A brief overview of the concept of epigenetics in aging and disease
Aging is an important risk factor for many diseases such as cancer, cardiovascular diseases, and neurological disorders, which is caused by a combination of genetic and environmental factors (such as diet, smoking, obesity, and stress) that result in changes at the molecular level. It results in the expression of genes and the reduction of physiological function.
Epigenetics includes mechanisms that regulate gene expression without changing the DNA sequence, such as modifying chromatin structure or regulating the binding of transcription machinery to DNA. Several studies have shown that disruption of epigenetic mechanisms increases gene expression changes in aging-related diseases.
The change of these epigenetic mechanisms is also related to the change of gene expression during aging processes of different tissues. In this article, the potential role of epigenetics in the onset of two age-related diseases, namely cancer and cardiovascular diseases, will be described.
Aging is associated with a gradual decline in many physiological processes, which is associated with an increased risk of serious diseases such as cancer, cardiovascular diseases, dementia, and type II diabetes in the elderly. It is interesting to note that the incidence of many cancers increases after the age of 50 and heart failure [1] (HF) increases from the age of 60 and most patients are over 70 years old.
This, along with the fact that the average life expectancy has increased, has made aging significant at both economic and social levels [1]. However, the mechanisms of initiation of these age-related diseases remain largely unknown.
The aging process begins due to a combination of random events including genetic and environmental factors (such as diet, smoking, obesity, and stress) which, at the molecular level, cause changes in gene expression and decrease in physiological function. For example, brain aging is associated with changes in the expression of genes encoding proteins involved in inflammatory and stress responses and neuropeptide metabolism, while the aged heart has an altered transcriptional profile implicated in cardiac dysfunction [2].
In addition, aging-related diseases are the result of gene expression disorders. For example, cancer is caused by a change in gene expression that leads to the acquisition of neoplastic cell characteristics (for example, an uncontrolled increase in cell proliferation, leading to loss of differentiation and the ability to metastasize to distant tissues). These changes can be caused by genetic mutations or random events that cause changes in gene expression mechanisms.
In general, the exposure of DNA, RNA and proteins to chemical changes during their lifetime disrupts their structure and function. The result of damage to nucleic acid and protein during aging is related to a decrease in the function of cells and organs, which inevitably leads to disease [4]. While heart failure is associated with two pathological processes of cardiac hypertrophy and cardiac fibrosis,
The main source is caused by changes in gene expression. Cardiac hypertrophy is associated with increased expression of fetal cardiac genes (such as Nppa, Nppb, Myh7, and skeletal alpha-actin) and suppression of adult genes (such as Myh6), whereas cardiac fibrosis results from increased expression of genes encoding extracellular matrix proteins. (such as collagen), processes whose underlying and specific mechanisms still remain unknown [5].
In the last decade, several researchers investigated epigenetic mechanisms in the regulation of gene expression and found that incorrect regulation of these mechanisms increases age-related diseases such as cancer and heart failure, and increased gene expression changes are responsible for the aging process in various tissues. Thus, altered epigenetic mechanisms that occur during aging predispose cells to transcriptional changes responsible for aging-related diseases.
Dysregulation of gene expression, and the multifactorial nature of epigenetic changes during the aging process and disease initiation, obscures their mechanisms of action: therefore, elucidating these mechanisms is crucial for understanding the origins of age-related diseases. In this brief review, the possible role of epigenetics in regulating the onset of two aging-related diseases, cancer and cardiovascular disease, will be discussed.
What is epigenetics and why is it important?
Epigenetics refers to all mechanisms of gene expression regulation, independent of DNA sequence, which can be classified into four main groups:
ATP-dependent chromatin remodeling complexes [2], DNA and histone modifications, and non-coding RNAs. These processes regulate gene expression by modulating chromatin structure or by controlling binding of transcription machinery to DNA.
An important feature of these mechanisms is that they can be regulated by a myriad of factors, including physiological and pathological stimuli, as well as by environmental factors such as diet, stress, physical activity, work habits, smoking, and alcohol consumption. [6-8].
ATP-dependent chromatin remodeling complexes are complexes containing several proteins that regulate gene expression by modifying the nucleosomal organization of DNA using energy from ATP hydrolysis.
Members of these several families act as transcription activators, which increase the formation of an open and accessible chromatin structure and enable the binding of proteins involved in transcription. For example, SWI/SNF complexes promote the formation of this structure through mechanisms involving nucleosome sliding, expulsion of H2A/H2B dimers, or removal of histone octamers from DNA.
Other chromatin remodeling agents, by organizing nucleosomes on DNA, cause the formation of chromatin structure in a very compact form and as a result prevent access to transcription factors and cause gene silencing [9].
DNA modifications include covalent modifications of DNA bases: the most studied modifications are methylation and hydroxymethylation of cytosine bases. DNA methylation mainly occurs on cytosine in genomic regions rich in CG dinucleotides. These genomic regions are called CpG islands and are found in most human and mouse genome promoters.
Cytosine methylation increases transcriptional repression. In mammals, the DNA methylation pattern is established and maintained by three DNA methyltransferase enzymes [3] (DNMTs): DNMT3A and DNMT3B are essential for “de novo” DNA methylation during development [10], while DNMT1 is essential for maintaining methylation patterns. It is required during cell division.
In addition, DNA hydroxymethylation is a product of 5-methylcytosine (5-mC) hydroxylation. A high level of 5hmC (5-hydroxymethylcytosine) in promoter and enhancer regions [4] is associated with a high degree of transcription [11].
Histone modifications are post-translational covalent modifications that include acetylation, methylation, phosphorylation, ubiquitination [5] and addition of SUMO groups [6]. Among these, the best studied are acetylation and methylation. Acetylation occurs on lysine residues in histone tails and allows transcription factor access as a result of neutralizing the positive charge of histone sequences [7].
Histone methylation is another important epigenetic marker whose effects on transcription depend on the specific position and degree of lysine and arginine methylation in the histone tail. Just like histone acetylation, methylation is a dynamic process resulting from the activity of two classes of enzymes: histone methyltransferases, which catalyze the transfer of a methyl group from S-adenosyl-methionine to lysine or arginine of histone residues, and histone demethylases, which demethylate tails. It catalyzes histone.
The last class of epigenetic mechanisms includes non-coding RNAs ([7]ncRNAs), which include types of RNAs that are not translated into proteins. Non-coding RNAs are classified according to their length: short and long. The class of short ncRNAs includes RNA molecules with a length of less than 200 nucleotides, such as PIWI [8] effector RNAs, small interfering RNAs ([9]siRNAs) and microRNAs (miRNAs).
In contrast, long ncRNAs (lncRNAs) include RNA molecules longer than 200 nucleotides. NcRNAs regulate the expression of proteins at the levels of transcription and translation. The lack of conserved species of lncRNA makes it more difficult to study, although their temporal and spatial expression can be key to understanding the regulation of chromatin structure, the application of transcription machinery and gene expression.
On the contrary, microRNAs inhibit the expression of genes by binding to the 3′-UTR [10] (untranslated region) of their target mRNAs, which leads to the degradation of the target mRNA and subsequently prevents protein translation [12].
Epigenetics in aging and disease and cancer
Cancer is caused by the accumulation of genetic and epigenetic changes, and about several types of cancer, the most important cause of the disease is age [13]. Genome disorders as a result of changes in the cellular environment, inflammation, reduction of immune system function and accumulation of DNA damage, lead to malignancy and carcinogenesis [14].
In an effort to elucidate the role of epigenetic regulation in cancer, several research groups have focused their attention over the past few decades on canonical epigenetic mechanisms that are disrupted during cancer.
Disruption of DNA methylation is one of the most common epigenetic disorders in cancer. Lack of DNA methylation in specific regulatory and repetitive elements such as Alu sequence and long dispersed nuclear sequence 1 (LINE1 [11]) increases the probability of tumor formation with increased genomic instability and disruption of chromosomal order [15, 16]. Conversely, in certain types of tumors, hypermethylation of CpG islands in the promoter regions of tumor suppressor genes is associated with cancer development (Figure 2) [17].
In addition, aberrant activity of enzymes that catalyze histone modifications are other carcinogenic factors [18]. For example, [12]EZH2 (enhancer of zeste homolog 2), the catalytic subunit of PRC2, which mediates the deposition of repressive H3K27me3, has been implicated in several types of cancer, such that its expression is increased in prostate cancer, breast cancer, lymphoma, and glioblastoma. [19-21].
Conversely, histone lysine demethylase JMJD2C, which catalyzes H3K9 demethylation, is associated with breast and esophageal cancer and prevents the suppression of genes involved in these lesions [22, 23]. Furthermore, the dynamic process of histone acetylation, which is generally associated with transcriptional activation, has been implicated in various types of cancer. The balance of activity of histone acetylases (HATs[13]) and histone deacetylases (HDACs[14]) is essential in maintaining cellular homeostasis by regulating chromatin structure and transcription states [24].
Indeed, aberrant regulation of several HATs has been found to be responsible for gene expression changes in the context of carcinogenesis. For example, the Gcn5 HAT has been implicated in breast cancer due to dysregulation of Wnt signaling [ 25 ]. In addition, altered expression of the MOZ gene and its paralog MORF, which encode two histone acetyltransferases act as transcriptional activators, are involved in the development of myeloid leukemia [26].
Finally, P300 and CBP HATs have been identified as key tumor suppressor proteins and their dysregulation has been described in many types of cancer [27]. On the contrary, HDACs are also involved in several cancers, so that their increased expression increases tumorigenesis in breast, prostate, and colorectal tissues through hypoacetylation of several gene loci [24].
Interestingly, deacetylation of non-histone proteins such as p53 and YY1 transcriptional repressors and STAT3 transcriptional activator is involved in the carcinogenesis of many types of cells [28].
Studies on the role of epigenetics in aging are largely focused on the effect of DNA methylation in this physiological process. The genomic distribution of 5-methylcytosine changes throughout the genome and at specific loci during aging. Interestingly, DNA methylation has been evaluated as a biomarker for determining the age of cells and tissues, and the methylation patterns of specific loci can express the age of different tissues.
Exposure to ROS, which increases DNA damage, inflammation, and the activity and function of DNMTs, has been shown to be associated with 5mC and 5hmc deposition and increased mutation rates [29]. In addition, studies have shown that damage to DNMT genes during aging causes a significant decrease in overall methylation levels in repetitive elements such as LTRs [15] (long terminal repeats), SINEs (short interspersed nuclear element) [16] and becomes LINE-1 (long scattered element-1) [30-34].
Studies have also shown that specific loci that contain hypomethylated enhancers are associated with genes whose expression is regulated during aging, and hypermethylation in CpG-rich islands has been shown to be associated with the initiation of carcinogenesis [35].
Misregulation of genes during aging is also associated with changes in histone methylation, therefore, changes in DNA and histone modifications that occur during aging can help determine the epigenome that is more likely to acquire epigenetic changes responsible for tumor initiation.
Finally, several non-coding RNAs have been described in the regulation of senescence-related cellular mechanisms, such as proliferation, differentiation, apoptosis, and senescence, which in turn contribute to increased carcinogenesis [ 36 ].
Some examples of long non-coding RNAs that have been studied in this field are MALAT1[17] (metastasis-associated lung adenocarcinoma transcript 1), SALNR and HOTAIR[18], which are involved in regulating cellular processes such as increased tumor cell proliferation, invasion, Metastasis, drug resistance and angiogenesis are essential, thus playing a key role in cancer progression as a result of aging [37].
Epigenetics in aging and cardiovascular diseases
Cardiovascular disease ([19]CVD), leading to heart failure and subsequently death, is the leading cause of mortality worldwide [38]. There are several risk factors associated with the development of CVD, including hypertension, diabetes, and obesity [39]. However, one of the main risk factors for CVD is age, whose prevalence, such as atherosclerosis [20], stroke [21] and myocardial infarction [22], increases in the elderly [40].
In elderly patients, various functional changes are observed in the heart, such as diastolic and systolic dysfunction, arrhythmia and atrial fibrillation [41].
As with all the pathophysiologies of aging, the high prevalence of CVD in the elderly population is associated with inflammation, oxidative stress, ROS production, apoptosis, myocardial deterioration and degeneration [42]. In addition, the inflammatory response leads to cardiac regeneration, causing significant changes in the extracellular matrix and the presence of pro-inflammatory and inflammatory markers (IL-6, TNFα, CRP) [42]. Cardiac remodeling subsequently leads to cardiac hypertrophy and fibrosis, an effect that has been seen in the hearts of elderly people and leads to cardiac dysfunction [43].
The development of fibrosis is considered as the starting point of several pathophysiologies, which starts with a wrong inflammatory response and leads to the structural and functional deterioration of many organs [44].
Mitochondria, which are essential for cardiac metabolic activity and ATP production, are of great importance for proper heart function [45]. Cardiac dysfunction in the elderly is associated with mitochondrial dysfunction as a result of oxidative stress and ROS production [41], factors that play a detrimental role on mitochondrial respiratory capacity [46].
Studies have shown that the development of atherosclerosis in the elderly population is associated with lipid oxidation as a result of mitochondrial dysfunction [47]. Oxidative stress also contributes to impaired calcium signaling, which is required to maintain the sarcoplasmic reticulum and muscle contraction [48].
Epigenetic disorders are associated with numerous cardiovascular injuries: Some of the key epigenetic mechanisms include DNA methylation and hydroxymethylation, chromatin remodeling, abnormal changes in histone modifications, and dysregulation of non-coding RNAs [49, 50].
DNA methylation, which is influenced by several environmental factors, is a key factor in the genetic regulation of genes necessary for cardiac homeostasis and regulates various cellular processes required for proper cardiac function. Global changes in DNA methylation that occur during aging are associated with the onset of multiple cardiovascular diseases [51].
Similar to the onset of cardiac hypertrophy, where cardiac remodeling leads to changes in gene expression similar to the embryonic stage, the same changes in DNA methylation patterns have been observed in aging [50]. Furthermore, changes in 5-hmC patterns in hypertrophic hearts also resemble the neonatal stage: These changes in methylation and hydroxymethylation are associated with the regulation of key cardiac genes such as MYH7, MYOCD, SRF and KLF4 [50], although such changes during cardiac aging are still unclear.
Non-coding RNAs have been of great interest in the regulation of heart homeostasis and the initiation of cardiovascular disease. In recent years, many studies have addressed the importance of a number of ncRNAs that are altered in cardiac damage and age-related cardiac damage. For example, microRNAs miR-21, miR-22, miR-34a and the miR17-92 cluster, which are significantly altered in cardiac aging, represent important proteins in fibroblast-myofibroblast transition [63], aging of cardiac fibroblasts [64]. , cardiac contraction [64] 65] and collagen synthesis [66], respectively.
Finally, a topic that has gained great importance in the last few years is whether RNA methylation can undergo epigenetic changes. Although several chemical modifications have been observed on RNA, methylation of N6-methyladenosine (RNA, m6A) is the most frequent modification in eukaryotic messenger RNAs. The role of these chemical changes on RNA in pathogenesis and aging has not yet been determined.
Recent studies have shown that RNA methylation is necessary to maintain cardiac homeostasis and is carried out through a mechanism by METTL3, a protein responsible for RNA methylation. This study showed that overexpression of METTL3 in vivo increased m6A and led to hypertrophic growth of the heart; furthermore, specific knockout of METTL3 in cardiomycetes resulted in decreased cardiac function after overload and during aging. became [68].
Collectively, these studies have shown several epigenetic mechanisms that regulate cardiac homeostasis and it has been clarified how disruption of these pathways can lead to the onset of cardiovascular damage. Many epigenetic mechanisms involved in CVD are also involved in the aging of multiple tissues. Despite this, the role of epigenetics in cardiovascular aging and in the onset of cardiovascular diseases in the elderly has not yet been determined.
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