Epigenetics of Aging
The aging phenotype is the result of a complex interaction between genetic, epigenetic and environmental factors, and it is among the most complex phenotypes studied to date. Evidence suggests that epigenetic factors, including DNA methylation, histone modifications and microRNA expression, may affect the aging process and may be one of the central mechanisms by which aging predisposes to many age-related diseases. The total number of altered methylation sites increases with increasing age, such that they could serve as a biomarker for chronological age. This chapter summarizes the mechanisms by which these epigenetic factors contribute to aging and how they may affect the complex physiology of aging, lifespan and age-associated diseases.
Aging has emerged as a major global public health issue . Life expectancy has increased steadily over the last two centuries , however, a significant proportion of the extra life years is associated with many types of morbidity. Age-related diseases, including cancer, cardiovascular diseases and dementia, are now the dominant health problems among the elderlies in most western countries. Identifying the underlying molecular changes that occur as part of the aging process and how they contribute to the development of age-related diseases will be critical for improving the health outcome for elderly patients, and in potential preventative strategies. The molecular basis of human aging is currently being investigated in many experimental contexts, including telomere shortening, DNA damage, degeneration of cellular or organ structures, genomic studies, and changes in gene expression. Both genome-wide association studies and candidate gene approaches have provided valuable information on the role of DNA in aging and disease risk. These approaches, however, do not provide information on differential genetic expression due to developmental or epigenetic changes .
Epigenetic changes refer to gene expression alteration that arise from chromosomal changes without DNA sequence modification. These changes, which collectively make up the epigenome, include; alternations in DNA methylation patterns, post translation modification of histones, chromatin remodeling, and non-coding RNAs (e.g., microRNAs) which in turn may affect gene expression and genomic instability during aging [64, 65]. Although the contribution of epigenetics to several human diseases such as cancer, metabolic diseases, and neurodegenerative disorders has been proved , the epigenetic variations in normal tissue due to aging is still poorly understood. Invertebrate model organisms, such as yeast, worms, or flies, have been extensively studied in the context of longevity, reporting fundamental clues about the mechanisms through epigenetic factors that contribute to aging . In contrast, the mechanisms by which epigenetics promote aging and age-related diseases in mammals are not well defined. In this regard, monozygotic twins are a good model for studying epigenetic changes linked to aging: they provide evidence that such changes can accumulate over time, as one individual may gradually undergo alterations that his or her twin (with identical DNA) does not [28, 77]. Inheritance of epigenetic modifications has been reported in a variety of taxa, ranging from plants , yeast , and flies [15, 49] as well as vertebrates such as mice [1, 37, 72] and humans . In general, DNA hypermethylation leads to gene silencing, and DNA hypomethylation endorses gene activation. DNA hypermethylation causing silencing of genes involved in the cell cycle, apoptosis, detoxification and cholesterol metabolism  has been reported. Aberrant regulation of epigenetic mechanisms can result in genomic imprinting disorders, such as Angelman syndrome and Prader-Willi syndrome, and may contribute to the heritability of many forms of cancer, asthma, Alzheimer’s disease, and autoimmune diseases such as systemic lupus erythematosus, rheumatoid arthritis, and multiple sclerosis [39, 42, 44].
Role of Epigenomic Modification in Aging
Aging is a complex physiological process that results in compromise of biological functions, increased susceptibility to age-related diseases, and eventually death . It is well recognized that human aging and longevity are influenced by both genetic and environmental factors. Inherited genetic mutations and polymorphisms resulting in alterations in gene function can explain some features of aging and age-related diseases. However, in addition to inherited genetic factors, aging is influenced by the gradual accumulation of molecular alterations since birth. Environmentally induced changes in the epigenetic processes involve alterations of gene expression without a change in DNA sequence, and can determine different aspects of aging, as well as pathogenesis of age-related diseases . Epigenetic changes can specifically play a role in the modulation of aging processes and healthy life extension . In particular, promoter methylation changes and associated gene silencing are the epigenetic changes seen in age-related diseases.
In addition to DNA methylation, several types of histone modifications have been demonstrated to occur both globally and at gene-specific loci during aging . Other epigenetic processes including histone modifications of Polycomb group proteins, chromosomal position effects, and methylation of ncRNAs are modulated with aging.
Common human age-related diseases are accompanied by a loss of genomic DNA methylation. Progressive loss of genomic DNA methylation has been demonstrated throughout the human genome , in mice, and in cell lines [78, 93, 94], although this decrease may be tissue and/or gene specific [70, 71, 95]. Age-related epigenetic changes have also been demonstrated in sperm cells; however, the direction of change over time appears to be gene specific . Within pairs of twins, differences in DNA methylation are greater in older than in younger monozygotic twins . The age-related decrease in long-term synaptic plasticity, especially long-term potentiation (LTP), manifesting as cognitive decline, is linked to histone acetylation and BDNF/trkB signaling. Indeed, treatment with histone deacetylase inhibitors or a neurotrophin receptor B agonist restores LTP in the hippocampus of old animals. These studies suggest that epigenetic changes may play a significant role in age-related diseases .
DNA Methylation and CpG Islands
DNA methylation occurs by the addition of a methyl group to the aromatic ring of a cytosine (5-mC), mostly located 5′ to a guanosine (CpG) . In mammalian genomes, approximately 70–80 % of CpG dinucleotides are methylated. However, stretches of CpG-rich sequences with low levels of DNA methylation, known as CpG islands, exist [10, 20]. CpG islands make up only 1 % of the human genome but contain 5 % of the CpG dinucleotides . CpG islands are often highly enriched at gene promoters, and approximately 60 % of all mammalian gene promoters are CpG-rich. The changes in DNA methylation patterns observed during aging are loss of DNA methylation at the genome-wide level in combination with gains in methylation levels in CpG islands in or near gene promoters . DNA methylation also recruits methyl-CpG-binding proteins, which recruit additional proteins that add silencing modifications to neighboring histones. This coordination between DNA methylation and silencing histone marks leads to compaction of chromatin and gene repression .
The mechanisms that keep CpG islands free of methylation appear to involve binding of transcription factors and other transcriptional machinery, or the act of transcription itself. However, CpG islands can become hypermethylated [60, 63] to silence specific genes during cellular differentiation, genomic imprinting, and X chromosome inactivation.
The methylation status of a DNA sequence can be determined using a variety of techniques such as the use of restriction enzymes (REs), which recognize short DNA sequences and cleave double-stranded DNA at specific sites within or adjacent to these sequences . Bisulfite sequencing refers to another technique that assesses DNA methylation through bisulfite conversion, which converts unmethylated cytosine residues to uracil residues. Methylated cytosine residues remain unmodified [5, 30].
An epigenome wide association scan (EWAS) identified age-related differentially methylated regions as well as differentially methylated regions associated with age-related phenotypes .
Because aging is associated with specific DNA methylation changes at specific CpG sites in the genome, some attempts were made to implement a model, or epigenetic signature, to predict the biological age. Several CpG sites show almost linear DNA methylation changes during aging. In 2011, a study was published showing a model for saliva samples of 34 male identical twin pairs aged 21–55 years. 88 CpG sites changes correlated significantly with age . Three of these sites were located in the promoters of EDARADD, TOM1L1, and NPTX2 genes. Other authors demonstrated that one single CpG site was associated with the age related gene ELOVL2 can explain 47 % of the variance of age with an accuracy of 3.7 years . Another group built an epigenetic aging signature using five CpG sites located in the genes NPTX2, TRIM58, GRIA2, KCNQ1DN and BIRC4BP. The average absolute difference between predicted and real chronological age was about 11 years . This model was improved, using only 3 CpG sites—located in the genes ITGA2B, ASPA, and PDE4C . This epigenetic aging signature has an age prediction with a mean absolute deviation from chronological age of less than 5 years. Furthermore, patients with acquired aplastic anemia or dyskeratosis congenita—two diseases associated with progressive bone marrow failure and severe telomere attrition—are predicted to be prematurely aged . Using human dermal fibroblasts, 75 CpG sites were differently methylated upon aging. From these sites, there was a large group within the INK4A/ARF/INK4b locus . These epigenetic modifications at specific CpG sites support the notion that aging represents a coordinated developmental mechanism that seems to be regulated in a cell type specific manner.
Whole genome bisulfite sequencing of DNA from CD4 + T cells of a centenarian and a newborn identified differentially methylated regions that were usually hypomethylated and less correlated with methylation of adjacent CpG dinucleotides in the centenarian . These results support the idea that small cumulative DNA methylation changes accumulate over a lifetime. While it is challenging to quantify these changes of tissue aging within an organism, an epigenetic method for doing just that was recently published . Using this method it was suggested for example, that heart tissue is actually characterized by a particularly slow aging rate. Age-related temporal changes in DNA methylation also show significant familial clustering, indicating that methylation maintenance is a familial trait . A study of DNA methylation in centenarians and their offspring compared with the offspring of non-long-lived individuals and young individuals showed that the offspring of the centenarians demonstrate delay in age related methylation changes . A paper by Hannum et al.  offers an explanation for this familial nature ; using methylome analysis to compare human aging rates in individuals of age 19–101, they identified specific methylation QTLs (including one at methyl CpG binding domain protein 4). Also, trans-generational epigenetic inheritance of extended lifespan has been demonstrated in C. elegans .
Aging of hematopoietic stem cells (HSCs) leads to functional impairment and is a possible cause for hematopoietic malignancies in the elderly. Examination of the HSC methylome from differently aged mice revealed an age-dependent hypermethylation of PRC2-regulated genes concomitant with a reduced transcription of genes Ezh2, Suz12 and Eed encoding PRC2 components . The data suggest that PRC2-mediated gene repression may decrease upon aging, thus allowing the DNA methylation machinery to more readily methylate PRC2 target genes.
Early evidence demonstrated that there is a global decrease in DNA methylation in different human tissues during aging . This loss was attributed to a progressive loss in DNA methylation in repetitive sequences—especially Alu elements—located throughout the genome . Paradoxically, and similarly to what happens in cancer, certain genes are hypermethylated. Specific age-related hypermethylation has been described at various developmentally regulated genes in various human tissues, such as MYOD1 in brain [16, 24, 41], PCDH10, and P2RX7 in intestine  or DDAH2 and TET2 in skin . The extent of this hypermethylation is not yet known, but de novo methylation in skin during aging was recently found to affect < 1 % of genes . Some authors have found significant enrichment of age-dependent CpG hypermethylation at DNA-binding factors and at transcription factors , suggesting that deregulation of these genes could affect a broad spectrum of biological pathways and, consequently, could explain the wide phenotypic alterations of aging. However, many of the genes that were demonstrated to be hypermethylated during aging belong to the senescence and apoptosis pathways . Interestingly, some classic tumor-suppressor genes that are commonly hypermethylated in tumorigenesis also undergo de novo methylation during aging in normal tissues . Thus, researchers have proposed a link between hypermethylation of specific tumor-suppressor genes (e.g., LOX, p16INK4α, RUNX3, and TIG1) and age in non-tumorigenic gastric epithelia . The three well-known, epigenetically regulated tumor-suppressor genes RARβ2, RASSF1A, and GSTP1 also become hypermethylated in premalignant prostate tissues in an age-dependent manner . Likewise, the putative tumor-suppressor gene TET2 is commonly hypermethylated in myeloproliferative tumors and in aged healthy skin .
Muscle atrophy, or sarcopenia is a degenerative loss of skeletal muscle mass, quality, and strength associated with normal human aging. In a genome wide study of DNA methylation in aged skeletal muscle, hypermethylation was found in comparison to samples of younger people .
DNA methylation dynamics can also influence brain function. 5-hydroxymethylcytosine (5-hmC) is a newly described epigenetic modification generated by the oxidation of 5-methylcytosine by the ten–eleven translocation family of enzymes [83, 88]. An increase of 5-hmC with age in the mouse brain as well as an age- and gene-expression level related enrichment of 5-hmC in genes implicated in neurodegeneration have been demonstrated. Many 5-hmC-regulated regions are dynamically modified during neurodevelopment and aging , suggesting that 5-hmC may play an important role in the etiology and course of age-related neurodegenerative disorders .
Histone Modification and Histone Variants
Epigenetic gene regulation is also controlled by changes in histones that make up the nucleosome. Chromatin, which is organized into repeating units called nucleosomes, is the complex of DNA, protein, and RNAs that comprises chromosomes . In mammalian cells, most of the chromatin exists in a condensed, transcriptionally silent form called heterochromatin. Euchromatin is less condensed, and contains most actively transcribed genes. Canonical nucleosomes consist of 147 bp of double-stranded DNA wrapped around an octamer of histone proteins, usually two copies of each of the core histones H2A, H2B, H3, and H4. However, there are several histone variants that can vary by a small number of amino acids or include large insertions . Often these histone variants are found at specific locations within the chromatin or are used to demarcate boundaries between heterochromatin and euchromatin regions.
Identification of proteins that read, write, or erase these marks is critical to help unravel the complexities of epigenetic regulation. Chromatin immunoprecipitation (ChIP) is a powerful assay to identify proteins that bind to chromatin and map protein binding throughout the genome using techniques such as microarray analysis or high-throughput sequencing .
The majority of histone-mediated regulation stems from histone modification, most often modification of the exposed amino termini of histones protruding from the nucleosome core. The predominant histone modifications include acetylation , methylation , phosphorylation , ubiquitination , and sumoylation , with thousands of potential combinations of modifications within a single nucleosome. Of these, histone acetylation and methylation are the best understood, and some general trends have been observed. Tri-methylation of histone H3, specifically the lysine at position 4 (H3K4me3), is associated with transcriptionally active chromatin, whereas H3K27me3 leads to compact chromatin, which represses gene expression. The term “histone code” is used to describe how different combinations of histone modifications affect transcription levels.
Increased histone H4K16 acetylation, H4K20 tri-methylation, or H3K4 tri-methylation, as well as decreased H3K9 methylation or H3K27 tri-methylation, constitute age-associated epigenetic marks [27, 38]. Early studies showed that global levels of K20H4me3 were increased in several organs of rats older than 30 months . An epigenetic change that may be linked to aging in mammals is decreased expression of sirtuin1 (SIRT1) resulting in the DNA damage-induced reorganization of chromatin (chromatin instability) [65, 81]. Most importantly, several studies on pharmacological activation of Sirtuins (e.g., using resveratrol) have revealed beneficial anti-apoptotic effects . This evidence makes Sirtuins potential targets for anti-aging therapies.
Noncoding RNAs and Longevity
It is likely that the effects of epigenetic changes manifest in part by effects on gene expression. There is increasing evidence that expression of noncoding RNAs, such as microRNAs (miRNAs) and long non-coding RNAs (lncRNAs), play a role in epigenetic gene regulation . miRNAs are small non-coding ncRNAs that were initially discovered in Caenorhabditis elegans and since, reported across the animal kingdom. In humans, thousands of miRNAs have been demonstrated in a variety of tissues with major impact on transcription and translational repression or gene silencing. The role of miRNAs in aging was demonstrated recently in C. elegans and in mice [47, 69]. miRNAs affect gene expression during the aging process in mice and modulate senescence in human cell lines . An miRNA expression array performed in the livers of mice aged 4–33 months old showed more upregulated than downregulated miRNAs during aging . Four miRNAs (miR-93, miR-669c, miR-214, and miR-709) were especially upregulated, and proteomic profiling of the same samples demonstrated a significant correlation between the aforementioned miRNAs and expression of the corresponding gene targets associated with mitochondrial function, oxidative stress, and proliferation . The list of miRNAs associated with mammalian aging is rapidly increasing. Some examples include: Link between upregulation of miR-143 and senescence-dependent growth arrest in human fibroblasts , increased expression of let-7 family members in skeletal muscle aging , and the role of miR-27 in the aging delayed model Ames mice . Models of premature aging, such as the Zmpste24-deficient mice also showed miRNA deregulation (miR-29) . Interestingly, miR-29 upregulation was described also in somatic tissues from old mice during physiological aging. Increased expression is strongly associated with DNA damage and the p53-pathway , which would reinforce the link between aging and tumorigenesis. Studies in C. elegans and mice have resulted with some important observations, such as; (a). miRNAs work in groups (packs) by coordinating and regulating gene expression/silencing resulting in age-dependent disease states or alternatively with longevity , (b). inherited epigenetic effects in miRNA loci lead to changes in gene expression that modulate longevity [56, 67], and (c). miRNAs that target members of the insulin/IGF-1 pathway (a known target for genetic disruption that leads to life extension) can predict up to 47 % of lifespan differences . The insulin/IGF pathway acts as a cascade of phosphorylation reactions that inactivates the transport of FOXO transcription factors (i.e., DAF-16) to the nucleus and the consequent inhibition of anti-aging genes such as oxidative stress or DNA damage genes. This observation on the role of IGF-1 was further supported by studies in long-lived mutant mice that showed that higher expression of three miRNAs altered IGF-1 signaling that in turn promoted long-lived phenomenon . de Lencastre et al. demonstrated that miRNAs could affect lifespan through disruption of multiple loci that are not necessarily associated with the insulin/IGF-1 pathway . Some loci illustrate positive effects on lifespan, promoting longevity, and some however demonstrate the opposite effect leading to a shorter lifespan . Such observations are also reported by Ugalde et al.; altered expression of two miRNAs promoted progeroid phenotype in a mouse model for a progeria syndrome through the effect on key components of the DNA-damage response pathways . A genome-wide miRNA screen for differential expression between long-lived individuals and controls revealed that 10 % of the miRNA microarray (863 miRNAs) demonstrated significant alterations in expression, of which only 16 were upregulated in the exceptional long-lived individuals. Most of these differentially expressed miRNAs have been associated with genes linked to major age-associated diseases, suggesting that regulation of key genes by miRNAs could promote longevity in humans . Longevity-selected lines of Drosophila show gene expression profiles that are similar to younger control flies . In humans, a cross-sectional analysis of individuals aged 50–90 and centenarians was used to identify a miRNA, miR-363*, whose expression declined with age but was preserved at youthful levels in the centenarians .
By definition, lncRNAs have a length of > 200 bp and no protein coding potential; moreover, they are more cell type-specific than protein coding mRNAs. lncRNAs participate in the regulation of protein localization, translation, posttranslational modifications, mRNA stability, and chromatin shaping, often by means of their secondary structure .
Using deep sequencing, it is possible to obtain information on Small noncoding RNAs that circulate in the blood. The serum levels of specific sncRNAs change markedly with age. The ability of circulating sncRNAs to transmit functions between cells and to regulate a broad spectrum of cellular functions, and the changes in their levels with age, implicate them in the manifestation of aging .
Aging epigenetics is an exciting new field that is rapidly evolving through significant progress in methods and analysis coupled with advancement in technology. Investigators have only just begun to explore the variation in the landscape of biological changes during aging. Probably the greatest barriers to progress in this area are the long period of time required for assessing longevity in humans and the enormous degree of variation among individual’s aging owing to environmental factors. The integration of DNA modifications, histone marks, and alterations of non-coding RNAs will surely pave the way to define reference epigenomes of aging. This reference will help identify epigenetic alterations associated with the complex process of aging and will have important ramifications on age-related diseases and therefore, life span.
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