Cellular senescence as the causal nexus of aging

Frontiers in Genetics

Volumn 7, Issue FEB, 2016, Pages

  Bhatia Dey, Naina ^a   Kanherkar, Riya R ^a   Stair, Susan E ^b   Makarev, Evgeny O ^b,c   Csoka, Antonei B ^a,c  

^a HOWARD UNIVERSITY   (United States)

^b Vision Genomics LLC   (United States)

^c JOHNS HOPKINS UNIVERSITY SCHOOL OF MEDICINE   (United States)

Author keywords

Aging; August weismann; Causal nexus; Germline; Immortality; Mortality; Proliferation; Senescence

Indexed keywords

AGING; ANEUPLOIDY; CELL PROLIFERATION; DIET RESTRICTION; DISORDERS OF MITOCHONDRIAL FUNCTIONS; EPIGENETICS; EXTRACELLULAR MATRIX; HUMAN; INFLAMMATION; LIFESPAN; METABOLIC REGULATION; MITOGENESIS; NONHUMAN; OXIDATIVE STRESS; PHENOTYPIC VARIATION; REVIEW; SENESCENCE; SIGNAL TRANSDUCTION; TELOMERE SHORTENING;

EID: 84962528127     PISSN: None     EISSN: 16648021     Source Type: Journal    
DOI: 10.3389/fgene.2016.00013     Document Type: Review

References (131)

1. Ahlqvist, K. J., Hämäläinen, R. H., Yatsuga, S., Uutela, M., Terzioglu, M., Götz, A., et al. (2012). Somatic progenitor cell vulnerability to mitochondrial DNA mutagenesis underlies progeroid phenotypes in Polg mutator mice. Cell Metab. 15, 100-109. doi: 10.1016/j.cmet.2011.11.012
2. Alcorta, D. A., Xiong, Y., Phelps, D., Hannon, G., Beach, D., and Barrett, J. C. (1996). Involvement of the cyclin-dependent kinase inhibitor p16 (INK4a) in replicative senescence of normal human fibroblasts. Proc. Natl. Acad. Sci. U.S.A. 93, 13742-13747. doi: 10.1073/pnas.93.24.13742
3. Allsopp, R. C., Vaziri, H., Patterson, C., Goldstein, S., Younglai, E. V., Futcher, A. B., et al. (1992). Telomere length predicts replicative capacity of human fibroblasts. Proc. Natl. Acad. Sci. U.S.A. 89, 10114-10118. doi: 10.1073/pnas.89.21.10114
4. Artandi, S. E., and Attardi, L. D. (2005). Pathways connecting telomeres and p53 in senescence, apoptosis, and cancer. Biochem. Biophys. Res. Commun. 331, 881-890. doi: 10.1016/j.bbrc.2005.03.211
5. Avis, N. E., and Deimling, G. T. (2008). Cancer survivorship and aging. Cancer 113, 3519-3529. doi: 10.1002/cncr.23941
6. Bahar, R., Hartmann, C. H., Rodriguez, K. A., Denny, A. D., Busuttil, R. A., Dollé, M. E., et al. (2006). Increased cell-to-cell variation in gene expression in ageing mouse heart. Nature 441, 1011-1014. doi: 10.1038/nature04844
7. Baines, H. L., Turnbull, D. M., and Greaves, L. C. (2014). Human stem cell aging: do mitochondrial DNA mutations have a causal role? Aging Cell 13, 201-205. doi: 10.1111/acel.12199
8. Baker, D. J., Dawlaty, M. M., Wijshake, T., Jeganathan, K. B., Malureanu, L., van Ree, J. H., et al. (2013). Increased expression of BubR1 protects against aneuploidy and cancer and extends healthy lifespan. Nat. Cell Biol. 15, 96-102. doi: 10.1038/ncb2643
9. Baker, D. J., Jeganathan, K. B., Cameron, J. D., Thompson, M., Juneja, S., Kopecka, A., et al. (2004). BubR1 insufficiency causes early onset of aging-associated phenotypes and infertility in mice. Nat. Genet. 36, 744-749. doi: 10.1038/ng1382
10. Baker, D. J., and Sedivy, J. M. (2013). Probing the depths of cellular senescence. J. Cell Biol. 202, 11-13. doi: 10.1083/jcb.201305155
11. Baker, D. J., Wijshake, T., Tchkonia, T., LeBrasseur, N. K., Childs, B. G., van de Sluis, B., et al. (2011). Clearance of p16Ink4a-positive senescent cells delays ageing-associated disorders. Nature 479, 232-236. doi: 10.1038/nature10600
12. Bartkova, J., Rezaei, N., Liontos, M., Karakaidos, P., Kletsas, D., Issaeva, N., et al. (2006). Oncogene-induced senescence is part of the tumorigenesis barrier imposed by DNA damage checkpoints. Nature 444, 633-637. doi: 10.1038/nature05268
13. Beerman, I., and Rossi, D. J. (2015). Epigenetic control of stem cell potential during homeostasis. Aging Dis. Cell Stem Cell 16, 613-625. doi: 10.1016/j.stem.2015.05.009
14. Benson, E. K., Lee, S. W., and Aaronson, S. A. (2010). Role of progerin-induced telomere dysfunction in HGPS premature cellular senescence. J. Cell Sci. 123, 2605-2612. doi: 10.1242/jcs.067306
15. Berdasco, M., and Esteller, M. (2012). Hot topics in epigenetic mechanisms of aging: 2011. Aging Cell 11, 181-186. doi: 10.1111/j.1474-9726.2012.00806.x
16. Bernal, G. M., Wahlstrom, J. S., Crawley, C. D., Cahill, K. E., Pytel, P., Liang, H., et al. (2014). Loss of Nfkb1 leads to early onset aging. Aging (Albany NY) 6, 931-943.
17. Bernardes de Jesus, B., Schneeberger, K., Vera, E., Tejera, A., Harley, C. B., and Blasco, M. A. (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. doi: 10.1111/j.1474-9726.2011.00700.x
18. Blagosklonny, M. V. (2003). Cell senescence and hypermitogenic arrest. EMBO Rep. 4, 358-362. doi: 10.1038/sj.embor.embor806
19. Bodnar, A. G. (2015). Cellular and molecular mechanisms of negligible senescence: insight from the sea urchin. Invertebr. Reprod. Dev. 59, 23-27. doi: 10.1080/07924259.2014.938195
20. Bodnar, A. G., Ouellette, M., Frolkis, M., Holt, S. E., Chiu, C. P., Morin, G. B., et al. (1998). Extension of life-span by introduction of telomerase into normal human cells. Science 279, 349-352. doi: 10.1126/science.279.5349.349
21. Boquoi, A., Arora, S., Chen, T., Litwin, S., Koh, J., and Enders, G. H. (2015). Reversible cell cycle inhibition and premature aging features imposed by conditional expression of p16Ink4a. Aging Cell 14, 139-147. doi: 10.1111/acel.12279
22. Botchkarev, V. A., Komarova, E. A., Siebenhaar, F., Botchkareva, N. V., Komarov, P. G., Maurer, M., et al. (2000). p53 is essential for chemotherapy-induced hair loss. Cancer Res. 60, 5002-5006.
23. Campisi, J. (2001). Cellular senescence as a tumor-suppressor mechanism. Trends Cell Biol. 11, S27-S31. doi: 10.1016/S0962-8924(01)02151-1
24. Campisi, J. (2013). Aging, cellular senescence, and cancer. Annu. Rev. Physiol. 75, 685-705. doi: 10.1146/annurev-physiol-030212-183653
25. Carreira, B. P., Morte, M. I., Santos, A. I., Lourenço, A. S., Ambrósio, A. F., Carvalho, C. M., et al. (2014). Nitric oxide from inflammatory origin impairs neural stem cell proliferation by inhibiting epidermal growth factor receptor signaling. Front. Cell Neurosci. 8:343. doi: 10.3389/fncel.2014.00343
26. Cerella, C., Grandjenette, C., Dicato, M., and Diederich, M. (2015). Roles of apoptosis and cellular senescence in cancer and aging. Curr. Drug Targets [Epub ahead of print].
27. Chang, S. (2005). Modeling aging and cancer in the telomerase knockout mouse. Mutat. Res. 576, 39-53. doi: 10.1016/j.mrfmmm.2004.08.020
28. Coppé, J. P., Patil, C. K., Rodier, F., Sun, Y., Muñoz, D. P., Goldstein, J., et al. (2008). Senescence-associated secretory phenotypes reveal cell-nonautonomous functions of oncogenic RAS and the p53 tumor suppressor. PLoS Biol. 6:e301. doi: 10.1371/journal.pbio.0060301
29. Cristofalo, V. J., Allen, R. G., Pignolo, R. J., Martin, B. G., and Beck, J. C. (1998). Relationship between donor age and the replicative lifespan of human cells in culture: a reevaluation. Proc. Natl. Acad. Sci. U.S.A. 95, 10614-10619. doi: 10.1073/pnas.95.18.10614
30. Cruickshanks, H. A., McBryan, T., Nelson, D. M., Vanderkraats, N. D., Shah, P. P., van Tuyn, J., et al. (2013). Senescent cells harbour features of the cancer epigenome. Nat. Cell Biol. 15, 1495-1506. doi: 10.1038/ncb2879
31. d'Adda di Fagagna, F., Reaper, P. M., Clay-Farrace, L., Fiegler, H., Carr, P., Von Zglinicki, T., et al. (2003). A DNA damage checkpoint response in telomere-initiated senescence. Nature 426, 194-198. doi: 10.1038/nature02118
32. Dai, C. Y., and Enders, G. H. (2000). p16 INK4a can initiate an autonomous senescence program. Oncogene 19, 1613-1622. doi: 10.1038/sj.onc.1203438
33. De Cecco, M., Jeyapalan, J., Zhao, X., Tamamori-Adachi, M., and Sedivy, J. M. (2011). Nuclear protein accumulation in cellular senescence and organismal aging revealed with a novel single-cell resolution fluorescence microscopy assay. Aging (Albany NY) 3, 955-967.
34. Di Micco R., Fumagalli, M., Cicalese, A., Piccinin, S., Gasparini, P., Luise, C., et al. (2006). Oncogene-induced senescence is a DNA damage response triggered by DNA hyper-replication. Nature 444, 638-642. doi: 10.1038/nature05327
35. Dimri, G. P., 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. U.S.A. 92, 9363-9367. doi: 10.1073/pnas.92.20.9363
36. Dominguez-Gerpe, L., and Araujo-Vilar, D. (2008). Prematurely aged children: molecular alterations leading to Hutchinson-Gilford progeria and Werner syndromes. Curr. Aging Sci. 1, 202-212. doi: 10.2174/1874609810801030202
37. Dunn, B. (2012). Cancer: solving an age-old problem. Nature 483, S2-S6. doi: 10.1038/483S2a
38. Fisher, G. J., Sachs, D. L., and Voorhees, J. J. (2014). Ageing: collagenase-mediated collagen fragmentation as a rejuvenation target. Br. J. Dermatol. 171, 446-449. doi: 10.1111/bjd.13267
39. Francis, N., Gregg, T., Owen, R., Ebert, T., and Bodnar, A. (2006). Lack of age-associated telomere shortening in long-and short-lived species of sea urchins. FEBS Lett. 580, 4713-4717. doi: 10.1016/j.febslet.2006.07.049
40. Freitas, P., and Carvalho, D. (2013). Lipodystrophy: beyond generalization? Panminerva Med. 55, 253-268.
41. Freund, A., Orjalo, A. V., Desprez, P. Y., and Campisi, J. (2010). Inflammatory networks during cellular senescence: causes and consequences. Trends Mol. Med. 16, 238-246. doi: 10.1016/j.molmed.2010.03.003
42. Fumagalli, M., Rossiello, F., Clerici, M., Barozzi, S., Cittaro, D., Kaplunov, J. M., et al. (2012). Telomeric DNA damage is irreparable and causes persistent DNA-damage-response activation. Nat. Cell Biol. 14, 355-365. doi: 10.1038/ncb2466
43. Gonzalez-Suarez, I., Redwood, A. B., and Gonzalo, S. (2009). Loss of A-type lamins and genomic instability. Cell Cycle 8, 3860-3865. doi: 10.4161/cc.8.23.10092
44. Hänzelmann, S., Beier, F., Gusmao, E. G., Koch, C. M., Hummel, S., Charapitsa, I., et al. (2015). Replicative senescence is associated with nuclear reorganization and with DNA methylation at specific transcription factor binding sites. Clin. Epigenetics 7:19. doi: 10.1186/s13148-015-0057-5
45. Hara, E., Smith, R., Parry, D., Tahara, H., Stone, S., and Peters, G. (1996). Regulation of p16CDKN2 expression and its implications for cell immortalization and senescence. Mol. Cell Biol. 3, 859-867. doi: 10.1128/MCB.16.3.859
46. Hayflick, L. (1965). The limited in vitro lifetime of human diploid cell strains. Exp. Cell Res. 37, 614-636. doi: 10.1016/0014-4827(65)90211-9
47. Hayflick, L. (1994). How and Why We Age? New York, NY: Ballantine Books.
48. Hayflick, L., and Moorhead, P. S. (1961). The serial cultivation of human diploid cell strains. Exp. Cell Res. 25, 585-621. doi: 10.1016/0014-4827(61)90192-6
49. Henderson, T. O., Ness, K. K., and Cohen, H. J. (2014). Accelerated aging among cancer survivors: from pediatrics to geriatrics. Am. Soc. Clin. Oncol. Educ. Book 2014, e423-e430. doi: 10.14694/EdBook_AM.2014.34.e423
50. Henriques, C. M., and Ferreira, M. G. (2012). Consequences of telomere shortening during lifespan. Curr. Opin. Cell Biol. 24, 804-808. doi: 10.1016/j.ceb.2012.09.007
51. Herbig, U., Ferreira, M., Condel, L., Carey, D., and Sedivy, J. M. (2006). Cellular senescence in aging primates. Science 311:1257. doi: 10.1126/science.1122446
52. Herbig, U., Jobling, W. A., Chen, B. P., Chen, D. J., and Sedivy, J. M. (2004). Telomere shortening triggers senescence of human cells through a pathway involving ATM, p53, and p21 (CIP1), but not p16(INK4a). Mol. Cell 14, 501-513. doi: 10.1016/S1097-2765(04)00256-4
53. Hernandez, D. G., Nalls, M. A., Gibbs, J. R., Arepalli, S., van der Brug, M., Chong, S., et al. (2011). Distinct DNA methylation changes highly correlated with chronological age in the human brain. Hum. Mol. Genet. 20, 1164-1172. doi: 10.1093/hmg/ddq561
54. Horvath, S. (2013). DNA methylation age of human tissues and cell types. Genome Biol. 14:R115. doi: 10.1186/gb-2013-14-10-r115
55. Houtkooper, R. H., Williams, R. W., and Auwerx, J. (2010). Metabolic networks of longevity. Cell 142, 9-14. doi: 10.1016/j.cell.2010.06.029
56. Jaskelioff, M., Muller, F. L., Paik, J. H., Thomas, E., Jiang, S., Adams, A. C., et al. (2011). Telomerase reactivation reverses tissue degeneration in aged telomerase-deficient mice. Nature 469, 102-106. doi: 10.1038/nature09603
57. Jeyapalan, J. C., Ferreira, M., Sedivy, J. M., and Herbig, U. (2007). Accumulation of senescent cells in mitotic tissue of aging primates. Mech. Ageing Dev. 128, 36-44. doi: 10.1016/j.mad.2006.11.008
58. Jurk, D., Wilson, C., Passos, J. F., Oakley, F., Correia-Melo, C., Greaves, L., et al. (2014). Chronic inflammation induces telomere dysfunction and accelerates ageing in mice. Nat. Commun. 2:4172. doi: 10.1038/ncomms5172
59. Kelly, D. P. (2011). Cell biology: ageing theories unified. Nature 470, 342-343. doi: 10.1038/nature09896
60. Kirkland, J. L. (2010). Perspectives on cellular senescence and short term dietary restriction in adults. Aging (Albany NY) 2, 542-544.
61. Koch, C. M., Joussen, S., Schellenberg, A., Lin, Q., Zenke, M., and Wagner, W. (2012). Monitoring of cellular senescence by DNA-methylation at specific CpG sites. Aging Cell 11, 366-369. doi: 10.1111/j.1474-9726.2011.00784.x
62. Kosar, M., Bartkova, J., Hubackova, S., Hodny, Z., Lukas, J., and Bartek, J. (2011). Senescence-associated heterochromatin foci are dispensable for cellular senescence, occur in a cell type-and insult-dependent manner and follow expression of p16 (ink4a). Cell Cycle 10, 457-468. doi: 10.4161/cc.10.3.14707
63. Kudlow, B. A., Stanfel, M. N., Burtner, C. R., Johnston, E. D., and Kennedy, B. K. (2008). Suppression of proliferative defects associated with processing-defective lamin A mutants by hTERT or inactivation of p53. Mol. Biol. Cell 19, 5238-5248. doi: 10.1091/mbc.E08-05-0492
64. Kukat, A., Edgar, D., Bratic, I., Maiti, P., and Trifunovic, A. (2011). Random mtDNA mutations modulate proliferation capacity in mouse embryonic fibroblasts. Biochem. Biophys. Res. Commun. 409, 394-399. doi: 10.1016/j.bbrc.2011.04.145
65. Kurz, D. J., Decary, S., Hong, Y., and Erusalimsky, J. D. (2000). Senescence-associated (beta)-galactosidase reflects an increase in lysosomal mass during replicative ageing of human endothelial cells. J. Cell Sci. 113(Pt 20), 3613-3622.
66. Lee, B. Y., Han, J. A., Im, J. S., Morrone, A., Johung, K., Goodwin, E. C., et al. (2006). Senescence-associated beta-galactosidase is lysosomal beta-galactosidase. Aging Cell 5, 187-195. doi: 10.1111/j.1474-9726.2006.00199.x
67. Lorenzini, A., Tresini, M., Austad, S. N., and Cristofalo, V. J. (2005). Cellular replicative capacity correlates primarily with species body mass not longevity. Mech. Aging Dev. 126, 1130-1133. doi: 10.1016/j.mad.2005.05.004
68. Maegawa, S., Hinkal, G., Kim, H. S., Shen, L., Zhang, L., Zhang, J., et al. (2010). Widespread and tissue specific age-related DNA methylation changes in mice. Genome Res. 20, 332-340. doi: 10.1101/gr.096826.109
69. Marioni, R. E., Shah, S., McRae, A. F., Chen, B. H., Colicino, E., Harris, S. E., et al. (2015). DNA methylation age of blood predicts all-cause mortality in later life. Genome Biol. 16:25. doi: 10.1186/s13059-015-0584-6
70. Masuda, K., Kuwano, Y., Nishida, K., and Rokutan, K. (2012). General RBP expression in human tissues as a function of age. Ageing Res. Rev. 11, 423-431. doi: 10.1016/j.arr.2012.01.005
71. Matsui, K., Ezoe, S., Oritani, K., Shibata, M., Tokunaga, M., Fujita, N., et al. (2012). NAD-dependent histone deacetylase, SIRT1, plays essential roles in the maintenance of hematopoietic stem cells. Biochem. Biophys. Res. Commun. 418, 811-817. doi: 10.1016/j.bbrc.2012.01.109
72. Mazzoccoli, G., Tevy, M. F., Borghesan, M., Delle Vergini, M. R., and Vinciguerra, M. (2014). Caloric restriction and aging stem cells: the stick and the carrot? Exp. Gerontol. 50, 137-148. doi: 10.1016/j.exger.2013.10.014
73. Mercken, E. M., Hu, J., Krzysik-Walker, S., Wei, M., Li, Y., McBurney, M. W., et al. (2014). SIRT1 but not its increased expression is essential for lifespan extension in caloric-restricted mice. Aging Cell 13, 193-196. doi: 10.1111/acel.12151
74. Miller, R. A. (2004). Accelerated aging': a primrose path to insight? Aging Cell 3, 47-51. doi: 10.1111/j.1474-9728.2004.00081.x
75. Moiseeva, O., Bourdeau, V., Roux, A., Deschenes-Simard, X., and Ferbeyre, G. (2009). Mitochondrial dysfunction contributes to oncogene-induced senescence. Mol. Cell Biol. 29, 4495-4507. doi: 10.1128/MCB.01868-08
76. Moiseeva, O., Mallette, F. A., Mukhopadhyay, U. K., Moores, A., and Ferbeyre, G. (2006). DNA damage signaling and p53-dependent senescence after prolonged beta-interferon stimulation. Mol. Biol. Cell 17, 1583-1592. doi: 10.1091/mbc.E05-09-0858
77. Nakagawa, S., Lagisz, M., Hector, K. L., and Spencer, H. G. (2012). Comparative and meta-analytic insights into life extension via dietary restriction. Aging Cell 11, 401-409. doi: 10.1111/j.1474-9726.2012.00798.x
78. Ness, K. K., Krull, K. R., Jones, K. E., Mulrooney, D. A., Armstrong, G. T., Green, D. M., et al. (2013). Physiologic frailty as a sign of accelerated aging among adult survivors of childhood cancer: a report from the St Jude Lifetime cohort study. J. Clin. Oncol. 31, 4496-4503. doi: 10.1200/JCO.2013.52.2268
79. Passos, J. F., Saretzki, G., Ahmed, S., Nelson, G., Richter, T., Peters, H., et al. (2007). Mitochondrial dysfunction accounts for the stochastic heterogeneity in telomere-dependent senescence. PLoS Biol. 5:e110. doi: 10.1371/journal.pbio.0050110
80. Pathai, S., Bajillan, H., Landay, A. L., and High, K. P. (2014). Is HIV a model of accelerated or accentuated aging? J. Gerontol. A Biol. Sci. Med. Sci. 69, 833-842. doi: 10.1093/gerona/glt168
81. Payne, B. A., and Chinnery, P. F. (2015). Mitochondrial dysfunction in aging: much progress but many unresolved questions. Biochim. Biophys. Acta 1847, 1347-1353. doi: 10.1016/j.bbabio.2015.05.022
82. Petralia, R. S., Mattson, M. P., and Yao, P. J. (2014). Aging and longevity in the simplest animals and the quest for immortality. Ageing Res. Rev. 16, 66-82. doi: 10.1016/j.arr.2014.05.003
83. Pfefferbaum, A., Rogosa, D. A., Rosenbloom, M. J., Chu, W., Sassoon, S. A., Kemper, C. A., et al. (2014). Accelerated aging of selective brain structures in human immunodeficiency virus infection: a controlled, longitudinal magnetic resonance imaging study. Neurobiol. Aging 235, 1755-1768. doi: 10.1016/j.neurobiolaging.2014.01.008
84. Potten, C. S., and Loeffler, M. (1990). Stem cells: attributes, cycles, spirals, pitfalls and uncertainties. Lessons for and from the crypt. Development 110, 1001-1020.
85. Pruitt, S. C., Freeland, A., Rusiniak, M. E., Kunnev, D., and Cady, G. K. (2013). Cdkn1b overexpression in adult mice alters the balance between genome and tissue ageing. Nat. Commun. 4:2626. doi: 10.1038/ncomms3626
86. Quan, T., Little, E., Quan, H., Qin, Z., Voorhees, J. J., Fisher, G. J., et al. (2013). Elevated matrix metalloproteinases and collagen fragmentation in photodamaged human skin: impact of altered extracellular matrix microenvironment on dermal fibroblast function. J. Invest. Dermatol. 133, 1362-1366. doi: 10.1038/jid.2012.509
87. Rando, T. A., and Chang, H. Y. (2012). Aging, rejuvenation, and epigenetic reprogramming: resetting the aging clock. Cell 148, 46-57. doi: 10.1016/j.cell.2012.01.003
88. Rickabaugh, T. M., Baxter, R. M., Sehl, M., Sinsheimer, J. S., Hultin, P. M., Hultin, L. E., et al. (2015). Acceleration of age-associated methylation patterns in HIV-1-infected adults. PLoS ONE 10:e0119201. doi: 10.1371/journal.pone.0119201
89. Rodier, F., and Campisi, J. (2011). Four faces of cellular senescence. J. Cell Biol. 192, 547-556. doi: 10.1083/jcb.201009094
90. Rohme, D. (1981). Evidence for a relatioship between longetivity of mammalian species and life spans of normal fibroblasts in vitro and erythrocytes in vivo. Proc. Natl. Acad. Sci. U.S.A. 78:5. doi: 10.1073/pnas.78.8.5009
91. Rowland, B. D., Denissov, S. G., Douma, S., Stunnenberg, H. G., Bernards, R., and Peeper, D. S. (2002). E2F transcriptional repressor complexes are critical downstream targets of p19(ARF)/p53-induced proliferative arrest. Cancer Cell 2, 55-65. doi: 10.1016/S1535-6108(02)00085-5
92. Saha, B., Zitnik, G., Johnson, S., Nguyen, Q., Risques, R. A., Martin, G. M., et al. (2013). DNA damage accumulation and TRF2 degradation in atypical Werner syndrome fibroblasts with LMNA mutations. Front. Genet. 4:129. doi: 10.3389/fgene.2013.00129
93. Sahin, E., Colla, S., Liesa, M., Moslehi, J., Müller, F. L., Guo, M., et al. (2011). Telomere dysfunction induces metabolic and mitochondrial compromise. Nature 470, 359-365. doi: 10.1038/nature09787
94. Salama, R., Sadaie, M., Hoare, M., and Narita, M. (2014). Cellular senescence and its effector programs. Genes Dev. 28, 99-114. doi: 10.1101/gad.235184.113
95. Salk, D., Bryant, E., Au, K., Hoehn, H., and Martin, G. M. (1981). Systematic growth studies, cocultivation, and cell hybridization studies of Werner syndrome cultured skin fibroblasts. Hum. Genet. 58, 310-316. doi: 10.1007/BF00294930
96. Salminen, A., and Kaarniranta, K. (2012). AMP-activated protein kinase (AMPK) controls the aging process via an integrated signaling network. Ageing Res. Rev. 11, 230-241. doi: 10.1016/j.arr.2011.12.005
97. Salminen, A., Ojala, J., Kaarniranta, K., Haapasalo, A., Hiltunen, M., and Soininen, H. (2011). Astrocytes in the aging brain express characteristics of senescence-associated secretory phenotype. Eur. J. Neurosci. 34, 3-11. doi: 10.1111/j.1460-9568.2011.07738.x
98. Schellenberg, A., Mauen, S., Koch, C. M., Jans, R., de Waele, P., and Wagner, W. (2014). Proof of principle: quality control of therapeutic cell preparations using senescence-associated DNA-methylation changes. BMC Res. Notes 7:254. doi: 10.1186/1756-0500-7-254
99. Schneider, E. L., and Mitsui, Y. (1976). The relationship between in vitro cellular aging and in vivo human age. Proc. Natl. Acad. Sci. U.S.A. 73:5. doi: 10.1073/pnas.73.10.3584
100. Sen, P., Dang, W., Donahue, G., Dai, J., Dorsey, J., Cao, X., et al. (2015). H3K36 methylation promotes longevity by enhancing transcriptional fidelity. Genes Dev. 29, 1362-1376. doi: 10.1101/gad.263707.115
101. Serrano, M., Lin, A. W., McCurrach, M. E., Beach, D., and Lowe, S. W. (1997). Oncogenic ras provokes premature cell senescence associated with accumulation of p53 and p16INK4a. Cell 88, 593-602. doi: 10.1016/S0092-8674(00)81902-9
102. Shah, P. P., Donahue, G., Otte, G. L., Capell, B. C., Nelson, D. M., Cao, K., et al. (2013). Lamin B1 depletion in senescent cells triggers large-scale changes in gene expression and the chromatin landscape. Genes Dev. 27, 1787-1799. doi: 10.1101/gad.223834.113
103. Shawi, M., and Autexier, C. (2008). Telomerase, senescence and ageing. Mech. Ageing Dev. 129, 3-10. doi: 10.1016/j.mad.2007.11.007
104. Shay, J. W. (1999). At the end of the millennium, a view of the end. Nat. Genet. 23, 382-383. doi: 10.1038/70480
105. Shay, J. W., and Wright, W. E. (2010). Telomeres and telomerase in normal and cancer stem cells. FEBS Lett. 584, 3819-3825. doi: 10.1016/j.febslet.2010.05.026
106. Shay, J. W., Wright, W. E., and Werbin, H. (1991). Defining the molecular mechanisms of human cell immortalization. Biochim. Biophys. Acta 1072, 1-7.
107. Shelton, D. N., Chang, E., Whittier, P. S., Choi, D., and Funk, W. D. (1999). Microarray analysis of replicative senescence. Curr. Biol. 9, 939-945. doi: 10.1016/S0960-9822(99)80420-5
108. Simonsen, J. L., Rosada, C., Serakinci, N., Justesen, J., Stenderup, K., Rattan, S. I., et al. (2002). Telomerase expression extends the proliferative life-span and maintains the osteogenic potential of human bone marrow stromal cells. Nat. Biotechnol. 20, 592-596. doi: 10.1038/nbt0602-592
109. Small, D. M., Bennett, N. C., Roy, S., Gabrielli, B. G., Johnson, D. W., and Gobe, G. C. (2012). Oxidative stress and cell senescence combine to cause maximal renal tubular epithelial cell dysfunction and loss in an in vitro model of kidney disease. Nephron. Exp. Nephrol. 122, 123-130. doi: 10.1159/000350726
110. Stein, G. H., Drullinger, L. F., Soulard, A., and Dulic, V. (1999). Differential roles for cyclin-dependent kinase inhibitors p21 and p16 in the mechanisms of senescence and differentiation in human fibroblasts. Mol. Cell Biol. 19, 2109-2117. doi: 10.1128/MCB.19.3.2109
111. Swindell, W. R. (2012). Dietary restriction in rats and mice: a meta-analysis and review of the evidence for genotype-dependent effects on lifespan. Ageing Res. Rev. 11, 254-270. doi: 10.1016/j.arr.2011.12.006
112. Takahashi, A., Ohtani, N., Yamakoshi, K., Iida, S., Tahara, H., Nakayama, K., et al. (2006). Mitogenic signalling and the p16INK4a-Rb pathway cooperate to enforce irreversible cellular senescence. Nat. Cell Biol. 8, 1291-1297. doi: 10.1038/ncb1491
113. Takai, H., Smogorzewska, A., and de Lange, T. (2003). DNA damage foci at dysfunctional telomeres. Curr. Biol. 13, 1549-1556. doi: 10.1016/S0960-9822(03)00542-6
114. Thompson, S. L., and Compton, D. A. (2010). Proliferation of aneuploid human cells is limited by a p53-dependent mechanism. J. Cell Biol. 188, 369-381. doi: 10.1083/jcb.200905057
115. Varga, R., Eriksson, M., Erdos, M. R., Olive, M., Harten, I., Kolodgie, F., et al. (2006). Progressive vascular smooth muscle cell defects in a mouse model of Hutchinson-Gilford progeria syndrome. Proc. Natl. Acad. Sci. U.S.A. 103, 3250-3255. doi: 10.1073/pnas.0600012103
116. Vaziri, H., and Benchimol, S. (1998). Reconstitution of telomerase activity in normal human cells leads to elongation of telomeres and extended replicative life span. Curr. Biol. 8, 279-282. doi: 10.1016/S0960-9822(98)70109-5
117. von Zglinicki, T. (2002). Oxidative stress shortens telomeres. Trends Biochem. Sci. 27, 339-344. doi: 10.1016/S0968-0004(02)02110-2
118. von Zglinicki, T., Saretzki, G., Docke, W., and Lotze, C. (1995). Mild hyperoxia shortens telomeres and inhibits proliferation of fibroblasts: a model for senescence? Exp. Cell Res. 220, 186-193. doi: 10.1006/excr.1995.1305
119. Wang, C., Jurk, D., Maddick, M., Nelson, G., Martin-Ruiz, C., and von Zglinicki, T. (2009). DNA damage response and cellular senescence in tissues of aging mice. Aging Cell 8, 311-323. doi: 10.1111/j.1474-9726.2009.00481.x
120. Wang, C., Maddick, M., Miwa, S., Jurk, D., Czapiewski, R., Saretzki, G., et al. (2010). Adult-onset, short-term dietary restriction reduces cell senescence in mice. Aging (Albany NY) 2, 555-566.
121. Wang, P., Han, L., Shen, H., Wang, P., Lv, C., Zhao, G., et al. (2014). Protein kinase D1 is essential for Ras-induced senescence and tumor suppression by regulating senescence-associated inflammation. Proc. Natl. Acad. Sci. U.S.A. 111, 7683-7688. doi: 10.1073/pnas.1310972111
122. Weismann, A. (1891). Essays Upon Heridity and Kindered Bilogical Problems. London: Clarendon Press.
123. West, M. D. (2003). Back to Immortality: the opportunities and challenges of therapeutic cloning. Life Extensions 9, 63-70.
124. White, R. R., Milholland, B., de Bruin, A., Curran, S., Laberge, R. M., van Steeg, H., et al. (2015). Controlled induction of DNA double-strand breaks in the mouse liver induces features of tissue ageing. Nat. Commun. 6:6790. doi: 10.1038/ncomms7790
125. Williams, G. C. (1957). Pleiotropy, natural selection and the evolution of senescence. Evolution 11, 398-411. doi: 10.2307/2406060
126. Xie, G., Wang, H., Yan, Z., Cai, L., Zhou, G., He, W., et al. (2015). Testing chemotherapeutic agents in the feather follicle identifies a selective blockade of cell proliferation and a key role for sonic hedgehog signaling in chemotherapy-induced tissue damage. J. Invest. Dermatol. 135, 690-700. doi: 10.1038/jid.2014.409
127. Zhang, W., Ji, W., Yang, J., Yang, L., Chen, W., and Zhuang, Z. (2008). Comparison of global DNA methylation profiles in replicative versus premature senescence. Life Sci. 83, 475-480. doi: 10.1016/j.lfs.2008.07.015
128. Zhu, Y., Tchkonia, T., Pirtskhalava, T., Gower, A. C., Ding, H., Giorgadze, N., et al. (2015). The Achilles' heel of senescent cells: from transcriptome to senolytic drugs. Aging Cell 14, 644-658. doi: 10.1111/acel.12344
129. Ziegler, D. V., Wiley, C. D., and Velarde, M. C. (2015). Mitochondrial effectors of cellular senescence: beyond the free radical theory of aging. Aging Cell 14, 1-7. doi: 10.1111/acel.12287
130. Zindy, F., Quelle, D. E., Roussel, M. F., and Sherr, C. J. (1997). Expression of the p16INK4a tumor suppressor versus other INK4 family members during mouse development and aging. Oncogene 15, 203-211. doi: 10.1038/sj.onc.1201178
131. Zwerschke, W., Mazurek, S., Stöckl, P., Hütter, E., Eigenbrodt, E., and Jansen-Dürr, P. (2003). Metabolic analysis of senescent human fibroblasts reveals a role for AMP in cellular senescence. Biochem. J. 376, 403-411. doi: 10.1042/bj20030816