title: Frailty is associated with the epigenetic clock but not with telomere length in a German cohort.
abstract: BACKGROUND
  The epigenetic clock, in particular epigenetic pre-aging quantified by the so-called DNA methylation age acceleration, has recently been suggested to closely correlate with a variety of disease phenotypes. There remains a dearth of data, however, on its association with telomere length and frailty, which can be considered major correlates of age on the genomic and clinical level, respectively.
  
  
  RESULTS
  In this cross-sectional observational study on altogether 1820 subjects from two subsets (n = 969 and n = 851; mean ± standard deviation age 62.1 ± 6.5 and 63.0 ± 6.7 years, respectively) of the ESTHER cohort study of the elderly general population in Germany, DNA methylation age was calculated based on a 353 loci predictor previously developed in a large meta-study, and the difference-based epigenetic age acceleration was calculated as predicted methylation age minus chronological age. No correlation of epigenetic age acceleration with telomere length was found in our study (p = 0.63). However, there was an association of DNA methylation age acceleration with a comprehensive frailty measure, such that the accumulated deficits significantly increased with increasing age acceleration. Quantitatively, about half an additional deficit was added per 6 years of methylation age acceleration (p = 0.0004). This association was independent from age, sex, and estimated leukocyte distribution, as well as from a variety of other confounding variables considered.
  
  
  CONCLUSIONS
  The results of the present study suggest that epigenetic age acceleration is correlated with clinically relevant aging-related phenotypes through pathways unrelated to cellular senescence as assessed by telomere length. Innovative approaches like Mendelian randomization will be needed to elucidate whether epigenetic age acceleration indeed plays a causal role for the development of clinical phenotypes.
authors.affiliation: German Cancer Research Center (DKFZ), Division of Clinical Epidemiology and Aging Research, 69120 Heidelberg, Germany.
authors.forename: Lutz Philipp
authors.initials: LP
authors.lastname: Breitling
authors.affiliation: German Cancer Research Center (DKFZ), Division of Clinical Epidemiology and Aging Research, 69120 Heidelberg, Germany.
authors.forename: Kai-Uwe
authors.initials: KU
authors.lastname: Saum
authors.affiliation: German Cancer Research Center (DKFZ), Division of Clinical Epidemiology and Aging Research, 69120 Heidelberg, Germany.
authors.forename: Laura
authors.initials: L
authors.lastname: Perna
authors.affiliation: German Cancer Research Center (DKFZ), Division of Clinical Epidemiology and Aging Research, 69120 Heidelberg, Germany ; Network Aging Research, University of Heidelberg, Heidelberg, Germany.
authors.forename: Ben
authors.initials: B
authors.lastname: Schöttker
authors.affiliation: Epidemiological Cancer Registry of Saarland, Saarbrücken, Germany.
authors.forename: Bernd
authors.initials: B
authors.lastname: Holleczek
authors.affiliation: German Cancer Research Center (DKFZ), Division of Clinical Epidemiology and Aging Research, 69120 Heidelberg, Germany ; Network Aging Research, University of Heidelberg, Heidelberg, Germany.
authors.forename: Hermann
authors.initials: H
authors.lastname: Brenner
mesh_terms: D000368:Aged; D000375:Aging / Q000235:genetics; D019588:Aging, Premature / Q000235:genetics; D003430:Cross-Sectional Studies; D019175:DNA Methylation; D044127:Epigenesis, Genetic; D005260:Female; D016330:Frail Elderly / Q000706:statistics & numerical data; D005858:Germany / Q000453:epidemiology; D006801:Humans; D008297:Male; D008875:Middle Aged; D059506:Telomere Shortening
keywords: CpG methylation; Cross-sectional study; Epigenetic age acceleration; Frailty index; General population; Telomere length