A., Ivanova, E., Mahoney, J.E., Kost-Alimova, M., Perry, S.R., Bronson, R., Liao, R., Mulligan, R., Shirihai, O.S., Chin, L., DePinho, R.A., Telomere dysfunction induces metabolic and mitochondrial compromise. Nature 470:7334 (2011), 359–365.
61. Saretzki, G., Murphy, M.P., von Zglinicki, T., MitoQ counteracts telomere shortening and elongates lifespan of fibroblasts under mild oxidative stress. Aging Cell 2:2 (2003), 141–143.
62. Serra, V., von Zglinicki, T., Lorenz, M., Saretzki, G., Extracellular superoxide dismutase is a major antioxidant in human fibroblasts and slows telomere shortening. J. Biol. Chem. 278:9 (2003), 6824–6830.
63. Suram, A., Kaplunov, J., Patel, P.L., Ruan, H., Cerutti, A., Boccardi, V., Fumagalli, M., Di Micco, R., Mirani, N., Gurung, R.L., Hande, M.P., d'Adda di Fagagna, F., Herbig, U., Oncogene-induced telomere dysfunction enforces cellular senescence in human cancer precursor lesions. EMBO J. 31:13 (2012), 2839–2851.
64. Takai, H., Smogorzewska, A., de Lange, T., DNA damage foci at dysfunctional telomeres. Curr. Biol. 13:17 (2003), 1549–1556.
65. van Deursen, J.M., The role of senescent cells in ageing. Nature 509:7501 (2014), 439–446.
66. von Zglinicki, T., Role of oxidative stress in telomere length regulation and replicative senescence. Ann. N. Y. Acad. Sci. 908 (2000), 99–110.
67. von Zglinicki, T., Oxidative stress shortens telomeres. Trends Biochem. Sci. 27:7 (2002), 339–344.
68. 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. 28:1 (2000), 64–74.
69. von Zglinicki, T., Saretzki, G., Docke, W., Lotze, C., Mild hyperoxia shortens telomeres and inhibits proliferation of fibroblasts: a model for senescence?. Exp. Cell Res. 220:1 (1995), 186–193.
70. Watson, J.D., Origin of concatemeric T7 DNA. Nat. New Biol. 239:94 (1972), 197–201.
71. Wong, K.K., Maser, R.S., Bachoo, R.M., Menon, J., Carrasco, D.R., Gu, Y., Alt, F.W., DePinho, R.A., Telomere dysfunction and Atm deficiency compromises organ homeostasis and accelerates ageing. Nature 421:6923 (2003), 643–648.
72. Wu, L., Multani, A.S., He, H., Cosme-Blanco, W., Deng, Y., Deng, J.M., Bachilo, O., Pathak, S., Tahara, H., Bailey, S.M., Deng, Y., Behringer, R.R., Chang, S., Pot1 deficiency initiates DNA damage checkpoint activation and aberrant homologous recombination at telomeres. Cell 126:1 (2006), 49–62.
73. Zhang, X., Wu, X., Tang, W., Luo, Y., Loss of p16(Ink4a) function rescues cellular senescence induced by telomere dysfunction. Int. J. Mol. Sci. 13:5 (2012), 5866–5877.
74. Zhong, Z., Shiue, L., Kaplan, S., de Lange, T., A mammalian factor that binds telomeric TTAGGG repeats in vitro. Mol. Cell. Biol. 12:11 (1992), 4834–4843.
75. Zhu, Y., Tchkonia, T., Pirtskhalava, T., Gower, A.C., Ding, H., Giorgadze, N., Palmer, A.K., Ikeno, Y., Hubbard, G.B., Lenburg, M., O'Hara, S.P., LaRusso, N.F., Miller, J.D., Roos, C.M., Verzosa, G.C., LeBrasseur, N.K., Wren, J.D., Farr, J.N., Khosla, S., Stout, M.B., McGowan, S.J., Fuhrmann-Stroissnigg, H., Gurkar, A.U., Zhao, J., Colangelo, D., Dorronsoro, A., Ling, Y.Y., Barghouthy, A.S., Navarro, D.C., Sano, T., Robbins, P.D., Niedernhofer, L.J., Kirkland, J.L., The Achilles' heel of senescent cells: from transcriptome to senolytic drugs. Aging Cell 14:4 (2015), 644–658.