Longitudinal changes in the genetic and environmental influences on the epigenetic clocks across old age: Evidence from two twin cohortsResearch in context

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: Epigenetic clock, DNA methylation, Aging, Heritability, Sources of variatio