The Epigenetics of Aging: Exploring Biomarkers and the Interplay Within the Aging Epigenome Open Access

Grant, Crystal (Spring 2020)

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The process of aging is poorly understood yet age remains the main predictor of physiological decline and disease development in humans. Aging is marked by widespread, reproducible changes to the epigenome. The most studied epigenetic modification is DNA methylation (DNAm), which shows robust, genome-wide changes with age. These DNAm changes have been used to construct highly accurate blood-based models of chronological age. Using these models, it was found that individuals with a predicted DNAm age higher than their actual chronological age are at increased risk of all-cause mortality. This measure, termed the participants’ epigenetic age acceleration, may then serve as a proxy for some measures of health. First, I present a study of how this age acceleration term contributes to longitudinal models of phenotypes associated with Type II Diabetes (T2D)—an age-related disease. I found that this epigenetic age acceleration term remained stable over the 16 years the participants were sampled, and that this term does associate with risk factors for T2D. Our results suggest that DNAm has the potential to act as a mediator between aging and diabetes-related phenotypes, or alternatively, that it may serve as a biomarker of these phenotypes. Next, I present work that aimed to uncover how variability in DNAm with age may be useful in modeling risk for developing adverse age-related phenotypes. I identified age-related variably methylated cytosines, then used these sites to construct a score indicating the amount of epigenetic drift an individual was undergoing. Though this score did not appear to contribute significantly to longitudinal models of aging phenotypes or mortality risk, other biomarkers that incorporate information about DNAm variability maybe be informative. Lastly, looking to other levels of the epigenome as part of a pilot study, I characterized changes in chromatin accessibility and three histone modifications with age. This led to the identification of regions of age-related change as well as the observation of which histone modifications can be informative in future aging studies. My dissertation work sheds light on which types of epigenetic changes can be used to inform biomarkers of biological aging, informing future studies of the epigenetics of aging. 

Table of Contents

Chapter I: Introduction 1

Epidemiology of Aging 1

Biomarkers of Aging 3

Epigenetics 5

Linear DNA Methylation Changes With Age 12

Changes in DNA Methylation Variability With Age 16

Chromatin, Histone Modifications, Gene Expression Changes With Age 19

Objectives 22

Chapter II: A longitudinal study of DNA methylation as a potential mediator of age-related diabetes risk 25

Abstract 26

Introduction 27

Methods 31

Results 38

Discussion 43

Conclusions 47

Tables and Figures 48

Chapter III: Modeling the impact of age-related epigenetic variability on aging-related phenotypes 67

Abstract 68

Introduction 69

Methods 71

Results 80

Discussion 86

Tables and Figures 88

Chapter IV: Profiling Chromatin Accessibility and Histone Modification Changes in Aging: An Integrative Approach 103

Abstract 104

Introduction 105

Results 108

Discussion 112

Methods 115

Tables and Figures 120

Chapter V: Discussion 142

Epigenetic Biomarkers of Aging Show Promise 142

Considerations for Populations Included in Future Epigenetics Studies 143

Future Directions for Biomarkers of Aging 147

Conclusions 149

References 151

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