Longitudinal changes in the genetic and environmental influences on the epigenetic clocks across old age

Evidence from two twin cohorts

Juulia Jylhävä, Jacob Hjelmborg, Mette Sørensen, Elizabeth Munoz, Qihua Tan, Ralf Kuja-Halkola, Jonas Mengel-From, Kaare Christensen, Lene Christiansen, Sara Hägg, Nancy L Pedersen, Chandra A Reynolds

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Abstract

Background: Measures based on DNA methylation, epigenetic clocks, have recently gained attraction as predictors of mortality and age-related pathologies. However, the origins of variation in these measures are not well understood. Methods: In a pooled sample of 104 Swedish and Danish twin pairs, we estimated, at the mean age of 70 (baseline) and 79 years (follow-up), the genetic and environmental influences on the Horvath and Levine clocks. Findings: A model incorporating additive genetic (A) and person-specific environmental (E) influences best explained the variation in both clocks. Heritability was estimated at 55% at baseline and at 51% at follow-up for the Horvath clock and 34% at baseline and 41% at follow-up for the Levine clock. For the Horvath clock, new sources of A influences emerged at follow-up, whereas for the Levine clock, the same A influences accounted for the genetic variance at both measurement occasions. The cross-time phenotypic correlations, 0·52 for the Horvath clock and 0·36 for the Levine clock, were mediated primarily by genetic factors, whereas the person-specific environmental factors were completely different at the two measurement occasions. Interpretation: For both clocks, new sources of person-specific environmental influences emerge with age. The epigenetic clocks might thus be responsive to new environmental stimuli even at old age. Fund: NIH (R01;AG04563;AG10175;AG028555) the MacArthur Foundation Research Network on Successful Aging, FAS/FORTE (97:0147:1B;2009-0795), Swedish Research Council (825-2007-7460;825-2009-6141;521-2013-8689;2015-03255;2015-06796;2018-02077), FORTE (2013-2292), the Strategic Research Program in Epidemiology at KI, VELUX FOUNDATION, NIA (P01-AG08761), the EU (FP7/2007-2011;259679) and The Danish National Program for Research Infrastructure 2007 (9-063256).

Original languageEnglish
JournalEBioMedicine
Volume40
Pages (from-to)710-716
ISSN2352-3964
DOIs
Publication statusPublished - Feb 2019

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Epigenomics
Clocks
Research
DNA Methylation
Epidemiology
Pathology
Aging of materials

Keywords

  • Aging
  • DNA methylation
  • Epigenetic clock
  • Heritability
  • Sources of variation

Cite this

@article{dfdb19657e1e47c583ca0e2ed1196e55,
title = "Longitudinal changes in the genetic and environmental influences on the epigenetic clocks across old age: Evidence from two twin cohorts",
abstract = "Background: Measures based on DNA methylation, epigenetic clocks, have recently gained attraction as predictors of mortality and age-related pathologies. However, the origins of variation in these measures are not well understood. Methods: In a pooled sample of 104 Swedish and Danish twin pairs, we estimated, at the mean age of 70 (baseline) and 79 years (follow-up), the genetic and environmental influences on the Horvath and Levine clocks. Findings: A model incorporating additive genetic (A) and person-specific environmental (E) influences best explained the variation in both clocks. Heritability was estimated at 55{\%} at baseline and at 51{\%} at follow-up for the Horvath clock and 34{\%} at baseline and 41{\%} at follow-up for the Levine clock. For the Horvath clock, new sources of A influences emerged at follow-up, whereas for the Levine clock, the same A influences accounted for the genetic variance at both measurement occasions. The cross-time phenotypic correlations, 0·52 for the Horvath clock and 0·36 for the Levine clock, were mediated primarily by genetic factors, whereas the person-specific environmental factors were completely different at the two measurement occasions. Interpretation: For both clocks, new sources of person-specific environmental influences emerge with age. The epigenetic clocks might thus be responsive to new environmental stimuli even at old age. Fund: NIH (R01;AG04563;AG10175;AG028555) the MacArthur Foundation Research Network on Successful Aging, FAS/FORTE (97:0147:1B;2009-0795), Swedish Research Council (825-2007-7460;825-2009-6141;521-2013-8689;2015-03255;2015-06796;2018-02077), FORTE (2013-2292), the Strategic Research Program in Epidemiology at KI, VELUX FOUNDATION, NIA (P01-AG08761), the EU (FP7/2007-2011;259679) and The Danish National Program for Research Infrastructure 2007 (9-063256).",
keywords = "Aging, DNA methylation, Epigenetic clock, Heritability, Sources of variation",
author = "Juulia Jylh{\"a}v{\"a} and Jacob Hjelmborg and Mette S{\o}rensen and Elizabeth Munoz and Qihua Tan and Ralf Kuja-Halkola and Jonas Mengel-From and Kaare Christensen and Lene Christiansen and Sara H{\"a}gg and Pedersen, {Nancy L} and Reynolds, {Chandra A}",
note = "Copyright {\circledC} 2019 The Authors. Published by Elsevier B.V. All rights reserved.",
year = "2019",
month = "2",
doi = "10.1016/j.ebiom.2019.01.040",
language = "English",
volume = "40",
pages = "710--716",
journal = "EBioMedicine",
issn = "2352-3964",
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Longitudinal changes in the genetic and environmental influences on the epigenetic clocks across old age : Evidence from two twin cohorts. / Jylhävä, Juulia; Hjelmborg, Jacob; Sørensen, Mette; Munoz, Elizabeth; Tan, Qihua; Kuja-Halkola, Ralf; Mengel-From, Jonas; Christensen, Kaare; Christiansen, Lene; Hägg, Sara; Pedersen, Nancy L; Reynolds, Chandra A.

In: EBioMedicine, Vol. 40, 02.2019, p. 710-716.

Research output: Contribution to journalJournal articleResearchpeer-review

TY - JOUR

T1 - Longitudinal changes in the genetic and environmental influences on the epigenetic clocks across old age

T2 - Evidence from two twin cohorts

AU - Jylhävä, Juulia

AU - Hjelmborg, Jacob

AU - Sørensen, Mette

AU - Munoz, Elizabeth

AU - Tan, Qihua

AU - Kuja-Halkola, Ralf

AU - Mengel-From, Jonas

AU - Christensen, Kaare

AU - Christiansen, Lene

AU - Hägg, Sara

AU - Pedersen, Nancy L

AU - Reynolds, Chandra A

N1 - Copyright © 2019 The Authors. Published by Elsevier B.V. All rights reserved.

PY - 2019/2

Y1 - 2019/2

N2 - Background: Measures based on DNA methylation, epigenetic clocks, have recently gained attraction as predictors of mortality and age-related pathologies. However, the origins of variation in these measures are not well understood. Methods: In a pooled sample of 104 Swedish and Danish twin pairs, we estimated, at the mean age of 70 (baseline) and 79 years (follow-up), the genetic and environmental influences on the Horvath and Levine clocks. Findings: A model incorporating additive genetic (A) and person-specific environmental (E) influences best explained the variation in both clocks. Heritability was estimated at 55% at baseline and at 51% at follow-up for the Horvath clock and 34% at baseline and 41% at follow-up for the Levine clock. For the Horvath clock, new sources of A influences emerged at follow-up, whereas for the Levine clock, the same A influences accounted for the genetic variance at both measurement occasions. The cross-time phenotypic correlations, 0·52 for the Horvath clock and 0·36 for the Levine clock, were mediated primarily by genetic factors, whereas the person-specific environmental factors were completely different at the two measurement occasions. Interpretation: For both clocks, new sources of person-specific environmental influences emerge with age. The epigenetic clocks might thus be responsive to new environmental stimuli even at old age. Fund: NIH (R01;AG04563;AG10175;AG028555) the MacArthur Foundation Research Network on Successful Aging, FAS/FORTE (97:0147:1B;2009-0795), Swedish Research Council (825-2007-7460;825-2009-6141;521-2013-8689;2015-03255;2015-06796;2018-02077), FORTE (2013-2292), the Strategic Research Program in Epidemiology at KI, VELUX FOUNDATION, NIA (P01-AG08761), the EU (FP7/2007-2011;259679) and The Danish National Program for Research Infrastructure 2007 (9-063256).

AB - Background: Measures based on DNA methylation, epigenetic clocks, have recently gained attraction as predictors of mortality and age-related pathologies. However, the origins of variation in these measures are not well understood. Methods: In a pooled sample of 104 Swedish and Danish twin pairs, we estimated, at the mean age of 70 (baseline) and 79 years (follow-up), the genetic and environmental influences on the Horvath and Levine clocks. Findings: A model incorporating additive genetic (A) and person-specific environmental (E) influences best explained the variation in both clocks. Heritability was estimated at 55% at baseline and at 51% at follow-up for the Horvath clock and 34% at baseline and 41% at follow-up for the Levine clock. For the Horvath clock, new sources of A influences emerged at follow-up, whereas for the Levine clock, the same A influences accounted for the genetic variance at both measurement occasions. The cross-time phenotypic correlations, 0·52 for the Horvath clock and 0·36 for the Levine clock, were mediated primarily by genetic factors, whereas the person-specific environmental factors were completely different at the two measurement occasions. Interpretation: For both clocks, new sources of person-specific environmental influences emerge with age. The epigenetic clocks might thus be responsive to new environmental stimuli even at old age. Fund: NIH (R01;AG04563;AG10175;AG028555) the MacArthur Foundation Research Network on Successful Aging, FAS/FORTE (97:0147:1B;2009-0795), Swedish Research Council (825-2007-7460;825-2009-6141;521-2013-8689;2015-03255;2015-06796;2018-02077), FORTE (2013-2292), the Strategic Research Program in Epidemiology at KI, VELUX FOUNDATION, NIA (P01-AG08761), the EU (FP7/2007-2011;259679) and The Danish National Program for Research Infrastructure 2007 (9-063256).

KW - Aging

KW - DNA methylation

KW - Epigenetic clock

KW - Heritability

KW - Sources of variation

U2 - 10.1016/j.ebiom.2019.01.040

DO - 10.1016/j.ebiom.2019.01.040

M3 - Journal article

VL - 40

SP - 710

EP - 716

JO - EBioMedicine

JF - EBioMedicine

SN - 2352-3964

ER -