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Epigenetic Clock: Just a Convenient Marker or an Active Driver of Aging?

Chapter
First Online:
Part of the Advances in Experimental Medicine and Biology book series (AEMB, volume 1178)

Abstract

A global DNA hypomethylation and local changes in the methylation levels of specific DNA loci occur during aging in mammals. Global hypomethylation mainly affects highly methylated repeat sequences, such as transposable elements; it is an essentially stochastic process usually referred to as “epigenetic drift.” Specific changes in DNA methylation affect various genome sequences and could be either hypomethylation or hypermethylation, but the prevailing tendencies are hypermethylation of promoter sequences associated with CpG islands and hypomethylation of CpG poor genes. Methylation levels of multiple CpG sites display a strong correlation to age common between individuals of the same species. Collectively, methylation of such CpG sites could be used as “epigenetic clocks” to predict biological age. Furthermore, the discrepancy between epigenetic and chronological ages could be predictive of all-cause mortality and multiple age-associated diseases. Random changes in DNA methylation (epigenetic drift) could also affect the aging phenotype, causing accidental changes in gene expression and increasing the transcriptional noise between cells of the same tissue. Both effects could become detrimental to tissue functioning and cause a gradual decline in organ function during aging. Strong evidence shows that epigenetic systems contribute to lifespan control in various organisms. Similar to other cell systems, the epigenome is prone to gradual degradation due to the genome damage, stressful agents and other aging factors. However, unlike mutations and many other hallmarks of aging, age-related epigenetic changes could be fully or partially reversed to a “young” state.

Keywords

Epigenetic clock Aging DNA methylation Epigenetic age Epigenetic reprogramming 
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Notes

Conflict of Interest

The authors confirm that this article content has no conflict of interest.

References

  1. 1.
    Holliday R (2006) Aging is no longer an unsolved problem in biology. Ann N Y Acad Sci 1067:1–9CrossRefPubMedGoogle Scholar
  2. 2.
    Lopez-Otin C, Blasco MA, Partridge L, Serrano M, Kroemer G (2013) The hallmarks of aging. Cell 153(6):1194–1217CrossRefPubMedPubMedCentralGoogle Scholar
  3. 3.
    Ashapkin VV, Kutueva LI, Vanyushin BF (2015) Aging epigenetics: accumulation of errors or realization of a specific program? Biochemistry (Moscow) 80(11):1406–1417CrossRefGoogle Scholar
  4. 4.
    Ashapkin VV, Kutueva LI, Vanyushin BF (2017) Aging as an epigenetic phenomenon. Curr Genomics 18(5):385–407CrossRefPubMedPubMedCentralGoogle Scholar
  5. 5.
    Sen P, Shah PP, Nativio R, Berger SL (2016) Epigenetic mechanisms of longevity and aging. Cell 166(4):822–839CrossRefPubMedPubMedCentralGoogle Scholar
  6. 6.
    Berdyshev GD, Korotaev GK, Boyarskikh GV, Vanyushin BF (1967) Nucleotide composition of DNA and RNA from somatic tissues of humpback salmon and its changes during spawning. Biokhimiia 32(5):988–993PubMedGoogle Scholar
  7. 7.
    Vanyushin BF, Nemirovsky LE, Klimenko VV, Vasiliev VK, Belozersky AN (1973) The 5-methylcytosine in DNA of rats: tissue and age specificity and the changes induced by hydrocortisone and other agents. Gerontologia 19(3):138–152CrossRefPubMedGoogle Scholar
  8. 8.
    Romanov GA, Vanyushin BF (1981) Methylation of reiterated sequences in mammalian DNAs: effects of the tissue type, age, malignancy and hormonal induction. Biochim Biophys Acta 653(2):204–218CrossRefPubMedGoogle Scholar
  9. 9.
    De Cecco M, Criscione SW, Peckham EJ, Hillenmeyer S, Hamm EA, Manivannan J et al (2013) Genomes of replicatively senescent cells undergo global epigenetic changes leading to gene silencing and activation of transposable elements. Aging Cell 12(2):247–256CrossRefPubMedPubMedCentralGoogle Scholar
  10. 10.
    De Cecco M, Ito T, Petrashen AP, Elias AE, Skvir NJ, Criscione SW (2019) L1 drives IFN in senescent cells and promotes age-associated inflammation. Nature 566(7742):73–78CrossRefPubMedPubMedCentralGoogle Scholar
  11. 11.
    Wilson VL, Smith RA, Mag S, Cutler RG (1987) Genomic 5-methyldeoxycytidine decreases with age. J Biol Chem 262(21):9948–9951PubMedGoogle Scholar
  12. 12.
    Singhal RP, Mays-Hoopes LL, Eichhorn GL (1987) DNA methylation in aging of mice. Mech Ageing Dev 41(3):199–210CrossRefPubMedGoogle Scholar
  13. 13.
    Wilson VL, Jones PA (1983) DNA methylation decreases in aging but not in immortal cells. Science 220(4601):1055–1057CrossRefPubMedGoogle Scholar
  14. 14.
    Wigler M, Levy D, Perucho M (1981) The somatic replication of DNA methylation. Cell 24(1):33–40CrossRefPubMedGoogle Scholar
  15. 15.
    Stein R, Gruenbaum Y, Pollack Y, Razin A, Cedar H (1982) Clonal inheritance of the pattern of DNA methylation in mouse cells. Proc Natl Acad Sci U S A 79(1):61–65CrossRefPubMedPubMedCentralGoogle Scholar
  16. 16.
    Issa J-PJ, 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(4):536–540CrossRefPubMedGoogle Scholar
  17. 17.
    Ahuja N, Li Q, Mohan AL, Baylin SB, Issa J-PJ (1998) Aging and DNA methylation in colorectal mucosa and cancer. Cancer Res 58(23):5489–5494PubMedGoogle Scholar
  18. 18.
    Waki T, Tamura G, Sato M, Motoyama T (2003) Age-related methylation of tumor suppressor and tumor-related genes: an analysis of autopsy samples. Oncogene 22(26):4128–4133CrossRefPubMedGoogle Scholar
  19. 19.
    So K, Tamura G, Honda T, Homma N, Waki T, Togawa N et al (2006) Multiple tumor suppressor genes are increasingly methylated with age in non-neoplastic gastric epithelia. Cancer Sci 97(11):1155–1158CrossRefPubMedGoogle Scholar
  20. 20.
    Fraga MF, Ballestar E, Paz MF, Ropero S, Setien F, Ballestar ML et al (2005) Epigenetic differences arise during the lifetime of monozygotic twins. Proc Natl Acad Sci U S A 102(30):10604–10609CrossRefPubMedPubMedCentralGoogle Scholar
  21. 21.
    Christensen BC, Houseman EA, Marsit CJ, Zheng S, Wrensch MR, Wiemels JL et al (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.1000602CrossRefPubMedPubMedCentralGoogle Scholar
  22. 22.
    Maegawa S, Hinka G, Kim HS, Shen L, Zhang L, Zhang J et al (2010) Widespread and tissue specific age-related DNA methylation changes in mice. Genome Res 20(3):332–340CrossRefPubMedPubMedCentralGoogle Scholar
  23. 23.
    Rakyan VK, Down TA, Maslau S, Andrew T, Yang T-P, Beyan H et al (2010) Human aging-associated DNA hypermethylation occurs preferentially at bivalent chromatin domains. Genome Res 20(4):434–439CrossRefPubMedPubMedCentralGoogle Scholar
  24. 24.
    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.0067378CrossRefPubMedPubMedCentralGoogle Scholar
  25. 25.
    Tserel L, KoldeR LM, Tretyakov K, Kasela S, Kisand K et al (2015) Age-related profiling of DNA methylation in CD8+ T cells reveals changes in immune response and transcriptional regulator genes. Sci Rep 5:13107.  https://doi.org/10.1038/srep13107CrossRefPubMedPubMedCentralGoogle Scholar
  26. 26.
    Hernandez DG, Nalls MA, Gibbs J, Arepalli S, van der Brug M, Chong S et al (2011) Distinct DNA methylation changes highly correlated with chronological age in the human brain. Hum Mol Genet 20(6):1164–1172CrossRefPubMedPubMedCentralGoogle Scholar
  27. 27.
    Martino D, Loke YJ, Gordon L, Ollikainen M, Cruickshank MN, Saffery R et al (2013) Longitudinal, genome-scale analysis of DNA methylation in twins from birth to 18 months of age reveals rapid epigenetic change in early life and pair-specific effects of discordance. Genome Biol 14:R42.  https://doi.org/10.1186/gb-2013-14-5-r42CrossRefPubMedPubMedCentralGoogle Scholar
  28. 28.
    Day K, Waite LL, Thalacker-Mercer A, West A, Bamman MM, Brooks JD et al (2013) Differential DNA methylation with age displays both common and dynamic features across human tissues that are influenced by CpG landscape. Genome Biol 14:R102.  https://doi.org/10.1186/gb-2013-14-9-r102CrossRefPubMedPubMedCentralGoogle Scholar
  29. 29.
    Zykovich A, Hubbard A, Flynn JM, Tarnopolsky M, Fraga MF, Kerksick C et al (2014) Genome-wide DNA methylation changes with age in disease-free human skeletal muscle. Aging Cell 13(2):360–366CrossRefPubMedGoogle Scholar
  30. 30.
    Bormann F, Rodrıguez-Paredes M, Hagemann S, Manchanda H, Kristof B, Gutekunst J et al (2016) Reduced DNA methylation patterning and transcriptional connectivity define human skin aging. Aging Cell 15(3):563–571CrossRefPubMedPubMedCentralGoogle Scholar
  31. 31.
    Maegawa S, Lu Y, Tahara T, Lee JT, Madzo J, Liang S et al (2017) Caloric restriction delays age-related methylation drift. Nat Commun 8:539.  https://doi.org/10.1038/s41467-017-00607-3CrossRefPubMedPubMedCentralGoogle Scholar
  32. 32.
    Masser DR, Hadad N, Porter HL, Mangold CA, Unnikrishnan A, Ford MM et al (2017) Sexually divergent DNA methylation patterns with hippocampal aging. Aging Cell 16(6):1342–1352CrossRefPubMedPubMedCentralGoogle Scholar
  33. 33.
    Hahn O, Gronke S, Stubbs TM, Ficz G, Hendrich O, Krueger F et al (2017) Dietary restriction protects from age-associated DNA methylation and induces epigenetic reprogramming of lipid metabolism. Genome Biol 18:56.  https://doi.org/10.1186/s13059-017-1187-1CrossRefPubMedPubMedCentralGoogle Scholar
  34. 34.
    Sziraki 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.12738CrossRefPubMedPubMedCentralGoogle Scholar
  35. 35.
    Lowe R, Barton C, Jenkins CA, Ernst C, Forman O, Fernandez-Twinn DS et al (2018) Ageing-associated DNA methylation dynamics are a molecular readout of lifespan variation among mammalian species. Genome Biol 19:22.  https://doi.org/10.1186/s13059-018-1397-1CrossRefPubMedPubMedCentralGoogle Scholar
  36. 36.
    Hjelmborg JB, Iachine I, Skytthe A, Vaupel JW, McGue M, Koskenvuo M et al (2006) Genetic influence on human lifespan and longevity. Hum Genet 119(3):312–321CrossRefGoogle Scholar
  37. 37.
    Sebastiani P, Nussbaum L, Andersen SL, Black MJ, Perls TT (2016) Increasing sibling relative risk of survival to older and older ages and the importance of precise definitions of “aging,” “life span,” and “longevity.”. J Gerontol A Biol Sci Med Sci 71(3):340–346CrossRefPubMedGoogle Scholar
  38. 38.
    Gentilini D, Mari D, Castaldi D, Remondini D, Ogliari G, Ostan R et al (2013) Role of epigenetics in human aging and longevity: genome-wide DNA methylation profile in centenarians and centenarians’ offspring. Age 35(5):1961–1973CrossRefPubMedGoogle Scholar
  39. 39.
    Cole JJ, Robertson NA, Rather MI, Thomson JP, McBryan T, Sproul D et al (2017) Diverse interventions that extend mouse lifespan suppress shared age-associated epigenetic changes at critical gene regulatory regions. Genome Biol 18:58.  https://doi.org/10.1186/s13059-017-1185-3CrossRefPubMedPubMedCentralGoogle Scholar
  40. 40.
    Bocklandt S, Lin W, Seh ME, Sanchez FJ, Sinsheimer JS, Horvath S et al (2011) Epigenetic predictor of age. PLoS One 6:e14821.  https://doi.org/10.1371/journal.pone.0014821CrossRefPubMedPubMedCentralGoogle Scholar
  41. 41.
    Koch CM, Wagner W (2011) Epigenetic aging signature to determine age in different tissues. Aging 3(10):1018–1027CrossRefPubMedPubMedCentralGoogle Scholar
  42. 42.
    Weidner CI, Lin Q, Koch CM, Eisele L, Beier F, Ziegler P et al (2014) Aging of blood can be tracked by DNA methylation changes at just three CpG sites. Genome Biol 15:R24.  https://doi.org/10.1186/gb-2014-15-2-r24CrossRefPubMedPubMedCentralGoogle Scholar
  43. 43.
    Zbieć-Piekarska R, Spólnicka M, Kupiec T, Parys-Proszek A, Makowska Ż, Pałeczka A et al (2015) Development of a forensically useful age prediction method based on DNA methylation analysis. Forensic Sci Int Genet 17:173–179CrossRefPubMedGoogle Scholar
  44. 44.
    Jung SE, Lim SM, Hong SR, Lee EH, Shin KJ, Lee HY (2019) DNA methylation of the ELOVL2, FHL2, KLF14, C1orf132/MIR29B2C, and TRIM59 genes for age prediction from blood, saliva, and buccal swab samples. Forensic Sci Int Genet 38:1–8CrossRefPubMedGoogle Scholar
  45. 45.
    Zbieć-Piekarska R, Spólnicka M, Kupiec T, Makowska Ż, Spas A, Parys-Proszek A et al (2015) Examination of DNA methylation status of the ELOVL2 marker may be useful for human age prediction in forensic science. Forensic Sci Int Genet 14:161–167CrossRefPubMedGoogle Scholar
  46. 46.
    Garagnani P, Bacalini MG, Pirazzini C, Gori D, Giuliani C, Mari D et al (2012) Methylation of ELOVL2 gene as a new epigenetic marker of age. Aging Cell 11(6):1132–1134CrossRefPubMedPubMedCentralGoogle Scholar
  47. 47.
    Bekaert B, Kamalandua A, Zapico SC, Van de Voorde W, Decorte R (2015) Improved age determination of blood and teeth samples using a selected set of DNA methylation markers. Epigenetics 10(10):922–930CrossRefPubMedPubMedCentralGoogle Scholar
  48. 48.
    Lee HY, Jung S-E, Oh YN, Choi A, Yang WI, Shin K-J (2015) Epigenetic age signatures in the forensically relevant body fluid of semen: a preliminary study. Forensic Sci Int Genet 19:28–34CrossRefPubMedGoogle Scholar
  49. 49.
    Hannum G, Guinney J, Zhao L, Zhang L, Hughes G, Sadda S et al (2013) Genome-wide methylation profiles reveal quantitative views of human aging rates. Mol Cell 49(2):359–367CrossRefPubMedGoogle Scholar
  50. 50.
    Horvath S, Erhart W, Brosch M, Ammerpohl O, von Schönfels W, Ahrens M et al (2014) Obesity accelerates epigenetic aging of human liver. Proc Natl Acad Sci U S A 111(43):15538–15543CrossRefPubMedPubMedCentralGoogle Scholar
  51. 51.
    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-r115CrossRefPubMedPubMedCentralGoogle Scholar
  52. 52.
    Horvath S, Mah V, Lu AT, Woo JS, Choi O-W, Jasinska AJ et al (2015) The cerebellum ages slowly according to the epigenetic clock. Aging (Albany NY) 7(5):294–305CrossRefGoogle Scholar
  53. 53.
    Horvath S, Oshima J, Martin GM, Lu AT, Quach A, Cohen H et al (2018) Epigenetic clock for skin and blood cells applied to Hutchinson Gilford Progeria Syndrome and ex vivo studies. Aging (Albany NY) 10(7):1758–1775CrossRefGoogle Scholar
  54. 54.
    Levine ME, Lu AT, Quach A, Chen BH, Assimes TL, Bandinelli S et al (2018) An epigenetic biomarker of aging for lifespan and healthspan. Aging (Albany NY) 10(4):573–591CrossRefGoogle Scholar
  55. 55.
    Lu AT, Quach A, Wilson JG, Reiner AP, Aviv A, Raj K et al (2019) DNA methylation GrimAge strongly predicts lifespan and healthspan. Aging (Albany NY) 11(2):303–327CrossRefGoogle Scholar
  56. 56.
    Knight AK, Craig JM, Theda C, Bækvad-Hansen M, Bybjerg-Grauholm J, Hansen CS et al (2016) An epigenetic clock for gestational age at birth based on blood methylation data. Genome Biol 17:206.  https://doi.org/10.1186/s13059-016-1068-zCrossRefPubMedPubMedCentralGoogle Scholar
  57. 57.
    Li C, Gao W, Gao Y, Yu C, Lv J, Lv R et al (2018) Age prediction of children and adolescents aged 6-17 years: an epigenome-wide analysis of DNA methylation. Aging (Albany NY) 10(5):1015–1026CrossRefGoogle Scholar
  58. 58.
    Jenkins TG, Aston KI, Pflueger C, Cairns BR, Carrell DT (2014) Age-associated sperm DNA methylation alterations: possible implications in offspring disease susceptibility. PLoS Genet 10:e1004458.  https://doi.org/10.1371/journal.pgen.1004458CrossRefPubMedPubMedCentralGoogle Scholar
  59. 59.
    Jenkins TG, Aston KI, Cairns BR, Smith A, Carrell DT (2017) Paternal germ line aging: DNA methylation age prediction from human sperm. BMC Genomics 19:763.  https://doi.org/10.1186/s12864-018-5153-4CrossRefGoogle Scholar
  60. 60.
    Horvath S, Pirazzini C, Bacalini MG, Gentilini D, Di Blasio AM, Delledonne M et al (2015) Decreased epigenetic age of PBMCs from Italian semi-supercentenarians and their offspring. Aging (Albany NY) 7(12):1159–1170CrossRefGoogle Scholar
  61. 61.
    Levine ME, Hosgood HD, Chen B, Absher D, Assimes T, Horvath S (2015) DNA methylation age of blood predicts future onset of lung cancer in the women’s health initiative. Aging (Albany NY) 7(9):690–699CrossRefGoogle Scholar
  62. 62.
    Zheng Y, Joyce BT, Colicino E, Liu L, Zhang W, Dai Q et al (2016) Blood epigenetic age may predict cancer incidence and mortality. EBioMedicine 5:68–73CrossRefPubMedPubMedCentralGoogle Scholar
  63. 63.
    Ambatipudi S, Horvath S, Perrier F, Cuenin C, Hernandez-Vargas H, Le Calvez-Kelm F et al (2017) DNA methylome analysis identifies accelerated epigenetic ageing associated with postmenopausal breast cancer susceptibility. Eur J Cancer 75:299–307CrossRefPubMedPubMedCentralGoogle Scholar
  64. 64.
    Durso DF, Bacalini MG, Sala C, Pirazzini C, Marasco E, Bonafé M et al (2017) Acceleration of leukocytes’ epigenetic age as an early tumor- and sex-specific marker of breast and colorectal cancer. Oncotarget 8(14):23237–23245CrossRefPubMedPubMedCentralGoogle Scholar
  65. 65.
    Marioni RE, Shah S, McRae AF, Chen BH, Colicino E, Harris SE et al (2015) DNA methylation age of blood predicts all-cause mortality in later life. Genome Biol 16:25.  https://doi.org/10.1186/s13059-015-0584-6CrossRefPubMedPubMedCentralGoogle Scholar
  66. 66.
    Perna L, Zhang Y, Mons U, Holleczek B, Saum K-U, Brenner H (2016) Epigenetic age acceleration predicts cancer, cardiovascular, and all-cause mortality in a German case cohort. Clin Epigenetics 8:64.  https://doi.org/10.1186/s13148-016-0228-zCrossRefPubMedPubMedCentralGoogle Scholar
  67. 67.
    Chen BH, Marioni RE, Colicino E, Peters MJ, Ward-Caviness CK, Tsai P-C et al (2016) DNA methylation-based measures of biological age: meta-analysis predicting time to death. Aging (Albany NY) 8(9):1844–1859CrossRefGoogle Scholar
  68. 68.
    Horvath S, Levine AJ (2015) HIV-1 infection accelerates age according to the epigenetic clock. J Infect Dis 212(10):1563–1573CrossRefPubMedPubMedCentralGoogle Scholar
  69. 69.
    Gross AM, Jaeger PA, Kreisberg JF, Licon K, Jepsen KL, Khosroheidari M et al (2016) Methylome-wide analysis of chronic HIV infection reveals five-year increase in biological age and epigenetic targeting of HLA. Mol Cell 62(2):157–168CrossRefPubMedPubMedCentralGoogle Scholar
  70. 70.
    Horvath S, Garagnani P, Bacalini MG, Pirazzini C, Salvioli S, Gentilini D (2015) Accelerated epigenetic aging in Down syndrome. Aging Cell 14(3):491–495CrossRefPubMedPubMedCentralGoogle Scholar
  71. 71.
    Levine ME, Lu AT, Bennett DA, Horvath S (2015) Epigenetic age of the pre-frontal cortex is associated with neuritic plaques, amyloid load, and Alzheimer’s disease related cognitive functioning. Aging (Albany NY) 7(12):1198–1211CrossRefGoogle Scholar
  72. 72.
    Horvath S, Ritz BR (2015) Increased epigenetic age and granulocyte counts in the blood of Parkinson’s disease patients. Aging (Albany NY) 7(12):1130–1142CrossRefGoogle Scholar
  73. 73.
    Carroll JE, Irwin MR, Levine M, Seeman TE, Absher D, Assimes T et al (2016) Epigenetic aging and immune senescence in women with insomnia symptoms: findings from the women’s health initiative study. Biol Psychiatry 81(2):136–144CrossRefPubMedPubMedCentralGoogle Scholar
  74. 74.
    Degerman S, Josefsson M, Adolfsson AN, Wennstedt S, Landfors M, Haider Z et al (2017) Maintained memory in aging is associated with young epigenetic age. Neurobiol Aging 55:167–171CrossRefPubMedGoogle Scholar
  75. 75.
    Zannas AS, Arloth J, Carrillo-Roa T, Iurato S, Röh S, Ressler KJ et al (2015) Lifetime stress accelerates epigenetic aging in an urban, African American cohort: relevance of glucocorticoid signaling. Genome Biol 16:266.  https://doi.org/10.1186/s13059-015-0828-5CrossRefPubMedPubMedCentralGoogle Scholar
  76. 76.
    Maierhofer A, Flunkert J, Oshima J, Martin GM, Haaf T, Horvath S (2017) Accelerated epigenetic aging in Werner syndrome. Aging (Albany NY) 9(4):1143–1152CrossRefGoogle Scholar
  77. 77.
    Quach A, Levine ME, Tanaka T, Lu AT, Chen BH, Ferrucci L et al (2017) Epigenetic clock analysis of diet, exercise, education, and lifestyle factors. Aging (Albany NY) 9(2):419–446CrossRefGoogle Scholar
  78. 78.
    Fiorito G, McCrory C, Robinson O, Carmeli C, Rosales CO, Zhang Y et al (2019) Socioeconomic position, lifestyle habits and biomarkers of epigenetic aging: a multi-cohort analysis. Aging (Albany NY) 11(7):2045–2070CrossRefGoogle Scholar
  79. 79.
    Florath I, Butterbach K, Müller H, Bewerunge-Hudler M, Brenner H (2014) Cross-sectional and longitudinal changes in DNA methylation with age: an epigenome-wide analysis revealing over 60 novel age-associated CpG sites. Hum Mol Genet 23(5):1186–1201CrossRefPubMedGoogle Scholar
  80. 80.
    Kananen L, Marttila S, Nevalainen T, Kummola L, Junttila I, Mononen N et al (2016) The trajectory of the blood DNA methylome ageing rate is largely set before adulthood: evidence from two longitudinal studies. Age (Dordr) 38:65.  https://doi.org/10.1007/s11357-016-9927-9CrossRefGoogle Scholar
  81. 81.
    Bacalini MG, Franceschi C, Gentilini D, Ravaioli F, Zhou X, Remondini D et al (2019) Molecular aging of human liver: an epigenetic/transcriptomic signature. J Gerontol A Biol Sci Med Sci 74(1):1–8PubMedGoogle Scholar
  82. 82.
    Polanowski AM, Robbins J, Chandler D, Jarman SN (2014) Epigenetic estimation of age in humpback whales. Mol Ecol Resour 14(5):976–987PubMedPubMedCentralGoogle Scholar
  83. 83.
    Thompson MJ, von Holdt B, Horvath S, Pellegrini M (2017) An epigenetic aging clock for dogs and wolves. Aging (Albany NY) 9(3):1055–1068CrossRefGoogle Scholar
  84. 84.
    Petkovich DA, Podolskiy DI, Lobanov AV, Lee S-G, Miller RA, Gladyshev VN (2017) Using DNA methylation profiling to evaluate biological age and longevity interventions. Cell Metab 25(4):954–960CrossRefPubMedPubMedCentralGoogle Scholar
  85. 85.
    Wang T, Tsui B, Kreisberg JF, Robertson NA, Gross AM, Yu MK et al (2017) Epigenetic aging signatures in mice livers are slowed by dwarfism, calorie restriction and rapamycin treatment. Genome Biol 18:57.  https://doi.org/10.1186/s13059-017-1186-2CrossRefPubMedPubMedCentralGoogle Scholar
  86. 86.
    Stubbs TM, Bonder MJ, Stark A-K, Krueger F, Ageing Clock Team BI, von Meyenn F et al (2017) Multi-tissue DNA methylation age predictor in mouse. Genome Biol 18:68.  https://doi.org/10.1186/s13059-017-1203-5CrossRefPubMedPubMedCentralGoogle Scholar
  87. 87.
    Thompson MJ, Chwiałkowska K, Rubbi L, Lusis AJ, Davis RC, Srivastava A et al (2018) A multi-tissue full lifespan epigenetic clock for mice. Aging (Albany NY) 10(10):2832–2854CrossRefGoogle Scholar
  88. 88.
    Han Y, Eipel M, Franzen J, Sakk V, Dethmers-Ausema B, Yndriago L et al (2018) Epigenetic age-predictor for mice based on three CpG sites. elife 7:e37462.  https://doi.org/10.7554/eLife.37462CrossRefPubMedPubMedCentralGoogle Scholar
  89. 89.
    Meer MV, Podolskiy DI, Tyshkovskiy A, Gladyshev VN (2018) A whole lifespan mouse multi-tissue DNA methylation clock. elife 7:e40675.  https://doi.org/10.7554/eLife.40675CrossRefPubMedPubMedCentralGoogle Scholar
  90. 90.
    Albert M, Peters AH (2009) Genetic and epigenetic control of early mouse development. Curr Opin Genet Dev 19(2):113–121CrossRefPubMedGoogle Scholar
  91. 91.
    Zhou L, Dean J (2015) Reprogramming the genome to totipotency in mouse embryos. Trends Cell Biol 25(2):82–91CrossRefPubMedGoogle Scholar
  92. 92.
    Yamanaka S, Blau HM (2010) Nuclear reprogramming to a pluripotent state by three approaches. Nature 465(7299):704–712CrossRefPubMedPubMedCentralGoogle Scholar
  93. 93.
    Marion RM, Blasco MA (2010) Telomere rejuvenation during nuclear reprogramming. Curr Opin Genet Dev 20(2):190–196CrossRefPubMedGoogle Scholar
  94. 94.
    Lapasset L, Milhavet O, Prieur A, Besnard E, Babled A, Ait-Hamou N et al (2011) Rejuvenating senescent and centenarian human cells by reprogramming through the pluripotent state. Genes Dev 25(21):2248–2253CrossRefPubMedPubMedCentralGoogle Scholar
  95. 95.
    Soria-Valles C, Lopez-Otin C (2016) iPSCs: on the road to reprogramming aging. Trends Mol Med 22(8):713–724CrossRefPubMedGoogle Scholar
  96. 96.
    Tan L, Ke Z, Tombline G, Macoretta N, Hayes K, Tian X et al (2017) Naked mole rat cells have a stable epigenome that resists iPSC reprogramming. Stem Cell Reports 9(5):1721–1734CrossRefPubMedPubMedCentralGoogle Scholar
  97. 97.
    Buganim Y, Faddah DA, Cheng AW, Itskovich E, Markoulaki S, Ganz K et al (2012) Single-cell expression analyses duringcellular reprogramming reveal an early stochastic and a late hierarchic phase. Cell 150(6):1209–1222CrossRefPubMedPubMedCentralGoogle Scholar
  98. 98.
    Polo JM, Anderssen E, Walsh RM, Schwarz BA, Nefzger CM, Lim SM et al (2012) A molecular roadmap of reprogramming somatic cells into iPS cells. Cell 151(7):1617–1632CrossRefPubMedPubMedCentralGoogle Scholar
  99. 99.
    Ocampo A, Reddy P, Martinez-Redondo P, Platero-Luengo A, Hatanaka F, Hishida T et al (2016) In vivo amelioration of age-associated hallmarks by partial reprogramming. Cell 167(7):1719–1733CrossRefPubMedPubMedCentralGoogle Scholar
  100. 100.
    Olova N, Simpson DJ, Marioni RE, Chandra T (2019) Partial reprogramming induces a steady decline in epigenetic age before loss of somatic identity. Aging Cell 18:e12877.  https://doi.org/10.1111/acel.12877CrossRefPubMedGoogle Scholar
  101. 101.
    Tanabe K, Nakamura M, Narita M, Takahashi K, Yamanaka S (2013) Maturation, not initiation, is the major roadblock during reprogramming toward pluripotency from human fibroblasts. Proc Natl Acad Sci U S A 110(30):12172–12179CrossRefPubMedPubMedCentralGoogle Scholar
  102. 102.
    Conboy IM, Conboy MJ, Wagers AJ, Girma ER, Weissman IL, Rando TA (2005) Rejuvenation of aged progenitor cells by exposure to a young systemic environment. Nature 433(7027):760–764CrossRefPubMedGoogle Scholar
  103. 103.
    Villeda SA, Luo J, Mosher KI, Zou B, Britschgi M, Bieri G et al (2011) The ageing systemic milieu negatively regulates neurogenesis and cognitive function. Nature 477(7362):90–94CrossRefPubMedPubMedCentralGoogle Scholar
  104. 104.
    Katsimpardi L, Litterman NK, Schein PA, Miller CM, Loffredo FS, Wojtkiewicz GR et al (2014) Vascular and neurogenic rejuvenation of the aging mouse brain by young systemic factors. Science 344(6184):630–634CrossRefPubMedPubMedCentralGoogle Scholar
  105. 105.
    Gontier G, Iyer M, Shea JM, Bieri G, Wheatley EG, Ramalho-Santos M et al (2018) Tet2 rescues age-related regenerative decline and enhances cognitive function in the adult mouse brain. Cell Rep 22(8):1974–1981CrossRefPubMedPubMedCentralGoogle Scholar
  106. 106.
    Liu Y, Conboy MJ, Mehdipour M, Liu Y, Tran TP, Blotnick A et al (2017) Application of bio-orthogonal proteome labeling to cell transplantation and heterochronic parabiosis. Nat Commun 8:643.  https://doi.org/10.1038/s41467-017-00698-yCrossRefPubMedPubMedCentralGoogle Scholar
  107. 107.
    Villeda SA, Plambeck KE, Middeldorp J, Castellano JM, Mosherm KI, Luo J et al (2014) Young blood reverses age-related impairments in cognitive function and synaptic plasticity in mice. Nat Med 20(6):659–663CrossRefPubMedPubMedCentralGoogle Scholar
  108. 108.
    Adler AS, Sinha S, Kawahara TLA, Zhang JY, Segal E, Chang HY (2007) Motif module map reveals enforcement of aging by continual NF-κB activity. Genes Dev 21(24):3244–3257CrossRefPubMedPubMedCentralGoogle Scholar
  109. 109.
    Rossi DJ, Bryder D, Zahn JM, Ahlenius H, Sonu R, Wagers AJ et al (2005) Cell intrinsic alterations underlie hematopoietic stem cell aging. Proc Natl Acad Sci U S A 102(26):9194–9199CrossRefPubMedPubMedCentralGoogle Scholar
  110. 110.
    Wullschleger S, Loewith R, Hall MN (2006) TOR signaling in growth and metabolism. Cell 124(3):471–484CrossRefGoogle Scholar
  111. 111.
    Chen C, Liu Y, Liu R, Ikenoue T, Guan K-L, Liu Y et al (2008) TSC – mTOR maintains quiescence and function of hematopoietic stem cells by repressing mitochondrial biogenesis and reactive oxygen species. J Exp Med 205(10):2397–2408CrossRefPubMedPubMedCentralGoogle Scholar
  112. 112.
    Chen C, Liu Y, Liu Y, Zheng P (2009) mTOR regulation and therapeutic rejuvenation of aging hematopoietic stem cells. Sci Signal 2:ra75.  https://doi.org/10.1126/scisignal.2000559CrossRefPubMedPubMedCentralGoogle Scholar
  113. 113.
    Jones MJ, Goodman SJ, Kobor MS (2015) DNA methylation and healthy human aging. Aging Cell 14(6):924–932CrossRefPubMedPubMedCentralGoogle Scholar

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Authors and Affiliations

  1. 1.Belozersky Institute of Physico-Chemical BiologyLomonosov Moscow State UniversityMoscowRussia

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