Aging, Longevity, Inflammation, and Cancer

Abstract: Cancer rates increase sharply with age in both sexes, and the majority of cases of cancer occur in patients over the age of 65 years. However, the incidence and mortality for cancer level off around 85‐90 years of age, followed by a plateau, or even a decline in the last decades of life. Therefore, it seems reasonable to conclude that centenarians are endowed with a peculiar resistance to cancer. Tumor progression is a complex process that depends on interactions between tumor and host cells. One aspect of the host response, the inflammatory response, is of particular interest because it includes the release of proinflammatory cytokines, some of which may promote tumor growth and hence influence survival. Data in the literature reviewed in this paper suggest that some kind of solid tumors are affected by regulatory cytokine genotypes. In particular proinflammatory genotypes characterized by a low IL‐10 producer or a high IL‐6 producer seem to be associated with a worse clinical outcome. On the other hand, recent evidence has linked IL‐10 and IL‐6 cytokine polymorphisms to longevity. In fact, those individuals who are genetically predisposed to produce high levels of IL‐6 have a reduced capacity to reach the extreme limits of human life, whereas the high IL‐10‐producer genotype is increased among centenarians. This opposite effect of IL‐6 and IL‐10 common gene polymorphisms in cancer and longevity is intriguing. These data prompt considerations of the role that antagonistic pleiotropy plays in disease and in longevity. Inflammatory genotypes may be both friends and enemies. In fact, they are an important and necessary part of the normal host responses to pathogens, but the overproduction of inflammatory cytokines might cause immune‐inflammatory diseases and eventually death. In fact, our immune system has evolved to control pathogens, so proinflammatory responses are likely to be evolutionarily programmed to resist fatal infections, and a high IL‐6 or a low IL‐10 production is associated with increased resistance to pathogens. However, decreased level of IL‐6 or increased level of IL‐10 might better control inflammatory responses and cancer development. These conditions might result in an increased chance of long‐life survival in an environment with a reduced antigen (i.e., pathogen) load.

[1]  C. Franceschi,et al.  The immunology of exceptional individuals: the lesson of centenarians. , 1995, Immunology today.

[2]  P. Calder,et al.  Symposium on ’Nutrition in the post-genomic era’ Plenary session 4: Genetic variation and diet-related disease , 2002, Proceedings of the Nutrition Society.

[3]  J. Jessup,et al.  Interleukin-6 Blood Level Is Associated With Circulating Carcinoembryonic Antigen and Prognosis in Patients With Colorectal Cancer , 2000, Annals of Surgical Oncology.

[4]  R. Nesse,et al.  Evolution and Healing: The New Science of Darwinian Medicine , 1994 .

[5]  C. Franceschi,et al.  -174 G>C polymorphism of interleukin 6 gene promoter affects interleukin 6 serum level in patients with colorectal cancer. , 2003, Clinical cancer research : an official journal of the American Association for Cancer Research.

[6]  G. Stanta,et al.  Cancer of the oldest old. What we have learned from autopsy studies. , 1997, Clinics in geriatric medicine.

[7]  F. Pociot,et al.  Cytokine gene polymorphism in human disease: on-line databases, Supplement 1 , 2001, Genes and Immunity.

[8]  G. Pawelec,et al.  Is human immunosenescence clinically relevant? Looking for 'immunological risk phenotypes'. , 2002, Trends in immunology.

[9]  J. Blay,et al.  Prognostic value of serum levels of interleukin 6 and of serum and plasma levels of vascular endothelial growth factor in hormone-refractory metastatic breast cancer patients , 2003, British Journal of Cancer.

[10]  A. Bateman,et al.  IL-10 promoter polymorphisms influence tumour development in cutaneous malignant melanoma , 2001, Genes and Immunity.

[11]  J. Ferlay,et al.  Cancer Incidence in Five Continents , 1970, Union Internationale Contre Le Cancer / International Union against Cancer.

[12]  Yuan‐Chang Chung,et al.  Serum interleukin‐6 levels reflect the disease status of colorectal cancer , 2003, Journal of surgical oncology.

[13]  C. Franceschi,et al.  Interleukin-10 promoter polymorphism in sporadic Alzheimer's disease , 2003, Genes and Immunity.

[14]  B. Iacopetta,et al.  The −174 G/C gene polymorphism in interleukin-6 is associated with an aggressive breast cancer phenotype , 2004, British Journal of Cancer.

[15]  L. Ferrucci,et al.  Association between longevity and cytokine gene polymorphisms. A study in Sardinian centenarians , 2004, Aging clinical and experimental research.

[16]  M. Álvarez-López,et al.  Interleukin-10, interleukin-6 and interferon-gamma gene polymorphisms in melanoma patients. , 2002, Melanoma research.

[17]  G. Neufeld,et al.  Interleukin 6 Induces the Expression of Vascular Endothelial Growth Factor (*) , 1996, The Journal of Biological Chemistry.

[18]  M. Lazarus,et al.  An investigation of polymorphism in the interleukin-10 gene promoter. , 1997, European journal of immunogenetics : official journal of the British Society for Histocompatibility and Immunogenetics.

[19]  C. Franceschi,et al.  A gender–dependent genetic predisposition to produce high levels of IL‐6 is detrimental for longevity , 2001, European journal of immunology.

[20]  J S Yudkin,et al.  The effect of novel polymorphisms in the interleukin-6 (IL-6) gene on IL-6 transcription and plasma IL-6 levels, and an association with systemic-onset juvenile chronic arthritis. , 1998, The Journal of clinical investigation.

[21]  D. Middleton,et al.  Interleukin-6-gene C/G 174 polymorphism in nonagenarian and octogenarian subjects in the BELFAST study. Reciprocal effects on IL-6, soluble IL-6 receptor and for IL-10 in serum and monocyte supernatants , 2003, Mechanisms of Ageing and Development.

[22]  G. Fontanini,et al.  Expression of interleukin 6 (IL-6) correlates with oestrogen receptor in human breast carcinoma , 1999, British Journal of Cancer.

[23]  T. Hirano,et al.  IL-6 signal transduction and its physiological roles: the signal orchestration model. , 2003, Reviews of physiology, biochemistry and pharmacology.

[24]  C. Brigati,et al.  Tumors and inflammatory infiltrates: Friends or foes? , 2004, Clinical & Experimental Metastasis.

[25]  F. Pociot,et al.  Cytokine gene polymorphism in human disease: on-line databases , 1999, Genes and Immunity.

[26]  Bente Klarlund Pedersen,et al.  Aging and proinflammatory cytokines , 2001, Current opinion in hematology.

[27]  T. Erlinger,et al.  C-reactive protein and the risk of incident colorectal cancer. , 2004, JAMA.

[28]  C. Franceschi,et al.  Chronic antigenic stress, immunosenescence and human survivorship over the 3 last centuries: heuristic value of a mathematical model , 2003, Mechanisms of Ageing and Development.

[29]  C. Franceschi,et al.  Inflammation, genetics, and longevity: further studies on the protective effects in men of IL-10 −1082 promoter SNP and its interaction with TNF-α −308 promoter SNP , 2003, Journal of medical genetics.

[30]  Gabriella,et al.  Expression of and Response to lnie rleukin 6 (IL6) in Human Mammary Tumors1 , 2006 .

[31]  Ji Hyun Jung,et al.  Interleukin 10 haplotype associated with increased risk of hepatocellular carcinoma. , 2003, Human molecular genetics.

[32]  L. Piantanelli.  Cancer and Aging: From the Kinetics of Biological Parameters to the Kinetics of Cancer Incidence and Mortality a , 1988, Annals of the New York Academy of Sciences.

[33]  D. W. Smith.  Resistance to Causes of Death: A Study of Cancer Mortality Resistance in the Oldest Old , 1999 .

[34]  S. Brod.  Unregulated inflammation shortens human functional longevity , 2000, Inflammation Research.

[35]  Stefano Landi,et al.  Association of common polymorphisms in inflammatory genes interleukin (IL)6, IL8, tumor necrosis factor alpha, NFKB1, and peroxisome proliferator-activated receptor gamma with colorectal cancer. , 2003, Cancer research.

[36]  C. Franceschi,et al.  HLA, aging, and longevity: a critical reappraisal. , 2000, Human immunology.

[37]  C. Gutiérrez,et al.  Interindividual variations in constitutive interleukin-10 messenger RNA and protein levels and their association with genetic polymorphisms1 , 2003, Transplantation.

[38]  C. Caruso,et al.  Immunological and immunogenetic markers of successful and unsuccessful ageing , 2002 .

[39]  B. Weber,et al.  Interleukin-6 -174G-->C polymorphism is associated with improved outcome in high-risk breast cancer. , 2003, Cancer research.

[40]  P. Bruzzi,et al.  Association of breast cancer and polymorphisms of interleukin-10 and tumor necrosis factor-alpha genes. , 2003, Clinical chemistry.

[41]  R. Coffman,et al.  Interleukin-10 and the interleukin-10 receptor. , 2001, Annual review of immunology.

[42]  C. Franceschi,et al.  Inflamm‐aging: An Evolutionary Perspective on Immunosenescence , 2000 .

[43]  Snejina Michailova,et al.  Immunological markers contributing to successful aging in Bulgarians , 2004, Experimental Gerontology.

[44]  P. Woo,et al.  Polymorphic haplotypes of the interleukin-10 5' flanking region determine variable interleukin-10 transcription and are associated with particular phenotypes of juvenile rheumatoid arthritis. , 1999, Arthritis and rheumatism.

[45]  W. Gianni,et al.  Geriatric oncology: a clinical approach to the older patient with cancer. , 2003, European journal of cancer.

[46]  F. Ando,et al.  Cancer incidence in old age , 2000, Mechanisms of Ageing and Development.

[47]  M. Jylhä,et al.  Lack of association between human longevity and polymorphisms of IL-1 cluster, IL-6, IL-10 and TNF-α genes in Finnish nonagenarians , 2001, Mechanisms of Ageing and Development.

[48]  M. Wilcox,et al.  Cardiovascular advantages among the offspring of centenarians. , 2003, The journals of gerontology. Series A, Biological sciences and medical sciences.

[49]  A. Mackiewicz,et al.  Expression of interleukin‐6, interleukin‐6 receptor, and glycoprotein 130 correlates with good prognoses for patients with breast carcinoma , 2000, Cancer.

[50]  C. Navarrete,et al.  Allele frequencies of polymorphisms of the tumour necrosis factor-alpha, interleukin-10, interferon-gamma and interleukin-2 genes in a North European Caucasoid group from the UK. , 2000, European journal of immunogenetics : official journal of the British Society for Histocompatibility and Immunogenetics.

[51]  M. Beckmann,et al.  An interleukin-6 gene promoter polymorphism influences the biological phenotype of ovarian cancer. , 2003, Cancer research.

[52]  R. Eeles,et al.  Influence of cytokine gene polymorphisms on the development of prostate cancer. , 2002, Cancer research.

[53]  Mitch Leslie,et al.  The age of cancer. , 2006, Science of aging knowledge environment : SAGE KE.

[54]  C. Franceschi,et al.  What studies on human longevity tell us about the risk for cancer in the oldest old: data and hypotheses on the genetics and immunology of centenarians , 2002, Experimental Gerontology.

[55]  T. Hirano,et al.  IL-6 in autoimmune disease and chronic inflammatory proliferative disease. , 2002, Cytokine & growth factor reviews.

[56]  J. Goedert,et al.  Increased risk of noncardia gastric cancer associated with proinflammatory cytokine gene polymorphisms. , 2003, Gastroenterology.

[57]  Eric M. Smith,et al.  IL-10 as a mediator in the HPA axis and brain , 1999, Journal of Neuroimmunology.

[58]  M. Bar‐eli,et al.  Regulation of tumor growth and metastasis by interleukin-10: the melanoma experience. , 1999, Journal of interferon & cytokine research : the official journal of the International Society for Interferon and Cytokine Research.

[59]  D. Middleton,et al.  Study of age-association with cytokine gene polymorphisms in an aged Irish population , 2003, Mechanisms of Ageing and Development.

[60]  C. M. Steel,et al.  Regulation of ICAM‐1 (CD54) expression in human breast cancer cell lines by interleukin 6 and fibroblast‐derived factors , 1994, International journal of cancer.

[61]  R. Dummer,et al.  HLA-G and IL-10 expression in human cancer--different stories with the same message. , 2003, Seminars in cancer biology.

[62]  Alberto Mantovani,et al.  Inflammation and cancer: back to Virchow? , 2001, The Lancet.