Early-Life Adjustment of Epigenetic Aging Clock

  • Alexander VaisermanEmail author
  • Oleh Lushchak
Part of the Healthy Ageing and Longevity book series (HAL, volume 9)


There is accumulating evidence that adult-life health status and rate of age-associated functional decline may be programmed early in life. The key role of epigenetic mechanisms in mediating these life-long effects, including DNA methylation histone modification and regulation by non-coding RNAs, has been demonstrated. Early-life environmental conditions were repeatedly shown to significantly affect life-course change of epigenetic patterns known as “epigenetic drift”. Epigenetic drift may arise following both stochastic errors in maintaining epigenetic marks and adaptive changes directly mediated by specific environmental cues. Recently, DNA methylation-based methods for determining rate of epigenetic aging were developed. Recent cohort studies using these methods have shown that ticking rate of epigenetic aging clock can be adjusted in early life, and that life-course dynamics of individual discrepancies between chronological and epigenetic age might be developmentally programmed. In this chapter, recent evidence suggestive of developmental programming of life-course dynamics of epigenetic drift is reviewed and discussed.


Developmental programming DNA methylation Aging-associated disorder Aging rate Epigenetic aging clock Epigenetic drift 


  1. Ambeskovic M, Roseboom TJ, Metz GAS (2018) Transgenerational effects of early environmental insults on aging and disease incidence. Neurosci Biobehav Rev.
  2. Bateson P, Gluckman P, Hanson M (2014) The biology of developmental plasticity and the predictive adaptive response hypothesis. J Physiol 592:2357–2368. Scholar
  3. Bianco-Miotto T, Craig JM, Gasser YP, van Dijk SJ, Ozanne SE (2017) Epigenetics and DOHaD: from basics to birth and beyond. J Dev Orig Health Dis 11:1–7. Scholar
  4. Binder AM, Corvalan C, Mericq V, Pereira A, Santos JL, Horvath S et al (2018) Faster ticking rate of the epigenetic clock is associated with faster pubertal development in girls. Epigenetics 13:85–94. Scholar
  5. Bleker LS, de Rooij SR, Painter RC, van der Velde N, Roseboom TJ (2016) Prenatal undernutrition and physical function and frailty at the age of 68 years: the Dutch Famine Birth Cohort Study. J Gerontol A Biol Sci Med Sci 71(10):1306–1314. Scholar
  6. Bloomfield SF, Rook GA, Scott EA, Shanahan F, Stanwell-Smith R, Turner P (2016) Time to abandon the hygiene hypothesis: new perspectives on allergic disease, the human microbiome, infectious disease prevention and the role of targeted hygiene. Perspect Public Health 136:213–224. Scholar
  7. Burns SB, Szyszkowicz JK, Luheshi GN, Lutz PE, Turecki G (2018) Plasticity of the epigenome during early-life stress. Semin Cell Dev Biol 77:115–132. Scholar
  8. Chen M, Baumbach J, Vandin F, Röttger R, Barbosa E, Dong M et al (2016) Differentially methylated genomic regions in birth-weight discordant twin pairs. Ann Hum Genet 80(2):81–87. Scholar
  9. Cortessis VK, Thomas DC, Levine AJ, Breton CV, Mack TM, Siegmund KD et al (2012) Environmental epigenetics: prospects for studying epigenetic mediation of exposure-response relationships. Hum Genet 131(10):1565–1589. Scholar
  10. Cunliffe VT (2015) Experience-sensitive epigenetic mechanisms, developmental plasticity, and the biological embedding of chronic disease risk. Wiley Interdiscip Rev Syst Biol Med 7(2):53–71. Scholar
  11. Feinberg AP, Koldobskiy MA, Göndör A (2016) Epigenetic modulators, modifiers and mediators in cancer aetiology and progression. Nat Rev Genet 17:284–299. Scholar
  12. Finer S, Iqbal MS, Lowe R, Ogunkolade BW, Pervin S, Mathews C et al (2016) Is famine exposure during developmental life in rural Bangladesh associated with a metabolic and epigenetic signature in young adulthood? A historical cohort study. BMJ Open 6(11):e011768. Scholar
  13. 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 USA 102:10604–10609. Scholar
  14. Fulop T, Larbi A, Dupuis G, Le Page A, Frost EH, Cohen AA et al (2018) Immunosenescence and inflamm-aging as two sides of the same coin: friends or foes? Front Immunol 8:1960. Scholar
  15. Garmendia ML, Corvalan C, Uauy R (2014) Assessing the public health impact of developmental origins of health and disease (DOHaD) nutrition interventions. Ann Nutr Metab 64:226–230. Scholar
  16. Godfrey KM, Lillycrop KA, Burdge GC, Gluckman PD, Hanson MA (2007) Epigenetic mechanisms and the mismatch concept of the developmental origins of health and disease. Pediatr Res 61:5R–10R. Scholar
  17. Gordon L, Joo JH, Andronikos R, Ollikainen M, Wallace EM, Umstad MP et al (2011) Expression discordance of monozygotic twins at birth: effect of intrauterine environment and a possible mechanism for fetal programming. Epigenetics 6(5):579–592CrossRefGoogle Scholar
  18. Gravina S, Vijg J (2010) Epigenetic factors in aging and longevity. Pflugers Arch 459:247–258. Scholar
  19. Greer EL, Maures TJ, Hauswirth AG, Green EM, Leeman DS, Maro GS et al (2010) Members of the H3K4 trimethylation complex regulate lifespan in a germline-dependent manner in C. elegans. Nature 466:383–387. Scholar
  20. Greer EL, Maures TJ, Ucar D, Hauswirth AG, Mancini E, Lim JP et al (2011) Transgenerational epigenetic inheritance of longevity in Caenorhabditis elegans. Nature 479:365–373. Scholar
  21. Greer EL, Becker B, Latza C, Antebi A, Shi Y (2016) Mutation of C. elegans demethylase spr-5 extends transgenerational longevity. Cell Res 26:229–238. Scholar
  22. Grolleau-Julius A, Ray D, Yung RL (2010) The role of epigenetics in aging and autoimmunity. Clin Rev Allergy Immunol 39:42–50. Scholar
  23. Heijmans BT, Tobi EW, Stein AD, Putter H, Blauw GJ, Susser ES et al (2008) Persistent epigenetic differences associated with prenatal exposure to famine in humans. Proc Natl Acad Sci USA 105:17046–17049. Scholar
  24. Heo HJ, Tozour JN, Delahaye F, Zhao Y, Cui L, Barzilai N et al (2016) Advanced aging phenotype is revealed by epigenetic modifications in rat liver after in utero malnutrition. Aging Cell 15:964–972. Scholar
  25. Hochberg Z, Feil R, Constancia M, Fraga M, Junien C, Carel JC et al (2011) Child health, developmental plasticity, and epigenetic programming. Endocr Rev 32:159–224. Scholar
  26. Holliday R (1987) The inheritance of epigenetic defects. Science 238:163–170CrossRefGoogle Scholar
  27. Horvath S (2013) DNA methylation age of human tissues and cell types. Genome Biol 14:R115. Scholar
  28. Horvath S, Raj K (2018) DNA methylation-based biomarkers and the epigenetic clock theory of ageing. Nat Rev Genet 19(6):371–384. Scholar
  29. Iurlaro M, von Meyenn F, Reik W (2017) DNA methylation homeostasis in human and mouse development. Curr Opin Genet Dev 43:101–109. Scholar
  30. Jasiulionis MG (2018) Abnormal epigenetic regulation of immune system during aging. Front Immunol 9:197. Scholar
  31. Jung M, Pfeifer GP (2015) Aging and DNA methylation. BMC Biol 13:7. Scholar
  32. 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(3):65. Scholar
  33. Kishimoto S, Uno M, Okabe E, Nono M, Nishida E (2017) Environmental stresses induce transgenerationally inheritable survival advantages via germline-to-soma communication in Caenorhabditis elegans. Nat Commun 8:14031. Scholar
  34. Kramer A, Bekeschus S, Bröker BM, Schleibinger H, Razavi B, Assadian O (2013) Maintaining health by balancing microbial exposure and prevention of infection: the hygiene hypothesis versus the hypothesis of early immune challenge. J Hosp Infect 83:S29–34. Scholar
  35. Last JM (ed) (1995) A dictionary of epidemiology, 3rd edn. Oxford University Press, New YorkGoogle Scholar
  36. 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):573–591. Scholar
  37. Li Y, Tollefsbol TO (2016) Age-related epigenetic drift and phenotypic plasticity loss: implications in prevention of age-related human diseases. Epigenomics 8:1637–1651. Scholar
  38. Li S, Wong EM, Dugué PA, McRae AF, Kim E, Joo JE et al (2018) Genome-wide average DNA methylation is determined in utero. Int J Epidemiol. Scholar
  39. Lumey LH, Stein AD, Kahn HS, van der Pal-de Bruin KM, Blauw GJ, Zybert PA et al (2007) Cohort profile: the Dutch Hunger Winter families study. Int J Epidemiol 36(6):1196–1204. Scholar
  40. Lumey LH, Stein AD, Susser E (2011) Prenatal famine and adult health. Annu Rev Public Health 32:237–262. Scholar
  41. Lumey LH, Terry MB, Delgado-Cruzata L, Liao Y, Wang Q, Susser E et al (2012) Adult global DNA methylation in relation to pre-natal nutrition. Int J Epidemiol 41:116–123. Scholar
  42. Maia Rda R, Wünsch Filho V (2013) Infection and childhood leukemia: review of evidence. Rev Saude Publica 47:1172–1185. Scholar
  43. Marioni RE, Suderman M, Chen BH, Horvath S, Bandinelli S, Morris T et al (2018) Tracking the epigenetic clock across the human life course: a meta-analysis of longitudinal cohort data. J Gerontol A Biol Sci Med Sci. Scholar
  44. 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. Scholar
  45. Mendelsohn AR, Larrick JW (2017) Epigenetic drift is a determinant of mammalian lifespan. Rejuvenation Res 20:430–436. Scholar
  46. Merkwirth C, Jovaisaite V, Durieux J, Matilainen O, Jordan SD, Quiros PM et al (2016) Two conserved histone demethylases regulate mitochondrial stress-induced longevity. Cell 165:1209–1223. Scholar
  47. Roseboom TJ, Painter RC, van Abeelen AF, Veenendaal MV, de Rooij SR (2011) Hungry in the womb: what are the consequences? Lessons from the Dutch famine. Maturitas 70(2):141–145. Scholar
  48. Simpkin AJ, Hemani G, Suderman M, Gaunt TR, Lyttleton O, Mcardle WL et al (2016) Prenatal and early life influences on epigenetic age in children: a study of mother-offspring pairs from two cohort studies. Hum Mol Genet 25:191–201. Scholar
  49. Simpkin AJ, Howe LD, Tilling K, Gaunt TR, Lyttleton O, McArdle WL et al (2017) The epigenetic clock and physical development during childhood and adolescence: longitudinal analysis from a UK birth cohort. Int J Epidemiol 46:549–558. Scholar
  50. Souren NY, Lutsik P, Gasparoni G, Tierling S, Gries J, Riemenschneider M et al (2013) Adult monozygotic twins discordant for intra-uterine growth have indistinguishable genome-wide DNA methylation profiles. Genome Biol 14(5):R44. Scholar
  51. Strachan DP (1989) Hay fever, hygiene, and household size. BMJ 299:1259–1260CrossRefGoogle Scholar
  52. Tan Q, Frost M, Heijmans BT, von Bornemann Hjelmborg J, Tobi EW, Christensen K et al (2014) Epigenetic signature of birth weight discordance in adult twins. BMC Genom 15:1062. Scholar
  53. Tarry-Adkins JL, Ozanne SE (2014) The impact of early nutrition on the ageing trajectory. Proc Nutr Soc 73(2):289–301. Scholar
  54. Tarry-Adkins JL, Ozanne SE (2017) Nutrition in early life and age-associated diseases. Ageing Res Rev 39:96–105. Scholar
  55. Tobi EW, Lumey LH, Talens RP, Kremer D, Putter H, Stein AD et al (2009) DNA methylation differences after exposure to prenatal famine are common and timing- and sex-specific. Hum Mol Genet 18:4046–4053. Scholar
  56. Tobi EW, Goeman JJ, Monajemi R, Gu H, Putter H, Zhang Y et al (2014) DNA methylation signatures link prenatal famine exposure to growth and metabolism. Nat Commun 5:5592. Scholar
  57. Tobi EW, Slieker RC, Stein AD, Suchiman HE, Slagboom PE, van Zwet EW et al (2015) Early gestation as the critical time-window for changes in the prenatal environment to affect the adult human blood methylome. Int J Epidemiol 44(4):1211–1223. Scholar
  58. Tobi EW, Slieker RC, Luijk R, Dekkers KF, Stein AD, Xu KM et al (2018) DNA methylation as a mediator of the association between prenatal adversity and risk factors for metabolic disease in adulthood. Sci Adv 4(1):eaao4364. Scholar
  59. Tsai PC, Van Dongen J, Tan Q, Willemsen G, Christiansen L, Boomsma DI et al (2015) DNA Methylation changes in the IGF1R gene in birth weight discordant adult monozygotic twins. Twin Res Hum Genet 18(6):635–646. Scholar
  60. Vaiserman AM (2008) Epigenetic engineering and its possible role in anti-aging intervention. Rejuvenation Res 11:39–42. Scholar
  61. Vaiserman AM (2010) Hormesis, adaptive epigenetic reorganization, and implications for human health and longevity. Dose Response 8:16–21. Scholar
  62. Vaiserman AM (2014) Early-life nutritional programming of longevity. J Dev Orig Health Dis 5(5):325–338. Scholar
  63. Vaiserman A (2015) Epidemiologic evidence for association between adverse environmental exposures in early life and epigenetic variation: a potential link to disease susceptibility? Clin Epigenetics 7:96. Scholar
  64. Vaiserman A, Koliada A, Lushchak O (2018) Developmental programming of aging trajectory. Ageing Res Rev 47:105–122. Scholar
  65. van Abeelen AF, Veenendaal MV, Painter RC, de Rooij SR, Dijkgraaf MG, Bossuyt PM et al (2012) Survival effects of prenatal famine exposure. Am J Clin Nutr 95(1):179–183. Scholar
  66. Xia B, de Belle JS (2016) Transgenerational programming of longevity and reproduction by post-eclosion dietary manipulation in Drosophila. Aging (Albany NY) 8:1115–1134. Scholar
  67. Xia B, Gerstin E, Schones DE, Huang W, Steven de Belle J (2016) Transgenerational programming of longevity through E(z)-mediated histone H3K27 trimethylation in Drosophila. Aging (Albany NY) 8:2988–3008. Scholar
  68. Yashin AI, Ukraintseva SV, De Benedictis G, Anisimov VN, Butov AA, Arbeev K et al (2001) Have the oldest old adults ever been frail in the past? A hypothesis that explains modern trends in survival. J Gerontol A Biol Sci Med Sci 56:B432–B442CrossRefGoogle Scholar

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© Springer Nature Switzerland AG 2019

Authors and Affiliations

  1. 1.Laboratory of EpigeneticsChebotarev Institute of GerontologyKievUkraine
  2. 2.Department of Biochemistry and BiotechnologyVasyl Stefanyk Precarpathian National UniversityIvano-FrankivskUkraine

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