Epigenetics of Aging and Age-Related Disorders

Epigenetics of Aging and Age-Related Disorders

C H A P T E R 36 Epigenetics of Aging and Age-Related Disorders Corinne Sidler, Olga Kovalchuk, and Igor Kovalchuk Department of Biological Sciences,...

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C H A P T E R

36 Epigenetics of Aging and Age-Related Disorders Corinne Sidler, Olga Kovalchuk, and Igor Kovalchuk Department of Biological Sciences, University of Lethbridge, Lethbridge, AB, Canada

36.1 INTRODUCTION Aging is a major risk factor for several morbidities including cancer, cardiovascular disease, and autoimmune disease. It is associated with the body’s altered capacity to cope with stress induced by metabolism, infection, and damage to cellular macromolecules. Understanding the molecular mechanisms that advance aging will help scientists to understand why aging individuals are more prone to diseases and why they may be less stress resistant. Cells in an aging body exhibit large differences from cells in a juvenile organism; these differences include changes in gene expression and DNA methylation patterns,1 shortening telomeres,2 and deteriorating genome maintenance.3 At the tissue, organ, and systemic levels, cells are exposed to altered stromal milieus caused by altered secretory profiles of senescent cells4 and a deteriorating immune system that is not able to mount immune responses toward new antigens equal to that of a younger immune system.5 In addition to the external environment of cells, the composition of tissues changes with age, ranging from altered proportions of cell types, such as an increase in adipose and connective tissue along with a reduction in muscle fibers in aging muscles, to changes in the shape and size of cells, such as the enlargement of myocytes in the heart. It becomes apparent that aging is a very complex process that occurs in many different cell types, tissues, and organs in parallel, and as they cooperate to provide function to organs, organ systems, and organisms, the deterioration of one system affects the function of other tissues. Thus studying how organisms age is challenging and requires various complex approaches, as will be outlined in this chapter. The functional decline of organ systems, such as the loss of muscle mass, aging of the immune system, and reduced tissue regeneration, predisposes aging individuals to a variety of age-related disorders, including cardiovascular diseases, higher susceptibility to infections, cancer, frailty, loss of hearing and vision. As populations get older this poses a problem for health care systems. Therefore, gaining a better mechanistic understanding of the causes and risk factors for these age-related disorders is a priority. In recent years epigenetic mechanisms have been increasingly recognized as playing important roles in health and disease. In addition, age-dependent changes in epigenetic regulation have been observed, indicating that epigenetic regulation may play an important role in aging. The following sections will examine the role of epigenetic regulation in aging and age-related disorders.

36.1.1 Models and Molecular Mechanisms Aging is characterized by the functional decline of an organism and its increased chance of death at any time. This is a very conserved phenomenon that occurs in unicellular organisms like budding yeast, multicellular eukaryotic organisms like Caenorhabditis elegans, and mammals alike. Therefore, scientists have been studying these various model systems for decades in an attempt to discover the molecular reasons for aging. The various model systems offer different benefits to research on aging: short-lived species are useful for the study of genetic mutations or pharmacological interventions that modify their life span, whereas model systems that exhibit the functional decline of specific organ systems are useful as models to study the causes and consequences of functional decline.6 Therefore, research on aging has traditionally followed these major directions. Model organisms such as budding yeast and the roundworm C. elegans have extensively been used to determine genes that, when mutated or silenced, modify life span. Such studies have

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TABLE 36.1

Mechanisms Affecting Aging

Level of change

Type of change

Cellular level

Deterioration of DNA repair and accumulation of DNA damage Telomere shortening Changes in protein homeostasis Mitochondrial dysfunction and oxidative stress Changes in epigenetic regulation

Cellular and tissue level

Nutrient sensing and signaling

Cellular and organismal level

Exhaustion of stem cells Chronic inflammation

Aging may be caused by various mechanisms at all levels from cellular to organismal.

resulted in a vast amount of data supporting the roles of insulin signaling, mitochondrial function, protein metabolism, and other processes in limiting life span.7 On the other hand, Drosophila, mice, and rats have proven to be valuable model organisms that can be used to seek a better understanding of the age-dependent functional decline of the immune system, neurocognitive functions, and the development of age-related pathologies. When considering aging at the level of the cell the most commonly used model system is the cellular senescence model, a model describing the analysis of mechanisms of terminal growth arrest of a cell. Normal human diploid cells have a finite life span after which they terminally exit the cell cycle.8 Several studies have shown that senescent cells accumulate in aging tissues in vivo.9, 10 However, the role that senescence may play in aging most likely depends on the cells or cell types undergoing senescence. While senescence is a feature of differentiated cells in most organs, the senescence of stem cells that are responsible for tissue renewal and repair is likely detrimental to the function of the tissue.11 Decreasing functionality of stem cells with age is observed, but it is still unclear whether this is due to stem cell aging or a result of the changing environment for stem cells within aging tissue.12 A recent study supports an active role of stem cell aging in age-dependent functional decline by showing that adult quiescent muscle stem cells switch to irreversible senescence in muscles of geriatric mice.13 Thus while senescent cells accumulate in the tissues of aging individuals, the involvement of senescence in aging seems to be dependent on the affected cell types and tissues. All these approaches have identified several mechanisms that affect aging, including telomere shortening, nutrient sensing and signaling (caloric restriction, and mutations in related signaling pathways, such as IGF1 and insulin signaling), TOR signaling that leads to increased life spans in several model organisms, mitochondrial dysfunction, and oxidative stress (which by causing damage to macromolecules of the cell may promote aging; on the other hand, mild mitochondrial dysfunction has also been linked to life span extension in lower organisms through an adaptive response termed mitohormesis), deterioration of DNA repair and accumulation of DNA damage, changes in protein homeostasis leading to the accumulation and aggregation of misfolded proteins, and changes in epigenetic regulation (Table 36.1).

36.2 EPIGENETICS OF AGING Over the past decade epigenetic mechanisms, including DNA methylation, histone modifications, and regulation of gene expression by noncoding RNAs, as well as miRNAs, have increasingly been recognized for playing roles in health and disease.14–16

36.2.1 DNA Methylation and Aging DNA methylation, which mainly affects cytosines in a CpG context in tissues of the adult human body, is a comparatively stable epigenetic mechanism. Methylation marks are introduced and maintained through replication and repair cycles by DNA methyltransferases (DNMTs), and can be actively or passively removed by failure of maintenance through several oxidation steps mediated by ten–eleven translocation (TET) enzymes17 or through deamination. DNA methylation in regions of repetitive DNA elements, including telomeres,18 centromeric DNA,19 and transposable elements,20 limits recombination and thus promotes genomic stability. In addition, DNA methylation affects transcriptional regulation both directly and indirectly: methylated CpGs within CpG islands in promoter regions of genes

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873 FIG. 36.1 DNA methylation changes in aging. DNA methylation changes in aging cells consist of global hypomethylation and site-specific hypermethylation within CpG islands and polycomb target sites that occur in many different tissues; and site-specific hypomethylation in gene-poor regions, in tissue-specific promoters, in regions associated with polycomb proteins, and in regions associated with activating histone marks that are typically tissue specific.

repress transcription of the associated gene; the imprinted loci of whole-genomic regions are methylated to ensure monoallelic expression of imprinted genes; and more globally DNA methylation patterns affect chromatin structure at the local to long range by affecting lamina attachment21 as well as nucleosome positioning and histone modification.22 Several trends in age-dependent changes in DNA methylation patterns have been observed (Fig. 36.1): (1) Global reduction in DNA methylation.22, 23 (2) Site-specific hypermethylation, preferentially within CpG islands and polycomb target sites.22–24 (3) Site-specific hypomethylation, preferentially in gene-poor regions, tissue-specific promoters, and regions associated with polycomb proteins or activating histone marks.22, 23, 25 (4) Hypermethylation observed in different tissues, while hypomethylation appears to be more tissue specific.25 These changes accumulate gradually. For instance, in the Heyn et al. study a 26-year-old showed a global DNA methylation pattern intermediate between those of a newborn and a centenarian.1 Such gradual changes result in increasingly dissimilar methylomes between individuals with increasing age,26, 27 termed the “epigenetic clock.” Gradual changes in DNA methylation may be influenced by a variety of internal and external factors, resulting in different changes in DNA methylation, as observed in monozygous twins. In a specific case, one twin accumulated ageassociated changes at a faster rate than the other twin, also showing evidence of faster aging.26 Such a discrepancy in the rate of accumulation of age-dependent changes in methylation (slower or faster) is often referred to as “epigenetic drift.” Hannum et al. have further shown that increased epigenetic drift is associated with increased rate of aging.27 On the other hand, sets of differentially methylated regions (DMRs) have been identified that show very robust ageassociated changes, the methylation status of which allows for relatively precise age prediction,25, 27 prompting formulation of an epigenetic clock model. Horvath’s bioinformatic analysis of 82 available Illumina DNA methylation array data sets identified 353 differentially methylated CpG sites that predicted age very robustly, independent of tissue identity. According to his model, DNA methylomes of cells from progeria patients predict ages higher than the biological age of patients, highlighting the model’s promise.25 Age-associated methylation changes affecting specific loci had already been studied before massive sequencing screens were feasible. For instance, senescence-associated heterochromatin foci are formed specifically at E2F target genes, resulting in the repression of proproliferative genes.28 Age-associated methylation-dependent transcriptional repression also affects genes with functions in tumor suppression, DNA repair and genome stability, metabolism, differentiation and growth, immune response, coagulation, and connective tissue homeostasis.29 However, the correspondence between DNA methylation and gene expression changes associated with age is low,7, 25, 30 so how hypermethylation at these sites affects aging remains to be understood. Even though DNA hypomethylation seems to be less site specific than DNA hypermethylation, observations that the loss of DNA methylation only occurs in senescing cell strains but not in immortalized cells,31, 32 and that the inhibition of DNA methylation can induce growth arrest in immortal cells,33 suggest that DNA hypomethylation does play an important role in the establishment of senescence. As age-associated hypomethylation occurs globally and affects repetitive genomic regions, like Alu-elements,34 it may impact genome stability. In summary, age-associated DNA methylation changes seem to have three major effects: (1) altered gene expression, (2) altered chromatin structure, and (3) altered protection of repetitive sequences. However, in all these roles DNA methylation is complemented by, or cooperative with, other epigenetic-regulatory mechanisms.

874 TABLE 36.2

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Changes in Histone Number, Histone Variant Number, and Histone Modifications Associated With Aging

Type

Young

Old

Conventional histones

High number

Low number

Histone modification

H3K9me2, H3K9me3, H3K27me3, H4K20me3, Bulk H4ac, K18ac, K28ac, H3K56ac

H4K16ac, H3K9me1, K20me1, K20me2, H4K20me3, H3K14ac, H4K8ac, H4K12ac

Histone variants

H3.1, H3.2, H2A.1

H3.3, H2A.2, γH2AX

Associated proteins

Caf-1, Asf1, SLBP, EZH2, Nurd, HDAC1, HP1, Sir2

HIRA

Young cells typically contain a higher number of core (conventional) histones associated with DNA. Histone modifications listed under “young” also occur in the cells of older organisms but prevail in younger cells. Similarly, histone modifications listed under “old” also occur in younger cells but are more prevalent in older cells. Similarly, proteins such as Caf-1, Asf1, Sir2, Nurd, and HDAC1, are expressed at a higher level in younger cells, whereas HIRA is expressed at a higher level in older cells.

36.2.2 Posttranslational Histone Modifications and Nucleosome Occupancy and Aging In addition to DNA methylation, histone density, posttranslational modifications of histones, and deposition of histone variants also affect the accessibility of DNA to regulatory and repair factors and thus impact gene expression pattern and genome stability. Similarly, a few general trends in histone-associated age-dependent changes are observed (Table 36.2): (1) Global reduction in expression and deposition of core histone proteins.35–37 (2) Altered nucleosome composition through changes in expression and incorporation of histone variants.38 (3) Altered pattern of posttranslational modifications of histones with pleiotropic effects on life span. The global reduction in histone proteins and consecutively reduced nucleosome occupancy complement the observed global loss of heterochromatin, reduced ASF1-mediated deposition of histones,39, 40 reduced expression,41 or the maturation of histone mRNA promoted by SLBP.42 Since overexpression of histones increases life span,37 this change in DNA packaging seems to be a crucial mediator of aging, likely through the loss of heterochromatin paired with increased genomic instability and altered gene expression profile. Furthermore, a shift in the incorporation of histone variants also seems to play a role in replicative aging. Cellular senescence is associated with increased incorporation of histone 3 variant H3.3 and its cleaved form H3.3cs1,38 which lacks the 21 N-terminal amino acids of the histone tail and thus some of the sites that are commonly posttranslationally modified (Table 36.2). Duarte et al. showed that this shift facilitates silencing of E2F/RB target genes, which might be explained by the permanent loss of activating H3K4 trimethylation.38 Similarly, increased deposition of the H2A variant macroH2A, within senescence-associated heterochromatin foci (SAHF), also contributes to the silencing of proliferation-promoting genes.43 Outside the regulation of proproliferative genes, altered histone variant deposition has also been associated with the expression of inflammatory genes, promoted by increased deposition of H2A variant H2A.J and removal of macroH2A1, thereby contributing to the senescence-associated secretory phenotype.44, 45 In an additional layer of regulation, histones are posttranslationally modified, giving rise to a plethora of combinations of modifications that affect the regulation of gene expression, DNA repair, chromatin structure, and DNA replication. Expression levels of histone-modifying enzymes change with age and are therefore likely to contribute to aging. 36.2.2.1 Histone Acetylation Changes in the acetylation levels of two lysine residues of histone 3 (namely, H3K56 and H4K16) have been linked to aging. Acetylation of H3K56 is regulated by histone acetyltransferase (HAT) ASF1 and histone deacetylase (HDAC) SIRT1 (PMID: 19411844). H3K56ac promotes adequate deposition of nucleosomes, genome stability, and transcriptional activation of histone gene expression.46, 47 While H3K56ac levels decrease with increasing age, deletion of the HDACs that remove this acetylation mark in yeast leads to accelerated aging48 (Table 36.2). This indicates that increased as well as decreased H3K56ac levels result in changes to chromatin structure and genome stability that promote aging. Acetylation of H4K16 in yeast is established by Sas2 and removed by Sir2.49, 50 While mutation of Sir2 shortens yeast life span, the introduction of an extra copy of Sir2 extends life span,50 indicating that high H4K16ac levels promote aging. In line with this, decreased Sir2 expression and increased levels of H4K16ac at rDNA and subtelomeric DNA regions are associated with increasing age,49 allowing for loss of silencing and increased recombination

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in these genomic regions. While this histone mark plays an important role in yeast aging, similar roles of sirtuins in mammalian aging have not been shown; sirtuins do seem to play a role in mammalian aging but are independent of histone deacetylation. For instance, SIRT3 has been shown to deacetylate FOXO3 in response to oxidative stress, thereby promoting mitochondrial homeostasis.51 Age-associated changes in histone acetylation are also involved in specific changes in transcription. For instance, the impairment in inducing H4K12 acetylation during learning in an aging mouse brain contributes to age-associated cognitive decline.52 36.2.2.2 Histone Methylation Similar to age-associated changes in histone acetylation and DNA methylation, changes in histone methylation mainly involve the global reduction of repressive marks, tissue-specific fluctuations of histone methylation patterns, and a site-specific increase or decrease in histone methylation corresponding to altered transcriptional regulation. Changes in methylation levels of several histone tail residues are linked with aging, including the most extensively studied ones: H3K4me3, H3K9me3, H3K27me3, H3K36me3, and H4K20me3 (Table 36.2). Two of these, H3K4me3 and H3K36me3, are traditionally considered activating histone marks, whereas H3K9me3, H3K27me3, and H4K20me3 are found in heterochromatin regions.53, 54 Several pieces of evidence support a role for altered H3K4me3 levels in aging. The deletion of methyltransferases ASH2 or SET2 in C. elegans extended life span, whereas the deletion of demethylase RBR2 shortened life span.55 Interestingly, these effects were dependent on an intact germline and were inheritable.56 Furthermore, H3K4me3 levels were found to decrease with age in Drosophila heads,57 while H3K4me2 levels increased at stress-associated gene promoters in the brains of macaques.58 While the mechanistic role of H3K4 methylation in aging requires further research, it seems that observed changes and effects are tissue and site specific, which is common to other gene-specific age-associated epigenetic changes. The link between H3K36me3, another activating histone mark, and longevity comes from the observation that the deletion of the histone methyltransferase (HMT) met-1, which catalyzes H3K36 trimethylation, results in a shortened life span,59 while the deletion of the histone demethylase Rph1, which removes the mark, results in an extended life span.60 Reduced H3K36me3 levels facilitate cryptic transcription initiation as well as altered transcription levels, and may thus contribute to an age-associated drift in gene expression stability. More recently, H3K36me3 marks have also been detected in regions of facultative and constitutive heterochromatin.61 On the other hand, levels of H3K9 trimethylation, which is a mark associated with constitutive and facultative heterochromatin, globally decrease with age. H3K9me3 is involved in heterochromatin formation in telomeric, subtelomeric, and pericentromeric regions in young cells62, 63 and with the establishment of SAHF in senescing cells.28 In line with this, age-associated reduction in expression levels of SUV39H1, the methyltransferase that establishes the H3K9me3 mark, corresponds with globally reduced H3K9 trimethylation and increased transcript levels in pericentric satellite regions64, 65; and reduced expression of Suv39h affects the regulation of telomere length66 and telomere nuclear architecture.67 Furthermore, heterochromatin regions enriched with repressive histone marks have been found to be associated with the nuclear lamina68 and are thought to contribute to the domain organization of chromosomes, with regions more distant to the nuclear lamina being more frequently transcriptionally active.69 Peric-Hupkes et al. showed that this domain organization changed with increasing differentiation of mouse-embryonic fibroblasts, resulting in differential gene expression. While a global reduction of SUV39H1 and H3K9me3 may promote genomic instability, site-specific changes in their association patterns may promote gene expression changes, like those mediated by the formation of SAHFs, that further add to the establishment of senescence. Similarly, H3K27 trimethylation globally decreases with age in some model systems, including C. elegans and cells from HGPS patients65, 70; increases in others, including the aging killifish brain71; or exhibits strong locus-specific changes, as observed in aging murine hematopoietic stem cells.72 Interestingly, nucleosomes of the naked mole rat, identified as having an exceptionally long life span and low cancer incidence, are characterized by higher H3K27 trimethylation levels than those of mice.73 The role of H3K27me3 changes in aging and is further supported by the observations that deletion of the demethylase that specifically removes the mark extends life span in C. elegans in an insulin-dependent manner,70, 74 while global reduction in H3K27me3 levels in HGPS patient cells is mediated by reduced expression of the methyltransferase EZH2 and precedes characteristic changes to nuclear architecture associated with the disease.65 A locus-specific increase in H3K27 trimethylation, mediating transcriptional repression of its target genes, promotes functional decline of muscle satellite cells and mesenchymal stem cells.75, 76

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36.2.2.3 Histone Ubiquitination An indication of the role of histone ubiquitination in aging comes from the observation that deletion of sgf73 or ubp8, which are part of the SAGA deubiquitinase complex, results in exceptional Sir2-dependent longevity in yeast.77 Ubp8 deubiquitinates monoubiquitinated H2B-K123, resulting in reduced and less stable nucleosome assembly at sites of newly synthesized DNA and can thus promote replication stress,78 which might contribute to aging. On the other hand, McCormick et al. suggest that deletion of sgf73 or ubp8 delays aging through allowing Sir2-dependent silencing of rDNA and telomere-proximal sequences.77 In contrast, the loss of Ataxin-7, the Drosophila homolog of sgf73, results in reduced H2B ubiquitination, neural and retinal degeneration, and early lethality.79 Thus, while histone ubiquitination seems to play a role in aging, its mechanisms seem to be more complex in higher organisms. Indeed, histone ubiquitination is also important for an efficient DNA damage response, and protein aggregates that are hallmarks of several age-associated neurodegenerative diseases have been shown to titrate ubiquitin away from the nucleus and render cells more susceptible to DNA damage.80 While many details, particularly of site-specific epigenetic regulation and its role in aging, are not completely understood, from the accumulating evidence it becomes clear that there are major trends common to epigenetic regulation through DNA methylation and histone-mediated regulation: (1) Reduction of heterochromatin in regions of constitutive heterochromatin. (2) Increase in tissue-specific differences. (3) Site-specific changes promoting transcriptional activation or repression. In the following sections we look more closely at RNA-mediated mechanisms that in some cases may contribute to localized changes in DNA methylation and histone-mediated regulation but that may also contribute to aging through independent functions.

36.2.3 ncRNA Expression and Aging In addition to DNA methylation and histone-related mechanisms, noncoding RNAs (ncRNAs) also impact global gene expression patterns, genome stability, and chromatin status. Short ncRNAs, like microRNAs (miRNAs), do so by inducing the cleavage of target mRNAs or through inhibiting the translation of target mRNAs. On the other hand, long ncRNAs have diverse functions including the induction of silencing or the activation of histone modification patterns by recruiting histone-modifying enzymes; the regulation of genome stability at loci, such as rDNA or telomeres; and the modulation of nuclear architecture, through base pairing with mRNAs, affecting posttranscriptional processing and translation.81, 82 The following sections highlight the accumulating evidence on age-associated changes in ncRNA-mediated regulation and their impact on aging. 36.2.3.1 miRNAs Various pieces of evidence indicate a role for miRNA in aging. On the one hand, several miRNAs in C. elegans impact life span.83 On the other hand, the overexpression of a number of miRNAs (miR-210, miR-376a*, miR-4865p, miR-494, and miR-542-5p) induces senescence-like phenotypes, SAHF formation, senescence-associated β-galactosidase activity, accumulation of DNA damage, and ROS in low-passage IMR90 cells.84 Differential expression of miRNAs during aging contributes to altered regulation of various age-associated processes, including IGF1 signaling, mTOR signaling, DNA damage response, stem cell depletion, oxidative stress85 and mitochondrial function,86 immune response, translation, and RNA processing.87 However, systematic analysis of miRNA expression patterns during healthy human aging, similar to studies assessing DNA methylation changes, have not been done until recently. Huan et al. showed that 127 miRNAs were significantly differentially expressed in an age-dependent manner in a healthy human study population, with most of them (81%) underrepresented in older individuals.87 The authors also found a set of 80 miRNAs that had expression patterns that were predictive of chronological age, similar to the studies done by Hannum and Horvath on DNA methylation. Furthermore, they identified 4682 target mRNAs that were strongly coexpressed with differentially expressed miRNAs,87 which underlines the important contribution of miRNA regulation to age-dependent changes in gene expression patterns. The overall reduction in miRNA expression with age results from locus-specific repression as well as downregulation of miRNA-processing factors, like Dicer, which can play a causative role as shown for cellular senescence.88 In addition to affecting local gene expression profiles, miRNAs may also play a role in systemic aging. Valadi et al. first described exosomes that were able to deliver functional miRNAs to different cells.89 Such exosomes were recently

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shown to play a crucial role in the systemic aging symptoms caused by a loss of hypothalamic stem cells, as the loss of these stem cells resulted in reduced exosome secretion.90 In another example, increased levels of circulating miR-31, secreted by senescent endothelial cells, were shown to inhibit differentiation of bone-mesenchymal stem cells.91 36.2.3.2 Other ncRNAs Although it is known that most of the human genome is transcribed,92 the diverse functions of the arising transcripts are incompletely understood. Comparative RNA-Seq of dividing vs. senescent human lung fibroblasts revealed differences in lncRNA expression patterns, and some of these expression changes were shown to play causative roles in senescence.93 Numerous ncRNAs directly or indirectly affect genome stability and/or the regulation of growth and therefore have the potential to affect aging processes.94 Of them, ncRNAs transcribed from repetitive regions, such as rDNA or telomeres, play roles in regulating the chromatin structure and stability of these loci. Accordingly, increased transcription of rDNA in yeast promotes rDNA instability and premature senescence,95 and cells expressing elevated levels of TERRA exhibit telomere dysfunction and chromosome instability.96 However, the roles of these ncRNAs in aging are likely complex. For instance, TERRA affects telomere maintenance and stability through several mechanisms involving the regulation of telomerase-mediated maintenance, formation of recombinogenic R loops that can promote recombination-dependent telomere maintenance, heterochromatin formation at telomeres, and telomere localization.97, 98 Altered expression of lncRNAs can also impact gene expression, as in the case of H19 lncRNA, which is expressed from the IGF2/H19 imprinted locus. H19 lncRNA recruits methyl-CpG-binding domain protein 1 (MBD1) to, and thereby mediates repression of, its target genes.99 Furthermore, a senescence-associated circular RNA, CircPVT1, with reduced levels in senescent cells, affects gene expression through binding to let-7 and reducing its available levels in the cell. let-7 is a miRNA that targets several proliferative mRNAs, thus increased let-7 availability in cells promotes a growth-inhibitory expression profile.100 As functions of individual ncRNAs become better understood they may lead to discoveries of many additional roles of noncoding transcripts in aging and senescence.

36.3 EPIGENETICS OF AGE-RELATED DISORDERS As discussed above, aging is associated with a plethora of epigenetic alterations. On the other hand, many of the diseases that show increased incidence with advanced age are also associated with altered epigenetic patterns that in some cases resemble age-dependent changes. However, whether such similarities constitute causal links between aging and respective diseases is not understood in most cases. Studies on monozygotic twins have shown that epigenetic differences account for most of the variation observed with age; for example, genetic mutations account for 20%–30% of the variation. In addition, the epigenetic differences between monozygotic twins were found to be greater when they spent less of their time together.26, 101 These and other studies support the strong effect environmental factors have on age-associated epigenetic drift. It is therefore conceivable that age-associated epigenetic changes translate cumulative environmental exposures into increased disease susceptibility. In the next section we highlight some examples where associations between age-related epigenetic changes and age-related increased risk of disease have been observed. As disease physiologies and functions of age-related epigenetic changes become better understood, further connections are likely to be discovered.

36.3.1 Cancer To proliferate indefinitely, cells need to overcome growth-limiting mechanisms, such as repression of oncogenes, expression of tumor suppressors, or telomere shortening. Malignant cells achieve this through accumulating changes to their genetic sequence or through changes in their gene expression profiles. In this regard the role of DNA methylation in cancer has been extensively studied. Not only do altered DNA methylation patterns contribute to differential expression patterns, but the methylated cytosine residue itself is hypermutatable and has been estimated to account for up to 5% of inheritable disease-associated mutations.102 While global DNA hypomethylation and site-specific DNA hypermethylation are observed both during aging and cancer, there are indications that the age-dependent increase in cancer risk cannot simply be explained by this. A recent study comparing age- and cancer-associated DNA methylation patterns showed that cancer-associated differential DNA methylation was more extensive than age-associated differential DNA methylation.102 Furthermore, hypermethylated CpG sites exhibited an association with similar chromatin signatures in aging and cancer, while

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hypomethylated sites were found in different chromatin contexts.102 These findings suggest that the epigenetic link between aging and cancer is more complex than previously assumed. Interestingly, locus-specific increases in DNA methylation levels are observed at the promoters of tumor suppressors with age in healthy tissues,103, 104 making them more susceptible to malignant transformation as observed for premalignant gastric lesions.105

36.3.2 Cardiovascular Diseases Cardiovascular diseases are a leading cause of death in the developed world. Studies investigating the correlation between epigenetic age acceleration (DNA methylation patterns typical of older chronological age in blood cells) and the incidence of cardiovascular disease and mortality have shown a slightly increased risk among subjects with “older” DNA methylation patterns.106, 107 This indicates an involvement of epigenetic mechanisms in age-related cardiovascular disease, be they causal or consequential. Several epigenome-wide association studies have further discovered risk factors for cardiovascular diseases, such as a role for methylation of the carnitine palmitoyltransferase-1A (CPT1A) gene in regulation of the blood lipid profile,108, 109 with increased CPT1A levels correlating with more favorable lipid profiles. However, whether differential methylation affects the expression levels of CPT1A is still unclear. With age there is a particularly high risk for cardiovascular morbidity caused by diseases that depend on neovascularization and endothelial repair (e.g., stroke, myocardial infarction, and limb ischemia).110 Neovascularization is thought to require functional endothelial progenitor cells to differentiate and replace damaged endothelial cells.111 However, as stem cells age they increasingly lose this ability.112 Epigenetic mechanisms play a role in this. Different studies have shown that MeCP2-dependent repression of SIRT1 expression contributes to the functional decline of progenitor cells.113, 114 Moreover, when it comes to atherosclerosis, gradual changes in DNA methylation with every replication cycle have been observed in different genes and associated with increased risk for atherosclerotic plaque formation; on the one hand, gradually decreasing methylation of the collagen gene COL15A1, which is also induced in atherosclerosis,115 and, on the other hand, a passage-dependent increase in DNA methylation have been observed in the promoter of the estrogen receptor beta gene and in atherosclerotic plaques.116

36.3.3 Immune Responses A functional immune system is characterized by the appropriate recognition of self vs. nonself antigens, followed by regulated activation of immune cell subpopulations that mediate the response to the antigen. Even though the ability to mount immune responses to novel antigens declines with age, aging and immunosenescence are also associated with an increasing incidence of autoimmune disorders; epigenetic changes may play a role in both. Bocker et al. showed that CpG sites in a set of differentiation-related genes that were methylated in hematopoietic progenitor cells exhibited decreased methylation levels during differentiation, as well as in progenitor cells from older individuals.117 This finding suggests that age-associated epigenetic changes contribute to haematopoietic stem cell aging. Furthermore, altered promoter accessibility and chromatin structure may also contribute to immunosenescence; naive and central memory CD8 T cells from older individuals show a trend toward more differentiated open chromatin and reduced promoter accessibility with resulting reduced transcription of respiratory chain genes.118 A better understanding of the role of epigenetic regulation in hematopoiesis and lymphoid and myeloid differentiation with age may well provide further explanations for decreasing immunocompetence with increasing age. There are various hypotheses as to what mediates this increased risk for autoimmune responses119; for instance, the accumulation of senescent, apoptosis-resistant T lymphocytes, also observed in several autoimmune disorders, and the reduced T cell repertoire, biased toward autoreactive T cells.120 While the exact mechanisms that mediate agedependent increased risk for developing autoimmune disorders is not completely understood, epigenetic regulation seems to be involved. For instance, the expression of lymphocyte function-associated antigen 1 (LFA-1) is regulated through DNA methylation of its promoter, which is hypomethylated during aging and in systemic lupus erythematosus.121, 122 This demethylation and overexpression of LFA-1 correlates with the autoreactivity of T cells.122 Furthermore, the analysis of age-related DNA methylome change in CD4+ T cells of healthy individuals revealed hypomethylation of sites related to T cell receptor signaling, apoptosis, mTOR signaling, and FCγR-mediated phagocytosis.123 These changes may result in altered regulation of T cells in the aging immune system and contribute to predisposition to autoimmune diseases.

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36.3.4 Neurodegenerative Disorders Interestingly, miRNA levels are higher in the brain, where they play important roles in neuronal development, than in other organs in humans and rodents. Changes in RNA-mediated regulation seem to be important to the pathophysiology of neurodegenerative disorders. For instance, the decline in miR-107 that targets beta-site amyloid precursor protein-cleaving enzyme 1 (BACE1) mRNA in brains of elderly patients with the earliest symptoms of Alzheimer disease (AD) may contribute to disease progression.124 In addition to miRNA involvement, several studies suggest the misplacement of chromatin modifiers and consequent alteration in chromatin architecture plays a role in disease pathogenesis. Accordingly, exposure of primary neuron cultures to β-amyloid resulted in relocalization of chromatin organization factor SATB1 to scaffolding/matrix attachment regions and altered gene expression.125 On the other hand, DNA methylation patterns in brain samples from patients with Huntington disease (HD) showed considerable age acceleration compared with healthy controls, with an average increase of 3.2 years.126 Mutant huntingtin has been shown to accumulate in nuclei and disrupt the nuclear architecture and nucleocytoplasmic transport,127 which might contribute to the altered epigenetic profile by causing a mislocalization of epigenetic modifiers. In contrast to AD and HD the role of epigenetics in the pathogenesis of Parkinson disease has not been extensively studied, but it has been described to be correlated with an increase in H3K14 and H3K18 acetylation and decreased H3K9 acetylation, which possibly impact gene expression patterns.128

36.4 CONCLUSIONS Considerable progress has been made in recent years in understanding regulatory pathways that are involved in aging and age-related diseases. Several studies have described age-dependent reduction in global and constitutive heterochromatin, affecting both DNA methylation and histone modifications as well as site-specific changes in DNA methylation and histone modification patterns. Global miRNA levels decline with age, contributing to altered gene expression profiles as well. Interestingly, by entering the circulatory system, altered miRNAs may affect aging on a systemic level. As the functional consequences of epigenetic changes and their roles in aging and age-related diseases become better understood, they may provide therapeutic targets to prolong the human health span.

Conflict of Interest Statement The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Acknowledgments This work was supported by grants from the DoE, NSERC, and CIHR to O.K. and a Natural Sciences and Engineering Research Council of Canada grant to I.K.

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