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TLR4 Polymorphisms and Ageing: Implications for the Pathophysiology of Age-Related Diseases

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Abstract

Introduction

Innate immunity provides a first line of host defense against infection by recognizing and killing microbes while simultaneously activating an instructive immune response. Toll-like receptors (TLRs) are principal mediators of rapid microbial recognition and function mainly by detection of pathogen-associated molecular patterns that do not exist in the host. Recognition of their ligands leads to a series of signaling events resulting in acute host responses, involved in killing pathogens.

Discussion

We describe the involvement of TLR4 polymorphisms in ageing, and in particular in age-related diseases, suggesting the crucial role of molecules of innate immunity in pathophysiology of these diseases. Hence, we observed that pro-inflammatory alleles may be related to unsuccessful ageing, such as Alzheimer’s disease, prostate cancer, and atherosclerosis; in contrast, the control of inflammation by anti-inflammatory alleles may result in increased longevity and successful ageing. Finally, a possible therapeutic approach to delay age-related diseases is outlined.

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References

  1. De Benedictis G, Franceschi C. The unusual genetics of human longevity. Sci Aging Knowledge Environ. 2006;2006(10):pe20. doi:10.1126/sageke.2006.10.pe20.

    PubMed  Google Scholar 

  2. Salvioli S, Olivieri F, Marchegiani F, Cardelli M, Santoro A, Bellavista E, et al. Genes, ageing and longevity in humans: problems, advantages and perspectives. Free Radic Res. 2006;40:1303–23. doi:10.1080/10715760600917136.

    PubMed  CAS  Google Scholar 

  3. Ostan R, Bucci L, Capri M, Salvioli S, Scurti M, Pini E, et al. Immunosenescence and immunogenetics of human longevity. Neuroimmunomodulation. 2008;15:224–40. doi:10.1159/000156466.

    PubMed  CAS  Google Scholar 

  4. Candore G, Balistreri CR, Listì F, Grimaldi MP, Vasto S, Colonna-Romano G, et al. Immunogenetics, gender, and longevity. Ann N Y Acad Sci. 2006;1089:516–37. doi:10.1196/annals.1386.051.

    PubMed  Google Scholar 

  5. Candore G, Colonna-Romano G, Balistreri CR, Di Carlo D, Grimaldi MP, Listì F, et al. Biology of longevity: role of the innate immune system. Rejuvenation Res. 2006;9:143–8. doi:10.1089/rej.2006.9.143.

    PubMed  CAS  Google Scholar 

  6. Candore G, Balistreri CR, Colonna-Romano G, Grimaldi MP, Lio D, Listi' F, et al. Immunosenescence and anti-immunosenescence therapies: the case of probiotics. Rejuvenation Res. 2008;11:425–32. doi:10.1089/rej.2008.0662.

    PubMed  CAS  Google Scholar 

  7. Pawelec G, Akbar A, Caruso C, Solana R, Grubeck-Loebenstein B, Wikby A. Human immunosenescence: is it infectious? Immunol Rev. 2005;205:257–68. doi:10.1111/j.0105-2896.2005.00271.

    PubMed  CAS  Google Scholar 

  8. Pawelec G, Derhovanessian E, Larbi A, Strindhall J, Wikby A. Cytomegalovirus and human immunosenescence. Rev Med Virol. 2009;19:47–56. doi:10.1002/rmv.598.

    PubMed  CAS  Google Scholar 

  9. Aw D, Silva AB, Palmer DB. Immunosenescence: emerging challenges for an ageing population. Immunology. 2007;120:435–46. doi:10.1111/j.1365-2567.2007.02555.x.

    PubMed  CAS  Google Scholar 

  10. Gruver AL, Hudson LL, Sempowski GD. Immunosenescence of ageing. J Pathol. 2007;211:144–56. doi:10.1002/path.2104.

    PubMed  CAS  Google Scholar 

  11. Troen BR. The biology of aging. Mt Sinai J Med. 2003;70:3–22.

    PubMed  Google Scholar 

  12. Franceschi C, Motta L, Motta M, Malaguarnera M, Capri M, Vasto S, et al. IMUSCE. The extreme longevity: the state of the art in Italy. Exp Gerontol. 2008;43:45–52. doi:10.1016/j.exger.2007.06.006.

    PubMed  Google Scholar 

  13. Capri M, Salvioli S, Monti D, Caruso C, Candore G, Vasto S, et al. Human longevity within an evolutionary perspective: the peculiar paradigm of a post-reproductive genetics. Exp Gerontol. 2008;43:53–60. doi:10.1016/j.exger.2007.06.004.

    PubMed  Google Scholar 

  14. Vasto S, Candore G, Balistreri CR, Caruso M, Colonna-Romano G, Grimaldi MP, et al. Inflammatory networks in ageing, age-related diseases and longevity. Mech Ageing Dev. 2007;128:83–91. doi:10.1016/j.mad.2006.11.015.

    PubMed  CAS  Google Scholar 

  15. Krabbe KS, Pedersen M, Bruunsgaard H. Inflammatory mediators in the elderly. Exp Gerontol. 2004;39:687–99. doi:10.1016/j.exger.2004.01.009.

    PubMed  CAS  Google Scholar 

  16. Kumagai Y, Takeuchi O, Akira S. Pathogen recognition by innate receptors. J Infect Chemother. 2008;14:86–92. doi:10.1007/s10156-008-0596-1.

    PubMed  CAS  Google Scholar 

  17. Takeuchi O, Akira S. Innate immunity to virus infection. Immunol Rev. 2009;227:75–86. doi:10.1111/j.1600-065X.2008.00737.x.

    PubMed  CAS  Google Scholar 

  18. Uematsu S, Akira S. Toll-like receptors (TLRs) and their ligands. Handb Exp Pharmacol. 2008;183:1–20. doi:10.1007/978-3-540-72167-3_1.

    PubMed  CAS  Google Scholar 

  19. Blander JM. Phagocytosis and antigen presentation: a partnership initiated by Toll-like receptors. Ann Rheum Dis. 2008;67(Suppl 3):iii44–9. doi:10.1136/ard.2008.097964.

    PubMed  CAS  Google Scholar 

  20. Netea MG, van de Veerdonk FL, Kullberg BJ, Van der Meer JW, Joosten LA. The role of NLRs and TLRs in the activation of the inflammasome. Expert Opin Biol Ther. 2008;8:1867–72. doi:10.1517/14712590802494212.

    PubMed  CAS  Google Scholar 

  21. Richards S, Watanabe C, Santos L, Craxton A, Clark EA. Regulation of B-cell entry into the cell cycle. Immunol Rev. 2008;224:183–200. doi:10.1111/j.1600-065X.2008.00652.x.

    PubMed  CAS  Google Scholar 

  22. Lu YC, Yeh WC, Ohashi PS. LPS/TLR4 signal transduction pathway. Cytokine. 2008;42:145–51. doi:10.1016/j.cyto.2008.01.006.

    PubMed  CAS  Google Scholar 

  23. Hashimoto C, Hudson KL, Anderson KV. The Toll gene of Drosophila, required for dorsal–ventral embryonic polarity, appears to encode a transmembrane protein. Cell. 1988;29(52):269–79.

    Google Scholar 

  24. Medzhitov R, Preston-Hurlburt P, Janeway CA Jr. A human homologue of the Drosophila Toll protein signals activation of adaptive immunity. Nature. 1997;388:394–7. doi:10.1038/41131.

    PubMed  CAS  Google Scholar 

  25. Tsan MF, Gao B. Endogenous ligands of Toll-like receptors. J Leukoc Biol. 2004;76:514–9. doi:10.1189/jlb.0304127.

    PubMed  CAS  Google Scholar 

  26. Zeytun A, van Velkinburgh JC, Pardington PE, Cary RR, Gupta G. Pathogen-specific innate immune response. Adv Exp Med Biol. 2007;598:342–57. doi:10.1007/978-0-387-71767-8_24.

    PubMed  Google Scholar 

  27. Miyake K. Innate immune sensing of pathogens and danger signals by cell surface Toll-like receptors. Semin Immunol. 2007;19:3–10. doi:org/10.1016/j.smim.2006.12.002.

    PubMed  CAS  Google Scholar 

  28. Ku C-L, Yang K, Bustamante J, Puel A, von Bernuth H, Santos OF, et al. Inherited disorders of human Toll-like receptor signaling: Immunological implications. Immunol Rev. 2005;203:10–20. doi:10.1111/j.0105-2896.2005.00235.x.

    PubMed  CAS  Google Scholar 

  29. Balistreri CR, Candore G, Colonna-Romano G, Grimaldi MP, Lio D, Listì F, et al. Role of TLR polymorphisms in immunosenescence. In: Fulop T, editor. Handbook on Immunosenescence. Netherlands: Springer; 2009. p. 659–70. doi:10.1007/978-1-4020-9062-2_1.

    Google Scholar 

  30. van Duin D, Shaw AC. Toll-like receptors in older adults. J Am Geriatr Soc. 2007;55:1438–44. doi:10.1111/j.1532-5415.2007.01300.x.

    PubMed  Google Scholar 

  31. Bruunsgaard H, Pedersen BK. Age-related inflammatory cytokines and disease. Immunol Allergy Clin North Am. 2003;23:15–39. doi:10.1016/S0889-8561(02)00056-5.

    PubMed  Google Scholar 

  32. Rink L, Cakman I, Kirchner H. Altered cytokine production in the elderly. Mech Ageing Dev. 1998;102:199–209. doi:10.1016/S0047-6374(97)00153-X.

    PubMed  CAS  Google Scholar 

  33. Fulop T, Larbi A, Douziech N, Fortin C, Guérard KP, Lesur O, et al. Signal transduction and functional changes in neutrophils with aging. Aging Cell. 2004;3:217–26. doi:10.1111/j.1474-9728.2004.00110.x.

    PubMed  CAS  Google Scholar 

  34. van Duin D, Mohanty S, Thomas V, Ginter S, Montgomery RR, Fikrig E, et al. Age-associated defect in human TLR-1/2 function. J Immunol. 2007;178:970–5.

    PubMed  Google Scholar 

  35. Franceschi C, Bonafè M, Valensin S, Olivieri F, De Luca M, Ottaviani E, et al. Inflamm-aging. An evolutionary perspective on immunosenescence. Ann N Y Acad Sci. 2000;908:244–54. doi:10.1111/j.1749-6632.2000.tb06651.x.

    Article  PubMed  CAS  Google Scholar 

  36. Agrawal A, Agrawal S, Gupta S. Dendritic cells in human aging. Exp Gerontol. 2007;42:421–6. doi:0.1007/s10875-007-9127-6.

    PubMed  CAS  Google Scholar 

  37. Rea IM, Candore G, Cavalloni L, Franceschi C, Colonna-Romano G, Lio D, et al. Longevity. In: Vandenbroeck K, editor. Cytokine gene polymorphisms in multifactorial conditions. Florida: CRC; 2006. p. 379–94. ISBN 9780849336195.

    Google Scholar 

  38. van Duin D, Allore HG, Mohanty S, Ginter S, Newman FK, Belshe RB, et al. Prevaccine determination of the expression of costimulatory B7 molecules in activated monocytes predicts influenza vaccine responses in young and older adults. J Infect Dis. 2007;195:1590–7. doi:10.1086/516788.

    PubMed  Google Scholar 

  39. Smirnova I, Poltorak A, Chan EK, McBride C, Beutler B. Phylogenetic variation and polymorphism at the toll-like receptor 4 locus (TLR4). Genome Biol. 2000;1(1):RESEARCH002.1–RESEARCH002.10.

    Google Scholar 

  40. Mushegian A, Medzhitov R. Evolutionary perspective on innate immune recognition. J Cell Biol. 2001;155:705–10. doi:10.1083/jcb.200107040.

    PubMed  CAS  Google Scholar 

  41. Ferwerda B, McCall MB, Alonso S, Giamarellos-Bourboulis EJ, Mouktaroudi M, Izagirre N, et al. TLR4 polymorphisms, infectious diseases, and evolutionary pressure during migration of modern humans. Proc Natl Acad Sci U S A. 2007;104:16645–50. doi:10.1073/pnas.0704828104.

    PubMed  Google Scholar 

  42. Ferwerda B, McCall MB, Verheijen K, Kullberg BJ, van der Ven AJ, Van der Meer JW, et al. Functional consequences of toll-like receptor 4 polymorphisms. Mol Med. 2008;14:346–52. doi:10.2119/2007-00135.

    PubMed  CAS  Google Scholar 

  43. Arbour NC, Lorenz E, Schutte BC, Zabner J, Kline JN, Jones M, et al. TLR4 mutations are associated with endotoxin hyporesponsiveness in humans. Nat Genet. 2000;25:187–91. doi:10.1038/76048.

    PubMed  CAS  Google Scholar 

  44. Balistreri CR, Candore G, Listì F, Fazio T, Gangi S, Incalcaterra E, et al. Role of TLR4 polymorphisms in inflammatory responses: implications for unsuccessful aging. Ann N Y Acad Sci. 2007;1119:203–7. doi:10.1196/annals.1404.003.

    PubMed  CAS  Google Scholar 

  45. Vasto S, Candore G, Listì F, Balistreri CR, Colonna-Romano G, Malavolta M, et al. Inflammation, genes and zinc in Alzheimer's disease. Brain Res Brain Res Rev. 2008;58:96–105. doi:10.1016/j.brainresrev.2007.12.001.

    CAS  Google Scholar 

  46. Akiyama H, Barger S, Barnum S, Bradt B, Bauer J, Cole GM, et al. Inflammation and Alzheimer's disease. Neurobiol Aging. 2000;21:383–421. doi:10.1016/S0197-4580(00)00124-X.

    PubMed  CAS  Google Scholar 

  47. Streit WJ, Miller KR, Lopes KO, Njie E. Microglial degeneration in the aging brain—bad news for neurons? Front Biosci. 2008;13:3423–38. doi:10.2741/2937.

    PubMed  CAS  Google Scholar 

  48. Fassbender K, Walter S, Kühl S, Landmann R, Ishii K, Bertsch T, et al. The LPS receptor (CD14) links innate immunity with Alzheimer's disease. FASEB J. 2004;18:203–5. doi:10.1096/fj.03-0364fje.

    PubMed  CAS  Google Scholar 

  49. Tang SC, Lathia JD, Selvaraj PK, Jo DG, Mughal MR, Cheng A, et al. Toll-like receptor-4 mediates neuronal apoptosis induced by amyloid beta-peptide and the membrane lipid peroxidation product 4-hydroxynonenal. Exp Neurol. 2008;213:114–21. doi:10.1016/j.expneurol.2008.05.014.

    PubMed  CAS  Google Scholar 

  50. Bsibsi M, Ravid R, Gveric D, van Noort JM. Broad expression of Toll-like receptors in the human central nervous system. J Neuropathol Exp Neurol. 2002;61:1013–21.

    PubMed  CAS  Google Scholar 

  51. Finch CE, Morgan TE. Systemic inflammation, infection, ApoE alleles, and Alzheimer disease: a position paper. Curr Alzheimer Res. 2007;4:185–9. doi:10.2174/156720507780362254.

    PubMed  CAS  Google Scholar 

  52. Candore G, Balistreri CR, Grimaldi MP, Listì F, Vasto S, Chiappelli M, et al. Polymorphisms of pro-inflammatory genes and Alzheimer’s disease risk: a pharmacogenomic approach. Mech Ageing Dev. 2007;128:67–75. doi:10.1016/j.mad.2006.11.013.

    PubMed  CAS  Google Scholar 

  53. Minoretti P, Gazzaruso C, Vito CD, Emanuele E, Bianchi M, Coen E, et al. Effect of the functional toll-like receptor 4 Asp299Gly polymorphism on susceptibility to late-onset Alzheimer's disease. Neurosci Lett. 2006;391:147–9. doi:10.1016/j.neulet.2005.08.047.

    PubMed  CAS  Google Scholar 

  54. Balistreri CR, Grimaldi MP, Chiappelli M, Licastro F, Castiglia L, Listì F, et al. Association between the polymorphisms of TLR4 and CD14 genes and Alzheimer's disease. Curr Pharm Des. 2008;14:2672–7. doi:10.2174/138161208786264089.

    PubMed  CAS  Google Scholar 

  55. Huang B, Zhao J, Li H, He KL, Chen Y, Chen SH, et al. Toll like receptors on tumor cells facilitate evasion of immune surveillance. Cancer Res. 2005;65:5009–14. doi:10.1158/0008-5472.CAN-05-0784.

    PubMed  CAS  Google Scholar 

  56. Kelly MG, Alvero AB, Chen R, Silasi DA, Abrahams VM, Chan S, et al. TLR-4 signaling promotes tumor growth and paclitaxel chemoresistance in ovarian cancer. Cancer Res. 2006;66:3859. doi:10.1158/0008-5472.CAN-05-3948.

    PubMed  CAS  Google Scholar 

  57. De Marzo AM, Platz EA, Sutcliffe S, Xu J, Grönberg H, Drake CG, et al. Inflammation in prostate carcinogenesis. Nat Rev Cancer. 2007;7:256–69. doi:10.1038/nrc2090.

    PubMed  Google Scholar 

  58. Vasto S, Carruba G, Lio D, Colonna-Romano G, Di Bona D, Candore G, et al. Inflammation, ageing and cancer. Mech Ageing Dev. 2009;130:40–5. doi:10.1016/j.mad.2008.06.003.

    PubMed  CAS  Google Scholar 

  59. Greten FR, Eckmann L, Greten TF, Park JM, Li ZW, Egan LJ, et al. IKKbeta links inflammation and tumorigenesis in a mouse model of colitis-associated cancer. Cell. 2004;118:285–96. doi:10.1016/j.cell.2004.07.013.

    PubMed  CAS  Google Scholar 

  60. Karin M, Greten FR. NF-kappaB: linking inflammation and immunity to cancer development and progression. Nat Rev Immunol. 2005;5:749–59. doi:10.1038/nri1703.

    PubMed  CAS  Google Scholar 

  61. van Maren WW, Jacobs JF, de Vries IJ, Nierkens S, Adema GJ. Toll-like receptor signalling on Tregs: to suppress or not to suppress? Immunology. 2008;124:445–52. doi:10.1111/j.1365-2567.2008.02871.x.

    PubMed  Google Scholar 

  62. Jemal A, Siegel R, Ward E, Hao Y, Xu J, Murray T, et al. Cancer statistics, 2008. CA Cancer J Clin. 2008;58:71–96. doi:10.3322/CA.2007.0010.

    PubMed  Google Scholar 

  63. Nelson WG, De Marzo AM, Isaacs WB. Prostate cancer. N Engl J Med. 2003;24(349):366–81.

    Google Scholar 

  64. Sardana G, Dowell B, Diamandis EP. Emerging biomarkers for the diagnosis and prognosis of prostate cancer. Clin Chem. 2008;54:1951–60. doi:10.1373/clinchem.2008.110668.

    PubMed  CAS  Google Scholar 

  65. Caruso C, Balistreri CR, Candore G, Carruba G, Colonna-Romano G, Di Bon AD, et al. Polymorphisms of pro-inflammatory genes and prostate cancer risk: a pharmacogenomic approach. Cancer Immunol Immunother. 2009. doi:10.1007/s00262-009-0658-y.

  66. Zheng SL, Augustsson-Bälter K, Chang B, Hedelin M, Li L, Adami HO, et al. Sequence variants of toll-like receptor 4 are associated with prostate cancer risk: results from the Cancer Prostate in Sweden Study. Cancer Res. 2004;64:2918–22. doi:10.1158/0008-5472.CAN-03-3280.

    PubMed  CAS  Google Scholar 

  67. Chen YC, Giovannucci E, Lazarus R, Kraft P, Ketkar S, Hunter DJ. Sequence variants of Toll-like receptor 4 and susceptibility to prostate cancer. Cancer Res. 2005;65:11771–8. doi:10.1158/0008-5472.CAN-05-2078.

    PubMed  CAS  Google Scholar 

  68. Cheng I, Plummer SJ, Casey G, Witte JS. Toll-like receptor 4 genetic variation and advanced prostate cancer risk. Cancer Epidemiol Biomarkers Prev. 2007;16:352–5. doi:10.1158/1055-9965.EPI-06-0429.

    PubMed  CAS  Google Scholar 

  69. Balistreri CR, Caruso C, Carruba G, Miceli V, Campisi I, Lio D, Colonna-Romano G. F. Listì F,Candore G. A pilot study on prostate cancer risk and pro-inflammatory genotypes: pathophysiology and therapeutic implications. Curr Pharm Des. 2009. (in press).

  70. Vink A, de Kleijn DP, Pasterkamp G. Functional role for toll-like receptors in atherosclerosis and arterial remodeling. Curr Opin Lipidol. 2004;15:515–21. doi:10.1097/00041433-200410000-00004.

    PubMed  CAS  Google Scholar 

  71. Pasterkamp G, Van Keulen JK, De Kleijn DP. Role of Toll-like receptor 4 in the initiation and progression of atherosclerotic disease. Eur J Clin Invest. 2004;34:328–34. doi:10.1111/j.1365-2362.2004.01338.x.

    PubMed  CAS  Google Scholar 

  72. Bjorkbacka H. Multiple roles of Toll-like receptor signaling in atherosclerosis. Curr Opin Lipidol. 2006;17:527–33.

    Article  PubMed  CAS  Google Scholar 

  73. Mullick AE, Tobias PS, Curtiss LK. Toll-like receptors and atherosclerosis: key contributors in disease and health? Immunol Res. 2006;34:193–209. doi:10.1385/IR:34:3:193.

    PubMed  CAS  Google Scholar 

  74. Frantz S, Ertl G, Bauersachs J. Mechanisms of disease: Toll-like receptors in cardiovascular disease. Nat Clin Pract Cardiovasc Med. 2007;4:444–54. doi:10.1038/ncpcardio0938.

    PubMed  CAS  Google Scholar 

  75. Stoll LL, Denning GM, Weintraub NL. Endotoxin, TLR4 signaling and vascular inflammation: potential therapeutic targets in cardiovascular disease. Curr Pharm Des. 2006;12:4229–45. doi:10.2174/138161206778743501.

    PubMed  CAS  Google Scholar 

  76. Kiechl S, Lorenz E, Reindl M, Wiedermann CJ, Oberhollenzer F, Bonora E, et al. Toll-like receptor 4 polymorphisms and atherogenesis. N Engl J Med. 2002;347:185–92. doi:10.1056/NEJMoa012673.

    PubMed  CAS  Google Scholar 

  77. Netea MG, Hijmans A, van Wissen S, Smilde TJ, Trip MD, Kullberg BJ, et al. Toll-like receptor-4 Asp299Gly polymorphism does not influence progression of atherosclerosis in patients with familial hypercholesterolaemia. Eur J Clin Invest. 2004;34:94–9. doi:10.1111/j.1365-2362.2004.01303.x.

    PubMed  CAS  Google Scholar 

  78. Norata GD, Garlaschelli K, Ongari M, Raselli S, Grigore L, Benvenuto F, et al. Effect of the Toll-like receptor 4 (TLR-4) variants on intima–media thickness and monocyte-derived macrophage response to LPS. J Intern Med. 2005;258:21–7. doi:10.1111/j.1365-2796.2005.01509.x.

    PubMed  CAS  Google Scholar 

  79. Labrum R, Bevan S, Sitzer M, Lorenz M, Markus HS. Toll receptor polymorphisms and carotid artery intima–media thickness. Stroke. 2007;38:1179–84. doi:10.1161/01.STR.0000260184.85257.2b.

    PubMed  Google Scholar 

  80. Hernesniemi JA, Raitakari OT, Kähönen M, Juonala M, Hutri-Kähönen N, Marniemi J, et al. Toll-like receptor 4 gene (Asp299Gly) polymorphism associates with carotid artery elasticity. The cardiovascular risk in young Finns study. Atherosclerosis. 2008;198:152–9. doi:10.1016/j.atherosclerosis.2007.09.024.

    PubMed  CAS  Google Scholar 

  81. Ameziane N, Beillat T, Verpillat P, Chollet-Martin S, Aumont MC, Seknadji P, et al. Association of the Toll-like receptor 4 gene Asp299Gly polymorphism with acute coronary events. Arterioscler Thromb Vasc Biol. 2003;23:e61–4. doi:10.1161/01.ATV.0000101191.92392.1D.

    PubMed  Google Scholar 

  82. Boekholdt SM, Agema WR, Peters RJ, Zwinderman AH, van der Wall EE, et al. REgression GRowth Evaluation Statin Study Group. Variants of toll-like receptor 4 modify the efficacy of statin therapy and the risk of cardiovascular events. Circulation. 2003;107:2416–21. doi:10.1161/01.CIR.0000068311.40161.28.

    PubMed  CAS  Google Scholar 

  83. Yang IA, Holloway JW, Ye S. Southampton Atherosclerosis Study (SAS) Group. TLR4 Asp299Gly polymorphism is not associated with coronary artery stenosis. Atherosclerosis. 2003;170:187–90. doi:10.1016/S0021-9150(03)00286-7.

    PubMed  CAS  Google Scholar 

  84. Edfeldt K, Bennet AM, Eriksson P, Frostegård J, Wiman B, Hamsten A, et al. Association of hypo-responsive toll-like receptor 4 variants with risk of myocardial infarction. Eur Heart J. 2004;25:1447–53. doi:10.1016/j.ehj.2004.05.004.

    PubMed  CAS  Google Scholar 

  85. Morange PE, Tiret L, Saut N, Luc G, Arveiler D, Ferrieres J, et al. PRIME Study Group. TLR4/Asp299Gly, CD14/C-260T, plasma levels of the soluble receptor CD14 and therisk of coronary heart disease: the PRIME study. Eur J Hum Genet. 2004;12:1041–9. doi:10.1038/sj.ejhg.5201277.

    PubMed  CAS  Google Scholar 

  86. Holloway JW, Yang IA, Ye S. Variation in the toll-like receptor 4 gene and susceptibility to myocardial infarction. Pharmacogenet Genomics. 2005;15:15–21. doi:10.1097/01213011-200501000-00003.

    PubMed  CAS  Google Scholar 

  87. Zee RY, Hegener HH, Gould J, Ridker PM. Toll-like receptor 4 Asp299Gly gene polymorphism and risk of atherothrombosis. Stroke. 2005;36:154–7. doi:10.1161/01.STR.0000149948.31879.f0.

    PubMed  CAS  Google Scholar 

  88. Koch W, Hoppmann P, Pfeufer A, Schömig A, Kastrati A. Toll-like receptor 4 gene polymorphisms and myocardial infarction: no association in a Caucasian population. Eur Heart J. 2006;27:2524–9. doi:10.1093/eurheartj/ehl231.

    PubMed  CAS  Google Scholar 

  89. Terry DF, Wilcox M, McCormick MA, Lawler E, Perls TT. Cardiovascular advantages among the offspring of centenarians. J Gerontol A Biol Sci Med Sci. 2003;58:M425–31.

    PubMed  Google Scholar 

  90. Terry DF, Wilcox MA, McCormick MA, Pennington JY, Schoenhofen EA, Andersen SL, et al. Lower all-cause, cardiovascular, and cancer mortality in centenarians' offspring. Am Geriatr Soc. 2004;52:2074–6. doi:10.1111/j.1532-5415.2004.52561.x.

    Google Scholar 

  91. Lio D, Candore G, Crivello A, Scola L, Colonna-Romano G, Cavallone L, et al. Opposite effects of interleukin 10 common gene polymorphisms in cardiovascular diseases and in successful ageing: genetic background of male centenarians is protective against coronary heart disease. J Med Genet. 2004;41:790–4. doi:10.1136/jmg.2004.019885.

    PubMed  CAS  Google Scholar 

  92. Grimaldi MP, Candore G, Vasto S, Caruso M, Caimi G, Hoffmann E, et al. Role of the pyrin M694V (A2080G) allele in acute myocardial infarction and longevity: a study in the Sicilian population. J Leukoc Biol. 2006;79:611–5. doi:10.1189/jlb.0705416.

    PubMed  CAS  Google Scholar 

  93. Listì F, Candore G, Balistreri CR, Caruso M, Incalcaterra E, Hoffmann E, et al. Connexin37 1019 gene polymorphism in myocardial infarction patients and centenarians. Atherosclerosis. 2007;191:460–1. doi:10.1016/j.atherosclerosis.2006.08.009.

    PubMed  Google Scholar 

  94. Listì F, Candore G, Grimaldi MP, Lio D, Colonna-Romano G, Orlando V, et al. Alpha1-antitrypsin heterozygosity plays a positive role in attainment of longevity. Biogerontology. 2007;8:139–45. doi:10.1007/s10522-006-9041-y.

    PubMed  Google Scholar 

  95. Nuzzo D, Vasto S, Balistreri CR, Di-Carlo D, Listì F, Caimi G, et al. Role of proinflammatory alleles in longevity and atherosclerosis: results of studies performed on -1562C/T MMP-9 in centenarians and myocardial infarction patients from Sicily. Ann N Y Acad Sci. 2006;1089:496–501. doi:10.1196/annals.1386.048.

    PubMed  Google Scholar 

  96. Listì F, Caruso C, Balistreri CR, Grimaldi MP, Caruso M, Caimi G, et al. PECAM-1/CD31 in infarction and longevity. Ann N Y Acad Sci. 2007;1100:132–9. doi:10.1196/annals.1395.011.

    PubMed  Google Scholar 

  97. Balistreri CR, Candore G, Caruso M, Incalcaterra E, Franceschi C, Caruso C. Role of polymorphisms of CC-chemokine receptor-5 gene in acute myocardial infarction and biological implications for longevity. Haematologica. 2008;93:637–8. doi:10.3324/haematol.12239.

    PubMed  CAS  Google Scholar 

  98. Listì F, Caruso M, Incalcaterra E, Hoffmann E, Caimi G, Balistreri CR, et al. Pro-inflammatory gene variants in myocardial infarction and longevity: implications for pharmacogenomics. Curr Pharm Des. 2008;14:2678–85. doi:10.2174/138161208786264115.

    PubMed  Google Scholar 

  99. Balistreri CR, Candore G, Colonna-Romano G, Lio D, Caruso M, Hoffmann E, et al. Role of Toll-like receptor 4 in acute myocardial infarction and longevity. JAMA. 2004;292:2339–40. doi:10.1001/jama.292.19.2339.

    PubMed  CAS  Google Scholar 

  100. Nebel A, Flachsbart F, Schäfer A, Nothnagel M, Nikolaus S, Mokhtari NE, et al. Role of the toll-like receptor 4 polymorphism Asp299Gly in longevity and myocardial infarction in German men. Mech Ageing Dev. 2007;128:409–11. doi:10.1016/j.mad.2007.04.001.

    PubMed  CAS  Google Scholar 

  101. Barzi F, Woodward M, Marfisi RM, Tavazzi L, Valagussa F, Marchioli R. GISSI-Prevenzione Investigators. Mediterranean diet and all-causes mortality after myocardial infarction: results from the GISSI-Prevenzione trial. Eur J Clin Nutr. 2003;57:604–11. doi:10.1038/sj.ejcn.1601575.

    PubMed  CAS  Google Scholar 

  102. Licastro F, Candore G, Lio D, Porcellini E, Colonna-Romano G, Franceschi C, et al. Caruso C. Innate immunity and inflammation in ageing: a key for understanding age-related diseases. Immun Ageing. 2005;2:8. doi:10.1186/1742-4933-2-8.

    PubMed  Google Scholar 

  103. Schroder NW, Schumann RR. Single nucleotide polymorphisms of Toll-like receptors and susceptibility to infectious disease. Lancet Infect Dis. 2005;5:156–64. doi:10.1016/S1473-3099(05)01308-3.

    PubMed  Google Scholar 

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Acknowledgments

This work was supported by the Italian Ministry of Health grant (molecular mechanisms of stem cancer cell survival control) to C. Caruso and by the Ministry of Education, University and Research (ex60%) grant to G. Candore and C. Caruso.

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Correspondence to Calogero Caruso.

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Balistreri, C.R., Colonna-Romano, G., Lio, D. et al. TLR4 Polymorphisms and Ageing: Implications for the Pathophysiology of Age-Related Diseases. J Clin Immunol 29, 406–415 (2009). https://doi.org/10.1007/s10875-009-9297-5

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  • DOI: https://doi.org/10.1007/s10875-009-9297-5

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