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DNA methylation, ageing and the influence of early life nutrition

  • Karen A. Lillycrop (a1), Samuel P. Hoile (a2), Leonie Grenfell (a2) and Graham C. Burdge (a2)

It is well established that genotype plays an important role in the ageing process. However, recent studies have suggested that epigenetic mechanisms may also influence the onset of ageing-associated diseases and longevity. Epigenetics is defined as processes that induce heritable changes in gene expression without a change in the DNA nucleotide sequence. The major epigenetic mechanisms are DNA methylation, histone modification and non-coding RNA. Such processes are involved in the regulation of tissue-specific gene expression, cell differentiation and genomic imprinting. However, epigenetic dysregulation is frequently seen with ageing. Relatively little is known about the factors that initiate such changes. However, there is emerging evidence that the early life environment, in particular nutrition, in early life can induce long-term changes in DNA methylation resulting in an altered susceptibility to a range of ageing-associated diseases. In this review, we will focus on the changes in DNA methylation that occur during ageing; their role in the ageing process and how early life nutrition can modulate DNA methylation and influence longevity. Understanding the mechanisms by which diet in early life can influence the epigenome will be crucial for the development of preventative and intervention strategies to increase well-being in later life.

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* Corresponding author: Dr K. A. Lillycrop, fax +44 (0)23 80795255, email
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1. Rakyan, VK, Down, TA, Maslau, S et al. (2010) Human aging-associated DNA hypermethylation occurs preferentially at bivalent chromatin domains. Genome Res 20, 434439.
2. Rodriguez-Rodero, S, Fernandez-Morera, JL, Menendez-Torre, E et al. (2011) Aging genetics and aging. Aging Dis 2, 186195.
3. Bird, A (2002) DNA methylation patterns and epigenetic memory. Genes Dev 16, 621.
4. Bird, A (1992) The essentials of DNA methylation. Cell 70, 58.
5. Bird, A (2001) Molecular biology. Methylation talk between histones and DNA. Science 294, 21132115.
6. Fuks, F, Hurd, PJ, Wolf, D et al. (2003) The methyl-CpG-binding protein MeCP2 links DNA methylation to histone methylation. J Biol Chem 278, 40354040.
7. Reik, W & Walter, J (2001) Genomic imprinting: parental influence on the genome. Nat Rev Genet 2, 2132.
8. Walsh, CP, Chaillet, JR & Bestor, TH (1998) Transcription of IAP endogenous retroviruses is constrained by cytosine methylation. Nat Genet 20, 116117.
9. Waterland, RA & Jirtle, RL (2003) Transposable elements: targets for early nutritional effects on epigenetic gene regulation. Mol Cell Biol 23, 52935300.
10. Reik, W, Dean, W & Walter, J (2001) Epigenetic reprogramming in mammalian development. Science 293, 10891093.
11. Reik, W, Santos, F & Dean, W (2003) Mammalian epigenomics: reprogramming the genome for development and therapy. Theriogenology 59, 2132.
12. Okano, M, Bell, DW, Haber, DA et al. (1999) DNA methyltransferases DNMT3a and DNMT3b are essential for de novo methylation and mammalian development. Cell 99, 247257.
13. Bacolla, A, Pradhan, S, Roberts, RJ et al. (1999) Recombinant human DNA (cytosine-5) methyltransferase. II. Steady-state kinetics reveal allosteric activation by methylated DNA. J Biol Chem 274, 3301133019.
14. Turner, BM (2000) Histone acetylation and an epigenetic code. Bioessays 22, 836845.
15. Brenner, C & Fuks, F (2007) A methylation rendezvous: reader meets writers. Dev Cell 12, 843844.
16. Nakayama, J, Rice, JC, Strahl, BD et al. (2001) Role of histone H3 lysine 9 methylation in epigenetic control of heterochromatin assembly. Science 292, 110113.
17. Strahl, BD, Ohba, R, Cook, RG et al. (1999) Methylation of histone H3 at lysine 4 is highly conserved and correlates with transcriptionally active nuclei in Tetrahymena. Proc Natl Acad Sci USA 96, 1496714972.
18. Lachner, M, O'Carroll, D, Rea, S et al. (2001) Methylation of histone H3 lysine 9 creates a binding site for HP1 proteins. Nature 410, 116120.
19. Fuks, F, Burgers, WA, Brehm, A et al. (2000) DNA methyltransferase Dnmt1 associates with histone deacetylase activity. Nat Genet 24, 8891.
20. Rountree, MR, Bachman, KE & Baylin, SB (2000) DNMT1 binds HDAC2 and a new co-repressor, DMAP1, to form a complex at replication foci. Nat Genet 25, 269277.
21. Vire, E, Brenner, C, Deplus, R et al. (2006) The Polycomb group protein EZH2 directly controls DNA methylation. Nature 439, 871874.
22. Scott, JM & Weir, DG (1998) Folic acid, homocysteine and one-carbon metabolism: a review of the essential biochemistry. J Cardiovasc Risk 5, 223227.
23. Ooi, SK & Bestor, TH (2008) The colorful history of active DNA demethylation. Cell 133, 11451148.
24. Miller, CA & Sweatt, JD (2007) Covalent modification of DNA regulates memory formation. Neuron 53, 857869.
25. Kersh, EN, Fitzpatrick, DR, Murali-Krishna, K et al. (2006) Rapid demethylation of the IFN-gamma gene occurs in memory but not naive CD8T cells. J Immunol 176, 40834093.
26. Tahiliani, M, Koh, KP, Shen, Y et al. (2009) Conversion of 5-methylcytosine to 5-hydroxymethylcytosine in mammalian DNA by MLL partner TET1. Science 324, 930935.
27. Ito, S, D'Alessio, AC, Taranova, OV et al. (2010) Role of Tet proteins in 5mC to 5hmC conversion, ES-cell self-renewal and inner cell mass specification. Nature 466, 11291133.
28. Bhattacharya, SK, Ramchandani, S, Cervoni, N et al. (1999) A mammalian protein with specific demethylase activity for mCpG DNA. Nature 397, 579583.
29. Zhu, B, Zheng, Y, Angliker, H et al. (2000) 5-Methylcytosine DNA glycosylase activity is also present in the human MBD4 (G/T mismatch glycosylase) and in a related avian sequence. Nucleic Acids Res 28, 41574165.
30. Barreto, G, Schafer, A, Marhold, J et al. (2007) Gadd45a promotes epigenetic gene activation by repair-mediated DNA demethylation. Nature 445, 671675.
31. Jost, JP (1993) Nuclear extracts of chicken embryos promote an active demethylation of DNA by excision repair of 5-methyldeoxycytidine. Proc Natl Acad Sci USA 90, 46844688.
32. Berdyshev, GD, Korotaev, GK, Boiarskikh, GV et al. (1967) Nucleotide composition of DNA and RNA from somatic tissues of humpback and its changes during spawning. Biokhimiia 32, 988993.
33. Bollati, V, Schwartz, J, Wright, R et al. (2009) Decline in genomic DNA methylation through aging in a cohort of elderly subjects. Mech Ageing Dev 130, 234239.
34. Drinkwater, RD, Blake, TJ, Morley, AA et al. (1989) Human lymphocytes aged in vivo have reduced levels of methylation in transcriptionally active and inactive DNA. Mutat Res 219, 2937.
35. Singhal, RP, Mays-Hoopes, LL & Eichhorn, GL (1987) DNA methylation in aging of mice. Mech Ageing Dev 41, 199210.
36. Casillas, MA Jr, Lopatina, N, Andrews, LG et al. (2003) Transcriptional control of the DNA methyltransferases is altered in aging and neoplastically-transformed human fibroblasts. Mol Cell Biochem 252, 3343.
37. Issa, JP, Ottaviano, YL, Celano, P et al. (1994) Methylation of the oestrogen receptor CpG island links ageing and neoplasia in human colon. Nat Genet 7, 536540.
38. Ahuja, N & Issa, JP (2000) Aging, methylation and cancer. Histol Histopathol 15, 835842.
39. Kang, GH, Lee, S, Kim, JS et al. (2003) Profile of aberrant CpG island methylation along the multistep pathway of gastric carcinogenesis. Lab Investig J Techn Methods Pathol 83, 635641.
40. Chen, YL, Ko, CJ, Lin, PY et al. (2012) Clustered DNA methylation changes in polycomb target genes in early-stage liver cancer. Biochem Biophys Res Commun 425, 290296.
41. Feinberg, AP, Irizarry, RA, Fradin, D et al. (2010) Personalized epigenomic signatures that are stable over time and covary with body mass index. Sci Transl Med 2, 49ra67.
42. Bjornsson, HT, Sigurdsson, MI, Fallin, MD et al. (2008) Intra-individual change over time in DNA methylation with familial clustering. J Am Med Assoc 299, 28772883.
43. Bell, JT & Spector, TD (2011) A twin approach to unraveling epigenetics. Trends Genet 27, 116125.
44. Fraga, MF, Ballestar, E, Paz, MF et al. (2005) Epigenetic differences arise during the lifetime of monozygotic twins. Proc Natl Acad Sci USA 102, 1060410609.
45. Talens, RP, Boomsma, DI, Tobi, EW et al. (2010) Variation, patterns, and temporal stability of DNA methylation: considerations for epigenetic epidemiology. FASEB J 24, 31353144.
46. Bocklandt, S, Lin, W, Sehl, ME et al. (2011) Epigenetic predictor of age. PloS ONE 6, e14821.
47. Ollikainen, M & Craig, JM (2011) Epigenetic discordance at imprinting control regions in twins. Epigenomics 3, 295306.
48. Gordon, L, Joo, JE, Powell, JE et al. (2012) Neonatal DNA methylation profile in human twins is specified by a complex interplay between intrauterine environmental and genetic factors, subject to tissue-specific influence. Genome Res 22, 13951406.
49. Dang, W, Steffen, KK, Perry, R et al. (2009) Histone H4 lysine 16 acetylation regulates cellular lifespan. Nature 459, 802807.
50. Shogren-Knaak, M, Ishii, H, Sun, JM et al. (2006) Histone H4-K16 acetylation controls chromatin structure and protein interactions. Science 311, 844847.
51. Pina, B, Martinez, P & Suau, P (1988) Differential acetylation of core histones in rat cerebral cortex neurons during development and aging. Eur J Biochem/FEBS 174, 311315.
52. O'Sullivan, RJ, Kubicek, S, Schreiber, SL et al. (2010) Reduced histone biosynthesis and chromatin changes arising from a damage signal at telomeres. Nat Struc Mol Biol 17, 12181225.
53. Chen, H, Gu, X, Su, IH et al. (2009) Polycomb protein Ezh2 regulates pancreatic β-cell Ink4a/Arf expression and regeneration in diabetes mellitus. Genes Dev 23, 975985.
54. Sarg, B, Koutzamani, E, Helliger, W et al. (2002) Postsynthetic trimethylation of histone H4 at lysine 20 in mammalian tissues is associated with aging. J Biol Chem 277, 3919539201.
55. Biron, VL, McManus, KJ, Hu, N et al. (2004) Distinct dynamics and distribution of histone methyl-lysine derivatives in mouse development. Dev Biol 276, 337351.
56. Villeponteau, B (1997) The heterochromatin loss model of aging. Exp Gerontol 32, 383394.
57. Zhang, R, Poustovoitov, MV, Ye, X et al. (2005) Formation of MacroH2A-containing senescence-associated heterochromatin foci and senescence driven by ASF1a and HIRA. Dev Cell 8, 1930.
58. Shumaker, DK, Dechat, T, Kohlmaier, A et al. (2006) Mutant nuclear lamin A leads to progressive alterations of epigenetic control in premature aging. Proc Natl Acad Sci USA 103, 87038708.
59. Kaeberlein, M, McVey, M & Guarente, L (1999) The SIR2/3/4 complex and SIR2 alone promote longevity in Saccharomyces cerevisiae by two different mechanisms. Genes Dev 13, 25702580.
60. Sommer, M, Poliak, N, Upadhyay, S et al. (2006) DeltaNp63alpha overexpression induces downregulation of Sirt1 and an accelerated aging phenotype in the mouse. Cell Cycle 5, 20052011.
61. Blander, G & Guarente, L (2004) The Sir2 family of protein deacetylases. Annu Rev Biochem 73, 417435.
62. Feser, J & Tyler, J (2011) Chromatin structure as a mediator of aging. FEBS Lett 585, 20412048.
63. Feinberg, AP & Vogelstein, B (1983) Hypomethylation distinguishes genes of some human cancers from their normal counterparts. Nature 301, 8992.
64. Feinberg, AP & Tycko, B (2004) The history of cancer epigenetics. Nat Rev Cancer 4, 143153.
65. Fraga, MF, Herranz, M, Espada, J et al. (2004) A mouse skin multistage carcinogenesis model reflects the aberrant DNA methylation patterns of human tumors. Cancer Res 64, 55275534.
66. Eden, A, Gaudet, F, Waghmare, A et al. (2003) Chromosomal instability and tumors promoted by DNA hypomethylation. Science 300, 455.
67. Esteller, M (2008) Epigenetics in cancer. N Engl J Med 358, 11481159.
68. Esteller, M, Corn, PG, Baylin, SB et al. (2001) A gene hypermethylation profile of human cancer. Cancer Res 61, 32253229.
69. Dejeux, E, Ronneberg, JA, Solvang, H et al. (2010) DNA methylation profiling in doxorubicin treated primary locally advanced breast tumours identifies novel genes associated with survival and treatment response. Mol Cancer 9, 68.
70. Rush, M, Appanah, R, Lee, S et al. (2009) Targeting of EZH2 to a defined genomic site is sufficient for recruitment of Dnmt3a but not de novo DNA methylation. Epigenetics 4, 404414.
71. Ohm, JE, McGarvey, KM, Yu, X et al. (2007) A stem cell-like chromatin pattern may predispose tumor suppressor genes to DNA hypermethylation and heritable silencing. Nat Genet 39, 237242.
72. Collado, M, Blasco, MA & Serrano, M (2007) Cellular senescence in cancer and aging. Cell 130, 223233.
73. Sharpless, NE & DePinho, RA (2007) How stem cells age and why this makes us grow old. Nat Rev Mol Cell Biol 8, 703713.
74. Janzen, V, Forkert, R, Fleming, HE et al. (2006) Stem-cell ageing modified by the cyclin-dependent kinase inhibitor p16INK4a. Nature 443, 421426.
75. Bracken, AP, Kleine-Kohlbrecher, D, Dietrich, N et al. (2007) The Polycomb group proteins bind throughout the INK4A-ARF locus and are disassociated in senescent cells. Genes Dev 21, 525530.
76. Bracken, AP & Helin, K (2009) Polycomb group proteins: navigators of lineage pathways led astray in cancer. Nat Rev Cancer 9, 773784.
77. Petronis, A (2006) Epigenetics and twins: three variations on the theme. Trends Genet 22, 347350.
78. Bahar, R, Hartmann, CH, Rodriguez, KA et al. (2006) Increased cell-to-cell variation in gene expression in ageing mouse heart. Nature 441, 10111014.
79. Godfrey, KM & Barker, DJ (2001) Fetal programming and adult health. Public Health Nutr 4, 611624.
80. Gluckman, PD, Hanson, MA & Pinal, C (2005) The developmental origins of adult disease. Matern Child Nutr 1, 130141.
81. Maleszka, R (2008) Epigenetic integration of environmental and genomic signals in honey bees. Epigenetics 3, 188192.
82. Kucharski, R, Maleszka, J, Foret, S et al. (2008) Nutritional control of reproductive status in honeybees via DNA methylation. Science 319, 18271830.
83. Wolff, GL, Kodell, RL, Moore, SR et al. (1998) Maternal epigenetics and methyl supplements affect agouti gene expression in Avy/a mice. FASEB J 12, 949957.
84. Lillycrop, KA, Phillips, ES, Jackson, AA et al. (2005) Dietary protein restriction of pregnant rats induces and folic acid supplementation prevents epigenetic modification of hepatic gene expression in the offspring. J Nutr 135, 13821386.
85. Lillycrop, KA, Slater-Jefferies, JL, Hanson, MA et al. (2007) Induction of altered epigenetic regulation of the hepatic glucocorticoid receptor in the offspring of rats fed a protein-restricted diet during pregnancy suggests that reduced DNA methyltransferase-1 expression is involved in impaired DNA methylation and changes in histone modifications. Br J Nutr 97, 10641073.
86. Lillycrop, KA, Phillips, ES, Torrens, C et al. (2008) Feeding pregnant rats a protein-restricted diet persistently alters the methylation of specific cytosines in the hepatic PPARα promoter of the offspring. Br J Nutr 100, 278282.
87. Gluckman, PD, Lillycrop, KA, Vickers, MH et al. (2007) Metabolic plasticity during mammalian development is directionally dependent on early nutritional status. Proc Natl Acad Sci USA 104, 1279612800.
88. Carone, BR, Fauquier, L, Habib, N et al. (2010) Paternally induced transgenerational environmental reprogramming of metabolic gene expression in mammals. Cell 143, 10841096.
89. Ng, SF, Lin, RC, Laybutt, DR et al. (2010) Chronic high-fat diet in fathers programs β-cell dysfunction in female rat offspring. Nature 467, 963966.
90. Tobi, EW, Lumey, LH, Talens, RP et al. (2009) DNA methylation differences after exposure to prenatal famine are common and timing- and sex-specific. Hum Mol Genet 18, 40464053.
91. Heijmans, BT, Tobi, EW, Stein, AD et al. (2008) Persistent epigenetic differences associated with prenatal exposure to famine in humans. Proc Natl Acad Sci USA 105, 1704617049.
92. Steegers-Theunissen, RP, Obermann-Borst, SA, Kremer, D et al. (2009) Periconceptional maternal folic acid use of 400 microg per day is related to increased methylation of the IGF2 gene in the very young child. PLoS ONE 4, e7845.
93. Godfrey, KM, Sheppard, A, Gluckman, PD et al. (2011) Epigenetic gene promoter methylation at birth is associated with child's later adiposity. Diabetes 60, 15281534.
94. Plagemann, A, Harder, T, Brunn, M et al. (2009) Hypothalamic proopiomelanocortin promoter methylation becomes altered by early overfeeding: an epigenetic model of obesity and the metabolic syndrome. J Physiol 587, 49634976.
95. Burdge, GC, Lillycrop, KA, Phillips, ES et al. (2009) Folic acid Supplementation during the juvenile–pubertal period in rats modifies the phenotype and epigenotype induced by prenatal nutrition. J Nutr 139, 10541060.
96. Ly, A, Lee, H, Chen, J et al. (2011) Effect of maternal and postweaning folic acid supplementation on mammary tumor risk in the offspring. Cancer Res 71, 988997.
97. Waterland, RA, Lin, JR, Smith, CA et al. (2006) Post-weaning diet affects genomic imprinting at the insulin-like growth factor 2 (Igf2) locus. Hum Mol Genet 15, 705716.
98. Christman, JK, Sheikhnejad, G, Dizik, M et al. (1993) Reversibility of changes in nucleic acid methylation and gene expression induced in rat liver by severe dietary methyl deficiency. Carcinogenesis 14, 551557.
99. Keyes, MK, Jang, H, Mason, JB et al. (2007) Older age and dietary folate are determinants of genomic and p16-specific DNA methylation in mouse colon. J Nutr 137, 17131717.
100. Hoile, SP, Irvine, NA, Kelsall, CJ et al. (2013) Maternal fat intake in rats alters 20:4n-6 and 22:6n-3 status and the epigenetic regulation of FADS2 in offspring liver. J Nutr Biochem 24, 12131220.
101. Cruzen, C & Colman, RJ (2009) Effects of caloric restriction on cardiovascular aging in non-human primates and humans. Clin Geriatr Med 25, 733743, ix–x.
102. Holloszy, JO & Fontana, L (2007) Caloric restriction in humans. Exp Gerontol 42, 709712.
103. Guarente, L & Picard, F (2005) Calorie restriction – the SIR2 connection. Cell 120, 473482.
104. Hass, BS, Hart, RW, Lu, MH et al. (1993) Effects of caloric restriction in animals on cellular function, oncogene expression, and DNA methylation in vitro . Mutat Res 295, 281289.
105. Chouliaras, L, van den Hove, DL, Kenis, G et al. (2011) Caloric restriction attenuates age-related changes of DNA methyltransferase 3a in mouse hippocampus. Brain, Behav Immun 25, 616623.
106. Li, Y, Liu, L & Tollefsbol, TO (2010) Glucose restriction can extend normal cell lifespan and impair precancerous cell growth through epigenetic control of hTERT and p16 expression. FASEB J 24, 14421453.
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