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DNA methylation associated with healthy aging of elderly twins

  • Sangkyu Kim
  • Jennifer Wyckoff
  • Anne-T Morris
  • Annemarie Succop
  • Ally Avery
  • Glen E. Duncan
  • S. Michal Jazwinski
Original Article
  • 220 Downloads

Abstract

Variation in healthy aging and lifespan is ascribed more to various non-genetic factors than to inherited genetic determinants, and a major goal in aging research is to reveal the epigenetic basis of aging. One approach to this goal is to find genomic sites or regions where DNA methylation correlates with biological age. Using health data from 134 elderly twins, we calculated a frailty index as a quantitative indicator of biological age, and by applying the Infinium HumanMethylation450K BeadChip technology to their leukocyte DNA samples, we obtained quantitative DNA methylation data on genome-wide CpG sites. We analyzed the health and epigenome data by taking two independent associative approaches: the parametric regression-based approach and a non-parametric machine learning approach followed by GO ontology analysis. Our results indicate that DNA methylation at CpG sites in the promoter region of PCDHGA3 is associated with biological age. PCDHGA3 belongs to clustered protocadherin genes, which are all located in a single locus on chromosome 5 in human. Previous studies of the clustered protocadherin genes showed that (1) DNA methylation is associated with age or age-related phenotypes; (2) DNA methylation can modulate gene expression; (3) dysregulated gene expression is associated with various pathologies; and (4) DNA methylation patterns at this locus are associated with adverse lifetime experiences. All these observations suggest that DNA methylation at the clustered protocadherin genes, including PCDHGA3, is a key mediator of healthy aging.

Keywords

DNA methylation Frailty index Biological age Protocadherin Aging 

Notes

Acknowledgments

We thank participants in our studies. We also thank the Mid-Atlantic Twin Registry at Virginia Commonwealth University and the University of Washington Twin Registry for recruiting twins and collecting health data.

Funding information

This study was supported by the National Institute of General Medical Sciences of the National Institutes of Health (P20GM103629) to S.M.J. and S.K.

Compliance with ethical standards

Conflict of interest

The authors declare that they have no conflict of interest.

Supplementary material

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References

  1. Aryee MJ, Jaffe AE, Corrada-Bravo H, Ladd-Acosta C, Feinberg AP, Hansen KD, Irizarry RA (2014) Minfi: a flexible and comprehensive Bioconductor package for the analysis of Infinium DNA methylation microarrays. Bioinformatics 30:1363–1369.  https://doi.org/10.1093/bioinformatics/btu049 CrossRefGoogle Scholar
  2. Assenov Y, Muller F, Lutsik P, Walter J, Lengauer T, Bock C (2014) Comprehensive analysis of DNA methylation data with RnBeads. Nat Methods 11:1138–1140.  https://doi.org/10.1038/nmeth.3115 CrossRefGoogle Scholar
  3. Barrell D, Dimmer E, Huntley RP, Binns D, O’Donovan C, Apweiler R (2009) The GOA database in 2009--an integrated Gene Ontology Annotation resource. Nucleic Acids Res 37:D396–D403.  https://doi.org/10.1093/nar/gkn803 CrossRefGoogle Scholar
  4. Barres R et al (2012) Acute exercise remodels promoter methylation in human skeletal muscle. Cell Metab 15:405–411.  https://doi.org/10.1016/j.cmet.2012.01.001 CrossRefGoogle Scholar
  5. Bell AC, Felsenfeld G (2000) Methylation of a CTCF-dependent boundary controls imprinted expression of the Igf2 gene. Nature 405:482–485.  https://doi.org/10.1038/35013100 CrossRefGoogle Scholar
  6. Bell JT, Spector TD (2011) A twin approach to unraveling epigenetics. Trends Genet 27:116–125.  https://doi.org/10.1016/j.tig.2010.12.005 CrossRefGoogle Scholar
  7. Bell JT, Tsai PC, Yang TP, Pidsley R, Nisbet J, Glass D, Mangino M, Zhai G, Zhang F, Valdes A, Shin SY, Dempster EL, Murray RM, Grundberg E, Hedman AK, Nica A, Small KS, The MuTHER Consortium, Dermitzakis ET, McCarthy MI, Mill J, Spector TD, Deloukas P (2012) Epigenome-wide scans identify differentially methylated regions for age and age-related phenotypes in a healthy ageing population. PLoS Genet 8:e1002629.  https://doi.org/10.1371/journal.pgen.1002629 CrossRefGoogle Scholar
  8. Binns D, Dimmer E, Huntley R, Barrell D, O’Donovan C, Apweiler R (2009) QuickGO: a web-based tool for Gene Ontology searching. Bioinformatics 25:3045–3046.  https://doi.org/10.1093/bioinformatics/btp536 CrossRefGoogle Scholar
  9. Bjornsson HT et al (2008) Intra-individual change over time in DNA methylation with familial clustering. JAMA 299:2877–2883.  https://doi.org/10.1001/jama.299.24.2877 CrossRefGoogle Scholar
  10. Bollati V, Schwartz J, Wright R, Litonjua A, Tarantini L, Suh H, Sparrow D, Vokonas P, Baccarelli A (2009) Decline in genomic DNA methylation through aging in a cohort of elderly subjects. Mech Ageing Dev 130:234–239.  https://doi.org/10.1016/j.mad.2008.12.003 CrossRefGoogle Scholar
  11. Borghol N, Suderman M, McArdle W, Racine A, Hallett M, Pembrey M, Hertzman C, Power C, Szyf M (2012) Associations with early-life socio-economic position in adult DNA methylation. Int J Epidemiol 41:62–74.  https://doi.org/10.1093/ije/dyr147 CrossRefGoogle Scholar
  12. Calvanese V, Lara E, Kahn A, Fraga MF (2009) The role of epigenetics in aging and age-related diseases. Ageing Res Rev 8:268–276.  https://doi.org/10.1016/j.arr.2009.03.004 CrossRefGoogle Scholar
  13. Cantone I, Fisher AG (2013) Epigenetic programming and reprogramming during development. Nat Struct Mol Biol 20:282–289.  https://doi.org/10.1038/nsmb.2489 CrossRefGoogle Scholar
  14. Castillo-Fernandez JE, Spector TD, Bell JT (2014) Epigenetics of discordant monozygotic twins: implications for disease. Genome Med 6:60.  https://doi.org/10.1186/s13073-014-0060-z CrossRefGoogle Scholar
  15. Chen WV, Maniatis T (2013) Clustered protocadherins. Development 140:3297–3302.  https://doi.org/10.1242/dev.090621 CrossRefGoogle Scholar
  16. Chen YA, Lemire M, Choufani S, Butcher DT, Grafodatskaya D, Zanke BW, Gallinger S, Hudson TJ, Weksberg R (2013) Discovery of cross-reactive probes and polymorphic CpGs in the Illumina Infinium HumanMethylation450 microarray. Epigenetics 8:203–209.  https://doi.org/10.4161/epi.23470 CrossRefGoogle Scholar
  17. Christensen BC, Houseman EA, Marsit CJ, Zheng S, Wrensch MR, Wiemels JL, Nelson HH, Karagas MR, Padbury JF, Bueno R, Sugarbaker DJ, Yeh RF, Wiencke JK, Kelsey KT (2009) Aging and environmental exposures alter tissue-specific DNA methylation dependent upon CpG island context. PLoS Genet 5:e1000602.  https://doi.org/10.1371/journal.pgen.1000602 CrossRefGoogle Scholar
  18. D’Aquila P, Montesanto A, Mandalà M, Garasto S, Mari V, Corsonello A, Bellizzi D, Passarino G (2017) Methylation of the ribosomal RNA gene promoter is associated with aging and age-related decline. Aging Cell 16:966–975.  https://doi.org/10.1111/acel.12603 CrossRefGoogle Scholar
  19. Dallosso AR, Hancock AL, Szemes M, Moorwood K, Chilukamarri L, Tsai HH, Sarkar A, Barasch J, Vuononvirta R, Jones C, Pritchard-Jones K, Royer-Pokora B, Lee SB, Owen C, Malik S, Feng Y, Frank M, Ward A, Brown KW, Malik K (2009) Frequent long-range epigenetic silencing of protocadherin gene clusters on chromosome 5q31 in Wilms’ tumor. PLoS Genet 5:e1000745.  https://doi.org/10.1371/journal.pgen.1000745 CrossRefGoogle Scholar
  20. El Hajj N, Dittrich M, Haaf T (2017) Epigenetic dysregulation of protocadherins in human disease. Semin Cell Dev Biol 69:172–182.  https://doi.org/10.1016/j.semcdb.2017.07.007 CrossRefGoogle Scholar
  21. Ernst J, Kellis M (2012) ChromHMM: automating chromatin-state discovery and characterization. Nat Methods 9:215–216.  https://doi.org/10.1038/nmeth.1906 CrossRefGoogle Scholar
  22. Ernst J, Kheradpour P, Mikkelsen TS, Shoresh N, Ward LD, Epstein CB, Zhang X, Wang L, Issner R, Coyne M, Ku M, Durham T, Kellis M, Bernstein BE (2011) Mapping and analysis of chromatin state dynamics in nine human cell types. Nature 473:43–49.  https://doi.org/10.1038/nature09906 CrossRefGoogle Scholar
  23. Feil R, Fraga MF (2012) Epigenetics and the environment: emerging patterns and implications. Nat Rev Genet 13:97–109.  https://doi.org/10.1038/nrg3142 CrossRefGoogle Scholar
  24. Fortin JP, Fertig E, Hansen K (2014) shinyMethyl: interactive quality control of Illumina 450k DNA methylation arrays in R. F1000Res 3:175.  https://doi.org/10.12688/f1000research.4680.2 CrossRefGoogle Scholar
  25. Fraga MF, Ballestar E, Paz MF, Ropero S, Setien F, Ballestar ML, Heine-Suner D, Cigudosa JC, Urioste M, Benitez J, Boix-Chornet M, Sanchez-Aguilera A, Ling C, Carlsson E, Poulsen P, Vaag A, Stephan Z, Spector TD, Wu YZ, Plass C, Esteller M (2005) Epigenetic differences arise during the lifetime of monozygotic twins. Proc Natl Acad Sci U S A 102:10604–10609.  https://doi.org/10.1073/pnas.0500398102 CrossRefGoogle Scholar
  26. Gentilini D, Mari D, Castaldi D, Remondini D, Ogliari G, Ostan R, Bucci L, Sirchia SM, Tabano S, Cavagnini F, Monti D, Franceschi C, di Blasio AM, Vitale G (2013) Role of epigenetics in human aging and longevity: genome-wide DNA methylation profile in centenarians and centenarians’ offspring. Age (Dordr) 35:1961–1973.  https://doi.org/10.1007/s11357-012-9463-1 CrossRefGoogle Scholar
  27. Gervin K, Hammero M, Akselsen HE, Moe R, Nygard H, Brandt I, Gjessing HK, Harris JR, Undlien DE, Lyle R (2011) Extensive variation and low heritability of DNA methylation identified in a twin study. Genome Res 21:1813–1821.  https://doi.org/10.1101/gr.119685.110 CrossRefGoogle Scholar
  28. Gudmundsson H, Gudbjartsson DF, Frigge M, Gulcher JR, Stefansson K (2000) Inheritance of human longevity in Iceland. Eur J Hum Genet 8:743–749.  https://doi.org/10.1038/sj.ejhg.5200527 CrossRefGoogle Scholar
  29. Halder R, Hennion M, Vidal RO, Shomroni O, Rahman RU, Rajput A, Centeno TP, van Bebber F, Capece V, Vizcaino JCG, Schuetz AL, Burkhardt S, Benito E, Sala MN, Javan SB, Haass C, Schmid B, Fischer A, Bonn S (2016) DNA methylation changes in plasticity genes accompany the formation and maintenance of memory. Nat Neurosci 19:102–110.  https://doi.org/10.1038/nn.4194 CrossRefGoogle Scholar
  30. Hannum G, Guinney J, Zhao L, Zhang L, Hughes G, Sadda SV, Klotzle B, Bibikova M, Fan JB, Gao Y, Deconde R, Chen M, Rajapakse I, Friend S, Ideker T, Zhang K (2013) Genome-wide methylation profiles reveal quantitative views of human aging rates. Mol Cell 49:359–367.  https://doi.org/10.1016/j.molcel.2012.10.016 CrossRefGoogle Scholar
  31. Hasegawa S, Kobayashi H, Kumagai M, Nishimaru H, Tarusawa E, Kanda H, Sanbo M, Yoshimura Y, Hirabayashi M, Hirabayashi T, Yagi T (2017) Clustered protocadherins are required for building functional neural circuits. Front Mol Neurosci 10:114.  https://doi.org/10.3389/fnmol.2017.00114 CrossRefGoogle Scholar
  32. Herskind AM, McGue M, Holm NV, Sorensen TI, Harvald B, Vaupel JW (1996) The heritability of human longevity: a population-based study of 2872 Danish twin pairs born 1870-1900. Hum Genet 97:319–323CrossRefGoogle Scholar
  33. Heyn H, Li N, Ferreira HJ, Moran S, Pisano DG, Gomez A, Diez J, Sanchez-Mut JV, Setien F, Carmona FJ, Puca AA, Sayols S, Pujana MA, Serra-Musach J, Iglesias-Platas I, Formiga F, Fernandez AF, Fraga MF, Heath SC, Valencia A, Gut IG, Wang J, Esteller M (2012) Distinct DNA methylomes of newborns and centenarians. Proc Natl Acad Sci U S A 109:10522–10527.  https://doi.org/10.1073/pnas.1120658109 CrossRefGoogle Scholar
  34. Hirayama T, Yagi T (2017) Regulation of clustered protocadherin genes in individual neurons. Semin Cell Dev Biol 69:122–130.  https://doi.org/10.1016/j.semcdb.2017.05.026 CrossRefGoogle Scholar
  35. Horvath S (2013) DNA methylation age of human tissues and cell types. Genome Biol 14:R115.  https://doi.org/10.1186/gb-2013-14-10-r115 CrossRefGoogle Scholar
  36. Hothorn T, Buhlmann P, Dudoit S, Molinaro A, van der Laan MJ (2006) Survival ensembles. Biostatistics 7:355–373.  https://doi.org/10.1093/biostatistics/kxj011 CrossRefGoogle Scholar
  37. Houseman EA, Accomando WP, Koestler DC, Christensen BC, Marsit CJ, Nelson HH, Wiencke JK, Kelsey KT (2012) DNA methylation arrays as surrogate measures of cell mixture distribution. BMC Bioinformatics 13:86.  https://doi.org/10.1186/1471-2105-13-86 CrossRefGoogle Scholar
  38. Jaffe AE, Irizarry RA (2014) Accounting for cellular heterogeneity is critical in epigenome-wide association studies. Genome Biol 15:R31.  https://doi.org/10.1186/gb-2014-15-2-r31 CrossRefGoogle Scholar
  39. Jaffe AE, Murakami P, Lee H, Leek JT, Fallin MD, Feinberg AP, Irizarry RA (2012) Bump hunting to identify differentially methylated regions in epigenetic epidemiology studies. Int J Epidemiol 41:200–209.  https://doi.org/10.1093/ije/dyr238 CrossRefGoogle Scholar
  40. Jazwinski SM, Kim S (2017) Metabolic and genetic markers of biological age. Front Genet 8:64.  https://doi.org/10.3389/fgene.2017.00064 CrossRefGoogle Scholar
  41. Johansson A, Enroth S, Gyllensten U (2013) Continuous aging of the human DNA methylome throughout the human lifespan. PLoS One 8:e67378.  https://doi.org/10.1371/journal.pone.0067378 CrossRefGoogle Scholar
  42. Jones MJ, Goodman SJ, Kobor MS (2015) DNA methylation and healthy human aging. Aging Cell 14:924–932.  https://doi.org/10.1111/acel.12349 CrossRefGoogle Scholar
  43. Kaminsky ZA, Tang T, Wang SC, Ptak C, Oh GHT, Wong AHC, Feldcamp LA, Virtanen C, Halfvarson J, Tysk C, McRae AF, Visscher PM, Montgomery GW, Gottesman II, Martin NG, Petronis A (2009) DNA methylation profiles in monozygotic and dizygotic twins. Nat Genet 41:240–245.  https://doi.org/10.1038/ng.286 CrossRefGoogle Scholar
  44. Kawaguchi M, Toyama T, Kaneko R, Hirayama T, Kawamura Y, Yagi T (2008) Relationship between DNA methylation states and transcription of individual isoforms encoded by the protocadherin-alpha gene cluster. J Biol Chem 283:12064–12075.  https://doi.org/10.1074/jbc.M709648200 CrossRefGoogle Scholar
  45. Kerber RA, O’Brien E, Smith KR, Cawthon RM (2001) Familial excess longevity in Utah genealogies. J Gerontol A Biol Sci Med Sci 56:B130–B139CrossRefGoogle Scholar
  46. Kim S, Jazwinski SM (2015) Quantitative measures of healthy aging and biological age. Healthy Aging Res 4  https://doi.org/10.12715/har.2015.4.26
  47. Kim TH, Abdullaev ZK, Smith AD, Ching KA, Loukinov DI, Green RD, Zhang MQ, Lobanenkov VV, Ren B (2007) Analysis of the vertebrate insulator protein CTCF-binding sites in the human genome. Cell 128:1231–1245.  https://doi.org/10.1016/j.cell.2006.12.048 CrossRefGoogle Scholar
  48. Kim S, Welsh DA, Cherry KE, Myers L, Jazwinski SM (2013) Association of healthy aging with parental longevity. Age (Dordr) 35:1975–1982.  https://doi.org/10.1007/s11357-012-9472-0 CrossRefGoogle Scholar
  49. Kim S, Welsh DA, Myers L, Cherry KE, Wyckoff J, Jazwinski SM (2015) Non-coding genomic regions possessing enhancer and silencer potential are associated with healthy aging and exceptional survival. Oncotarget 6:3600–3612Google Scholar
  50. Kim S, Myers L, Wyckoff J, Cherry KE, Jazwinski SM (2017) The frailty index outperforms DNA methylation age and its derivatives as an indicator of biological age. Geroscience 39:83–92.  https://doi.org/10.1007/s11357-017-9960-3 CrossRefGoogle Scholar
  51. Lee KW, Pausova Z (2013) Cigarette smoking and DNA methylation. Front Genet 4:132.  https://doi.org/10.3389/fgene.2013.00132 CrossRefGoogle Scholar
  52. Leek JT, Johnson WE, Parker HS, Jaffe AE, Storey JD (2012) The sva package for removing batch effects and other unwanted variation in high-throughput experiments. Bioinformatics 28:882–883.  https://doi.org/10.1093/bioinformatics/bts034 CrossRefGoogle Scholar
  53. Levine ME et al. (2018) An epigenetic biomarker of aging for lifespan and healthspan. Aging (Albany NY) 10:573–591  https://doi.org/10.18632/aging.101414 CrossRefGoogle Scholar
  54. Lister R, Mukamel EA, Nery JR, Urich M, Puddifoot CA, Johnson ND, Lucero J, Huang Y, Dwork AJ, Schultz MD, Yu M, Tonti-Filippini J, Heyn H, Hu S, Wu JC, Rao A, Esteller M, He C, Haghighi FG, Sejnowski TJ, Behrens MM, Ecker JR (2013) Global epigenomic reconfiguration during mammalian brain development. Science 341:1237905.  https://doi.org/10.1126/science.1237905 CrossRefGoogle Scholar
  55. Maffei VJ, Kim S, Blanchard E, Luo M, Jazwinski SM, Taylor CM, Welsh DA (2017) Biological aging and the human gut microbiota. J Gerontol A Biol Sci Med Sci 72:1474–1482.  https://doi.org/10.1093/gerona/glx042 CrossRefGoogle Scholar
  56. Maksimovic J, Gordon L, Oshlack A (2012) SWAN: subset-quantile within array normalization for illumina infinium HumanMethylation450 BeadChips. Genome Biol 13:R44.  https://doi.org/10.1186/gb-2012-13-6-r44 CrossRefGoogle Scholar
  57. Martinowich K et al (2003) DNA methylation-related chromatin remodeling in activity-dependent BDNF gene regulation. Science 302:890–893.  https://doi.org/10.1126/science.1090842 CrossRefGoogle Scholar
  58. Marttila S, Kananen L, Häyrynen S, Jylhävä J, Nevalainen T, Hervonen A, Jylhä M, Nykter M, Hurme M (2015) Ageing-associated changes in the human DNA methylome: genomic locations and effects on gene expression. BMC Genomics 16:179.  https://doi.org/10.1186/s12864-015-1381-z CrossRefGoogle Scholar
  59. Maurano MT, Wang H, Kutyavin T, Stamatoyannopoulos JA (2012) Widespread site-dependent buffering of human regulatory polymorphism. PLoS Genet 8:e1002599.  https://doi.org/10.1371/journal.pgen.1002599 CrossRefGoogle Scholar
  60. McClay JL et al (2014) A methylome-wide study of aging using massively parallel sequencing of the methyl-CpG-enriched genomic fraction from blood in over 700 subjects. Hum Mol Genet 23:1175–1185.  https://doi.org/10.1093/hmg/ddt511 CrossRefGoogle Scholar
  61. Meissner A, Mikkelsen TS, Gu H, Wernig M, Hanna J, Sivachenko A, Zhang X, Bernstein BE, Nusbaum C, Jaffe DB, Gnirke A, Jaenisch R, Lander ES (2008) Genome-scale DNA methylation maps of pluripotent and differentiated cells. Nature 454:766–770.  https://doi.org/10.1038/nature07107 CrossRefGoogle Scholar
  62. Mitchell BD, Hsueh WC, King TM, Pollin TI, Sorkin J, Agarwala R, Schäffer AA, Shuldiner AR (2001) Heritability of life span in the Old Order Amish. Am J Med Genet 102:346–352  https://doi.org/10.1002/ajmg.1483 [pii]
  63. Mitnitski AB, Mogilner AJ, Rockwood K (2001) Accumulation of deficits as a proxy measure of aging. ScientificWorldJournal 1:323–336.  https://doi.org/10.1100/tsw.2001.58 CrossRefGoogle Scholar
  64. Molumby MJ, Keeler AB, Weiner JA (2016) Homophilic protocadherin cell-cell interactions promote dendrite complexity. Cell Rep 15:1037–1050.  https://doi.org/10.1016/j.celrep.2016.03.093 CrossRefGoogle Scholar
  65. Monahan K, Rudnick ND, Kehayova PD, Pauli F, Newberry KM, Myers RM, Maniatis T (2012) Role of CCCTC binding factor (CTCF) and cohesin in the generation of single-cell diversity of protocadherin-alpha gene expression. Proc Natl Acad Sci U S A 109:9125–9130.  https://doi.org/10.1073/pnas.1205074109 CrossRefGoogle Scholar
  66. Moore AZ, Hernandez DG, Tanaka T, Pilling LC, Nalls MA, Bandinelli S, Singleton AB, Ferrucci L (2016) Change in epigenome-wide DNA methylation over 9 years and subsequent mortality: results from the InCHIANTI Study. J Gerontol A Biol Sci Med Sci 71:1029–1035.  https://doi.org/10.1093/gerona/glv118 CrossRefGoogle Scholar
  67. Nitzsche A, Paszkowski-Rogacz M, Matarese F, Janssen-Megens EM, Hubner NC, Schulz H, de Vries I, Ding L, Huebner N, Mann M, Stunnenberg HG, Buchholz F (2011) RAD21 cooperates with pluripotency transcription factors in the maintenance of embryonic stem cell identity. PLoS One 6:e19470.  https://doi.org/10.1371/journal.pone.0019470 CrossRefGoogle Scholar
  68. Ong C-T, Corces VG (2014) CTCF: an architectural protein bridging genome topology and function. Nat Rev Genet 15:234–246.  https://doi.org/10.1038/nrg3663 CrossRefGoogle Scholar
  69. Ortega A et al. (2016) New cell adhesion molecules in human ischemic cardiomyopathy. PCDHGA3 implications in decreased stroke volume and ventricular dysfunction. PLoS One 11:e0160168  https://doi.org/10.1371/journal.pone.0160168 CrossRefGoogle Scholar
  70. Peters TJ, Buckley MJ, Statham AL, Pidsley R, Samaras K, V Lord R, Clark SJ, Molloy PL (2015) De novo identification of differentially methylated regions in the human genome. Epigenetics Chromatin 8:6–16.  https://doi.org/10.1186/1756-8935-8-6 CrossRefGoogle Scholar
  71. Phipson B, Maksimovic J, Oshlack A (2016) missMethyl: an R package for analyzing data from Illumina’s HumanMethylation450 platform. Bioinformatics 32:286–288.  https://doi.org/10.1093/bioinformatics/btv560 CrossRefGoogle Scholar
  72. Pogribny IP, Beland FA (2009) DNA hypomethylation in the origin and pathogenesis of human diseases. Cell Mol Life Sci 66:2249–2261.  https://doi.org/10.1007/s00018-009-0015-5 CrossRefGoogle Scholar
  73. Rakyan VK, Down TA, Maslau S, Andrew T, Yang TP, Beyan H, Whittaker P, McCann OT, Finer S, Valdes AM, Leslie RD, Deloukas P, Spector TD (2010) Human aging-associated DNA hypermethylation occurs preferentially at bivalent chromatin domains. Genome Res 20:434–439.  https://doi.org/10.1101/gr.103101.109 CrossRefGoogle Scholar
  74. Ritchie ME, Phipson B, Wu D, Hu Y, Law CW, Shi W, Smyth GK (2015) Limma powers differential expression analyses for RNA-sequencing and microarray studies. Nucleic Acids Res 43:e47.  https://doi.org/10.1093/nar/gkv007 CrossRefGoogle Scholar
  75. Rockwood K, Andrew M, Mitnitski A (2007) A comparison of two approaches to measuring frailty in elderly people. J Gerontol A Biol Sci Med Sci 62:738–743 doi:62/7/738 [pii]Google Scholar
  76. Salpea P, Russanova VR, Hirai TH, Sourlingas TG, Sekeri-Pataryas KE, Romero R, Epstein J, Howard BH (2012) Postnatal development- and age-related changes in DNA-methylation patterns in the human genome. Nucleic Acids Res 40:6477–6494.  https://doi.org/10.1093/nar/gks312 CrossRefGoogle Scholar
  77. Sandovici I, Smith NH, Nitert MD, Ackers-Johnson M, Uribe-Lewis S, Ito Y, Jones RH, Marquez VE, Cairns W, Tadayyon M, O'Neill LP, Murrell A, Ling C, Constancia M, Ozanne SE (2011) Maternal diet and aging alter the epigenetic control of a promoter-enhancer interaction at the Hnf4a gene in rat pancreatic islets. Proc Natl Acad Sci U S A 108:5449–5454.  https://doi.org/10.1073/pnas.1019007108 CrossRefGoogle Scholar
  78. Saunderson EA, Spiers H, Mifsud KR, Gutierrez-Mecinas M, Trollope AF, Shaikh A, Mill J, Reul JMHM (2016) Stress-induced gene expression and behavior are controlled by DNA methylation and methyl donor availability in the dentate gyrus. Proc Natl Acad Sci U S A 113:4830–4835.  https://doi.org/10.1073/pnas.1524857113 CrossRefGoogle Scholar
  79. Schreiner D, Weiner JA (2010) Combinatorial homophilic interaction between gamma-protocadherin multimers greatly expands the molecular diversity of cell adhesion. Proc Natl Acad Sci U S A 107:14893–14898.  https://doi.org/10.1073/pnas.1004526107 CrossRefGoogle Scholar
  80. Searle SD, Mitnitski A, Gahbauer EA, Gill TM, Rockwood K (2008) A standard procedure for creating a frailty index. BMC Geriatr 8:24.  https://doi.org/10.1186/1471-2318-8-24 CrossRefGoogle Scholar
  81. Slieker RC et al (2016) Age-related accrual of methylomic variability is linked to fundamental ageing mechanisms. Genome Biol 17:191.  https://doi.org/10.1186/s13059-016-1053-6 CrossRefGoogle Scholar
  82. Starnawska A, Tan Q, McGue M, Mors O, Børglum AD, Christensen K, Nyegaard M, Christiansen L (2017) Epigenome-wide association study of cognitive functioning in middle-aged monozygotic twins. Front Aging Neurosci 9:413.  https://doi.org/10.3389/fnagi.2017.00413 CrossRefGoogle Scholar
  83. Straussman R, Nejman D, Roberts D, Steinfeld I, Blum B, Benvenisty N, Simon I, Yakhini Z, Cedar H (2009) Developmental programming of CpG island methylation profiles in the human genome. Nat Struct Mol Biol 16:564–571.  https://doi.org/10.1038/nsmb.1594 CrossRefGoogle Scholar
  84. Strobl C, Boulesteix AL, Zeileis A, Hothorn T (2007) Bias in random forest variable importance measures: illustrations, sources and a solution. BMC Bioinformatics 8:25.  https://doi.org/10.1186/1471-2105-8-25 CrossRefGoogle Scholar
  85. Strobl C, Boulesteix AL, Kneib T, Augustin T, Zeileis A (2008) Conditional variable importance for random forests. BMC Bioinformatics 9:307.  https://doi.org/10.1186/1471-2105-9-307 CrossRefGoogle Scholar
  86. Strobl C, Malley J, Tutz G (2009) An introduction to recursive partitioning: rationale, application, and characteristics of classification and regression trees, bagging, and random forests. Psychol Methods 14:323–348.  https://doi.org/10.1037/a0016973 CrossRefGoogle Scholar
  87. Suderman M, McGowan PO, Sasaki A, Huang TCT, Hallett MT, Meaney MJ, Turecki G, Szyf M (2012) Conserved epigenetic sensitivity to early life experience in the rat and human hippocampus. Proc Natl Acad Sci U S A 109(Suppl 2):17266–17272.  https://doi.org/10.1073/pnas.1121260109 CrossRefGoogle Scholar
  88. Svane AM, Soerensen M, Lund J, Tan Q, Jylhävä J, Wang Y, Pedersen N, Hägg S, Debrabant B, Deary I, Christensen K, Christiansen L, Hjelmborg J (2018) DNA methylation and all-cause mortality in middle-aged and elderly Danish twins Genes (Basel) 9  https://doi.org/10.3390/genes9020078 CrossRefGoogle Scholar
  89. Sziráki A, Tyshkovskiy A, Gladyshev VN (2018) Global remodeling of the mouse DNA methylome during aging and in response to calorie restriction. Aging Cell 17:e12738.  https://doi.org/10.1111/acel.12738 CrossRefGoogle Scholar
  90. Szyf M, Bick J (2013) DNA methylation: a mechanism for embedding early life experiences in the genome. Child Dev 84:49–57.  https://doi.org/10.1111/j.1467-8624.2012.01793.x CrossRefGoogle Scholar
  91. Talens RP, Christensen K, Putter H, Willemsen G, Christiansen L, Kremer D, Suchiman HED, Slagboom PE, Boomsma DI, Heijmans BT (2012) Epigenetic variation during the adult lifespan: cross-sectional and longitudinal data on monozygotic twin pairs. Aging Cell 11:694–703.  https://doi.org/10.1111/j.1474-9726.2012.00835.x CrossRefGoogle Scholar
  92. Toyoda S, Kawaguchi M, Kobayashi T, Tarusawa E, Toyama T, Okano M, Oda M, Nakauchi H, Yoshimura Y, Sanbo M, Hirabayashi M, Hirayama T, Hirabayashi T, Yagi T (2014) Developmental epigenetic modification regulates stochastic expression of clustered protocadherin genes, generating single neuron diversity. Neuron 82:94–108.  https://doi.org/10.1016/j.neuron.2014.02.005 CrossRefGoogle Scholar
  93. Triche TJ Jr, Weisenberger DJ, Van Den Berg D, Laird PW, Siegmund KD (2013) Low-level processing of Illumina Infinium DNA methylation beadarrays. Nucleic Acids Res 41:e90.  https://doi.org/10.1093/nar/gkt090 CrossRefGoogle Scholar
  94. Wang H, Maurano MT, Qu H, Varley KE, Gertz J, Pauli F, Lee K, Canfield T, Weaver M, Sandstrom R, Thurman RE, Kaul R, Myers RM, Stamatoyannopoulos JA (2012) Widespread plasticity in CTCF occupancy linked to DNA methylation. Genome Res 22:1680–1688.  https://doi.org/10.1101/gr.136101.111 CrossRefGoogle Scholar
  95. Weidner CI, Wagner W (2014) The epigenetic tracks of aging. Biol Chem 395:1307–1314.  https://doi.org/10.1515/hsz-2014-0180 CrossRefGoogle Scholar
  96. Weiner JA, Jontes JD (2013) Protocadherins, not prototypical: a complex tale of their interactions, expression, and functions. Front Mol Neurosci 6:4.  https://doi.org/10.3389/fnmol.2013.00004 CrossRefGoogle Scholar
  97. Willemsen G, Ward KJ, Bell CG, Christensen K, Bowden J, Dalgård C, Harris JR, Kaprio J, Lyle R, Magnusson PKE, Mather KA, Ordoňana JR, Perez-Riquelme F, Pedersen NL, Pietiläinen KH, Sachdev PS, Boomsma DI, Spector T (2015) The concordance and heritability of type 2 diabetes in 34,166 twin pairs from international twin registers: the Discordant Twin (DISCOTWIN) Consortium. Twin Res Hum Genet 18:762–771.  https://doi.org/10.1017/thg.2015.83 CrossRefGoogle Scholar
  98. Wilson AS, Power BE, Molloy PL (2007) DNA hypomethylation and human diseases. Biochim Biophys Acta 1775:138–162.  https://doi.org/10.1016/j.bbcan.2006.08.007 CrossRefGoogle Scholar
  99. Wong CCY, Caspi A, Williams B, Craig IW, Houts R, Ambler A, Moffitt TE, Mill J (2014) A longitudinal study of epigenetic variation in twins. Epigenetics 5:516–526.  https://doi.org/10.4161/epi.5.6.12226 CrossRefGoogle Scholar
  100. Zhang X, Takata K, Cui W, Miyata-Takata T, Sato Y, Noujima-Harada M, Yoshino T (2016) Protocadherin gamma A3 is expressed in follicular lymphoma irrespective of BCL2 status and is associated with tumor cell growth. Mol Med Rep 14:4622–4628.  https://doi.org/10.3892/mmr.2016.5808 CrossRefGoogle Scholar

Copyright information

© American Aging Association 2018

Authors and Affiliations

  1. 1.Tulane Center for Aging and Department of MedicineTulane University Health Sciences CenterNew OrleansUSA
  2. 2.Virginia Commonwealth UniversityMid-Atlantic Twin RegistryRichmondUSA
  3. 3.University of Washington Twin RegistrySeattleUSA
  4. 4.Washington State Twin RegistryWashington State University – Health Sciences SpokaneSpokaneUSA

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