Epigenetics of Aging and Longevity

Translational Epigenetics vol 4

Alexey Moskalev, Alexander Vaiserman, Alexey Moskalev, Alexander M. Vaiserman

• Publisher: Academic Press
• Year: 2017
• ISBN:
  9780128110836
• Topic: Medicine
• Subtopic: Genetics in Medicine

Epigenetics of Aging and Longevity provides an in-depth analysis of the epigenetic nature of aging and the role of epigenetic factors in mediating the link between early-life experiences and life-course health and aging. Chapters from leading international contributors explore the effect of adverse conditions in early-life that may result in disrupted epigenetic pathways, as well as the potential to correct these disrupted pathways via targeted therapeutic interventions. Intergenerational epigenetic inheritance, epigenetic drug discovery, and the role of epigenetic mechanisms in regulating specific age-associated illnesses—including cancer and cardiovascular, metabolic, and neurodegenerative diseases—are explored in detail.

This book will help researchers in genomic medicine, epigenetics, and biogerontology better understand the epigenetic determinants of aging and longevity, and ultimately aid in developing therapeutics to extend the human life-span and treat age-related disease.

• Offers a comprehensive overview of the epigenetic nature of aging, as well as the impact of epigenetic factors on longevity and regulating age-related disease
• Provides readers with clinical and epidemiological evidence for the role of epigenetic mechanisms in mediating the link between early-life experiences, life-course health and aging trajectory
• Applies current knowledge of epigenetic regulatory pathways towards developing therapeutic interventions for age-related diseases and extending the human lifespan

Section 1

Epigenetic Mechanisms in Aging

Outline

Chapter 1. Aging Epigenetics: Changes and Challenges

Chapter 2. Defective DNA Methylation/Demethylation Processes Define Aging-Dependent Methylation Patterns

Chapter 3. S-Adenosylmethionine Metabolism and Aging

Chapter 4. The Epigenetic Clock and Aging

Chapter 5. The Epigenetic Regulation of Telomere Maintenance in Aging

Chapter 6. Living Long and Aging Well: Are Lifestyle Factors the Epigenetic Link in the Longevity Phenotype?

Chapter 7. Epigenetic Biomarkers for Biological Age

Chapter 8. The Role of Noncoding RNAs in Genome Stability and Aging

Chapter 9. Intratissue DNA Methylation Heterogeneity in Aging

Chapter 1

Aging Epigenetics

Changes and Challenges

Duygu Ucar¹, and Bérénice A. Benayoun^{2 1}The Jackson Laboratory for Genomic Medicine, Farmington, CT, United States ²University of Southern California, Los Angeles, CA, United States

Abstract

Aging is the largest risk factor for many diseases, and the aging population is one of the fastest growing in the Western world. Therefore it has become ever more important to improve our understanding of cellular and molecular mechanisms that underlie human aging to promote healthy aging. However, this is a daunting task since aging is a complex phenomenon that manifests itself differently in different cell types, individuals, and even species with strong links to genetic and environmental drivers. In recent years, epigenetic alterations including DNA methylation, posttranslation modifications of histone proteins, chromatin structure, DNA–protein interactions, and noncoding RNA, have been established as one of the most conserved hallmarks of aging. Here, we review recent work in understanding aging-associated epigenetic changes in mammalian cells and recent advances in technology that has the potential to drive this research further—potentially to the bedside to slow down or reverse the hallmarks of aging.

Keywords

Aging; Chromatin; Epigenetics; Epigenomics; Senescence

Chapter Outline

1. Introduction

2. Epigenetic Alterations and the Aging Process

2.1 The ‘Aging Epigenome’

2.1.1 Histone Deposition and Chromatin Structure in Aging

2.1.2 DNA Methylation

2.1.3 Posttranslation Modifications of Histone Proteins

2.2 Impact of Environmental Stimuli on the Aging Epigenome

3. Significance of the Aging Epigenome

3.1 Age-Related Loss of Transcriptional Precision

3.2 Links Between Epigenetic and Genomic Instability With Age

4. The Power of Genomics: Global Versus Genome-Wide Locus-Specific Age-Related Changes

4.1 DNA-Methylation Profiling in Aged Human Cells

4.2 Lessons From Genome-Wide Profiling of Chromatin Landscape With Aging

4.3 Advances in Epigenome Profiling in Human Cells

5. Emerging Challenges in the Field of Aging Epigenomics

5.1 Toward Epigenetic Longevity Drugs?

5.2 Sex-Dimorphism and Implications

5.3 Epigenomics of Immune System Aging

5.4 The Challenges of Multiomic Data Integration and Interpretation

5.5 Accounting for Cell Intrinsic Versus Cell Composition–Derived Changes With Epigenomic Aging

6. Conclusions

List of Acronyms and Abbreviations

Glossary

Acknowledgments

References

1. Introduction

Aging corresponds to the breakdown of cellular and tissue function over time, which is associated with increased prevalence of chronic diseases (e.g., neurodegenerative and metabolic disorders, cancer), ultimately leading to death. Evidence in invertebrate model organisms and human studies support the idea that aging is regulated at the genetic level but also by nongenetic factors [1,2]. Interestingly, even the lifespan of isogenic individuals reveals large differences between the first and last death in controlled environments [3], suggesting that even small environment variations may dramatically impact aging and lifespan. A number of environmental modulators of the aging process include dietary interventions [4], upregulated stress response [5], physical exercise [6], and circadian rhythms [7].

The strictest definition of ‘epigenetics’ only covers phenotypic changes that are heritable through generations without underlying changes to the genetic material [8]. However, in the broader definition, which will be used hereafter, ‘epigenetics’ encompasses alterations at the level of chromatin that may play a significant role in regulating gene expression. In eukaryotic cells, chromatin corresponds to a nucleoproteic structural polymer, whose basic units are nucleosomes. Nucleosomes are composed of ∼150 bp DNA fragments wrapped around octamers of histone proteins, each unit containing two H2A, H2B, H3, and H4 histone proteins, which can be replaced by functional histone variants at specific loci (e.g., H2A.Z, H3.3, CENP-A) [9]. Chromatin can be found in two main states: euchromatin, a loose compartment permissive to transcription, and heterochromatin, a compact compartment that contains repressed regions of the genome. According to the ‘histone code’ hypothesis, combinations of histone posttranslational modifications are thought to modulate the accessibility and expression of underlying genes [10]. DNA methylation constitutes another layer of epigenetic regulation, the most well-studied type of which occurs in ‘CpG’ dinucleotides [11]. A final key layer of epigenetic regulation is attained through modulation of nucleosome positioning by ATP-dependent chromatin remodelers (e.g., SWI/SNF), which impacts regulatory sequence accessibility and higher-order chromatin compaction [12]. Several classes of noncoding RNAs (i.e., miRNAs, circRNAs, and lncRNAs) have been found to be able to modify transcriptional regulation and sometimes impact the chromatin landscape [13–15].

Epigenetic alterations are considered one of the hallmarks (pillars) of the aging process [16,17], a role supported by many changes to chromatin marks throughout life and by the impact of interference with chromatin regulatory complexes on the lifespan of model organisms [18–20,209]. Interestingly, accumulating evidence suggests that age-related epigenomic changes may interact with other hallmarks of aging, such as genome instability or loss of protein homeostasis [19]. Emerging evidence suggests that specific species of these ncRNA may become misregulated with aging [22–25] and may even partially drive aging or age-related diseases phenotypes [22,25,26]. In this review, we will focus on the potential impact and changes in DNA and histone modifications throughout aging.

To this date, most of the knowledge of chromatin regulation remodeling with age has relied on global assessment of changes. Only a few studies have attempted to interrogate genome-wide locus-specific epigenomic changes with aging, with the exception of DNA methylation studies. Understanding the global and locus-specific epigenomic changes that accumulate during aging, identifying corresponding molecular regulators of health and lifespan, will be crucial to eventually increase healthy youthful years of life, and potentially reverse some aspects of aging.

2. Epigenetic Alterations and the Aging Process

2.1. The ‘Aging Epigenome’

The pervasiveness of age-related alterations in chromatin regulation across cell types and species is now well documented (recently reviewed in Refs. [18–21]). These epigenomic alterations are t...