Abstract
Although many hypotheses have been proposed to explain the strong link between aging and cancer, the exact mechanisms responsible for the increased frequency of occurrence of cancer with advancing age have not been fully defined. Recent evidence indicates that malregulation of the apoptotic process may be involved in some aging process as well as in the development of cancer. Although it is still under debate how apoptosis is expressed during aging in vivo, this phenomenon is an important factor in unwinding the complicated mechanisms that link cancer and aging. In this review, we report on the discussion at the symposium of the 27th annual meeting of the Japanese society for biomedical gerontology, regarding recent findings from aging and carcinogenesis studies using animal models, the characteristics of cancer in patients with Werner’s syndrome, the epigenetic changes in human cancers and aging, and the characteristics of human cancers in the elderly. It was concluded that apoptosis plays a role in the aging process and carcinogenesis in vivo, likely as an inherent protective mechanism against various kinds of damages to genes/chromosomes.
Similar content being viewed by others
References
Ershler WB, Longo DL (1997) Aging and cancer: issues of basic and clinical science. J Natl Cancer Inst 89:1489–1497
Denduluri N, Ershler WB (2004) Aging biology and cancer. Semin Oncol 31:137–148
Edwards BK, Howe HL, Ries LA, Thun MJ, Rosenberg HM, Yancik R, Wingo PA, Jemal A, Feigal EG (2002) Annual report to the nation on the status of cancer, 1973–1999, featuring implications of age and aging on US cancer burden. Cancer 94:2766–2792
Sarasin A (2003) An overview of the mutagenesis and carcinogenesis. Mutat Res 544:99–106
Shay JW, Roninson IB (2004) Hallmarks of senescence in carcinogenesis and cancer therapy. Oncogene 23:2919–2933
Guarente L, Kenyon C (2000) Genetic pathways that regulate ageing in model organisms. Nature 408:255–262
Gems D, Partridge L (2001) Insulin/IGF signaling and ageing seeing the bigger picture. Curr Opin Genet Dev 11:287–292
Warner HR, Hodes RJ, Pocinki K (1997) What does cell death have to do with aging? Am J Geriatr Soc 45:1140–1146
Higami Y, Shimokawa I (2000) Apoptosis in the aging process. Cell Tissue Res 301:125–132
Sharpless NE, DePinho RA (2004) Telomeres, stem cells, senescence, and cancer. J Clin Invest 113:160–168
Mori H, Colman SM, Xiao Z, Ford AM, Healy LE, Donaldson C, Hows JM, Navarrete C, Greaves M (2002) Chromosome translocations and covert leukemic clones are generated during normal fetal development. Proc Natl Acad Sci U S A 99:8242–8247
Liu Y, Hernandez AM, Shibata D, Cortopassi GA (1994) BCL2 translocation frequency rises with age in humans. Proc Natl Acad Sci U S A 91:8910–8914
Ershler WB (1993) The influence of an aging immune system on cancer incidence and progression. J Gerontol 48:B3–B7
Cui Z, Willingham MC (2004) The effect of aging on cellular immunity against cancer in SR/CR mice. Cancer Immunol Immunother 53:473–478
Yuasa Y (2002) DNA methylation in cancer and ageing. Mech Ageing Dev 123:1649–1654
DePinho RA (2000) The age of cancer. Nature 408:248–254
Kirschner M, Pujol G, Radu A (2002) Oligonucleotide microarray data mining: search for age-dependent gene expression. Biochem Biophys Res Com 298:772–778
Hirokawa K (1992) Understanding the mechanism of the age-related decline in immune function. Nutr Rev 50:361–366
Hirokawa K (1999) Age-related changes of signal transduction in T cells. Exp Gerontol 34:7–18
Pawelec G, Effros RB, Caruso C, Remarque E, Barnett Y, Solana R (1999) T cells and aging (update February 1999). Front Biosci 4:d216-d269
Burns EA, Leventhal EA (2000) Aging, immunity, and cancer. Cancer Control 7:513–522
Baker DG (1997) Natural pathogens of laboratory mice, rats, and rabbits and their effects on research. Clin Microbiol Rev 11:231–266
Yamaguchi S, Kitagawa M, Inoue M, Tejima Y, Kimura M, Aizawa S, Utsuyama M, Hirokawa K (2001) Role of lymphoid cells in age-related change of susceptibility to Friend leukemia virus-induced leukemia. Mech Ageing Dev 122:219–232
Kitagawa M, Matsubara O, Kasuga T (1986) Dynamics of lymphocytic subpopulations in Friend leukemia virus-induced leukemia. Cancer Res 46:3034–3039
Chesebro B, Miyazawa M, Britt WJ (1990) Host genetic control of spontaneous and induced immunity to Friend murine retrovirus infection. Ann Rev Immunol 8:477–499
Kitagawa M, Kamisaku H, Sado T, Kasuga T (1993) Friend leukemia virus-induced leukemogenesis in fully H-2 incompatible C57BL6 → C3H radiation bone marrow chimeras. Leukemia 7:1041–1046
Cinader B, Van der Gaag HC, Koh SW, Axelrad AA (1987) Friend virus replication as a function of age. Mech Ageing Dev 40:181–191
Stewart DR, Kirschmann DA, Blank KJ, Murasko DM (1994) Devrease between young and aged mice in susceptibility to Friend virus. Mech Ageing Dev 73:145–155
Weksler ME, Russo C, Siskind GW (1989) Peripheral T-cells select the B-cell repertoire in old mice. Immunol Rev 110:173–185
Hirokawa K (1998) Immunity and ageing. In: Pathy MSJ (ed) Principle and practice of geriatric medicine. Wiley, London, pp 35–47
Utsuyama M, Wakikawa A, Tamura T, Nariuchi H, Hirokawa K (1997) Impairment of signal transduction in T cells from old mice. Mech Ageing Dev 93:131–144
Pawelec G, Hirokawa K, Fulop T (2001) Altered T cell signalling in ageing. Mech Ageing Dev 122:1613–1637
Gardner MB (1993) Genetic control of retroviral disease in aging wild mice. Genetica 91:199–209
Utsuyama M, Hirokawa K (2003) Radiation-induced-thymic lymphoma occurs in young, but not in old mice. Exp Gerontol 74:319–325
Kaplan HS, Brown MB, Paull J (1953) Influence of bone marrow injections in involution and neoplasia of mouse thymus after systemic irradiation. J Natl Cancer Inst 14:303–316
Anisimov VN, Prokudina EA (1986) Carcinogenesis and ageing—VII. Carcinogenic effect of single total-body X-ray irradiation in young and old female rats. Exp Pathol 29:165–171
Wong KK, Chang S, Weiler SR, Ganesan S, Chaudhuri J, Zhu C, Artandi SE, Rudolph KL, Gottlieb GJ, Chin L, Alt FW, DePinho RA (2000) Telomere dysfunction impairs DNA repair and enhances sensitivity to ionizing radiation. Nat Genet 26:85–88
Anisimov VN, Turusov VS (1981) Modifying effect of aging on chemical carcinogenesis. A review. Mech Ageing Dev 15:399–414
Anisimov VN (1982) Carcinogenesis and ageing—III. The role of age in initiation and promotion of carcinogenesis. Exp Pathol 22:131–147
Anisimov VN (1983) Carcinogenesis and aging. Adv Cancer Res 40:365–424
Balducci L, Wallace C, Khansur T, Vance RB, Thigpen JT, Hardy C (1986) Nutrition, cancer, and aging: an annotated review. I. Diet, carcinogeneis, and aging. J Am Geriatr Soc 34:127–136
Zimmerman JA, Carter TH (1989) Altered cellular responses to chemical carcinogens in aged animals. J Gerontol 44:19–24
Ebbesen P (1984) Cancer and normal ageing. Mech Ageing Dev 25:269–283
Doria G, Biozzi G, Mouton D, Covelli V (1997) Genetic control of immune responsiveness, aging and tumor incidence. Mech Ageing Dev 96:1–13
Hirokawa K, Utsuyama M, Goto H, Kuramoto K (1984) Differential rate of age-related decline in immune functions in genetically defined mice with different tumor incidence and life span. Gerontology 30:223–233
Sato K, Bloom ET, Hirokawa K, Makinodan T (1986) Increased susceptibility of old mice to plasmacytoma induction. J Gerontol 41:24–29
Miller RA (1991) Gerontology as oncology. Research on aging as the key to the understanding of cancer. Cancer 68(11 suppl):2496–2501
Weindruch R (1989) Dietry restriction, tumors, and aging in rodents. J Gerontol 44:67–71
Walter CA, Grabowski DT, Street KA, Conrad CC, Richardson A (1997) Analysis and modulation of DNA repair in aging. Mech Ageing Dev 98:203–222
Walter CA, Zhou ZQ, Manguino D, Ikeno Y, Reddick R, Nelson J, Intano G, Herbert DC, MaMahan CA, Hanes M (2001) Mutant and genetically modified mice as models for studying the relationship between aging and carcinogenesis. Ann N Y Acad Sci 928:132–140
Anisimov VN (2001) Mutant and genetically modified mice as models for studying the relationship between aging and carcinogenesis. Mech Ageing Dev 122:1221–1255
Anisimov VN (2003) Aging and cancer in transgenic and mutant mice. Front Biosci 8:s883–s902
Cao L, Li W, Kim S, Brodie SG, Deng C-X (2003) Senescence, aging, and malignant transformation mediated by p53 in mice lacking Brca1 full-length isoform. Genes Dev 17:201–213
Harada Y, Shiomi N, Koike M, Ikawa M, Okabe M, Hirota S, Kitamura Y, Kitagawa M, Matsunaga T, Nikaido O, Shiomi T (1999) Postnatal growth failure, short life span, and early onset of cellular senescence and subsequent immortaliztion in mice lacking the xeroderma pigmentosum group G gene. Mol Cell Biol 19:2366–2372
Robert L (2002) Cell-matrix interactions in cancer spreading—effect of aging. Semin Cancer Biol 12:157–163
Hirayama R, Sato K, Hirokawa K, Chang MP, Mishima Y, Makinodan T (1984) Different metastatic modes of malignant melanoma implanted in the ear of young and old mice. Cancer Immunol Immunother 18:209–214
Hirayama R, Takemura K, Hihei Z, Ichikawa W, Takagi Y, Mishima Y, Utsuyama M, Hirokawa K (1993) Differential effect of host microenvironment and systemic humoral factors on the implantation and the growth rate of metastatic tumor in parabiotic mice constructed between young and old mice. Mech Ageing Dev 71:213–221
Kanno J, Wakikawa A, Utsuyama M, Hirokawa K (1997) Effect of restraint stress on immune system and experimental B16 melanoma metastasis in aged mice. Mech Ageing Dev 93:107–117
Duker NJ (2002) Chromosome breakage syndromes and cancer. Am J Med Genet 115:125–129
Goto M, Rubenstein M, Weber J, Drayana D (1992) Genetic linkage of Werner’s syndrome to five markers on chromosome 8. Nature 355:735–738
Goto M (1997) Hierarchical deterioration of body systems in Werner’s syndrome: implications for normal ageing. Mech Ageing Dev 98:239–254
Yu CE, Oshim J, Fu YH, Wijsman EM, Hisama F, Alisch R, Matthews S, Nakura J, Miki T, Ouais S, Martin GM, Mulligan J, Schellenberg GD (1996) Positional cloning of the Werner’s syndrome gene. Science 272:258–262
Shen J-C, Loeb LA (2001) Unwinding the molecular basis of the Werner syndrome. Mech Ageing Dev 122:921–944
Chen L, Lee L, Kudlow BA, Dos Santos HG, Sletvoid O, Shafeghati Y, Botha EG, Garg A, Hanson NB, Martin GM, Mian IS, Kennedy BK, Oshima J (2003) LMNA mutaions in atypical Werner’s syndrome. Lancet 362:440–445
Satoh M, Imai M, Sugimoto M, Goto M, Furuichi Y (1999) Prevalence of Werner’s syndrome heterozygotes in Japan. Lancet 353:1766
Ishikawa Y, Sugano H, Matsumoto T, Furuichi Y, Miller RW, Goto M (1999) Unusual features of thyroid carcinomas in Japanese patients with Werner syndrome and possible genotype-phenotype relations to cell type and race. Cancer 85:1345–1352
Ishikawa Y, Miller RW, Machinami R, Sugano H, Goto M (2000) Atypical osteosarcomas in Werner syndrome (adult progeria). Jpn J Cancer Res 91:1345–1349
Goto M, Miller RW, Ishikawa Y, Sugano H (1996) Excess of rare cancers in Werner syndrome (adult progeria). Cancer Epidemiol Biomarkers Prev 5:239–246
Parry DM, Mulvihill JJ, Miller RW, Berg K, Carter CL (1987) Strategies for controlling cancer through genetics. Cancer Res 47:6814–6817
Opresko PL, cheng WH, von Kobe C, Harrison JA, Bohr VA (2003) Werner syndrome and the function of the Werner protein: what they can teach us about the molecular aging process. Carcinogenesis 24:791–802
Jones PA, Laird PW (1999) Cancer epigenetics comes of age. Nat Genet 21:163–167
Baylin SB, Herman JG (2000) DNA hypermethylation in tumorigenesis. Trends Genet 16:168–174
Wutz A, Smrzka OW, Schweifer N, Schellander K, Wagner EF, Barlow DP (1997) Imprinted expression of the Igf2r gene depends on an intronic CpG island. Nature 389:745–749
Lyon MF (1999) X-chromosome inactivation. Curr Biol 9:R235–R237
Bestor TH (2000) The DNA methyltransferases of mammals. Hum Mol Genet 9:2395–2402
Esteller M, Corn PG, Baylin SB, Herman JG (2001) A gene hypermethylation profile of human cancer. Cancer Res 61:3225–3229
Jubb AM, Bell SM, Quirke P (2001) Methylation and colorectal cancer. J Pathol 195:111–134
Issa J-P, 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
Ahuja N, Li Q, Mohan AL, Baylin SB, Issa J-P (1998) Aging and DNA methylation in colorectal mucosa and cancer. Cancer Res 58:5489–5494
Habuchi T, Takahashi T, Kaminuma H, Wang L, Tsuchiya N, Satoh S, Akao T, Sato K, Ogawa O, Knowles MA, Kato T (2001) Hypermethylation at 9q32–33 tumour suppressor region is age-related in normal urothelium and an early and frequent alteration in bladder cancer. Oncogene 20:531–537
Issa J-P, Ahuja N, Toyota M, Bronner MP, Brentnall TA (2001) Accelerated age-related CpG island methylation in ulcerative colitis. Cancer Res 61:3573–3577
Toyota M, Ahuja N, Ohe-Toyota M, Herman JG, Baylin SB, Issa J-P (1999) CpG island methylator phenotype in colorectal cancer. Proc Natl Acad Sci U S A 96:8681–8686
Nakajima T, Akiyama Y, Shiraishi J, Arai T, Yanagisawa Y, Arai M, Fukuda Y, Sawabe M, Satoh K, Kamiyama R, Hirokawa K, Yuasa Y (2001) Age-related hypermethylation of the hMLH1 promotor in gastric cancers. Int J Cancer 94:208–211
Arai T, Esaki Y, Sawabe M, Nonma N, Nakamira K, Takubo K (2004) Hypermethylation of the hMLH1 promotor with absent hMLH1 expression in medullary-type poorly differentiated colorectal adenocarcinoma in the elderly. Mod Pathol 17:172–179
Artandi SE, Chang S, Lee SL, Alson S, Gottlieb GJ, Chin L, DePinho RA (2000) Telomere dysfunction promotes non-reciprocal translocations and epithelial cancers in mice. Nature 406:641–645
Artandi SE, Alson S, Tietze MK, Sharpless NE, Ye S, Greenberg RA, Gastrillon DH, Horner JW, Weiler SR, Carrasco RD, DePinho RA (2002) Constitutive telomerase expression promotes mammary carcinomas in aging mice. Proc Natl Acad Sci U S A 99:8191–8196
O‘Hagan RC, Chang S, Maser RS, Mohan R, Artandi SE, Chin L, DePinho RA (2002) Telomere dysfunction provokes regional amplification and deletion in cancer genomes. Cancer Cell 2:149–155
Ania BJ, Suman VJ, Fairbanks VF, Rademacher DM, Melton LJ 3rd (1997) Incidence of anemia in older people: an epidemiologic study in a well defined population. J Am Geriatr Soc 45:825–831
Balducci L, Hardy CL, Lyman GH (2001) Hematopoietic growth factors in the older cancer patient. Curr Opin Hematol 8:170–187
Balducci L (2003) Anemia, cancer, and aging. Cancer Control 10:478–486
Hamerman D, Merman JW, Albers GW, Brown DL, Silver D (1999) Emerging evidence for inflammation in conditions frequently affecting older adults: report of a symposium. J Am Geriatr Soc 47:1016–1025
Pinto A, Filippi RD, Frigeri F, Corazzeli G, Normanno N (2003) Aging and the hematopoietic system. Crit Rev Oncol Hematol 48S:S3–S12
Ogawa T, Kitagawa M, Hirokawa K (2000) Age-related changes of human bone marrow: a histometric estimation of proliferative cells, apoptotic cells, T cells, B cells and macrophages. Mech Ageing Dev 117:57–68
Kitagawa M, Yamaguchi S, Takahashi M, Tanizawa T, Hirokawa K, Kamiyama R (1998) Localization of Fas and Fas ligand in bone marrow cells demonstrating myelodysplasia. Leukemia 12:486–492
Kitagawa M, Saito I, Kuwata T, Yoshida S, Yamaguchi S, Takahashi M, Tanizawa T, Kamiyama R, Hirokawa K (1997) Overexpression of tumor necrosis factor (TNF)-α and interferon (IFN)-γ by bone marrow cells from patients with myelodysplastic syndromes. Leukemia 11:2049–2054
Kitagawa M, Takahashi M, Yamaguchi S, Inoue M, Ogawa S, Hirokawa K, Kamiyama R (1999) Expression of inducible nitric oxide synthase (NOS) in bone marrow cells of myelodysplastic syndromes. Leukemia 13:699–703
Sawanobori M, Yamaguchi S, Hasegawa M, Inoue M, Suzuki K, Kamiyama R, Hirokawa K, Kitagawa M (2003) Expression of TNF receptors and related signaling molecules in the bone marrow from patients with myelodysplastic syndromes. Leuk Res 27:583–591
Yamamoto K, Abe S, Nakagawa Y, Suzuki K, Hasegawa M, Inoue M, Kurata M, Hirokawa K, Kitagawa M (2004) Expression of IAP family proteins in myelodysplastic syndromes transforming to overt leukemia. Leuk Res 28:1203-11
Ferry JA (2002) Angioimmunoblastic T-cell lymphoma. Adv Anat Pathol 9:272–279
Dogan A, Attygalle AD, Kyriakou C (2003) Angioimmunoblastic T-cell lymphoma. Br J Haematol 121:681–691
Yamaguchi S, Kitagawa M, Inoue M, Tomizawa N, Kamiyama R, Hirokawa K (2000) Cell dynamics and expression of tumor necrosis factor (TNF)-α, interleukin-6, and TNF receptors in angioimmunoblastic lymphadenopathy-type T cell lymphoma. Exp Mol Pathol 68:85–94
Esaki Y, Hirokawa K, Yamashiro M (1987) Multiple gastric cancers in the aged. Cancer 59:560–565
Esaki Y, Hirayama R, Hirokawa K (1990) A comparison of patterns of metastasis in gastric cancer, compared by histologic type and age. Cancer 65:2086–2090
Arai T, Esaki Y, Inoshita N, Kasahara I, Sawabe M, Honma N, Takubo K (2004) Pathologic characteristics of gastric cancer in the elderly: a retrospective study of 994 surgical cases. Gastric Cancer 7:154–159
Arai T, Takubo K, Sawabe M, Esaki Y (2000) Pathologic characteristics of colorectal cancer in the elderly. J Clin Gastroenterol 31:67–72
Arai T, Sawabe M, Takubo K, Kanazawa K, Esaki Y (2001) Multiple colorectal cancers in the elderly: a retrospective study of both surgical and autopsy cases. J Gastroenterol 36:748–752
Kaesberg PR, Ershler WB (1989) The importance of immunosenescence in the incidence and malignant properties of cancer in hosts of advanced age. J Gerontol 44:63–66
Pili R, Guo Y, Chang J, Nakanishi H, Martin GR, Passaniti A (1994) Altered angiogenesis underlying age-dependent changes in tumor growth. J Natl Cancer Inst 86:1303–1314
Macieira-Coelho A (2003) The decline of the clinical incidence of cancers during human senescence. Grontology 49:341–349
Ershler WB (1992) Explanations for reduced tumor proliferative capacity with age. Exp Gerontol 27:551–558
Tanaka K, Nagaoka S, Takemura T, Arai T, Sawabe M, Takubo K, Sugihara K, Kitagawa M, Hirokawa K (2002) Incidence of apoptosis increases with age in colorectal cancer. Exp Gerontol 37:1469–1479
Seidler HBK, Utsuyama M, Nagaoka S, Takemura T, Kitagawa M, Hirokawa K (2004) Expression level of Wnt signaling components possibly influence the behavior of colorectal cancer in different age groups. Exp Mol Pathol 76:224–233
Endo T, Abe S, Seidler HBK, Nagaoka S, Takemura T, Utsuyama M, Kitagawa M, Hirokawa K (2004) Expression of IAP family proteins in colorectal cancer in different age groups. Cancer Immunol Immunother (in press)
Tsujimoto Y (2003) Cell death regulation by the Bcl-2 Protein family in the mitochondria. J Cell Physiol 195:158–167
Abraham MC, Shaham S (2004) Death without caspases, caspases without death. Trends Cell Biol 14:184–193
Cregan SP, Dawson VL, Slack RS (2004) Role of AIF in caspase-dependent and caspase-independent cell death. Oncogene 23:2785–2796
Donovan M, Cotter TG (2004) Control of mitochondrial integrity by Bcl-2 family members and caspase-independent cell death. Biochem Biophys Acta 1644:133–147
Nagaoka S, Shiraishi J, Utsuyama M, Seki S, Takemura T, Kitagawa M, Sawabe M, Takubo K, Hirokawa K (2003) Poor prognosis of colorectal cancer in patients over 80 years old is associated with down-regulation of tumor suppressor genes. J Clin Gastroenterol 37:48–54
Wang E (1997) Regulation of apoptosis resistance and ontogeny of age-dependent diseases. Exp Gerontol 32:471–484
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Kitagawa, M., Utsuyama, M., Kurata, M. et al. Cancer and aging: symposium of the 27th annual meeting of the Japanese society for biomedical gerontology, Tokyo. Cancer Immunol Immunother 54, 623–634 (2005). https://doi.org/10.1007/s00262-004-0622-9
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00262-004-0622-9