title: Accelerated epigenetic aging in Werner syndrome.
abstract: Individuals suffering from Werner syndrome (WS) exhibit many clinical signs of accelerated aging. While the underlying constitutional mutation leads to accelerated rates of DNA damage, it is not yet known whether WS is also associated with an increased epigenetic age according to a DNA methylation based biomarker of aging (the "Epigenetic Clock"). Using whole blood methylation data from 18 WS cases and 18 age matched controls, we find that WS is associated with increased extrinsic epigenetic age acceleration (p=0.0072) and intrinsic epigenetic age acceleration (p=0.04), the latter of which is independent of age-related changes in the composition of peripheral blood cells. A multivariate model analysis reveals that WS is associated with an increase in DNA methylation age (on average 6.4 years, p=0.011) even after adjusting for chronological age, gender, and blood cell counts. Further, WS might be associated with a reduction in naïve CD8+ T cells (p=0.025) according to imputed measures of blood cell counts. Overall, this study shows that WS is associated with an increased epigenetic age of blood cells which is independent of changes in blood cell composition. The extent to which this alteration is a cause or effect of WS disease phenotypes remains unknown.
authors.affiliation: Institute of Human Genetics, Julius Maximilians University, Würzburg, Germany.
authors.forename: Anna
authors.initials: A
authors.lastname: Maierhofer
authors.affiliation: Institute of Human Genetics, Julius Maximilians University, Würzburg, Germany.
authors.forename: Julia
authors.initials: J
authors.lastname: Flunkert
authors.affiliation: Department of Pathology, University of Washington, Seattle, WA 98105, USA.|Department of Clinical Cell Biology and Medicine, Graduate School of Medicine, Chiba University, Chiba, Japan.
authors.forename: Junko
authors.initials: J
authors.lastname: Oshima
authors.affiliation: Department of Pathology, University of Washington, Seattle, WA 98105, USA.
authors.forename: George M
authors.initials: GM
authors.lastname: Martin
authors.affiliation: Institute of Human Genetics, Julius Maximilians University, Würzburg, Germany.|Joint last authors.
authors.forename: Thomas
authors.initials: T
authors.lastname: Haaf
authors.affiliation: Department of Human Genetics, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA 90095, USA.|Department of Biostatistics, Fielding School of Public Health, University of California Los Angeles, Los Angeles, CA 90095, USA.|Joint last authors.
authors.forename: Steve
authors.initials: S
authors.lastname: Horvath
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000375:Aging; D019588:Aging, Premature / Q000235:genetics*; D015415:Biomarkers; D001772:Blood Cell Count; D001773:Blood Cells / Q000648:ultrastructure; D018414:CD8-Positive T-Lymphocytes; D004249:DNA Damage; D019175:DNA Methylation; D044127:Epigenesis, Genetic; D005260:Female; D006801:Humans; D018655:Lymphocyte Count; D008297:Male; D008875:Middle Aged; D012727:Sex Characteristics; D014898:Werner Syndrome / Q000235:genetics*
chemical_list: D015415:Biomarkers
keywords: DNA methylation; Werner syndrome; epigenetic clock; epigenetics; progeria