Skip to main content
SpringerLink
Log in

Age-Related Genomic Hypomethylation

  • Chapter
  • First Online:
Epigenetics of Aging

Abstract

Aging is a multi-factorial process of the progressive gradual decline of cellular functions with the passage of time. It is clear that aging affects the mammalian epigenome, including hypomethylation of DNA. DNA methylation is a crucial biological process that controls maintenance of genomic integrity and an accurate expression of genetic information. The accurate status of DNA methylation is balanced in mature cells, but with age this balance is strongly shifted in favor of DNA demethylation. Therefore, DNA hypomethylation that occurs during normal aging appears to be a critical risk factor contributing to the development of chronic age-related human pathological states. This review describes the involvement of DNA hypomethylation in the pathogenesis of several major age-related human diseases, including cancer, atherosclerosis, Alzheimer’s disease, psychiatric disorders, and autoimmune pathologies.

The views expressed in this chapter do not necessarily represent those of the US Food and Drug Administration.

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Log in via an institution
Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 129.00
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 169.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD 169.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

References

  • Agrawal, A., Murphy, R.F., and Agrawal, D.K. 2007. DNA methylation in breast and colorectal cancers. Mod. Pathol. 20:711–721.

    Article  PubMed  CAS  Google Scholar 

  • Ahuja, N., and Issa, J.P. 2000. Aging, methylation and cancer. Histol. Histopathol. 15:835–842.

    PubMed  CAS  Google Scholar 

  • Allis, C.D., Jenuwein, T., and Reinberg, D. 2007. Epigenetics. Cold Spring Harbor: Cold Spring Harbor Laboratory Press.

    Google Scholar 

  • Arita, K., Ariyoshi, M., Tochio, H., Nakamura, Y., and Shirakawa, M. 2008. Recognition of hemi-methylated DNA by the SRA protein UHRF1 by a base flipping mechanism. Nature 455: 818–821.

    Article  PubMed  CAS  Google Scholar 

  • Arnaud, M., Dante, R., and Niveleau, A. 1985. DNA methyltransferases in normal and avian sarcoma virus-transformed rat cells. Quantitation of 5-methyldeoxycytidine in DNA and enzyme kinetics study. Biochim. Biophys. Acta 826:108–112.

    PubMed  CAS  Google Scholar 

  • Avvakumov, G.V., Walker, J.R., Xue, S., Li, Y., Duan, S., Bronner, C., Arrowsmith, C.H., and Dhe-Paganon, S. 2008. Structural basis for recognition of hemimethylated DNA by the SRA domain of human UHRF1. Nature 455:822–825.

    Article  PubMed  CAS  Google Scholar 

  • Bandyopadhyay, D., and Medrano, E.E. 2003. The emerging role of epigenetics in cellular and organismal aging. Exp. Gerontol. 38:1299–1307.

    Article  PubMed  CAS  Google Scholar 

  • Barbot, W., Dupressoir, A., Lazar, V., and Heidmann, T. 2002. Epigenetic regulation of an IAP retrotransposon in the aging mouse: progressive demethylation and de-silencing of the element by its repetitive induction. Nucleic Acids Res. 30:2365–2373.

    Article  PubMed  CAS  Google Scholar 

  • Bedford, M.T., and van Helden, P.D. 1987. Hypomethylation of DNA in pathological conditions of the human prostate. Cancer Res. 47:5274–5276.

    PubMed  CAS  Google Scholar 

  • Berdishev, G.D., Korotaev, G.K., Bojarskikh, G.V., and Vanyushin, B.F. 1967. Nucleotide composition of DNA and RNA from somatic tissues of humpback salmon and its changes during spawning. Biochemistry (Mosc.) 32:988–993.

    Google Scholar 

  • Bertram, C., and Hass, R. 2008. Cellular responses to reactive oxygen species-induced DNA damage and aging. Biol. Chem. 389:211–220.

    Article  PubMed  CAS  Google Scholar 

  • Bestor, T.H. 2000. The DNA methyltransferases of mammals. Hum. Mol. Genet. 9:2395–2402.

    Article  PubMed  CAS  Google Scholar 

  • Casillas, M.A., Lopatina, N., Andrews, L.G., and Tollefsbol, T.O. 2003. Transcriptional control of the DNA methyltransferases is altered in aging and neoplastically-transformed human fibroblasts. Mol. Cell. Biochem. 252:33–43.

    Article  PubMed  CAS  Google Scholar 

  • Castro, R., Rivera, I., Struys, E.A., Jansen, E.E.W., Ravasco, P., Camilo, M.E., Blom, H.J., Jakobs, C., and de Almeida, I.T. 2003. Increased homocysteine and S-adenosylhomocysteine concentrations and DNA hypomethylation in vascular disease. Clin. Chem. 49:1292–1296.

    Article  PubMed  CAS  Google Scholar 

  • Cerda, S., and Weitzman, S.A. 1997. Influence of oxygen radical injury on DNA methylation. Mutat. Res. 386:141–152.

    Article  PubMed  CAS  Google Scholar 

  • Chen, J.H., Hales, C.N., and Ozanne, S.E. 2007. DNA damage, cellular senescence and organismal ageing: causal or correlative? Nucleic Acids Res. 35:7417–7428.

    Article  PubMed  CAS  Google Scholar 

  • Chen, R.Z., Pettersson, U., Beard, C., Jackson-Grusby, L., and Jaenisch, R. 1998. DNA hypomethylation leads to elevated mutation rates. Nature 395:89–93.

    Article  PubMed  CAS  Google Scholar 

  • Chen, Z., Karaplis, A.C., Ackerman, S.L., Pogribny, I.P., Melnyk, S., Lussier-Cacan, S., Chen, M.F., Pai, A., John, S.W., Smith, R.S., Bottiglieri, T., Bagley, P., Selhub, J., Rudnicki, M.A., James, S.J., and Rozen, R.A. 2001. Mice deficient in methylenetetrahydrofolate reductase exhibit hyperhomocysteinemia and decreased methylation capacity, with neuropathology and aortic lipid deposition. Hum. Mol. Genet. 10:433–443.

    Article  PubMed  CAS  Google Scholar 

  • Chiang, P.K., Gordon, R.K., Tal, J., Zeng, G.C., Doctor, B.P., Pardhasaradhi, K., and McCann, P.P. 1996. S-Adenosylmethionine and methylation. FASEB J. 10:471–480.

    PubMed  CAS  Google Scholar 

  • Coleman, W.B., and Tsongalis, G.J. 2006. Molecular mechanisms of human carcinogenesis. EXS. 96:321–349.

    PubMed  CAS  Google Scholar 

  • Creusot, F., Acs, G., and Christman, J.K. 1982. Inhibition of DNA methyltransferase and induction of Friend erythroleukemia cell differentiation by 5-azacytidine and 5-aza-2Ęą-deoxycytidine. J. Biol. Chem. 257:2041–2048.

    PubMed  CAS  Google Scholar 

  • Das, H.K. 2008. Transcriptional regulation of the presenilin-1 gene: implication in Alzheimer’s disease. Front. Biosci. 13:822–832.

    Article  PubMed  CAS  Google Scholar 

  • Dennis, K., Fan, T., Geiman T., Yan, Q., and Muegge, K. 2001. Lsh, a member of the SNF2 family, is required for genome-wide methylation. Genes Dev. 15:2940–2944.

    Article  PubMed  CAS  Google Scholar 

  • DePinho, R.A. 2000. The age of cancer. Nature 408:248–254.

    Article  PubMed  CAS  Google Scholar 

  • Dong, C., Yoon, W., and Goldschmidt-Clermont, J. 2002. DNA methylation and atherosclerosis. J. Nutr. 132:2406S–2409S.

    PubMed  CAS  Google Scholar 

  • Drinkwater, R.D., Blake, T.J., Morley, A.A., and Turner, D.R. 1989. Human lymphocytes aged in vivo have reduced levels of methylation in transcriptionally active and inactive DNA. Mutat. Res. 219:29–37.

    PubMed  CAS  Google Scholar 

  • Dunn, B.K. 2003. Hypomethylation: one side of a larger picture. Ann. NY. Acad. Sci. 983:28–42.

    Article  PubMed  CAS  Google Scholar 

  • Eden, A., Gaudet, F., Waghmare, A., and Jaenisch, R. 2003. Chromosomal instability and tumors promoted by DNA hypomethylation. Science 300:455.

    Article  PubMed  CAS  Google Scholar 

  • Egger, G., Liang, G., Aparicio, A., and Jones, P.A. 2004. Epigenetics in human disease and prospects for epigenetic therapy. Nature 429:457–463.

    Article  PubMed  CAS  Google Scholar 

  • Ehrlich, M. 2006. Cancer-linked DNA hypomethylation and its relationship to hypermethylation. Curr. Top. Microbiol. Immunol. 310:251–274.

    Article  PubMed  CAS  Google Scholar 

  • Ehrlich, M., Woods, C.B., Yu, M.C., Dubeau, L., Yang, F., Campan, M., Weisenberger, D.J., Long, T., Youn, B., Fiala, E.S., and Laird, P.W. 2006. Quantitative analysis of associations between DNA hypermethylation, hypomethylation, and DNMT RNA levels in ovarian tumors. Oncogene 25:2636–2645.

    Article  PubMed  CAS  Google Scholar 

  • Fairweather, D.S., Fox, M., and Margison, G.P. 1987. The in vitro lifespan of MRC-5 cells is shortened by 5-azacytidine-induced demethylation. Exp. Cell Res. 168:153–159.

    Article  PubMed  CAS  Google Scholar 

  • Fallest-Strobl, P.C., Koch, D.D., Stein, J.H., and McBribe, P.E. 1997. Homocysteine: a new risk factor for atherosclerosis. Am. Fam. Physician. 56:1607–1612.

    PubMed  CAS  Google Scholar 

  • Feinberg, A.P. 2007. Phenotypic plasticity and the epigenetics of human disease. Nature 447: 433–440.

    Article  PubMed  CAS  Google Scholar 

  • Feinberg, A.P., and Vogelstein, B. 1983. Hypomethylation distinguishes genes of some human cancers from their normal counterparts. Nature 301:89–92.

    Article  PubMed  CAS  Google Scholar 

  • Feinberg, A.P., Gehrke, C.W., Kuo, K.C., and Ehrlich, M. 1988. Reduced genomic 5-methyl-cytosine in human colonic neoplasia. Cancer Res. 48:1159–1161.

    PubMed  CAS  Google Scholar 

  • Feinberg, A.P., and Tycko, B. 2004. The history of cancer epigenetics. Nat. Rev. Cancer 4:143–153.

    PubMed  CAS  Google Scholar 

  • Feinberg, A.P. 2008. Epigenetics at the epicenter of modern medicine. JAMA 2999:1345–1350.

    Article  Google Scholar 

  • Flatau, E., Bogenmann, E., and Jones, P.A. 1983. Variable 5-methylcytosine levels in human tumor cell lines and fresh pediatric tumor explants. Cancer Res. 43:4901–4905.

    PubMed  CAS  Google Scholar 

  • Fraga, M.F., Herranz, M., Espada, J., Ballestar, E., Paz, M.F., Ropero, S., Erkek, E., Bozdogan, O., Peinado, H., Niveleau, A., Mao, J.H., Balmain, A., Cano, A., and Esteller, M. 2004. A mouse skin multistage carcinogenesis model reflects the aberrant DNA methylation patterns of human cancers. Cancer Res. 64:5527–5534.

    Article  PubMed  CAS  Google Scholar 

  • Fraga, M.A., and Esteller, M. 2007. Epigenetics and aging: the targets and the marks. Trends Genet. 23:413–418.

    Article  PubMed  CAS  Google Scholar 

  • Fuso, A., Seminara, L., Cavallaro, R.A., D’Anselmi, F., and Scarpa, S. 2005. S-adenosylmethionine/homocysteine cycle alterations modify DNA methylation status with consequent deregulation of PS1 and BACE and beta-amyloid production. Mol. Cell. Neurosci. 28:195–204.

    Article  PubMed  CAS  Google Scholar 

  • Fuso, A., Cavallaro, R.A., Zampelli, A., D’Anselmi, F., Piscopo, P., Confaloni, A., and Scarpa, S. 2007. gamma-Secretase is differentially modulated by alterations of homocysteine cycle in neuroblastoma and glioblastoma cells. J. Alzheimer’s Dis. 11:275–290.

    CAS  Google Scholar 

  • Gama-Sosa, M.A., Slagel, V.A., Trewyn, R.W., Oxenhandler, R., Kuo, K.C., Gehrke, C.M., and Erhlich, M. 1983a. The 5-methylcytosine content of DNA from human tumors. Nucleic Acids Res. 11:6883–6894.

    Article  PubMed  CAS  Google Scholar 

  • Gama-Sosa, M.A., Wang, R.Y., Kuo, K.C., Gehrke, C.W., and Ehrlich, M. 1983b. The 5-methylcytosine content of highly repeated sequences in human DNA. Nucleic Acids Res. 11:3087–3095.

    Article  PubMed  CAS  Google Scholar 

  • Gaudet, F., Hodgson, J.G., Eden, A., Jackson-Grusby, L., Dausman, J., Gray, J.W., Leonhardt, H., and Jaenisch, R. 2003. Induction of tumors in mice by genomic hypomethylation. Science 300:489–492.

    Article  PubMed  CAS  Google Scholar 

  • Goll, M.G., and Bestor, T.H. 2005. Eukaryotic cytosine methyltransferases. Annu. Rev. Biochem. 74:481–514.

    Article  PubMed  CAS  Google Scholar 

  • Gorbunova, V., Seluanov, A., Mao, Z., and Hine, C. 2007. Changes in DNA repair during aging. Nucleic Acids Res. 35:7466–7474.

    Article  PubMed  CAS  Google Scholar 

  • Goronzy, J.J., and Weyand, C.M. 2003. Aging, autoimmunity and arthritis: T-cell senescence and contraction T-cell repertoire diversity – catalysts of autoimmunity and chronic inflammation. Arthritis Res. Ther. 5:225–234.

    Article  PubMed  CAS  Google Scholar 

  • Gowher, H., Liebert, K., Hermann, A., Xu, G., and Jeltsch, A. 2005. Mechanism of stimulation of catalytic activity of Dnmt3A and Dnmt3B DNA-(cytosine-C5)-methyltransferases by Dnmt3L. J. Biol. Chem. 280:13341–13348.

    Article  PubMed  CAS  Google Scholar 

  • Grunau, C., Brun, M.E., Rivals, I., Hindermann, W., Favre-Mercuret, M., Granier, G., and De Sario, A. 2008. BAGE hypomethylation, a new epigenetic biomarker for colon cancer detection. Cancer Epidemiol. Biomarkers Prev. 17:1374–1379.

    Article  PubMed  CAS  Google Scholar 

  • Guerrero-Preston, R., Santella, R.M., Blanco, A., Desai, M., Berdasco, M., and Fraga, M. Global DNA hypomethylation in liver cancer cases and controls: a phase I preclinical biomarker development study. Epigenetics 2:223–226.

    Google Scholar 

  • Hamm, S., Just, G., Lacoste, N., Moitessier, N., Szyf, M., and Mamer, O. 2008. On the mechanism of demethylation of 5-methylcytosine in DNA. Bioorg. Med. Chem. Lett. 18: 1046–1049.

    Article  PubMed  CAS  Google Scholar 

  • Hardy, J., and Selkoe, D.J. 2002. The amyloid hypothesis of Alzheimer’s disease: progress and problems on the road to therapeutics. Science 297:353–356.

    Article  PubMed  CAS  Google Scholar 

  • Hashimoto, H., Horton, J.R., Zhang, X., Bostick, M., Jacobsen, S.E., and Cheng, X. 2008. The SRA domain of UHRF1 flips 5-methylcytosine out of the DNA helix. Nature 455:826–829.

    Article  PubMed  CAS  Google Scholar 

  • Hiltunen, M.O., Turunen, M.P., Häkkinen, T.P., Rutanen, J., Hedman, M., Mäkinen, K., Turunen, A.M., Aalto-Setälä, K., and Ylä-Herttuala, S. 2002. DNA hypomethylation and methyltransferase expression in atherosclerotic lesions. Vasc. Med. 7:5–11.

    Article  PubMed  Google Scholar 

  • Hiltunen, M.O., and Ylä-Herttuala, S. 2003. DNA methylation, smooth muscle cells, and atherogenesis. Arterioscler. Thromb. Vasc. Biol. 23:1750–1753.

    Article  CAS  Google Scholar 

  • Hoffmann, M.J., and Schulz, W.A. 2005. Causes and consequences of DNA hypomethylation in human cancer. Biochem. Cell. Biol. 83:296–321.

    Article  PubMed  CAS  Google Scholar 

  • Holliday, R. 1985. The significance of DNA methylation in cellular aging. Basic Life Sci. 35: 269–283.

    PubMed  CAS  Google Scholar 

  • Holliday, R. 1986. Strong effects of 5-azacytidine on the in vitro lifespan of human diploid fibroblasts. Exp. Cell Res. 166:543–552.

    Article  PubMed  CAS  Google Scholar 

  • Holliday, R. 1987. The inheritance of epigenetic defects. Science 238:163–170.

    Article  PubMed  CAS  Google Scholar 

  • Hornsby, P.J., Yang, L., and Gunter, L.E. 1992. Demethylation of satellite I DNA during senescence of bovine adrenocortical cells in culture. Mutat. Res. 275:13–19.

    PubMed  CAS  Google Scholar 

  • Howard, G., Eiges, R., Gaudet, F., Jaenisch, R., and Eden, A. 2008. Activation and transposition of endogenous retroviral elements in hypomethylation induced tumors in mice. Oncogene 27: 404–408.

    Article  PubMed  CAS  Google Scholar 

  • Issa, J.P. 2003. Age-related epigenetic changes and the immune system. Clin. Immunol. 109: 103–108.

    Article  PubMed  CAS  Google Scholar 

  • Jager, R.D., Mieler W.F., and Miller, J.W. 2008. Age-related macular degeneration. N. Engl. J. Med. 358:2606–2617.

    Article  PubMed  CAS  Google Scholar 

  • James, S.J., Melnyk, S., Pogribna, M., Pogribny, I.P., and Caudill, M.A. 2002. Elevation of S-adenosylhomocysteine and DNA hypomethylation: potential epigenetic mechanism for homocysteine-related pathology. J. Nutr. 132:2361S–2366S.

    PubMed  CAS  Google Scholar 

  • Jones, P.A., and Baylin, S.B. 2007. The epigenomics of cancer. Cell 128:683–692.

    Article  PubMed  CAS  Google Scholar 

  • Kangaspeska, S., Stride, B., MĂ©tivier, R., Polycarpou-Schwarz, M., Ibberson, D., Carmouche, R.P., Benes, V., Gannon, F., and Reid, G. 2008. Transient cyclical methylation of promoter DNA. Nature 452:112–115.

    Article  PubMed  CAS  Google Scholar 

  • Kaplan, M.J., Lu, Q., Wu, A., Attwood, J., and Richardson, B. 2004. Demethylation of promoter regulatory elements contributes to perforin overexpression in CD4+ lupus T cells. J. Immunol. 172:3652–3661.

    PubMed  CAS  Google Scholar 

  • Karpf, A.R., and Matsui, S. 2005. Genetic disruption of cytosine DNA methyltransferase enzymes induces chromosomal instability in human cancer cells. Cancer Res. 65:8635–8639.

    Article  PubMed  CAS  Google Scholar 

  • Kimura, H., and Shiota, K. 2003. Methyl-CpG-binding protein, MeCP2, is target molecule for maintenance DNA methyltransferase, Dnmt1. J. Biol. Chem. 278:4806–4812.

    Article  PubMed  CAS  Google Scholar 

  • Kuo, H.K., Sorond, F.A., Chen, J.H., Hashmi, A., Milberg, W.P., and Lipsitz, L.A. 2005. The role of homocysteine in multisystem age-related problems: a systematic review. J. Gerontol. A Biol. Sci. Med. Sci. 60:1190–1201.

    PubMed  Google Scholar 

  • Laner, T., Schultz, W.A., Engers, R., MĂĽller, M., and Florl, A.R. 2005. Hypomethylation of the XIST gene promoter in prostate cancer. Oncol. Res. 15:257–264.

    PubMed  CAS  Google Scholar 

  • Li, E., Bestor, T.H., and Jaenisch, R. 1992. Targeted mutation of the DNA methyltransferase gene results in embryonic lethality. Cell 69:915–926.

    Article  PubMed  CAS  Google Scholar 

  • Li, G., Weyand, C., and Goronzy, J.J. 2008. Epigenetic mechanisms of age-dependent KIR2DL4 expression in T cells. J. Leukoc. Biol. 84:824–834.

    Google Scholar 

  • Liang, G., Chan, M.F., Tomigahara, Y., Tsai, Y.C., Gonzales, F.A., Li, E., Laird, P.W., and Jones, P.A. 2002. Cooperativity between DNA methyltransferases in the maintenance methylation of repetitive elements. Mol. Cell. Biol. 22:480–491.

    Article  PubMed  CAS  Google Scholar 

  • Liu, C., Xu, D., Sjöberg, J., Forsell, P., Björkholm, M., and Claesson, H.E. 2004. Transcriptional regulation of 15-lipoxygenase expression by promoter methylation. Exp. Cell Res. 297:61–67.

    Article  PubMed  CAS  Google Scholar 

  • Lopatina, N., Haskell, J.F., Andrews, L.G., Poole, J.C., Saldanha, S., and Tollefsbol, T. 2002. Differential maintenance and de novo methylating activity by three DNA methyltransferases in aging and immortalized fibroblasts. J. Cell. Biochem. 84:324–334.

    Article  PubMed  CAS  Google Scholar 

  • Loriot, A., De Plaen, E., Boon, T., and De Smet, C. 2006. Transient down-regulation of DNMT1 methyltransferase leads to activation and stable hypomethylation of MAGE-A1 in melanoma cells. J. Biol. Chem. 281:10118–10126.

    Article  PubMed  CAS  Google Scholar 

  • Lu, Q., Kaplan, M., Ray, D., Ray, D., Zacharek, S., Gutsch, D., and Richardson, B. 2002. Demethylation of INGAL (CD11a) regulatory sequences in systemic lupus erythematosus. Arthritis Rheum. 46:1282–1291.

    Article  PubMed  CAS  Google Scholar 

  • Lund, G., Andersson, L., Lauria, M., Lindholm, M., Fraga, M.F., Villar-Garea, A., Ballestar, E., Esteller, M., and Zaina, S. 2004. DNA methylation polymorphisms precede any histological sign of atherosclerosis in mice lacking apolipoprotein E. J. Biol. Chem. 279: 29147–29154.

    Article  PubMed  CAS  Google Scholar 

  • Mason, J.B. 2003. Biomarkers of nutrient exposure and status in one-carbon (methyl) metabolism. J. Nutr. 133:941S–947S.

    PubMed  CAS  Google Scholar 

  • Mays-Hoopes, L.L., Brown, A., and Huang, R.C.C. 1983. Methylation and rearrangement of mouse intracisternal A particle genes in development, adding, and myeloma. Mol. Cell. Biol. 3: 1371–1380.

    PubMed  CAS  Google Scholar 

  • Mensah, G.A., and Brown, D.W. 2007. An overview of cardiovascular disease burden in the United States. Health Aff. (Millwood). 26:38–48.

    Article  Google Scholar 

  • MĂ©tivier, R., Gallais, R., Tiffoche, C., Le PĂ©ron, C., Jurkowska, R.Z., Carmouche, R.P., Ibberson, D., Barath, P., Demay, F., Reid, G., Benes, V., Jeltsch, A., Gannon, F., and Salbert, G. 2008. Cyclical DNA methylation of a transcriptionally active promoter. Nature 452:45–50.

    Article  PubMed  CAS  Google Scholar 

  • Moore, L.E., Pfeiffer, R.M., Poscablo, C., Real, F.X., Kogevinas, M., Silverman, D., GarcĂ­a-Closas, R., Chanock, S., TardĂłn, A., Serra, C., Carrato, A., Dosemeci, M., GarcĂ­a-Closas, M., Esteller, M., Fraga, M., Rothman, N., and Malats, N. 2008. Genomic DNA hypomethylation as a biomarker for bladder cancer susceptibility in the Spanish Bladder Cancer Study: a case-control study. Lancet Oncol. 9:359–366.

    Article  PubMed  CAS  Google Scholar 

  • Morris, M.S. 2003. Homocysteine and Alzheimer’s disease. Lancet Neurol. 2:425–428

    Article  PubMed  CAS  Google Scholar 

  • Myant, K., and Stancheva, I. 2008. LSH cooperates with DNA methyltransferases to repress transcription. Mol. Cell. Biol. 28:215–226.

    Article  PubMed  CAS  Google Scholar 

  • Nehler, M.R., Taylor, L.M., Jr., and Porter, J.M. 1997. Homocysteinemia as a risk factor for atherosclerosis: a review. Cardiovasc. Surg. 5:559–567.

    Article  PubMed  CAS  Google Scholar 

  • Newman, P.E. 1999. Can reduced folic acid and vitamin B12 levels cause deficient DNA methylation producing mutations which initiate atherosclerosis? Med. Hypothesis 53:421–424.

    Article  CAS  Google Scholar 

  • Nguyen, S., Meletis, K., Fu, D., Jhaveri, S., and Jaenisch, R. 2007. Ablation of de novo DNA methyltransferase Dnmt3a in the nervous system leads to neuromuscular defects and shortened lifespan. Dev. Dyn. 236:1663–1676.

    Article  PubMed  CAS  Google Scholar 

  • Niculescu, M.D., and Zeisel, S.H. 2002. Diet, methyl donors and DNA methylation: interactions between dietary folate, methionine and choline. J. Nutr. 132:2333S–2335S.

    PubMed  CAS  Google Scholar 

  • Nijhout, H.F., Reed, M.C., Anderson, D.F., Mattingly, J.C., James, S.J., and Ulrich, C.M. 2006. Long-range allosteric interactions between the folate and methionine cycles stabilize DNA methylation reaction rate. Epigenetics, 1:81–87.

    PubMed  Google Scholar 

  • Okano, M., Bell, D.W., Haber, D.A., and Li, E. 1999. DNA methyltransferases Dnmt3a and Dnmt3b are essential for de novo methylation and mammalian development. Cell 99: 247–257.

    Article  PubMed  CAS  Google Scholar 

  • Ono, T., Shinya, K., Uehara, Y., and Okada, S. 1989. Endogenous virus genomes become hypomethylated tissue-specifically during aging process of C57BL mice. Mech. Ageing Dev. 50:27–36.

    Article  PubMed  CAS  Google Scholar 

  • Ono, T., Takahashi, N., and Okada, S. 1989a. Age-associated changes in DNA methylation and mRNA level of the c-myc gene in spleen and liver of mice. Mutat. Res. 219:39–50.

    PubMed  CAS  Google Scholar 

  • Ono, T., Uehara, Y., Kurishita, A., Tawa, R., and Sakurai, H. 1993. Biological significance of DNA methylation in the ageing process. Age Ageing. 22:S34–S43.

    PubMed  CAS  Google Scholar 

  • Oomen, A.M., Griffin, J.B., Sarath, G., and Zempleni, J. 2005. Roles of nutrients in epigenetic events. J. Nutr. Biochem. 16:74–77.

    Article  CAS  Google Scholar 

  • Pastorino, L., and Lu, K.P. 2006. Pathogenic mechanisms in Alzheimer’s disease. Eur. J. Pharmacol. 545:29–38.

    Article  PubMed  CAS  Google Scholar 

  • Pogribny, I.P., Tryndyak, V.P., Boureiko, A., Melnyk, S., Bagnyukova, T.V., Montgomery, B., and Rusyn, I. 2008. Mechanisms of peroxisome proliferator-induced DNA hypomethylation in rat liver. Mut. Res. 644:17–23.

    CAS  Google Scholar 

  • Prelog, M., 2006. Aging of the immune system: a risk factor for autoimmunity? Autoimmun. Rev. 5:136–139.

    Article  PubMed  CAS  Google Scholar 

  • Raines, E.W., and Ross, R. 1995. Biology of atherosclerotic plaque formation: possible role of growth factor lesion development and the potential impact of soy. J. Nutr. 125: 624S–630S.

    PubMed  CAS  Google Scholar 

  • Ravindran, C.R., and Ticku, M.K. 2005. Methylation of NMDA receptor NR2B gene as a function of age in the mouse brain. Neurosci. Lett. 380:223–228.

    Article  PubMed  CAS  Google Scholar 

  • Ray, D., Wu, A., Wilkinson, J.E., Murphy, H.S., Lu, Q., Kluve-Beckerman, B., Liepnieks, J.J., Benson, M., Yung, R., and Richardson, B. 2006. Aging in heterozygous Dnmt1-deficient mice: effects on survival, the DNA methylation genes, and the development of amyloidosis. J. Gerontol. A Biol. Sci. Med. Sci. 61:115–124.

    PubMed  Google Scholar 

  • Refsum, H., Nurk, E., Smith, A.D., Ueland, P.M., Gjesdal C.G., Bjelland, I., Tverdal, A., Tell, G.S., NygĂĄrd, O., and Vollset, S.E. 2006. The Hordaland Homocysteine Study: a community-based study of homocysteine, its determinants, and associations with disease. J. Nutr. 136: 1731S–1740S.

    PubMed  CAS  Google Scholar 

  • Richardson, B.C. 2002. Role of DNA methylation in the regulation of cell function: autoimmunity, aging and cancer. J. Nutr. 132:2401S–2405S.

    PubMed  CAS  Google Scholar 

  • Richardson, B. 2003a. DNA methylation and autoimmune disease. Clin. Immunol. 109:72–79.

    Article  PubMed  CAS  Google Scholar 

  • Richardson, B. 2003b. Impact of aging on DNA methylation. Ageing Res. Rev. 2:245–261.

    Article  PubMed  CAS  Google Scholar 

  • Rodriguez, J., Frigola, J., Vendrell, E., Riques, R.A., Fraga, M.F., Morales, C., Moreno, V., Esteller, M., Capellá, G., Ribas, M., and Peinado, M.A. 2006. Chromosomal instability correlates with genome-wide DNA demethylation in human primary colorectal cancers. Cancer Res. 66: 8462–8468.

    Article  PubMed  CAS  Google Scholar 

  • Rollins, R.A., Haghighi, F., Edwards, J.R., Das, R., Zhang, M.Q., Ju, J., and Bestor, T.H. 2006. Large-scale structure of genomic methylation patterns. Genome Res. 16:157–163.

    Article  PubMed  CAS  Google Scholar 

  • Romanov, G.A., and Vanyushin, B.F. 1981. Methylation of reiterated sequences in mammalian DNAs. Effects of the tissue type, age, malignancy and hormonal induction. Biochim. Biophys. Acta 653: 204–218.

    PubMed  CAS  Google Scholar 

  • Ross, R. 1999. Atherosclerosis – an inflammatory disease. N. Engl. J. Med. 340:115–126.

    Article  PubMed  CAS  Google Scholar 

  • Rozen, R. 2000. Genetic modulation of homocysteinemia. Semin. Thromb. Hemost. 26:255–261.

    Article  CAS  Google Scholar 

  • Sato, N., Maitra, A., Fukushima, N., van Heek, N.T., Matsubayashi, H., Iacobuzio-Donahue, C.A., Rosty, C., and Coggins, M. 2003. Frequent hypomethylation of multiple genes overexpressed in pancreatic ductal adenocarcinoma. Cancer Res. 63:4158–4166.

    PubMed  CAS  Google Scholar 

  • Schulz, R.J. 2007. Homocysteine as a biomarker for cognitive dysfunction in the elderly. Curr. Opin. Clin. Nutr. Metab. Care. 10:718–723.

    Article  PubMed  CAS  Google Scholar 

  • Selhub, J. 2002. Folate, vitamin B12 and vitamin B6 and one carbon metabolism. J. Nutr. Health Aging. 6:39–42.

    PubMed  CAS  Google Scholar 

  • Seivwright, C., Macnab, J.C., and Adams, R.L. 1993. S-adenosylmethionine metabolism in herpes simplex virus type 2-infected cells. J. Gen. Virol. 74:1405–1407.

    Article  PubMed  CAS  Google Scholar 

  • Singhal, R.P., Mays-Hoopes, L.L., and Eichhorn, G.L. 1987. DNA methylation in aging of mice. Mech. Ageing Dev. 41:199–210.

    Article  PubMed  CAS  Google Scholar 

  • Spry, M., Scott, T., Pierce, H., and D’Orazio, J.A. 2007. DNA repair pathways and hereditary cancer susceptibility syndromes. Front. Biosci. 12:4191–4207.

    Article  PubMed  CAS  Google Scholar 

  • Sun, L.Q., Lee, D.W., Zhang, Q., Xiao, W., Raabe, E.H., Meeker, A., Miao, D., Huso, D.L., and Arceci, R.J. 2004. Growth retardation and premature aging phenotypes in mice with disruption of the SNF-2-like gene, PASG. Genes Dev. 18:1035–1046.

    Article  CAS  Google Scholar 

  • Sun, L.Q., and Arceci R.J. 2005. Altered epigenetic patterning leading to replicative senescence and reduced longevity. Cell Cycle 4:3–5.

    PubMed  CAS  Google Scholar 

  • Suuronen, T., Nuutinen, T., Ryhänen, T., Kaarniranta, K., and Salminen, A. 2007. Epigenetic regulation of clusterin/apolipoprotein J expression in retinal pigment epithelial cells. Biochem. Biophys. Res. Commun. 357:397–401.

    Article  PubMed  CAS  Google Scholar 

  • Tohgi, H., Utsugisawa, K., Nagane, Y., Yoshimura, M., Genda, Y., and Ukitsu, M. 1999. Reduction with age in methylcytosine in the promoter region -224 approximately -101 of the amyloid precursor protein gene in autopsy human cortex. Brain Res. Mol. Brain Res. 70:288–292.

    Article  PubMed  CAS  Google Scholar 

  • Tost, J. 2008. Epigenetics. Norfolk: Caister Academic Press.

    Google Scholar 

  • Uhl, J., Klan, N., Rose, M., Entian, K.D., Werz, O., and Steinhilber, D. 2002. The 5-lipoxygenase promoter is regulated by DNA methylation. J. Biol. Chem. 277:4374–4379.

    Article  PubMed  CAS  Google Scholar 

  • Ulrey, C.L., Liu, L., Andrews, L.G., and Tollefsbol, T.O. 2005. The impact of metabolism on DNA methylation. Hum. Mol. Genet. 14:R139–R147.

    Article  PubMed  CAS  Google Scholar 

  • Valinluck, V., and Sowers, L.C. 2007. Endogenous cytosine damage products alter the site selectivity of human DNA maintenance methyltransferase DNMT1. Cancer Res. 67:946–950.

    Article  PubMed  CAS  Google Scholar 

  • Vanyushin, B.F., Korotaev, G.K., Mazin, A.L., and Berdishev, G.D. 1969. Investigation of some characteristics of the primary and secondary structure of DNA from the liver of spawning humpback salmon. Biochemistry (Mosc.) 34:191–198.

    CAS  Google Scholar 

  • Vanyushin, B.F., Tkacheva, S.G., and Belozersky, A.N. 1970. Rare bases in animal DNA. Nature 225:948–949.

    Article  PubMed  CAS  Google Scholar 

  • Vanyushin, B.F., Nemirovsky, L.E., Klimenko, V.V., Vasiliev, V.K., and Belozersky, A.N. 1973. The 5-methylcytosine in DNA of rats. Tissue and age specificity and the changes induced by hydrocortisone and other agents. Gerontologia 19:138–152.

    Article  PubMed  CAS  Google Scholar 

  • Verdile, G., Gandy, S.E., and Martins, R.N. 2007. The role of presenilin and its interacting proteins in the biogenesis of Alzheimer’s beta amyloid. Neurochem. Res. 32:609–623.

    Article  PubMed  CAS  Google Scholar 

  • Vijg, J. 2008. The role of DNA damage and repair in aging: New approaches to an old problem. Mech. Ageing Dev. 129:498–502.

    Article  PubMed  CAS  Google Scholar 

  • West, R.L., Lee, J.M., and Maroun, L.E. 1995. Hypomethylation of the amyloid precursor protein gene in the brain of an Alzheimer’s disease patient. J. Mol. Neurosci. 6:141–146.

    Article  PubMed  CAS  Google Scholar 

  • Wilson, V.L., and Jones, P.A. 1983. DNA methylation decreases in aging but not in immortal cells. Science 220:1055–1057.

    Article  PubMed  CAS  Google Scholar 

  • Wilson, V.L., Smith, R.A., Ma, S., and Cutler, R.G. 1987. Genomic 5-methyldeoxycytidine decreases with age. J. Biol. Chem. 262:9948–9951.

    PubMed  CAS  Google Scholar 

  • Wilson, A.S., Power, B.E., and Molloy, P.L. 2007. DNA hypomethylation and human diseases. Biochim. Biophys. Acta 1775:138–162.

    PubMed  CAS  Google Scholar 

  • Wolfe, M.S. 2007. When loss is gain: reduced presenilin proteolytic function leads to increased Aβ42/Aβ40. EMBO Reports 8:136–140.

    Article  PubMed  CAS  Google Scholar 

  • Worthley, S.G., Osende, J.I., Helft, G., Badimon, J.J., and Fuster, V. 2001. Coronary artery disease: pathogenesis and acute coronary syndromes. Mt. Sinai J. Med. 68:167–181.

    PubMed  CAS  Google Scholar 

  • Wu, H., Chen, Y., Liang, J., Shi, B., Wu G., Zhang, Y., Wang, D., Li, R., Yi, X., Zhang, H., Sun, L., and Shang, Y. 2005. Hypomethylation-linked activation of PAX2 mediates tamoxifen-stimulated endometrial carcinogenesis. Nature 438:981–987.

    Article  PubMed  CAS  Google Scholar 

  • Yenbutr, P., Hilakivi-Clarke, L., and Passaniti, A. 1998. Hypomethylation of an exon I estrogen receptor CpG island in spontaneous and carcinogen-induced mammary tumorigenesis in the rat. Mech. Ageing Dev. 106:93–102.

    Article  CAS  Google Scholar 

  • Yi, P., Melnyk, S., Pogribna, M., Pogribny, I.P., Hine, R.J., and James, S.J. 2000. Increase in plasma homocysteine associated with parallel increases in plasma S-adenosylhomocysteine and lymphocyte DNA hypomethylation. J. Biol. Chem. 275: 29318–29323.

    Article  PubMed  CAS  Google Scholar 

  • Yideng, J., Jianzhong, Z., Ying, H., Juan, S., Jinge, Z., Shenglan, W., Xiaoqun, H., and Shuren, W. 2007. Homocysteine-mediated expression of SAHH, DMNTs, MBD2, and DNA hypomethylation potential pathogenic mechanism in VSMCs. DNA Cell. Biol. 26:603–611.

    Article  PubMed  CAS  Google Scholar 

  • Yoder, J.A., Walsh, C.P., and Bestor, T.H. 1997. Cytosine methylation and the ecology of intragenomic parasites. Trends Genet. 13:335–340.

    Article  PubMed  CAS  Google Scholar 

  • Yung, R.L., and Julius, A. 2008. Epigenetics, aging, and autoimmunity. Autoimmunity 41: 329–335.

    Article  PubMed  CAS  Google Scholar 

  • Zaina, S., Lindholm, M.W., and Lund, G. 2005. Nutrition and aberrant DNA methylation patterns in atherosclerosis: more than just hyperhomocysteinemia? J. Nutr. 135:5–8.

    PubMed  CAS  Google Scholar 

  • Zhang, Z., Deng, C., Lu, Q., and Richardson, B. 2002. Age-dependent DNA methylation changes in the ITGAL (CD11a) promoter. Mech. Ageing Dev. 123:1257–1268.

    PubMed  CAS  Google Scholar 

  • Zhao, L., and Funk, C.D. 2004. Lipoxygenase pathways in atherosclerosis. Trends Cardiovasc. Med. 14:191–195.

    Article  PubMed  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Division of Biochemical Toxicology, National Center for Toxicological Research, 72079, Jefferson, AR, USA

    Igor P. Pogribny

  2. Belozersky Institute of Physico-Chemical Biology, Lomonosov Moscow State University, 119899, Moscow, Russia

    Boris F. Vanyushin

Authors
  1. Igor P. Pogribny
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Boris F. Vanyushin
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Igor P. Pogribny .

Editor information

Editors and Affiliations

  1. Dept. Biology, University of Alabama, Birmingham, University Blvd. 1300, Birmingham, 35294-1170, U.S.A.

    Trygve O. Tollefsbol

Rights and permissions

Reprints and permissions

Copyright information

© 2010 Springer Science+Business Media, LLC

About this chapter

Cite this chapter

Pogribny, I.P., Vanyushin, B.F. (2010). Age-Related Genomic Hypomethylation. In: Tollefsbol, T. (eds) Epigenetics of Aging. Springer, New York, NY. https://doi.org/10.1007/978-1-4419-0639-7_2

Download citation

Publish with us

Policies and ethics

Search

Navigation