Senescent cells: SASPected drivers of age-related pathologies

Biogerontology

Volumn 15, Issue 6, 2014, Pages 627-642

  Ovadya, Yossi ^a   Krizhanovsky, Valery ^a  

^a WEIZMANN INSTITUTE OF SCIENCE   (Israel)

Author keywords

Age related diseases; Cellular senescence; Immune surveillance

Indexed keywords

AGING; ALZHEIMER DISEASE; ATHEROSCLEROSIS; BIOACCUMULATION; CANCER IMMUNOTHERAPY; CATARACT; CELL CYCLE ARREST; CELL DAMAGE; CHRONIC INFLAMMATION; CHRONIC OBSTRUCTIVE LUNG DISEASE; DEGENERATIVE DISEASE; DETERIORATION; EPIGENETICS; GENOMIC INSTABILITY; HUMAN; IMMUNE SYSTEM; IMMUNOSURVEILLANCE; MICROENVIRONMENT; NON INSULIN DEPENDENT DIABETES MELLITUS; NONHUMAN; OSTEOPOROSIS; PHENOTYPE; PROTEIN HOMEOSTASIS; REVIEW; SENESCENCE; SENESCENCE ASSOCIATED SECRETORY PHENOTYPE; TELOMERE; AGED; ANIMAL; CELL AGING; DIABETES MELLITUS, TYPE 2; DNA DAMAGE; GENETICS; IMMUNOLOGY; MOUSE; NEOPLASMS; PATHOLOGY; PHYSIOLOGY; PROGERIA; PULMONARY DISEASE, CHRONIC OBSTRUCTIVE;

AGED; AGING; ALZHEIMER DISEASE; ANIMALS; ATHEROSCLEROSIS; CATARACT; CELL AGING; DIABETES MELLITUS, TYPE 2; DNA DAMAGE; GENOMIC INSTABILITY; HUMANS; IMMUNOLOGIC SURVEILLANCE; MICE; NEOPLASMS; OSTEOPOROSIS; PROGERIA; PULMONARY DISEASE, CHRONIC OBSTRUCTIVE;

EID: 84914818823     PISSN: 13895729     EISSN: 15736768     Source Type: Journal    
DOI: 10.1007/s10522-014-9529-9     Document Type: Review

References (151)

1. Abramov AY, Canevari L, Duchen MR (2004) Beta-amyloid peptides induce mitochondrial dysfunction and oxidative stress in astrocytes and death of neurons through activation of NADPH oxidase. J Neurosci 24:565–575. doi:10.1523/JNEUROSCI.4042-03.2004
2. Acosta JC et al (2008) Chemokine signaling via the CXCR2 receptor reinforces senescence. Cell 133:1006–1018
3. Akiyama H et al (2000) Inflammation and Alzheimer’s disease. Neurobiol Aging 21:383–421
4. Allaman I, Gavillet M, Belanger M, Laroche T, Viertl D, Lashuel HA, Magistretti PJ (2010) Amyloid-beta aggregates cause alterations of astrocytic metabolic phenotype: impact on neuronal viability. J Neurosci 30:3326–3338. doi:10.1523/JNEUROSCI.5098-09.2010
5. Allen, D. and A. Vasavada (2006) Cataract and surgery for cataract. BMJ 333(7559): 128–132.
6. Alwan A (2011) Global status report on noncommunicable diseases 2010. World Health Organization
7. Aoshiba K, Nagai A (2009) Senescence hypothesis for the pathogenetic mechanism of chronic obstructive pulmonary disease. Proc Am Thorac Soc 6:596–601. doi:10.1513/pats.200904-017RM
8. Asbell PA, Dualan I, Mindel J, Brocks D, Ahmad M, Epstein S (2005) Age-related cataract. Lancet 365:599–609. doi:10.1016/S0140-6736(05)17911-2
9. Babizhayev MA, Vishnyakova KS, Yegorov YE (2011) Telomere-dependent senescent phenotype of lens epithelial cells as a biological marker of aging and cataractogenesis: the role of oxidative stress intensity and specific mechanism of phospholipid hydroperoxide toxicity in lens and aqueous. Fundam Clin Pharmacol 25:139–162. doi:10.1111/j.1472-8206.2010.00829.x
10. Baker DJ, Jeganathan KB, Malureanu L, Perez-Terzic C, Terzic A, van Deursen JM (2006) Early aging-associated phenotypes in Bub3/Rae1 haploinsufficient mice. J Cell Biol 172:529–540. doi:10.1083/jcb.200507081
11. Baker DJ et al (2011) Clearance of p16Ink4a-positive senescent cells delays ageing-associated disorders. Nature 479:232–236. doi:10.1038/nature10600
12. Baker DJ, Weaver RL, van Deursen JM (2013) p21 both attenuates and drives senescence and aging in BubR1 progeroid mice Cell reports 3:1164–1174
13. Baxter MA, Wynn RF, Jowitt SN, Wraith JE, Fairbairn LJ, Bellantuono I (2004) Study of telomere length reveals rapid aging of human marrow stromal cells following in vitro expansion. Stem Cells 22:675–682. doi:10.1634/stemcells.22-5-675
14. Benisch P et al (2012) The transcriptional profile of mesenchymal stem cell populations in primary osteoporosis is distinct and shows overexpression of osteogenic inhibitors. PLoS ONE 7:e45142. doi:10.1371/journal.pone.0045142
15. Bernhagen J et al (2007) MIF is a noncognate ligand of CXC chemokine receptors in inflammatory and atherogenic cell recruitment. Nat Med 13:587–596. doi:10.1038/nm1567
16. Bhat R et al (2012) Astrocyte senescence as a component of Alzheimer’s disease. PLoS ONE 7:e45069. doi:10.1371/journal.pone.0045069
17. Blackburn EH, Greider CW, Szostak JW (2006) Telomeres and telomerase: the path from maize, Tetrahymena and yeast to human cancer and aging. Nat Med 12:1133–1138. doi:10.1038/nm1006-1133
18. Braumuller H et al (2013) T-helper-1-cell cytokines drive cancer into senescence. Nature 494:361–365. doi:10.1038/nature11824
19. Budovsky A, Muradian KK, Fraifeld VE (2006) From disease-oriented to aging/longevity-oriented studies. Rejuvenation Res 9:207–210. doi:10.1089/rej.2006.9.207
20. Burton DG et al (2009) Microarray analysis of senescent vascular smooth muscle cells: a link to atherosclerosis and vascular calcification. Exp Gerontol 44:659–665. doi:10.1016/j.exger.2009.07.004
21. Campisi J, d’Adda di Fagagna F (2007) Cellular senescence: when bad things happen to good cells. Nat Rev Mol Cell Biol 8:729–740
22. Campisi J (2013) Aging, cellular senescence, and cancer. Annu Rev Physiol 75:685–705. doi:10.1146/annurev-physiol-030212-183653
23. Campisi J, Andersen JK, Kapahi P, Melov S (2011) Cellular senescence: a link between cancer and age-related degenerative disease? Semin Cancer Biol 21:354–359. doi:10.1016/j.semcancer.2011.09.001
24. Collado M et al (2005) Tumour biology: senescence in premalignant tumours. Nature 436:642
25. Congdon NG, Friedman DS, Lietman T (2003) Important causes of visual impairment in the world today. JAMA 290:2057–2060. doi:10.1001/jama.290.15.2057
26. Coppe JP et al (2008) Senescence-associated secretory phenotypes reveal cell-nonautonomous functions of oncogenic RAS and the p53 tumor suppressor. PLoS Biol 6:2853–2868
27. Cutler RG, Mattson MP (2006) The adversities of aging. Ageing Res Rev 5:221–238. doi:10.1016/j.arr.2006.05.002
28. Demidenko ZN, Zubova SG, Bukreeva EI, Pospelov VA, Pospelova TV, Blagosklonny MV (2009) Rapamycin decelerates cellular senescence. Cell Cycle 8:1888–1895
29. DePinho RA (2000) The age of cancer. Nature 408:248–254. doi:10.1038/35041694
30. di Fagagna FDA et al (2003) A DNA damage checkpoint response in telomere-initiated senescence. Nature 426:194–198. doi:10.1038/nature02118
31. Di Leonardo A, Linke SP, Clarkin K, Wahl GM (1994) DNA damage triggers a prolonged p53-dependent G1 arrest and long-term induction of Cip1 in normal human fibroblasts. Genes Dev 8:2540–2551
32. Dimri GP et al (1995) A biomarker that identifies senescent human cells in culture and in aging skin in vivo. Proc Natl Acad Sci USA 92:9363–9367
33. Ding G, Franki N, Kapasi AA, Reddy K, Gibbons N, Singhal PC (2001) Tubular cell senescence and expression of TGF-beta1 and p21(WAF1/CIP1) in tubulointerstitial fibrosis of aging rats. Exp Mol Pathol 70:43–53. doi:10.1006/exmp.2000.2346
34. Ding Z et al (2012) Telomerase reactivation following telomere dysfunction yields murine prostate tumors with bone metastases. Cell 148:896–907. doi:10.1016/j.cell.2012.01.039
35. Donath MY, Shoelson SE (2011) Type 2 diabetes as an inflammatory disease. Nat Rev Immunol 11:98–107
36. Erusalimsky JD, Kurz DJ (2005) Cellular senescence in vivo: its relevance in ageing and cardiovascular disease. Exp Gerontol 40:634–642. doi:10.1016/j.exger.2005.04.010
37. Feldser DM, Greider CW (2007) Short telomeres limit tumor progression in vivo by inducing senescence. Cancer Cell 11:461–469. doi:10.1016/j.ccr.2007.02.026
38. Fernandez AF et al (2012) A DNA methylation fingerprint of 1628 human samples. Genome Res 22:407–419. doi:10.1101/gr.119867.110
39. Fontana L (2009) Modulating human aging and age-associated diseases. Biochim Biophys Acta 1790:1133–1138. doi:10.1016/j.bbagen.2009.02.002
40. Freund A, Orjalo AV, Desprez PY, 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
41. Freund A, Laberge RM, Demaria M, Campisi J (2012) Lamin B1 loss is a senescence-associated biomarker. Mol Biol Cell 23:2066–2075. doi:10.1091/mbc.E11-10-0884
42. Geissmann F, Manz MG, Jung S, Sieweke MH, Merad M, Ley K (2010) Development of monocytes, macrophages, and dendritic cells. Science 327:656–661. doi:10.1126/science.1178331
43. Ginaldi L, Di Benedetto MC, De Martinis M (2005) Osteoporosis, inflammation and ageing. Immun Ageing 2:14. doi:10.1186/1742-4933-2-14
44. Glass CK, Saijo K, Winner B, Marchetto MC, Gage FH (2010) Mechanisms underlying inflammation in neurodegeneration. Cell 140:918–934. doi:10.1016/j.cell.2010.02.016
45. Gorenne I, Kavurma M, Scott S, Bennett M (2006) Vascular smooth muscle cell senescence in atherosclerosis. Cardiovasc Res 72:9–17. doi:10.1016/j.cardiores.2006.06.004
46. Gorgoulis VG et al (2005) p53-dependent ICAM-1 overexpression in senescent human cells identified in atherosclerotic lesions. Lab Invest 85:502–511. doi:10.1038/labinvest.3700241
47. Goronzy JJ, Weyand CM (2013) Understanding immunosenescence to improve responses to vaccines. Nat Immunol 14:428–436
48. Hayakawa Y, Smyth MJ (2006) NKG2D and cytotoxic effector function in tumor immune surveillance. Semin Immunol 18:176–185. doi:10.1016/j.smim.2006.03.005
49. Hayflick L (1965) The limited in vitro lifetime of human diploid cell strains. Exp Cell Res 37:614–636
50. Hazeldine J, Lord JM (2013) The impact of ageing on natural killer cell function and potential consequences for health in older adults. Ageing Res Rev 12:1069–1078
51. Hecker L et al. (2014) Reversal of persistent fibrosis in aging by targeting Nox4-Nrf2 redox imbalance. Sci Trans Med 6. 10.1126/scitranslmed.3008182
52. Hekimi S (2006) How genetic analysis tests theories of animal aging. Nat Genet 38:985–991. doi:10.1038/ng1881
53. Hemann MT, Strong MA, Hao LY, Greider CW (2001) The shortest telomere, not average telomere length, is critical for cell viability and chromosome stability. Cell 107:67–77
54. Herbig U, Jobling WA, Chen BP, Chen DJ, Sedivy JM (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
55. Herbig U, Ferreira M, Condel L, Carey D, Sedivy JM (2006) Cellular senescence in aging primates. Science 311:1257. doi:10.1126/science.1122446
56. Herndler-Brandstetter D, Weinberger B, Pfister G, Weiskopf D, Grubeck-Loebenstein B (2011) The aging of the adaptive immune system. Curr Immunol Rev 7:94–103
57. Herranz D, Munoz-Martin M, Canamero M, Mulero F, Martinez-Pastor B, Fernandez-Capetillo O, Serrano M (2010) Sirt1 improves healthy ageing and protects from metabolic syndrome-associated cancer. Nat Commun 1:3. doi:10.1038/ncomms1001
58. Hoal-van Helden EG, van Helden PD (1989) Age-related methylation changes in DNA may reflect the proliferative potential of organs. Mutat Res 219:263–266
59. Hoeijmakers JH (2009) DNA damage, aging, and cancer. N Engl J Med 361:1475–1485. doi:10.1056/NEJMra0804615
60. Holdt LM, Sass K, Gabel G, Bergert H, Thiery J, Teupser D (2011) Expression of Chr9p21 genes CDKN2B (p15(INK4b)), CDKN2A (p16(INK4a), p14(ARF)) and MTAP in human atherosclerotic plaque. Atherosclerosis 214:264–270. doi:10.1016/j.atherosclerosis.2010.06.029
61. Houghton AM (2013) Mechanistic links between COPD and lung cancer. Nat Rev Cancer 13:233–245
62. Iannello A, Raulet DH (2013) Immune Surveillance of Unhealthy Cells by Natural Killer Cells Cold Spring Harb Symp Quant Biol. doi:10.1101/sqb.2013.78.020255
63. Issa JP, Ottaviano YL, Celano P, Hamilton SR, Davidson NE, Baylin SB (1994) Methylation of the oestrogen receptor CpG island links ageing and neoplasia in human colon. Nat Genet 7:536–540. doi:10.1038/ng0894-536
64. Issa JP, Vertino PM, Boehm CD, Newsham IF, Baylin SB (1996) Switch from monoallelic to biallelic human IGF2 promoter methylation during aging and carcinogenesis. Proc Natl Acad Sci USA 93:11757–11762
65. Jacobs JJ, de Lange T (2004) Significant role for p16INK4a in p53-independent telomere-directed senescence. Curr Biol 14:2302–2308. doi:10.1016/j.cub.2004.12.025
66. Janzen V et al (2006) Stem-cell ageing modified by the cyclin-dependent kinase inhibitor p16INK4a. Nature 443:421–426
67. Joyce JA, Pollard JW (2009) Microenvironmental regulation of metastasis. Nat Rev Cancer 9:239–252. doi:10.1038/nrc2618
68. Kanfi Y et al (2012) The sirtuin SIRT6 regulates lifespan in male mice. Nature 483:218–221. doi:10.1038/nature10815
69. Kang TW et al (2011) Senescence surveillance of pre-malignant hepatocytes limits liver cancer development. Nature 479:547–551. doi:10.1038/nature10599
70. Kassem M, Marie PJ (2011) Senescence-associated intrinsic mechanisms of osteoblast dysfunctions. Aging Cell 10:191–197. doi:10.1111/j.1474-9726.2011.00669.x
71. Klose RJ, Bird AP (2006) Genomic DNA methylation: the mark and its mediators. Trends Biochem Sci 31:89–97. doi:10.1016/j.tibs.2005.12.008
72. Knudson AG (2000) Chasing the cancer demon. Annu Rev Genet 34:1–19. doi:10.1146/annurev.genet.34.1.1
73. Kouzarides T (2007) Chromatin modifications and their function. Cell 128:693–705. doi:10.1016/j.cell.2007.02.005
74. Krishnamurthy J, Torrice C, Ramsey MR, Kovalev GI, Al-Regaiey K, Su L, Sharpless NE (2004) Ink4a/Arf expression is a biomarker of aging. J Clin Invest 114:1299–1307. doi:10.1172/JCI22475
75. Krizhanovsky V et al (2008) Senescence of activated stellate cells limits liver fibrosis. Cell 134:657–667
76. Krtolica A, Parrinello S, Lockett S, Desprez PY, Campisi J (2001) Senescent fibroblasts promote epithelial cell growth and tumorigenesis: a link between cancer and aging. Proc Natl Acad Sci USA 98:12072–12077
77. Kuilman T et al (2008) Oncogene-induced senescence relayed by an interleukin-dependent inflammatory network. Cell 133:1019–1031
78. Laberge RM et al (2012) Glucocorticoids suppress selected components of the senescence-associated secretory phenotype. Aging Cell 11:569–578. doi:10.1111/j.1474-9726.2012.00818.x
79. Lambers C et al (2009) T cell senescence and contraction of T cell repertoire diversity in patients with chronic obstructive pulmonary disease. Clin Exp Immunol 155:466–475. doi:10.1111/j.1365-2249.2008.03835.x
80. Liang R, Bates DJ, Wang E (2009) Epigenetic control of microRNA expression and aging. Curr Genom 10:184–193. doi:10.2174/138920209788185225
81. Libby P (2002) Inflammation in atherosclerosis. Nature 420:868–874. doi:10.1038/nature01323
82. Liu D, Hornsby PJ (2007) Senescent human fibroblasts increase the early growth of xenograft tumors via matrix metalloproteinase secretion. Cancer Res 67:3117–3126. doi:10.1158/0008-5472.CAN-06-3452
83. Lopez-Otin C, Blasco MA, Partridge L, Serrano M, Kroemer G (2013) The hallmarks of aging. Cell 153:1194–1217. doi:10.1016/j.cell.2013.05.039
84. Lujambio A et al (2013) Non-cell-autonomous tumor suppression by p53. Cell 153:449–460. doi:10.1016/j.cell.2013.03.020
85. Lv XX et al (2013) Rupatadine protects against pulmonary fibrosis by attenuating PAF-mediated senescence in rodents. Plos One 8:e68631. doi:10.1371/journal.pone.0068631
86. Maegawa S 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
87. Malavolta M, Basso A, Piacenza F, Costarelli L, Giacconi R, Mocchegiani E (2013) Peripheral mononuclear cell rejuvenation for senescence surveillance in Alzheimer disease. Curr Pharm Des 19:1720–1726
88. Mantovani A, Biswas SK, Galdiero MR, Sica A, Locati M (2013) Macrophage plasticity and polarization in tissue repair and remodelling. J Pathol 229:176–185. doi:10.1002/path.4133
89. Mao Z, Tian X, Van Meter M, Ke Z, Gorbunova V, Seluanov A (2012) Sirtuin 6 (SIRT6) rescues the decline of homologous recombination repair during replicative senescence. Proc Natl Acad Sci USA 109:11800–11805. doi:10.1073/pnas.1200583109
90. Markowski DN, Thies HW, Gottlieb A, Wenk H, Wischnewsky M, Bullerdiek J (2013) HMGA2 expression in white adipose tissue linking cellular senescence with diabetes. Genes Nutr 8:449–456
91. Martens UM, Chavez EA, Poon SS, Schmoor C, Lansdorp PM (2000) Accumulation of short telomeres in human fibroblasts prior to replicative senescence. Exp Cell Res 256:291–299. doi:10.1006/excr.2000.4823
92. Martinez P, Blasco MA (2011) Telomeric and extra-telomeric roles for telomerase and the telomere-binding proteins. Nat Rev Cancer 11:161–176. doi:10.1038/nrc3025
93. Min JN, Whaley RA, Sharpless NE, Lockyer P, Portbury AL, Patterson C (2008) CHIP deficiency decreases longevity, with accelerated aging phenotypes accompanied by altered protein quality control. Mol Cell Biol 28:4018–4025. doi:10.1128/MCB.00296-08
94. Minagawa S et al (2011) Accelerated epithelial cell senescence in IPF and the inhibitory role of SIRT6 in TGF-beta-induced senescence of human bronchial epithelial cells. Am J Physiol Lung Cell Mol Physiol 300:L391–401. doi:10.1152/ajplung.00097.2010
95. Minamino T, Komuro I (2007) Vascular cell senescence: contribution to atherosclerosis. Circ Res 100:15–26. doi:10.1161/01.RES.0000256837.40544.4a
96. Minamino T, Miyauchi H, Yoshida T, Ishida Y, Yoshida H, Komuro I (2002) Endothelial cell senescence in human atherosclerosis: role of telomere in endothelial dysfunction. Circulation 105:1541–1544
97. Minamino T et al (2009) A crucial role for adipose tissue p53 in the regulation of insulin resistance. Nat Med 15:1082–1087. doi:10.1038/nm.2014
98. Moiseeva O et al (2013) Metformin inhibits the senescence-associated secretory phenotype by interfering with IKK/NF-kappaB activation. Aging Cell 12:489–498. doi:10.1111/acel.12075
99. Moskalev AA, Shaposhnikov MV, Plyusnina EN, Zhavoronkov A, Budovsky A, Yanai H, Fraifeld VE (2013) The role of DNA damage and repair in aging through the prism of Koch-like criteria. Ageing Research Rev 12:661–684
100. Murray PJ, Wynn TA (2011) Protective and pathogenic functions of macrophage subsets. Nat Rev Immunol 11:723–737. doi:10.1038/nri3073
101. Narita M et al (2003) Rb-mediated heterochromatin formation and silencing of E2F target genes during cellular senescence. Cell 113:703–716
102. Paoletti R, Gotto AM Jr, Hajjar DP (2004) Inflammation in atherosclerosis and implications for therapy. Circulation 109:III20–III26. doi:10.1161/01.CIR.0000131514.71167.2e
103. Parrinello S, Samper E, Krtolica A, Goldstein J, Melov S, Campisi J (2003) Oxygen sensitivity severely limits the replicative lifespan of murine fibroblasts. Nat Cell Biol 5:741–747. doi:10.1038/ncb1024
104. Pazolli E, Alspach E, Milczarek A, Prior J, Piwnica-Worms D, Stewart SA (2012) Chromatin remodeling underlies the senescence-associated secretory phenotype of tumor stromal fibroblasts that supports cancer progression. Cancer Res 72:2251–2261. doi:10.1158/0008-5472.CAN-11-3386
105. Pendergrass WR et al (1999) Cellular proliferation potential during aging and caloric restriction in rhesus monkeys (Macaca mulatta). J Cell Physiol 180:123–130. doi:10.1002/(SICI)1097-4652(199907)180:1<123:AID-JCP14>3.0.CO;2-W
106. Perry VH, Nicoll JA, Holmes C (2010) Microglia in neurodegenerative disease. Nat Rev Neurol 6:193–201. doi:10.1038/nrneurol.2010.17
107. Pribluda A et al (2013) A senescence-inflammatory switch from cancer-inhibitory to cancer-promoting mechanism. Cancer Cell 24:242–256. doi:10.1016/j.ccr.2013.06.005
108. Qian BZ, Pollard JW (2010) Macrophage diversity enhances tumor progression and metastasis. Cell 141:39–51. doi:10.1016/j.cell.2010.03.014
109. Rattan SI (2014) Aging is not a disease: implications for intervention. Aging Dis 5:196
110. Reginster JY, Burlet N (2006) Osteoporosis: a still increasing prevalence. Bone 38:S4–9. doi:10.1016/j.bone.2005.11.024
111. Ressler S, Bartkova J, Niederegger H, Bartek J, Scharffetter-Kochanek K, Jansen-Durr P, Wlaschek M (2006) p16INK4A is a robust in vivo biomarker of cellular aging in human skin. Aging Cell 5:379–389. doi:10.1111/j.1474-9726.2006.00231.x
112. Rhein V, Baysang G, Rao S, Meier F, Bonert A, Muller-Spahn F, Eckert A (2009) Amyloid-beta leads to impaired cellular respiration, energy production and mitochondrial electron chain complex activities in human neuroblastoma cells. Cell Mol Neurobiol 29:1063–1071. doi:10.1007/s10571-009-9398-y
113. Rhodes CJ (2005) Type 2 diabetes-a matter of ß-cell life and death? Science 307:380–384
114. Rielland M et al (2014) Senescence-associated SIN3B promotes inflammation and pancreatic cancer progression. J Clin Invest 124:2125–2135. doi:10.1172/JCI72619
115. Ryu SJ, Oh YS, Park SC (2007) Failure of stress-induced downregulation of Bcl-2 contributes to apoptosis resistance in senescent human diploid fibroblasts. Cell Death Differ 14:1020–1028. doi:10.1038/sj.cdd.4402091
116. Sagiv A, Krizhanovsky V (2013) Immunosurveillance of senescent cells: the bright side of the senescence program. Biogerontology 14:617–628. doi:10.1007/s10522-013-9473-0
117. Sagiv A, Biran A, Yon M, Simon J, Lowe SW, Krizhanovsky V (2013) Granule exocytosis mediates immune surveillance of senescent cells. Oncogene 32:1971–1977. doi:10.1038/Onc.2012.206
118. Salama R, Sadaie M, Hoare M, Narita M (2014) Cellular senescence and its effector programs. Genes Dev 28:99–114. doi:10.1101/gad.235184.113
119. Saretzki G, Sitte N, Merkel U, Wurm RE, von Zglinicki T (1999) Telomere shortening triggers a p53-dependent cell cycle arrest via accumulation of G-rich single stranded DNA fragments. Oncogene 18:5148–5158. doi:10.1038/sj.onc.1202898
120. Schott JM, Revesz T (2013) Inflammation in Alzheimer’s disease: insights from immunotherapy. Brain 136:2654–2656. doi:10.1093/brain/awt231
121. Sedelnikova OA, Redon CE, Dickey JS, Nakamura AJ, Georgakilas AG, Bonner WM (2010) Role of oxidatively induced DNA lesions in human pathogenesis. Mutat Res 704:152–159. doi:10.1016/j.mrrev.2009.12.005
122. Semerad CL, Liu F, Gregory AD, Stumpf K, Link DC (2002) G-CSF is an essential regulator of neutrophil trafficking from the bone marrow to the blood. Immunity 17:413–423
123. Serrano M, Lin AW, McCurrach ME, Beach D, Lowe SW (1997) Oncogenic ras provokes premature cell senescence associated with accumulation of p53 and p16INK4a. Cell 88:593–602
124. Shaw AC, Goldstein DR, Montgomery RR (2013) Age-dependent dysregulation of innate immunity. Nat Rev Immunol 13:875–887. doi:10.1038/nri3547
125. Shi ST, Gronthos S, Chen SQ, Reddi A, Counter CM, Robey PG, Wang CY (2002) Bone formation by human postnatal bone marrow stromal stem cells is enhanced by telomerase expression. Nat Biotechnol 20:587–591. doi:10.1038/Nbt0602-587
126. Shimi T et al (2011) The role of nuclear lamin B1 in cell proliferation and senescence. Genes Dev 25:2579–2593. doi:10.1101/gad.179515.111
127. Shivshankar P, Boyd AR, Le Saux CJ, Yeh I, Orihuela CJ (2011) Cellular senescence increases expression of bacterial ligands in the lungs and is positively correlated with increased susceptibility to pneumococcal pneumonia. Aging Cell 10:798–806
128. Shivshankar P, Brampton C, Miyasato S, Kasper M, Thannickal VJ, Le Saux CJ (2012) Caveolin-1 Deficiency Protects from Pulmonary Fibrosis by Modulating Epithelial Cell Senescence in Mice. Am J Respir Cell Mol Biol 47:28–36. doi:10.1165/rcmb.2011-0349OC
129. So K et al (2006) Multiple tumor suppressor genes are increasingly methylated with age in non-neoplastic gastric epithelia. Cancer Sci 97:1155–1158. doi:10.1111/j.1349-7006.2006.00302.x
130. Soriani A et al (2009) ATM-ATR-dependent up-regulation of DNAM-1 and NKG2D ligands on multiple myeloma cells by therapeutic agents results in enhanced NK-cell susceptibility and is associated with a senescent phenotype. Blood 113:3503–3511
131. Soskic V, Groebe K, Schrattenholz A (2008) Nonenzymatic posttranslational protein modifications in ageing. Exp Gerontol 43:247–257. doi:10.1016/j.exger.2007.12.001
132. Stein GH, Drullinger LF, Soulard A, 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
133. Stout MB, Tchkonia T, Kirkland JL (2014) The aging adipose organ: lipid redistribution, inflammation, and cellular senescence. In: adipose tissue and adipokines in health and disease. Springer, pp 69–80
134. Swindell WR, Masternak MM, Kopchick JJ, Conover CA, Bartke A, Miller RA (2009) Endocrine regulation of heat shock protein mRNA levels in long-lived dwarf mice. Mech Ageing Dev 130:393–400. doi:10.1016/j.mad.2009.03.004
135. Tacutu R, Budovsky A, Yanai H, Fraifeld VE (2011) Molecular links between cellular senescence, longevity and age-related diseases—a systems biology perspective. Aging 3:1178–1191
136. Takai H, Smogorzewska A, de Lange T (2003) DNA damage foci at dysfunctional telomeres. Curr Biol 13:1549–1556
137. Tchkonia T, Zhu Y, van Deursen J, Campisi J, Kirkland JL (2013) Cellular senescence and the senescent secretory phenotype: therapeutic opportunities. J Clin Invest 123:966–972. doi:10.1172/JCI64098
138. Thannickal VJ (2013) Mechanistic links between aging and lung fibrosis. Biogerontology 14:609–615. doi:10.1007/s10522-013-9451-6
139. Tyner SD et al (2002) p53 mutant mice that display early ageing-associated phenotypes. Nature 415:45–53
140. Vlahos R, Bozinovski S (2014) Recent advances in pre-clinical mouse models of COPD. Clin Sci 126:253–265. doi:10.1042/CS20130182
141. von Zglinicki T (2002) Oxidative stress shortens telomeres. Trends Biochem Sci 27:339–344
142. Wang E (1995) Senescent human fibroblasts resist programmed cell death, and failure to suppress bcl2 is involved. Cancer Res 55:2284–2292
143. Wang JC, Bennett M (2012) Aging and atherosclerosis: mechanisms, functional consequences, and potential therapeutics for cellular senescence. Circ Res 111:245–259. doi:10.1161/CIRCRESAHA.111.261388
144. WHO (2014) The top 10 causes of death. May 2014 Available at: who int/mediacentre/factsheets/fs310/en/
145. Wilson VL, Jones PA (1983) DNA methylation decreases in aging but not in immortal cells. Science 220:1055–1057
146. Wilson VL, Smith RA, Ma S, Cutler RG (1987) Genomic 5-methyldeoxycytidine decreases with age. J Biol Chem 262:9948–9951
147. Xue W et al (2007) Senescence and tumour clearance is triggered by p53 restoration in murine liver carcinomas. Nature 445:656–660
148. Yoshimoto S et al (2013) Obesity-induced gut microbial metabolite promotes liver cancer through senescence secretome. Nature 499:97–101. doi:10.1038/nature12347
149. Yudoh K, Nishioka K (2004) Telomerized presenescent osteoblasts prevent bone mass loss in vivo. Gene Ther 11:909–915. doi:10.1038/sj.gt.3302234
150. Zhong L et al (2010) The histone deacetylase Sirt6 regulates glucose homeostasis via Hif1alpha. Cell 140:280–293. doi:10.1016/j.cell.2009.12.041
151. Zhou S, Greenberger JS, Epperly MW, Goff JP, Adler C, Leboff MS, Glowacki J (2008) Age-related intrinsic changes in human bone-marrow-derived mesenchymal stem cells and their differentiation to osteoblasts. Aging Cell 7:335–343. doi:10.1111/j.1474-9726.2008.00377.x