Advertisement

Targeting Senescent Cells to Improve Human Health

  • Tobias Wijshake
  • Jan M. A. van Deursen
Chapter
Part of the Healthy Ageing and Longevity book series (HAL)

Abstract

The number of people reaching old age is expected to increase dramatically, and concomitantly age-related diseases, such as diabetes, chronic kidney disease, cardiovascular disease, cancer and neurodegenerative disorders. To improve health and quality of life at more advanced ages, it will be necessary to identify and characterize the molecular pathways and events that drive aging and aging-associated diseases. It was proposed that cellular senescence contributes to age-related pathologies, but definitive evidence has long been lacking. However, recent studies on BubR1 hypomorphic mice, which model a human progeroid syndrome referred mosaic variegated aneuploidy (MVA) syndrome, provide strong in vivo evidence senescent cells are causally implicated in aging-associated phenotypes and demonstrate that selective elimination of senescent cells can delay age-related tissue deterioration. These studies identify senescent cells and the senescence-associated secretory phenotype (SASP) they produce, as therapeutic targets for treatment of age-related disease and tissue/organ dysfunction. Here, we describe the formation and features of senescent cells, the evidence that cellular senescence drives age-related dysfunction, the accumulation of senescent cells at sites of pathology in chronic diseases, and potential therapeutic approaches specifically directed against senescent cells to improve human health.

Keywords

Cellular senescence Senescence-associated secretory phenotype (SASP) Aging Age-related diseases Senotherapeutics Healthspan Longevity 

References

  1. Acosta JC, Banito A, Wuestefeld T et al (2013) A complex secretory program orchestrated by the inflammasome controls paracrine senescence. Nat Cell Biol 15:978–990. doi: 10.1038/ncb2784 PubMedPubMedCentralCrossRefGoogle Scholar
  2. Adams PD (2009) Healing and hurting: molecular mechanisms, functions, and pathologies of cellular senescence. Mol Cell 36:2–14. doi: 10.1016/j.molcel.2009.09.021 PubMedCrossRefGoogle Scholar
  3. Adamus J, Aho S, Meldrum H et al (2014) p16INK4A influences the aging phenotype in the living skin equivalent. J Invest Dermatol 134:1131–1133. doi: 10.1038/jid.2013.468 PubMedPubMedCentralCrossRefGoogle Scholar
  4. Alder JK, Chen JJ-L, Lancaster L et al (2008) Short telomeres are a risk factor for idiopathic pulmonary fibrosis. Proc Natl Acad Sci U S A 105:13051–13056. doi: 10.1073/pnas.0804280105 PubMedPubMedCentralCrossRefGoogle Scholar
  5. Alzheimer’s Association (2011) 2011 Alzheimer’s disease facts and figures. Alzheimers Dement 7:208–244. doi: 10.1016/j.jalz.2011.02.004 CrossRefGoogle Scholar
  6. 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 PubMedCrossRefGoogle Scholar
  7. Aoshiba K, Tsuji T, Nagai A (2003) Bleomycin induces cellular senescence in alveolar epithelial cells. Eur Respir J 22:436–443PubMedCrossRefGoogle Scholar
  8. Aoshiba K, Zhou F, Tsuji T, Nagai A (2012) DNA damage as a molecular link in the pathogenesis of COPD in smokers. Eur Respir J 39:1368–1376. doi: 10.1183/09031936.00050211 PubMedCrossRefGoogle Scholar
  9. Aoshiba K, Tsuji T, Kameyama S et al (2013) Senescence-associated secretory phenotype in a mouse model of bleomycin-induced lung injury. Exp Toxicol Pathol 65:1053–1062. doi: 10.1016/j.etp.2013.04.001 PubMedCrossRefGoogle Scholar
  10. Armanios MY, Chen JJ-L, Cogan JD et al (2007) Telomerase mutations in families with idiopathic pulmonary fibrosis. N Engl J Med 356:1317–1326. doi: 10.1056/NEJMoa066157 PubMedCrossRefGoogle Scholar
  11. Baker DJ, Jeganathan KB, Cameron JD 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 PubMedCrossRefGoogle Scholar
  12. Baker DJ, Perez-Terzic C, Jin F et al (2008) Opposing roles for p16Ink4a and p19Arf in senescence and ageing caused by BubR1 insufficiency. Nat Cell Biol 10:825–836. doi: 10.1038/ncb1744 PubMedPubMedCentralCrossRefGoogle Scholar
  13. Baker DJ, Wijshake T, Tchkonia T et al (2011a) Clearance of p16Ink4a-positive senescent cells delays ageing-associated disorders. Nature 479:232–236. doi: 10.1038/nature10600 PubMedPubMedCentralCrossRefGoogle Scholar
  14. Baker RG, Hayden MS, Ghosh S (2011b) NF-κB, inflammation, and metabolic disease. Cell Metab 13:11–22. doi: 10.1016/j.cmet.2010.12.008 PubMedPubMedCentralCrossRefGoogle Scholar
  15. 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. doi: 10.1016/j.celrep.2013.03.028 PubMedPubMedCentralCrossRefGoogle Scholar
  16. Barzilai N, Huffman DM, Muzumdar RH, Bartke A (2012) The critical role of metabolic pathways in aging. Diabetes 61:1315–1322. doi: 10.2337/db11-1300 PubMedPubMedCentralCrossRefGoogle Scholar
  17. Bernet JD, Doles JD, Hall JK et al (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. doi: 10.1038/nm.3465 PubMedPubMedCentralCrossRefGoogle Scholar
  18. Bhat R, Crowe EP, Bitto A et al (2012) Astrocyte senescence as a component of Alzheimer’s disease. PLoS One 7:e45069. doi: 10.1371/journal.pone.0045069 PubMedPubMedCentralCrossRefGoogle Scholar
  19. Bhaumik D, Scott GK, Schokrpur S et al (2009) MicroRNAs miR-146a/b negatively modulate the senescence-associated inflammatory mediators IL-6 and IL-8. Aging (Albany NY) 1:402–411CrossRefGoogle Scholar
  20. Bitto A, Sell C, Crowe E et al (2010) Stress-induced senescence in human and rodent astrocytes. Exp Cell Res 316:2961–2968. doi: 10.1016/j.yexcr.2010.06.021 PubMedCrossRefGoogle Scholar
  21. Block ML, Zecca L, Hong J-S (2007) Microglia-mediated neurotoxicity: uncovering the molecular mechanisms. Nat Rev Neurosci 8:57–69. doi: 10.1038/nrn2038 PubMedCrossRefGoogle Scholar
  22. Bower JE, Ganz PA, Aziz N, Fahey JL (2002) Fatigue and proinflammatory cytokine activity in breast cancer survivors. Psychosom Med 64:604–611PubMedCrossRefGoogle Scholar
  23. Brack AS, Conboy MJ, Roy S et al (2007) Increased Wnt signaling during aging alters muscle stem cell fate and increases fibrosis. Science 317:807–810. doi: 10.1126/science.1144090 PubMedCrossRefGoogle Scholar
  24. Braun H, Schmidt BMW, Raiss M et al (2012) Cellular senescence limits regenerative capacity and allograft survival. J Am Soc Nephrol 23:1467–1473. doi: 10.1681/ASN.2011100967 PubMedPubMedCentralCrossRefGoogle Scholar
  25. Burtner CR, Kennedy BK (2010) Progeria syndromes and ageing: what is the connection? Nat Rev Mol Cell Biol 11:567–578. doi: 10.1038/nrm2944 PubMedCrossRefGoogle Scholar
  26. Campisi J (2013) Aging, cellular senescence, and cancer. Annu Rev Physiol 75:685–705. doi: 10.1146/annurev-physiol-030212-183653 PubMedPubMedCentralCrossRefGoogle Scholar
  27. 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. doi: 10.1038/nrm2233 PubMedCrossRefGoogle Scholar
  28. 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 PubMedPubMedCentralGoogle Scholar
  29. Cesari M, Penninx BWJH, Pahor M et al (2004) Inflammatory markers and physical performance in older persons: the InCHIANTI study. J Gerontol A Biol Sci Med Sci 59:242–248PubMedCrossRefGoogle Scholar
  30. Chakkalakal JV, Jones KM, Basson MA, Brack AS (2012) The aged niche disrupts muscle stem cell quiescence. Nature 490:355–360. doi: 10.1038/nature11438 PubMedPubMedCentralCrossRefGoogle Scholar
  31. Chen Y, Swanson RA (2003) Astrocytes and brain injury. J Cereb Blood Flow Metab 23:137–149PubMedCrossRefGoogle Scholar
  32. Chen Q, Liu K, Robinson AR et al (2013) DNA damage drives accelerated bone aging via an NF-κB-dependent mechanism. J Bone Miner Res 28:1214–1228. doi: 10.1002/jbmr.1851 PubMedPubMedCentralCrossRefGoogle Scholar
  33. Chien Y, Scuoppo C, Wang X et al (2011) Control of the senescence-associated secretory phenotype by NF-κB promotes senescence and enhances chemosensitivity. Genes Dev 25:2125–2136. doi: 10.1101/gad.17276711 PubMedPubMedCentralCrossRefGoogle Scholar
  34. Chilosi M, Carloni A, Rossi A, Poletti V (2013) Premature lung aging and cellular senescence in the pathogenesis of idiopathic pulmonary fibrosis and COPD/emphysema. Transl Res 162:156–173. doi: 10.1016/j.trsl.2013.06.004 PubMedCrossRefGoogle Scholar
  35. Chinta SJ, Lieu CA, Demaria M et al (2013) Environmental stress, ageing and glial cell senescence: a novel mechanistic link to Parkinson’s disease? J Intern Med 273:429–436. doi: 10.1111/joim.12029 PubMedPubMedCentralCrossRefGoogle Scholar
  36. Chinta SJ, Woods G, Rane A et al (2014) Cellular senescence and the aging brain. Exp Gerontol. doi: 10.1016/j.exger.2014.09.018 PubMedGoogle Scholar
  37. Collado M, Blasco MA, Serrano M (2007) Cellular senescence in cancer and aging. Cell 130:223–233. doi: 10.1016/j.cell.2007.07.003 PubMedCrossRefGoogle Scholar
  38. Collins CJ, Sedivy JM (2003) Involvement of the INK4a/Arf gene locus in senescence. Aging Cell 2:145–150PubMedCrossRefGoogle Scholar
  39. Conboy IM, Rando TA (2005) Aging, stem cells and tissue regeneration: lessons from muscle. Cell Cycle 4:407–410PubMedCrossRefGoogle Scholar
  40. Conboy IM, Conboy MJ, Wagers AJ et al (2005) Rejuvenation of aged progenitor cells by exposure to a young systemic environment. Nature 433:760–764. doi: 10.1038/nature03260 PubMedCrossRefGoogle Scholar
  41. Coppé J-P, Kauser K, Campisi J, Beausejour CM (2006) Secretion of vascular endothelial growth factor by primary human fibroblasts at senescence. J Biol Chem 281:29568–29574. doi: 10.1074/jbc.M603307200 PubMedCrossRefGoogle Scholar
  42. Coppé J-P, Patil CK, Rodier F et al (2008) Senescence-associated secretory phenotypes reveal cell-nonautonomous functions of oncogenic RAS and the p53 tumor suppressor. PLoS Biol 6:2853–2868. doi: 10.1371/journal.pbio.0060301 PubMedCrossRefGoogle Scholar
  43. Cosgrove BD, Gilbert PM, Porpiglia E et al (2014) Rejuvenation of the muscle stem cell population restores strength to injured aged muscles. Nat Med 20:255–264. doi: 10.1038/nm.3464 PubMedPubMedCentralCrossRefGoogle Scholar
  44. Cunningham C (2013) Microglia and neurodegeneration: the role of systemic inflammation. Glia 61:71–90. doi: 10.1002/glia.22350 PubMedCrossRefGoogle Scholar
  45. Darrat I, Ahmad N, Seidman K, Seidman MD (2007) Auditory research involving antioxidants. Curr Opin Otolaryngol Head Neck Surg 15:358–363. doi: 10.1097/MOO.0b013e3282efa641 PubMedCrossRefGoogle Scholar
  46. de Jong PTVM (2006) Age-related macular degeneration. N Engl J Med 355:1474–1485. doi: 10.1056/NEJMra062326 PubMedCrossRefGoogle Scholar
  47. Demaria M, Ohtani N, Youssef SA et al (2014) An essential role for senescent cells in optimal wound healing through secretion of PDGF-AA. Dev Cell 31:722–733. doi: 10.1016/j.devcel.2014.11.012 PubMedPubMedCentralCrossRefGoogle Scholar
  48. Demaria M, Desprez P-Y, Campisi J, Velarde MC (2015) Cell autonomous and Non-autonomous effects of senescent cells in the skin. J Invest Dermatol. doi: 10.1038/jid.2015.108 PubMedPubMedCentralGoogle Scholar
  49. DePinho RA (2000) The age of cancer. Nature 408:248–254. doi: 10.1038/35041694 PubMedCrossRefGoogle Scholar
  50. Dimri GP, Lee X, Basile G 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 92:9363–9367PubMedPubMedCentralCrossRefGoogle Scholar
  51. Donath MY, Shoelson SE (2011) Type 2 diabetes as an inflammatory disease. Nat Rev Immunol 11:98–107. doi: 10.1038/nri2925 PubMedCrossRefGoogle Scholar
  52. Doorn KJ, Lucassen PJ, Boddeke HW et al (2012) Emerging roles of microglial activation and non-motor symptoms in Parkinson’s disease. Prog Neurobiol 98:222–238. doi: 10.1016/j.pneurobio.2012.06.005 PubMedCrossRefGoogle Scholar
  53. Dorshkind K, Montecino-Rodriguez E, Signer RAJ (2009) The ageing immune system: is it ever too old to become young again? Nat Rev Immunol 9:57–62. doi: 10.1038/nri2471 PubMedCrossRefGoogle Scholar
  54. Du J, Klein JD, Hassounah F et al (2014) Aging increases CCN1 expression leading to muscle senescence. Am J Physiol Cell Physiol 306:C28–C36. doi: 10.1152/ajpcell.00066.2013 PubMedPubMedCentralCrossRefGoogle Scholar
  55. 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 PubMedCrossRefGoogle Scholar
  56. Fischer BM, Wong JK, Degan S et al (2013) Increased expression of senescence markers in cystic fibrosis airways. Am J Physiol Lung Cell Mol Physiol 304:L394–L400. doi: 10.1152/ajplung.00091.2012 PubMedPubMedCentralCrossRefGoogle Scholar
  57. Flanary BE, Streit WJ (2003) Telomeres shorten with age in rat cerebellum and cortex in vivo. J Anti Aging Med 6:299–308. doi: 10.1089/109454503323028894 PubMedCrossRefGoogle Scholar
  58. Flanary BE, Streit WJ (2004) Progressive telomere shortening occurs in cultured rat microglia, but not astrocytes. Glia 45:75–88. doi: 10.1002/glia.10301 PubMedCrossRefGoogle Scholar
  59. Fletcher AE (2010) Free radicals, antioxidants and eye diseases: evidence from epidemiological studies on cataract and age-related macular degeneration. Ophthalmic Res 44:191–198. doi: 10.1159/000316476 PubMedCrossRefGoogle Scholar
  60. Franceschi C, Capri M, Monti D et al (2007) Inflammaging and anti-inflammaging: a systemic perspective on aging and longevity emerged from studies in humans. Mech Ageing Dev 128:92–105. doi: 10.1016/j.mad.2006.11.016 PubMedCrossRefGoogle Scholar
  61. Freund A, Orjalo AV, Desprez P-Y, 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 PubMedPubMedCentralCrossRefGoogle Scholar
  62. Freund A, Patil CK, Campisi J (2011) p38MAPK is a novel DNA damage response-independent regulator of the senescence-associated secretory phenotype. EMBO J 30:1536–1548. doi: 10.1038/emboj.2011.69 PubMedPubMedCentralCrossRefGoogle Scholar
  63. Fukazawa R, Ikegam E, Watanabe M et al (2007) Coronary artery aneurysm induced by Kawasaki disease in children show features typical senescence. Circ J 71:709–715PubMedCrossRefGoogle Scholar
  64. Fumagalli M, Rossiello F, Clerici 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 PubMedPubMedCentralCrossRefGoogle Scholar
  65. Gates GA, Mills JH (2005) Presbycusis. Lancet 366:1111–1120. doi: 10.1016/S0140-6736(05)67423-5 PubMedCrossRefGoogle Scholar
  66. Gilbert LA, Hemann MT (2010) DNA damage-mediated induction of a chemoresistant niche. Cell 143:355–366. doi: 10.1016/j.cell.2010.09.043 PubMedPubMedCentralCrossRefGoogle Scholar
  67. Golledge J, Kuivaniemi H (2013) Genetics of abdominal aortic aneurysm. Curr Opin Cardiol 28:290–296. doi: 10.1097/HCO.0b013e32835f0d55 PubMedCrossRefGoogle Scholar
  68. 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 PubMedCrossRefGoogle Scholar
  69. Gregor MF, Hotamisligil GS (2011) Inflammatory mechanisms in obesity. Annu Rev Immunol 29:415–445. doi: 10.1146/annurev-immunol-031210-101322 PubMedCrossRefGoogle Scholar
  70. Hamshere ML, Holmans PA, Avramopoulos D et al (2007) Genome-wide linkage analysis of 723 affected relative pairs with late-onset Alzheimer’s disease. Hum Mol Genet 16:2703–2712. doi: 10.1093/hmg/ddm224 PubMedCrossRefGoogle Scholar
  71. Hartman TK, Wengenack TM, Poduslo JF, van Deursen JM (2007) Mutant mice with small amounts of BubR1 display accelerated age-related gliosis. Neurobiol Aging 28:921–927. doi: 10.1016/j.neurobiolaging.2006.05.012 PubMedCrossRefGoogle Scholar
  72. Hayflick L, Moorhead PS (1961) The serial cultivation of human diploid cell strains. Exp Cell Res 25:585–621PubMedCrossRefGoogle Scholar
  73. Hebert LE, Weuve J, Scherr PA, Evans DA (2013) Alzheimer disease in the United States (2010–2050) estimated using the 2010 census. Neurology 80:1778–1783. doi: 10.1212/WNL.0b013e31828726f5 PubMedPubMedCentralCrossRefGoogle Scholar
  74. Hecker L, Logsdon NJ, Kurundkar D et al (2014) Reversal of persistent fibrosis in aging by targeting Nox4-Nrf2 redox imbalance. Sci Transl Med 6:231ra47. doi: 10.1126/scitranslmed.3008182 PubMedPubMedCentralCrossRefGoogle Scholar
  75. Herbig U, Ferreira M, Condel L et al (2006) Cellular senescence in aging primates. Science 311:1257. doi: 10.1126/science.1122446 PubMedCrossRefGoogle Scholar
  76. Holdt LM, Sass K, Gäbel G et al (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 PubMedCrossRefGoogle Scholar
  77. Iannello A, Thompson TW, Ardolino M et al (2013) p53-dependent chemokine production by senescent tumor cells supports NKG2D-dependent tumor elimination by natural killer cells. J Exp Med 210:2057–2069. doi: 10.1084/jem.20130783 PubMedPubMedCentralCrossRefGoogle Scholar
  78. Ito K, Barnes PJ (2009) COPD as a disease of accelerated lung aging. Chest 135:173–180. doi: 10.1378/chest.08-1419 PubMedCrossRefGoogle Scholar
  79. Jeyapalan JC, Ferreira M, Sedivy JM, 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 PubMedPubMedCentralCrossRefGoogle Scholar
  80. Johmura Y, Shimada M, Misaki T et al (2014) Necessary and sufficient role for a mitosis skip in senescence induction. Mol Cell 55:73–84. doi: 10.1016/j.molcel.2014.05.003 PubMedCrossRefGoogle Scholar
  81. Jun J-I, Lau LF (2010) The matricellular protein CCN1 induces fibroblast senescence and restricts fibrosis in cutaneous wound healing. Nat Cell Biol 12:676–685. doi: 10.1038/ncb2070 PubMedPubMedCentralCrossRefGoogle Scholar
  82. Jurk D, Wilson C, Passos JF et al (2014) Chronic inflammation induces telomere dysfunction and accelerates ageing in mice. Nat Commun 2:4172. doi: 10.1038/ncomms5172 PubMedPubMedCentralCrossRefGoogle Scholar
  83. Kang T-W, Yevsa T, Woller N et al (2011) Senescence surveillance of pre-malignant hepatocytes limits liver cancer development. Nature 479:547–551. doi: 10.1038/nature10599 PubMedCrossRefGoogle Scholar
  84. Kaplon J, Zheng L, Meissl K et al (2013) A key role for mitochondrial gatekeeper pyruvate dehydrogenase in oncogene-induced senescence. Nature 498:109–112. doi: 10.1038/nature12154 PubMedCrossRefGoogle Scholar
  85. Katsimpardi L, Litterman NK, Schein PA et al (2014) Vascular and neurogenic rejuvenation of the aging mouse brain by young systemic factors. Science 344:630–634. doi: 10.1126/science.1251141 PubMedPubMedCentralCrossRefGoogle Scholar
  86. Kelly J, Ali Khan A, Yin J et al (2007) Senescence regulates macrophage activation and angiogenic fate at sites of tissue injury in mice. J Clin Invest 117:3421–3426. doi: 10.1172/JCI32430 PubMedPubMedCentralCrossRefGoogle Scholar
  87. Kenyon GS, Booth JB, Prasher DK, Rudge P (1985) Neuro-otological abnormalities in xeroderma pigmentosum with particular reference to deafness. Brain 108(Pt 3):771–784PubMedCrossRefGoogle Scholar
  88. Kim WY, Sharpless NE (2006) The regulation of INK4/ARF in cancer and aging. Cell 127:265–275. doi: 10.1016/j.cell.2006.10.003 PubMedCrossRefGoogle Scholar
  89. Krenning L, Feringa FM, Shaltiel IA et al (2014) Transient activation of p53 in G2 phase is sufficient to induce senescence. Mol Cell 55:59–72. doi: 10.1016/j.molcel.2014.05.007 PubMedCrossRefGoogle Scholar
  90. Krishnamurthy J, Torrice C, Ramsey MR et al (2004) Ink4a/Arf expression is a biomarker of aging. J Clin Invest 114:1299–1307. doi: 10.1172/JCI22475 PubMedPubMedCentralCrossRefGoogle Scholar
  91. Krishnamurthy J, Ramsey MR, Ligon KL et al (2006) p16INK4a induces an age-dependent decline in islet regenerative potential. Nature 443:453–457. doi: 10.1038/nature05092 PubMedCrossRefGoogle Scholar
  92. Krizhanovsky V, Yon M, Dickins RA et al (2008) Senescence of activated stellate cells limits liver fibrosis. Cell 134:657–667. doi: 10.1016/j.cell.2008.06.049 PubMedPubMedCentralCrossRefGoogle Scholar
  93. Krtolica A, Parrinello S, Lockett S et al (2001) Senescent fibroblasts promote epithelial cell growth and tumorigenesis: a link between cancer and aging. Proc Natl Acad Sci U S A 98:12072–12077. doi: 10.1073/pnas.211053698 PubMedPubMedCentralCrossRefGoogle Scholar
  94. Kuilman T, Michaloglou C, Vredeveld LCW et al (2008) Oncogene-induced senescence relayed by an interleukin-dependent inflammatory network. Cell 133:1019–1031. doi: 10.1016/j.cell.2008.03.039 PubMedCrossRefGoogle Scholar
  95. Kuilman T, Michaloglou C, Mooi WJ, Peeper DS (2010) The essence of senescence. Genes Dev 24:2463–2479. doi: 10.1101/gad.1971610 PubMedPubMedCentralCrossRefGoogle Scholar
  96. Laberge R-M, Awad P, Campisi J, Desprez P-Y (2012) Epithelial-mesenchymal transition induced by senescent fibroblasts. Cancer Microenviron 5:39–44. doi: 10.1007/s12307-011-0069-4 PubMedPubMedCentralCrossRefGoogle Scholar
  97. Lawless C, Wang C, Jurk D et al (2010) Quantitative assessment of markers for cell senescence. Exp Gerontol 45:772–778. doi: 10.1016/j.exger.2010.01.018 PubMedCrossRefGoogle Scholar
  98. Le Maitre CL, Freemont AJ, Hoyland JA (2007) Accelerated cellular senescence in degenerate intervertebral discs: a possible role in the pathogenesis of intervertebral disc degeneration. Arthritis Res Ther 9:R45. doi: 10.1186/ar2198 PubMedPubMedCentralCrossRefGoogle Scholar
  99. Le ONL, Rodier F, Fontaine F et al (2010) Ionizing radiation-induced long-term expression of senescence markers in mice is independent of p53 and immune status. Aging Cell 9:398–409. doi: 10.1111/j.1474-9726.2010.00567.x PubMedPubMedCentralCrossRefGoogle Scholar
  100. Levine AJ, Oren M (2009) The first 30 years of p53: growing ever more complex. Nat Rev Cancer 9:749–758. doi: 10.1038/nrc2723 PubMedPubMedCentralCrossRefGoogle Scholar
  101. Liton PB, Challa P, Stinnett S et al (2005) Cellular senescence in the glaucomatous outflow pathway. Exp Gerontol 40:745–748. doi: 10.1016/j.exger.2005.06.005 PubMedPubMedCentralCrossRefGoogle Scholar
  102. Litteljohn D, Mangano E, Clarke M et al (2010) Inflammatory mechanisms of neurodegeneration in toxin-based models of Parkinson’s disease. Parkinsons Dis 2011:713517. doi: 10.4061/2011/713517 PubMedPubMedCentralGoogle Scholar
  103. 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 PubMedCrossRefGoogle Scholar
  104. Loffredo FS, Steinhauser ML, Jay SM et al (2013) Growth differentiation factor 11 is a circulating factor that reverses age-related cardiac hypertrophy. Cell 153:828–839. doi: 10.1016/j.cell.2013.04.015 PubMedPubMedCentralCrossRefGoogle Scholar
  105. López-Otín C, Blasco MA, Partridge L et al (2013) The hallmarks of aging. Cell 153:1194–1217. doi: 10.1016/j.cell.2013.05.039 PubMedPubMedCentralCrossRefGoogle Scholar
  106. Lv X-X, Wang X-X, Li K 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 PubMedPubMedCentralCrossRefGoogle Scholar
  107. Markowski DN, Thies HW, Gottlieb A et al (2013) HMGA2 expression in white adipose tissue linking cellular senescence with diabetes. Genes Nutr 8:449–456. doi: 10.1007/s12263-013-0354-6 PubMedPubMedCentralCrossRefGoogle Scholar
  108. Martin JA, Brown TD, Heiner AD, Buckwalter JA (2004) Chondrocyte senescence, joint loading and osteoarthritis. Clin Orthop Relat Res (427 Suppl) S96–103Google Scholar
  109. Matsumoto T, Baker DJ, d’Uscio LV et al (2007) Aging-associated vascular phenotype in mutant mice with low levels of BubR1. Stroke 38:1050–1056. doi: 10.1161/01.STR.0000257967.86132.01 PubMedCrossRefGoogle Scholar
  110. Matthews C, Gorenne I, Scott S et al (2006) Vascular smooth muscle cells undergo telomere-based senescence in human atherosclerosis: effects of telomerase and oxidative stress. Circ Res 99:156–164. doi: 10.1161/01.RES.0000233315.38086.bc PubMedCrossRefGoogle Scholar
  111. Mimura T, Joyce NC (2006) Replication competence and senescence in central and peripheral human corneal endothelium. Invest Ophthalmol Vis Sci 47:1387–1396. doi: 10.1167/iovs.05-1199 PubMedCrossRefGoogle Scholar
  112. Minagawa S, Araya J, Numata T et al (2011) Accelerated epithelial cell senescence in IPF and the inhibitory role of SIRT6 in TGF-β-induced senescence of human bronchial epithelial cells. Am J Physiol Lung Cell Mol Physiol 300:L391–L401. doi: 10.1152/ajplung.00097.2010 PubMedPubMedCentralCrossRefGoogle Scholar
  113. Minamino T, Miyauchi H, Yoshida T et al (2002) Endothelial cell senescence in human atherosclerosis: role of telomere in endothelial dysfunction. Circulation 105:1541–1544PubMedCrossRefGoogle Scholar
  114. Minamino T, Orimo M, Shimizu I 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 PubMedCrossRefGoogle Scholar
  115. Moiseeva O, Deschênes-Simard X, St-Germain E et al (2013) Metformin inhibits the senescence-associated secretory phenotype by interfering with IKK/NF-κB activation. Aging Cell 12:489–498. doi: 10.1111/acel.12075 PubMedCrossRefGoogle Scholar
  116. Morgan JT, Raghunathan VK, Chang Y-R, et al (2015) The intrinsic stiffness of human trabecular meshwork cells increases with senescence. Oncotarget 6(17):15362–15374Google Scholar
  117. Muñoz-Espín D, Serrano M (2014) Cellular senescence: from physiology to pathology. Nat Rev Mol Cell Biol 15:482–496. doi: 10.1038/nrm3823 PubMedCrossRefGoogle Scholar
  118. Muñoz-Espín D, Cañamero M, Maraver A et al (2013) Programmed cell senescence during mammalian embryonic development. Cell 155:1104–1118. doi: 10.1016/j.cell.2013.10.019 PubMedCrossRefGoogle Scholar
  119. Naesens M (2011) Replicative senescence in kidney aging, renal disease, and renal transplantation. Discov Med 11:65–75PubMedGoogle Scholar
  120. Nardella C, Clohessy JG, Alimonti A, Pandolfi PP (2011) Pro-senescence therapy for cancer treatment. Nat Rev Cancer 11:503–511. doi: 10.1038/nrc3057 PubMedCrossRefGoogle Scholar
  121. Naylor RM, Baker DJ, van Deursen JM (2013) Senescent cells: a novel therapeutic target for aging and age-related diseases. Clin Pharmacol Ther 93:105–116. doi: 10.1038/clpt.2012.193 PubMedPubMedCentralCrossRefGoogle Scholar
  122. Nelson G, Wordsworth J, Wang C et al (2012) A senescent cell bystander effect: senescence-induced senescence. Aging Cell 11:345–349. doi: 10.1111/j.1474-9726.2012.00795.x PubMedPubMedCentralCrossRefGoogle Scholar
  123. Newgard CB, Sharpless NE (2013) Coming of age: molecular drivers of aging and therapeutic opportunities. J Clin Invest 123:946–950. doi: 10.1172/JCI68833 PubMedPubMedCentralCrossRefGoogle Scholar
  124. Niccoli T, Partridge L (2012) Ageing as a risk factor for disease. Curr Biol 22:R741–R752. doi: 10.1016/j.cub.2012.07.024 PubMedCrossRefGoogle Scholar
  125. Nikolich-Zugich J (2008) Ageing and life-long maintenance of T-cell subsets in the face of latent persistent infections. Nat Rev Immunol 8:512–522. doi: 10.1038/nri2318 PubMedCrossRefGoogle Scholar
  126. Ohtani N, Yamakoshi K, Takahashi A, Hara E (2004) The p16INK4a-RB pathway: molecular link between cellular senescence and tumor suppression. J Med Invest 51:146–153PubMedCrossRefGoogle Scholar
  127. Pajvani UB, Trujillo ME, Combs TP et al (2005) Fat apoptosis through targeted activation of caspase 8: a new mouse model of inducible and reversible lipoatrophy. Nat Med 11:797–803. doi: 10.1038/nm1262 PubMedCrossRefGoogle Scholar
  128. Palmer AK, Tchkonia T, LeBrasseur NK et al (2015) Cellular senescence in type 2 diabetes: a therapeutic opportunity. Diabetes 64:2289–2298. doi: 10.2337/db14-1820 PubMedCrossRefGoogle Scholar
  129. Parrinello S, Coppé J-P, Krtolica A, Campisi J (2005) Stromal-epithelial interactions in aging and cancer: senescent fibroblasts alter epithelial cell differentiation. J Cell Sci 118:485–496. doi: 10.1242/jcs.01635 PubMedCrossRefGoogle Scholar
  130. Passos JF, Nelson G, Wang C et al (2010) Feedback between p21 and reactive oxygen production is necessary for cell senescence. Mol Syst Biol 6:347. doi: 10.1038/msb.2010.5 PubMedPubMedCentralCrossRefGoogle Scholar
  131. Peng J, Stevenson FF, Oo ML, Andersen JK (2009) Iron-enhanced paraquat-mediated dopaminergic cell death due to increased oxidative stress as a consequence of microglial activation. Free Radic Biol Med 46:312–320. doi: 10.1016/j.freeradbiomed.2008.10.045 PubMedPubMedCentralCrossRefGoogle Scholar
  132. Pérez-Mancera PA, Young ARJ, Narita M (2014) Inside and out: the activities of senescence in cancer. Nat Rev Cancer 14:547–558. doi: 10.1038/nrc3773 PubMedCrossRefGoogle Scholar
  133. Perry VH, Nicoll JAR, Holmes C (2010) Microglia in neurodegenerative disease. Nat Rev Neurol 6:193–201. doi: 10.1038/nrneurol.2010.17 PubMedCrossRefGoogle Scholar
  134. Pertusa M, García-Matas S, Rodríguez-Farré E et al (2007) Astrocytes aged in vitro show a decreased neuroprotective capacity. J Neurochem 101:794–805. doi: 10.1111/j.1471-4159.2006.04369.x PubMedCrossRefGoogle Scholar
  135. Price JS, Waters JG, Darrah C et al (2002) The role of chondrocyte senescence in osteoarthritis. Aging Cell 1:57–65PubMedCrossRefGoogle Scholar
  136. Quigley HA, Broman AT (2006) The number of people with glaucoma worldwide in 2010 and 2020. Br J Ophthalmol 90:262–267. doi: 10.1136/bjo.2005.081224 PubMedPubMedCentralCrossRefGoogle Scholar
  137. Raghu G, Weycker D, Edelsberg J et al (2006) Incidence and prevalence of idiopathic pulmonary fibrosis. Am J Respir Crit Care Med 174:810–816. doi: 10.1164/rccm.200602-163OC PubMedCrossRefGoogle Scholar
  138. Rapin I, Weidenheim K, Lindenbaum Y et al (2006) Cockayne syndrome in adults: review with clinical and pathologic study of a new case. J Child Neurol 21:991–1006PubMedPubMedCentralCrossRefGoogle Scholar
  139. Ressler S, Bartkova J, Niederegger H et al (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 PubMedCrossRefGoogle Scholar
  140. Roberts S, Evans EH, Kletsas D et al (2006) Senescence in human intervertebral discs. Eur Spine J 15(Suppl 3):S312–S316. doi: 10.1007/s00586-006-0126-8 PubMedCrossRefGoogle Scholar
  141. Rodier F, Coppé J-P, Patil CK et al (2009) Persistent DNA damage signalling triggers senescence-associated inflammatory cytokine secretion. Nat Cell Biol 11:973–979. doi: 10.1038/ncb1909 PubMedPubMedCentralCrossRefGoogle Scholar
  142. Roninson IB (2003) Tumor cell senescence in cancer treatment. Cancer Res 63:2705–2715PubMedGoogle Scholar
  143. Rossi DJ, Bryder D, Seita J et al (2007) Deficiencies in DNA damage repair limit the function of haematopoietic stem cells with age. Nature 447:725–729. doi: 10.1038/nature05862 PubMedCrossRefGoogle Scholar
  144. Roubenoff R (2000) Sarcopenia and its implications for the elderly. Eur J Clin Nutr 54(Suppl 3):S40–S47PubMedCrossRefGoogle Scholar
  145. Schmitz KH, Cappola AR, Stricker CT et al (2007) The intersection of cancer and aging: establishing the need for breast cancer rehabilitation. Cancer Epidemiol Biomarkers Prev 16:866–872. doi: 10.1158/1055-9965.EPI-06-0980 PubMedCrossRefGoogle Scholar
  146. Sedelnikova OA, Horikawa I, Zimonjic DB et al (2004) Senescing human cells and ageing mice accumulate DNA lesions with unrepairable double-strand breaks. Nat Cell Biol 6:168–170. doi: 10.1038/ncb1095 PubMedCrossRefGoogle Scholar
  147. Sene A, Khan AA, Cox D et al (2013) Impaired cholesterol efflux in senescent macrophages promotes age-related macular degeneration. Cell Metab 17:549–561. doi: 10.1016/j.cmet.2013.03.009 PubMedPubMedCentralCrossRefGoogle Scholar
  148. Shah PP, Donahue G, Otte GL 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 PubMedPubMedCentralCrossRefGoogle Scholar
  149. Shapiro SD, Ingenito EP (2005) The pathogenesis of chronic obstructive pulmonary disease: advances in the past 100 years. Am J Respir Cell Mol Biol 32:367–372. doi: 10.1165/rcmb.F296 PubMedCrossRefGoogle Scholar
  150. Sharpless NE, DePinho RA (2007) How stem cells age and why this makes us grow old. Nat Rev Mol Cell Biol 8:703–713. doi: 10.1038/nrm2241 PubMedCrossRefGoogle Scholar
  151. Shivshankar P, Brampton C, Miyasato S et al (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 PubMedPubMedCentralCrossRefGoogle Scholar
  152. Sinha M, Jang YC, Oh J et al (2014) Restoring systemic GDF11 levels reverses age-related dysfunction in mouse skeletal muscle. Science 344:649–652. doi: 10.1126/science.1251152 PubMedPubMedCentralCrossRefGoogle Scholar
  153. Sohn JJ, Schetter AJ, Yfantis HG et al (2012) Macrophages, nitric oxide and microRNAs are associated with DNA damage response pathway and senescence in inflammatory bowel disease. PLoS One 7:e44156. doi: 10.1371/journal.pone.0044156 PubMedPubMedCentralCrossRefGoogle Scholar
  154. Sone H, Kagawa Y (2005) Pancreatic beta cell senescence contributes to the pathogenesis of type 2 diabetes in high-fat diet-induced diabetic mice. Diabetologia 48:58–67. doi: 10.1007/s00125-004-1605-2 PubMedCrossRefGoogle Scholar
  155. Song Z, Wang Y, Xie L et al (2008) Expression of senescence-related genes in human corneal endothelial cells. Mol Vis 14:161–170PubMedPubMedCentralGoogle Scholar
  156. Sousa-Victor P, Gutarra S, García-Prat L et al (2014) Geriatric muscle stem cells switch reversible quiescence into senescence. Nature 506:316–321. doi: 10.1038/nature13013 PubMedCrossRefGoogle Scholar
  157. Spear PD (1993) Neural bases of visual deficits during aging. Vision Res 33:2589–2609PubMedCrossRefGoogle Scholar
  158. Spoor M, Nagtegaal AP, Ridwan Y et al (2012) Accelerated loss of hearing and vision in the DNA-repair deficient Ercc1(δ/-) mouse. Mech Ageing Dev 133:59–67. doi: 10.1016/j.mad.2011.12.003 PubMedCrossRefGoogle Scholar
  159. Storer M, Mas A, Robert-Moreno A et al (2013) Senescence is a developmental mechanism that contributes to embryonic growth and patterning. Cell 155:1119–1130. doi: 10.1016/j.cell.2013.10.041 PubMedCrossRefGoogle Scholar
  160. Streit WJ (2006) Microglial senescence: does the brain’s immune system have an expiration date? Trends Neurosci 29:506–510. doi: 10.1016/j.tins.2006.07.001 PubMedCrossRefGoogle Scholar
  161. Strindhall J, Nilsson B-O, Löfgren S et al (2007) No immune risk profile among individuals who reach 100 years of age: findings from the Swedish NONA immune longitudinal study. Exp Gerontol 42:753–761. doi: 10.1016/j.exger.2007.05.001 PubMedCrossRefGoogle Scholar
  162. Sun Y, Campisi J, Higano C et al (2012) Treatment-induced damage to the tumor microenvironment promotes prostate cancer therapy resistance through WNT16B. Nat Med 18:1359–1368. doi: 10.1038/nm.2890 PubMedPubMedCentralCrossRefGoogle Scholar
  163. Tabas I (2010) Macrophage death and defective inflammation resolution in atherosclerosis. Nat Rev Immunol 10:36–46. doi: 10.1038/nri2675 PubMedPubMedCentralCrossRefGoogle Scholar
  164. Tchkonia T, Morbeck DE, von Zglinicki T et al (2010) Fat tissue, aging, and cellular senescence. Aging Cell 9:667–684. doi: 10.1111/j.1474-9726.2010.00608.x PubMedPubMedCentralCrossRefGoogle Scholar
  165. Tchkonia T, Zhu Y, van Deursen J et al (2013) Cellular senescence and the senescent secretory phenotype: therapeutic opportunities. J Clin Invest 123:966–972. doi: 10.1172/JCI64098 PubMedPubMedCentralCrossRefGoogle Scholar
  166. Thomas B, Beal MF (2011) Molecular insights into Parkinson’s disease. F1000 Med Rep 3:7. doi: 10.3410/M3-7 PubMedPubMedCentralCrossRefGoogle Scholar
  167. Tsai KKC, Chuang EY-Y, Little JB, Yuan Z-M (2005) Cellular mechanisms for low-dose ionizing radiation-induced perturbation of the breast tissue microenvironment. Cancer Res 65:6734–6744. doi: 10.1158/0008-5472.CAN-05-0703 PubMedCrossRefGoogle Scholar
  168. Tsuji T, Aoshiba K, Nagai A (2004) Cigarette smoke induces senescence in alveolar epithelial cells. Am J Respir Cell Mol Biol 31:643–649. doi: 10.1165/rcmb.2003-0290OC PubMedCrossRefGoogle Scholar
  169. Uchida Y, Ando F, Shimokata H et al (2008) The effects of aging on distortion-product otoacoustic emissions in adults with normal hearing. Ear Hear 29:176–184PubMedCrossRefGoogle Scholar
  170. van Deursen JM (2014) The role of senescent cells in ageing. Nature 509:439–446. doi: 10.1038/nature13193 PubMedPubMedCentralCrossRefGoogle Scholar
  171. Verdijk LB, Dirks ML, Snijders T et al (2012) Reduced satellite cell numbers with spinal cord injury and aging in humans. Med Sci Sports Exerc 44:2322–2330. doi: 10.1249/MSS.0b013e3182667c2e PubMedCrossRefGoogle Scholar
  172. 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 PubMedCrossRefGoogle Scholar
  173. Wang W, Wu J, Zhang Z, Tong T (2001) Characterization of regulatory elements on the promoter region of p16(INK4a) that contribute to overexpression of p16 in senescent fibroblasts. J Biol Chem 276:48655–48661. doi: 10.1074/jbc.M108278200 PubMedCrossRefGoogle Scholar
  174. Wang C, Jurk D, Maddick M et al (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 PubMedCrossRefGoogle Scholar
  175. Wang J, Geiger H, Rudolph KL (2011) Immunoaging induced by hematopoietic stem cell aging. Curr Opin Immunol 23:532–536. doi: 10.1016/j.coi.2011.05.004 PubMedCrossRefGoogle Scholar
  176. Weber C, Noels H (2011) Atherosclerosis: current pathogenesis and therapeutic options. Nat Med 17:1410–1422. doi: 10.1038/nm.2538 PubMedCrossRefGoogle Scholar
  177. Wei H, Mao Q, Liu L et al (2011) Changes and function of circulating endothelial progenitor cells in patients with cerebral aneurysm. J Neurosci Res 89:1822–1828. doi: 10.1002/jnr.22696 PubMedCrossRefGoogle Scholar
  178. Xue W, Zender L, Miething C et al (2007) Senescence and tumour clearance is triggered by p53 restoration in murine liver carcinomas. Nature 445:656–660. doi: 10.1038/nature05529 PubMedPubMedCentralCrossRefGoogle Scholar
  179. Yasuno K, Bilguvar K, Bijlenga P et al (2010) Genome-wide association study of intracranial aneurysm identifies three new risk loci. Nat Genet 42:420–425. doi: 10.1038/ng.563 PubMedPubMedCentralCrossRefGoogle Scholar
  180. Yu H-M, Zhao Y-M, Luo X-G et al (2012) Repeated lipopolysaccharide stimulation induces cellular senescence in BV2 cells. Neuroimmunomodulation 19:131–136. doi: 10.1159/000330254 PubMedCrossRefGoogle Scholar
  181. Zhang H, Pan K-H, Cohen SN (2003) Senescence-specific gene expression fingerprints reveal cell-type-dependent physical clustering of up-regulated chromosomal loci. Proc Natl Acad Sci U S A 100:3251–3256. doi: 10.1073/pnas.2627983100 PubMedPubMedCentralCrossRefGoogle Scholar
  182. Zhu Y, Tchkonia T, Pirtskhalava T et al (2015) The Achilles’ heel of senescent cells: from transcriptome to senolytic drugs. Aging Cell. doi: 10.1111/acel.12344 Google Scholar
  183. Zou Y, Zhang N, Ellerby LM et al (2012) Responses of human embryonic stem cells and their differentiated progeny to ionizing radiation. Biochem Biophys Res Commun 426:100–105. doi: 10.1016/j.bbrc.2012.08.043 PubMedPubMedCentralCrossRefGoogle Scholar
  184. Züchner S, Gilbert JR, Martin ER et al (2008) Linkage and association study of late-onset Alzheimer disease families linked to 9p21.3. Ann Hum Genet 72:725–731. doi: 10.1111/j.1469-1809.2008.00474.x PubMedPubMedCentralCrossRefGoogle Scholar

Copyright information

© Springer International Publishing Switzerland 2016

Authors and Affiliations

  1. 1.Molecular Genetics, University Medical Center GroningenUniversity of GroningenGroningenThe Netherlands
  2. 2.Departments of Pediatric and Adolescent Medicine and Department of Biochemistry and Molecular BiologyMayo Clinic College of MedicineRochesterUSA

Personalised recommendations