Accelerated epigenetic aging in Werner syndrome.

Thomas Haaf,Julia Flunkert,George M. Martin,Anna Maierhofer,Junko Oshima,Steve Horvath

doi:10.18632/aging.101217

Thomas Haaf, Julia Flunkert + Show 4 more

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https://doi.org/10.18632/aging.101217

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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.

Highlights

Werner syndrome (WS, OMIM: 277700) is an autosomal recessive progeroid syndrome characterized by the appearance of multiple features of aging beginning in early adulthood
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
This study shows that WS is associated with an increased epigenetic age of blood cells which is independent of changes in blood cell composition

Summary

Introduction

Werner syndrome (WS, OMIM: 277700) is an autosomal recessive progeroid syndrome characterized by the appearance of multiple features of aging beginning in early adulthood. Several recent studies have proposed to measure the physiological age of tissue samples by combining the DNA methylation levels of multiple dinucleotide markers, known as Cytosine phosphate Guanines or CpGs [3,4,5,6,7]. The “Epigenetic Clock” was developed to measure the age of sorted human cell types (CD4+ T cells or neurons), all tissues, and organs including blood, brain, breast, kidney, liver, and lung [6]. The utility of the epigenetic clock method using various tissues and organs has been demonstrated in studies of Alzheimer's disease [16], centenarian status [10, 17], Down syndrome [18], HIV infection [19], Huntington's disease [20], obesity [21], lifetime stress [22], menopause [23], osteoarthritis [24], and Parkinson's disease [25]. Despite many diverse applications of the epigenetic clock, we are not aware of any studies that have analyzed epigenetic aging rates in WS

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