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This report is written by MaltSci based on the latest literature and research findings

How does DNA methylation change with aging? ​

Abstract ​

Aging is a multifaceted biological process marked by a gradual decline in physiological function and increased vulnerability to age-related diseases. One critical mechanism driving the aging process is DNA methylation, an essential epigenetic modification that regulates gene expression and cellular differentiation. This review synthesizes current knowledge on how DNA methylation patterns change with aging, emphasizing the importance of these alterations in understanding the molecular basis of aging and developing potential therapeutic strategies. Research indicates that aging is generally associated with global DNA hypomethylation, which can lead to the relaxation of gene expression regulation and contribute to the development of age-related pathologies such as cancer and autoimmune diseases. However, changes in DNA methylation are not uniform; specific genes and genomic regions may exhibit hypermethylation, particularly at promoter sites, resulting in transcriptional silencing. This complexity is further influenced by environmental factors, such as diet and oxidative stress, which can modulate DNA methylation patterns. Recent advancements in high-throughput sequencing technologies have enabled comprehensive mapping of DNA methylation changes across the genome, providing insights into the mechanisms driving these alterations and their biological implications. The review also discusses the potential of DNA methylation as a biomarker for biological age, highlighting the development of epigenetic clocks and predictive models that may offer insights into individual health status and susceptibility to age-related diseases. Understanding the interplay between DNA methylation and aging is crucial for elucidating the molecular underpinnings of aging and developing targeted interventions to promote healthy aging.

Outline ​

This report will discuss the following questions.

  • 1 Introduction
  • 2 Overview of DNA Methylation
    • 2.1 Mechanisms of DNA Methylation
    • 2.2 Functions of DNA Methylation in Gene Regulation
  • 3 Aging and Its Biological Implications
    • 3.1 Theories of Aging
    • 3.2 Age-Related Cellular Changes
  • 4 Changes in DNA Methylation with Aging
    • 4.1 Global Changes in Methylation Patterns
    • 4.2 Tissue-Specific Methylation Changes
  • 5 DNA Methylation as a Biomarker of Aging
    • 5.1 Epigenetic Clocks
    • 5.2 Predictive Models of Biological Age
  • 6 Implications for Health and Disease
    • 6.1 Age-Related Diseases and Methylation
    • 6.2 Potential Therapeutic Interventions
  • 7 Conclusion

1 Introduction ​

Aging is a complex biological process characterized by a progressive decline in physiological function and an increased susceptibility to age-related diseases. One of the pivotal molecular mechanisms underpinning the aging process is DNA methylation, an essential epigenetic modification that regulates gene expression and cellular differentiation. As organisms age, significant alterations in DNA methylation patterns occur, influencing a myriad of biological functions and contributing to the pathogenesis of various age-related disorders. Understanding how DNA methylation changes with aging is crucial for elucidating the molecular underpinnings of aging and developing potential therapeutic interventions.

The significance of DNA methylation in the context of aging has garnered considerable attention in recent years. Research indicates that age-associated changes in DNA methylation may serve as biomarkers for biological age, providing insights into individual health status and susceptibility to age-related diseases [1][2]. These findings suggest that DNA methylation is not only a passive marker of aging but also an active player in the aging process itself. For instance, studies have demonstrated that global DNA hypomethylation is commonly observed in various tissues as organisms age, leading to the relaxation of gene expression regulation and potentially contributing to the development of age-related pathologies, including cancer and autoimmune diseases [3][4].

Current research on the relationship between aging and DNA methylation reveals a dynamic landscape of epigenetic changes that are tissue-specific and context-dependent. While some studies report a general trend of hypomethylation with age, others highlight specific genes and genomic regions that undergo hypermethylation [5][6]. This complexity is further underscored by the influence of environmental factors, such as diet and oxidative stress, which can modulate DNA methylation patterns and subsequently impact aging [6][7]. Furthermore, recent advancements in high-throughput sequencing technologies have enabled comprehensive mapping of DNA methylation changes across the genome, facilitating a deeper understanding of the mechanisms driving these alterations and their biological implications [8][9].

This review aims to synthesize the current knowledge on the interplay between DNA methylation and aging, structured as follows: First, we will provide an overview of DNA methylation, including its mechanisms and functions in gene regulation (Section 2). Next, we will discuss the biological implications of aging, exploring various theories of aging and the cellular changes that accompany this process (Section 3). Following this, we will delve into the specific changes in DNA methylation associated with aging, examining both global and tissue-specific alterations (Section 4). We will then evaluate the potential of DNA methylation as a biomarker for aging, highlighting the development of epigenetic clocks and predictive models of biological age (Section 5). Finally, we will discuss the implications of these changes for health and disease, considering the relationship between DNA methylation alterations and age-related conditions, as well as potential therapeutic interventions (Section 6). By integrating these diverse strands of research, this review seeks to illuminate the complex relationship between DNA methylation and aging, ultimately contributing to the ongoing discourse in aging research and healthcare.

2 Overview of DNA Methylation ​

2.1 Mechanisms of DNA Methylation ​

DNA methylation is a critical epigenetic modification that plays a significant role in gene expression regulation, and its dynamics change considerably with aging. The process of aging is associated with complex biochemical changes in DNA methylation patterns, which can have profound implications for gene expression and overall health.

One of the primary observations in the context of aging is the overall trend of decreased global DNA methylation, often referred to as the genomic hypomethylation hypothesis. This hypothesis posits that as organisms age, there is a generalized reduction in DNA methylation levels across various tissues, which can lead to the relaxation of gene expression regulation and potentially contribute to the development of age-related diseases, including cancer [3].

However, it is important to note that while global hypomethylation is a common trend, age-related changes in DNA methylation are not uniform across all genomic regions. Specific loci may exhibit hypermethylation, particularly at gene promoters, which can lead to transcriptional silencing. For instance, Gautrey et al. (2014) demonstrated that extensive and variable methylation changes occur at gene promoters in the elderly, which can phenocopy the methylation patterns observed in cancer cells [4]. This suggests that certain age-related changes in DNA methylation may increase the risk of malignancies as individuals age.

Mechanistically, DNA methylation patterns are established and maintained by DNA methyltransferases (DNMTs). With aging, the expression and activity of these enzymes can be altered, leading to disrupted methylation homeostasis. For example, Yung et al. (2001) studied the effects of a heterozygous Dnmt1 null mutation and found that while aged control mice exhibited hypomethylated DNA and signs of autoimmunity, knockout mice showed an unexpected increase in DNA methylation and a slower progression of autoimmune symptoms [10]. This highlights the complexity of DNA methylation dynamics in aging, where alterations in methylation can have different outcomes depending on the context.

Moreover, local DNA sequence and CpG density significantly influence age-associated DNA methylation changes. Higham et al. (2022) reported that changes in methylation with age occur largely independently of variations in cell type proportions, particularly at low CpG density loci, which are more prone to change [8]. This finding suggests that the local genomic context plays a crucial role in determining how methylation patterns evolve with age.

In addition to these patterns, age-related changes in DNA methylation have been observed even during childhood, indicating that the epigenetic landscape is shaped early in life. Gervin et al. (2016) found that specific CpGs associated with aging were identified in children, suggesting that the epigenetic effects of aging can begin well before adulthood [5].

In conclusion, DNA methylation changes with aging through a combination of global hypomethylation and localized hypermethylation at specific gene promoters. The dynamics of these changes are influenced by a range of factors, including the expression of DNA methyltransferases, local genomic context, and potentially early-life epigenetic programming. These changes in DNA methylation are critical for understanding the molecular underpinnings of aging and the development of age-related diseases.

2.2 Functions of DNA Methylation in Gene Regulation ​

DNA methylation is a critical epigenetic modification that plays a significant role in gene regulation and is influenced by aging. As individuals age, DNA methylation patterns undergo substantial changes, which can impact gene expression and contribute to various age-related diseases.

Aging is associated with a complex interplay of changes in DNA methylation. It has been observed that global DNA methylation levels tend to decrease over time, a phenomenon known as the genomic hypomethylation hypothesis of aging. This decrease is particularly pronounced in repetitive DNA sequences and certain regulatory regions, leading to a relaxation of gene expression control and potentially resulting in abnormal gene expression patterns associated with aging and diseases [3].

However, the changes in DNA methylation are not uniform across the genome. Specific genes and regulatory regions may experience increases in methylation, contributing to the silencing of gene expression. For instance, certain genes have been found to show progressive increases in promoter methylation with age, which can permanently silence their expression once a critical threshold is reached [11]. Additionally, studies have shown that the aging process is marked by site-specific incidences of hypermethylation alongside the overall trend of hypomethylation [6].

Research has highlighted that DNA methylation changes can also vary significantly among different tissues and cell types. For example, a study on CD4+ T cells demonstrated that aging is associated with distinct epigenetic changes, including both transcriptional and methylation alterations that influence immune function [7]. Similarly, in skeletal muscle, the aging process was linked to changes in the methylation of retroelements, indicating that the context of aging can lead to specific patterns of methylation that reflect tissue-specific aging phenotypes [12].

Moreover, environmental factors such as dietary restriction have been shown to modulate age-related DNA methylation changes. Caloric restriction can shift DNA methylation patterns, thereby delaying the age-associated methylation drift and its impact on gene expression [13].

In summary, the relationship between aging and DNA methylation is multifaceted. Aging typically leads to a global decrease in DNA methylation levels, accompanied by specific increases in methylation at certain genes, contributing to altered gene expression. These changes are not uniform and can vary by tissue type, indicating a complex regulatory mechanism that influences aging and associated pathologies. Continued research is essential to further elucidate the mechanisms underlying these changes and their implications for age-related diseases and overall health.

3 Aging and Its Biological Implications ​

3.1 Theories of Aging ​

DNA methylation, an essential epigenetic modification, undergoes significant changes as organisms age, influencing gene expression and contributing to various age-related diseases. The biochemistry of aging is intricate, with notable alterations in proteins, lipids, and nucleic acids, particularly DNA. One of the key mechanisms by which aging impacts gene expression is through the modification of DNA methylation patterns.

Research indicates that aging is generally associated with a net decrease in global DNA methylation levels across various tissues. This decrease is thought to lead to a relaxation of gene expression regulation, potentially resulting in abnormal gene expression patterns that can contribute to the development of age-related diseases, including malignancies and autoimmune disorders [2][3]. Specifically, a study found that in T cells, aging is characterized by a progressive loss of 5-methylcytosine content, particularly within DNA repeated sequences and regulatory regions, which can permanently silence gene expression once a critical methylation density is achieved [11].

Moreover, specific studies have shown that the DNA methylation landscape is not uniform across the genome during aging. For instance, a comprehensive analysis of the mouse DNA methylome revealed that changes are not consistent, with some sites exhibiting accelerated methylation changes in late life. These alterations were associated with genes and promoters enriched for aging-related pathways, underscoring a fundamental link between DNA methylation and the aging process [14].

Interestingly, certain mutations affecting DNA methyltransferase enzymes, which maintain methylation patterns, can lead to unexpected outcomes in the context of aging. For example, a study involving a heterozygous dnmt1 null mutation demonstrated that while aged control mice showed expected patterns of hypomethylation and signs of immune senescence, the knockout mice exhibited increased DNA methylation and a slower progression of autoimmunity and senescence [10]. This suggests that the relationship between DNA methylation and aging is complex and may vary depending on specific genetic contexts.

Additionally, the phenomenon of "regression toward the mean" has been observed in the context of retroelements within aging skeletal muscle, where hypermethylation occurs in weakly methylated copies, while those with stronger methylation levels show hypomethylation. This pattern illustrates the dynamic nature of DNA methylation changes as organisms age [12].

The global hypomethylation hypothesis posits that an overall decrease in DNA methylation correlates with aging, a concept supported by numerous studies across various tissues [3]. However, it is essential to recognize that while global levels may decline, specific regions may experience hypermethylation, indicating a more nuanced understanding of how methylation patterns change with age [15].

In conclusion, the changes in DNA methylation with aging are characterized by both global hypomethylation and region-specific alterations, which together contribute to the biological aging process and the onset of age-related diseases. Understanding these changes provides critical insights into the molecular mechanisms underlying aging and highlights potential avenues for therapeutic interventions aimed at mitigating the effects of aging.

3.2 Age-Related Cellular Changes ​

DNA methylation is a crucial epigenetic modification that plays a significant role in gene expression regulation, and its changes during aging have profound biological implications. As individuals age, the patterns of DNA methylation undergo notable alterations, which can influence cellular functions and contribute to various age-related diseases.

Aging is associated with complex biochemical changes, including those affecting DNA methylation. One of the prominent observations is that DNA methylation generally decreases with age, a phenomenon referred to as genomic hypomethylation. This reduction in global DNA methylation is believed to relax gene expression regulation, potentially leading to abnormal gene expression patterns that are implicated in aging and age-related diseases, including malignancies and autoimmune disorders [2][3][10].

However, the changes in DNA methylation are not uniform across all genes or tissues. For instance, specific genes may experience hypermethylation, while others may become hypomethylated as a function of aging [6]. A study highlighted that among the CpG sites analyzed, 28,196 unique differentially methylated CpGs were identified, reflecting a general trend of hypermethylation and hypomethylation across various genes [16].

Moreover, the age-related changes in DNA methylation are influenced by the local genomic context. For example, research has shown that low CpG density regions are particularly susceptible to change with age, with specific polymorphisms affecting the trajectories of methylation at these sites [8]. The alterations in methylation patterns are often linked to developmental and neurological pathways, underscoring their significance in aging [9].

In addition to the overall decrease in global methylation, intra-individual variations have been observed. For instance, longitudinal studies have documented changes in DNA methylation over time, showing that the methylation status of specific genes can shift significantly, which may correlate with the aging process [7][15]. These findings suggest that while aging is characterized by a general decline in DNA methylation, the specific changes can vary widely between individuals and across different tissues.

Furthermore, the relationship between DNA methylation and aging is also evidenced by the presence of DNA methylation clocks, which utilize methylation patterns to estimate biological age. Discrepancies between chronological age and DNA methylation age have been associated with increased mortality risk, indicating that altered methylation profiles may serve as biomarkers for biological aging [1].

In summary, DNA methylation changes with aging reflect a complex interplay of global hypomethylation and localized hypermethylation, influenced by genetic and environmental factors. These changes are critical in understanding the molecular mechanisms of aging and the development of age-related diseases, emphasizing the need for further research to unravel the intricacies of the aging methylome and its implications for health and longevity.

4 Changes in DNA Methylation with Aging ​

4.1 Global Changes in Methylation Patterns ​

Aging is associated with significant alterations in DNA methylation patterns, which play a crucial role in regulating gene expression and cellular function. The changes in DNA methylation with age can be characterized by both global and site-specific modifications.

Globally, the genomic hypomethylation hypothesis suggests that there is an overall decrease in global DNA methylation levels as organisms age. This decrease may lead to the relaxation of gene expression regulation, potentially resulting in abnormal gene expression and contributing to age-related diseases. Various studies have confirmed that most tissues exhibit a decline in global DNA methylation with age, although this may vary depending on specific regions or sites within the genome [3].

At the same time, certain specific regions of the genome experience hypermethylation as aging progresses. For instance, hypermethylation has been observed in weakly methylated retroelement copies in aged skeletal muscles, while more strongly methylated copies may undergo hypomethylation, reflecting a "regression toward the mean" within these families [12]. This indicates that the dynamics of DNA methylation changes are not uniform across the genome and may depend on the specific context of the DNA sequence and its regulatory elements.

Research has also highlighted that the transition of the methylome throughout the lifespan is not linear. For example, a study on mice showed that both highly and poorly methylated sites tended to move toward intermediate levels, suggesting a trend towards entropy in the methylation landscape with age [14]. This increase in entropy reflects the accumulation of molecular damage and the loss of established methylation patterns that were elaborately established during earlier developmental stages.

Moreover, dietary interventions, such as calorie restriction, have been shown to influence DNA methylation patterns significantly. Calorie restriction not only shifts the overall methylation pattern but also promotes age-related remodeling of the methylome, contributing to lifespan extension [13]. Such interventions may target specific genes involved in metabolic processes, thereby delaying age-related changes in DNA methylation and associated gene expression [17].

Overall, the changes in DNA methylation with aging represent a complex interplay between global hypomethylation and site-specific hypermethylation, influenced by various factors including genetic background, environmental exposures, and dietary habits. Understanding these dynamics is essential for elucidating the mechanisms underlying aging and developing potential interventions aimed at mitigating age-related decline in health and function.

4.2 Tissue-Specific Methylation Changes ​

DNA methylation undergoes significant changes with aging, characterized by both global and tissue-specific alterations. Aging is associated with a complex interplay of DNA methylation dynamics that can influence gene expression and contribute to various age-related diseases.

Aging leads to a progressive loss of 5-methylcytosine content, primarily within DNA repeated sequences and regulatory areas of genes. This phenomenon has been observed across different tissues, indicating a generalized pattern of hypomethylation as individuals age. However, specific genes may exhibit increased promoter methylation, which can silence gene expression once a critical density of methylation is reached. This mosaic pattern of methylation changes introduces variability within tissues and can affect immune function and other biological processes as seen in aging cells [11].

Research indicates that DNA methylation patterns are not uniform across all tissues. For instance, a study analyzing 283 human samples from blood, brain, kidney, and skeletal muscle found both common and tissue-specific age-associated CpG sites (ageCGs). Tissue-specific ageCGs were often located outside of CpG islands and exhibited decreased methylation, while common ageCGs tended to show increased methylation. This suggests that tissue-specific gene expression may protect against the general trend of age-dependent methylation changes [18].

In skeletal muscle, age-related methylation changes were found to be more closely associated with gene expression related to myofiber contraction, whereas kidney-specific ageCGs showed a greater increase in methylation compared to other tissues [18]. Additionally, studies in rats have demonstrated that aging and nutritional factors induce tissue-specific changes in global DNA methylation status, highlighting the influence of external factors on epigenetic profiles [19].

The genomic hypomethylation hypothesis of aging posits that global DNA methylation decreases with age, leading to a relaxation of gene expression regulation. However, it has been observed that while global methylation may decline, specific regions can still exhibit significant changes that do not align with the overall trend [3]. For example, DNA methylation analysis in aging mice has revealed that progressive age-dependent changes can begin before adulthood, indicating a lifelong trajectory of methylation alterations [20].

In summary, DNA methylation changes with aging are characterized by both global hypomethylation and tissue-specific variations. These alterations can significantly impact gene expression, potentially contributing to age-related diseases and influencing the overall aging process. The complexity of these changes underscores the need for further investigation into the mechanisms driving DNA methylation dynamics across different tissues and how they relate to aging phenotypes.

5 DNA Methylation as a Biomarker of Aging ​

5.1 Epigenetic Clocks ​

DNA methylation is a critical epigenetic modification that significantly influences gene expression and is recognized as a biomarker of aging. As individuals age, specific patterns of DNA methylation undergo changes that can be quantitatively assessed, leading to the development of what are known as "epigenetic clocks." These clocks utilize the methylation status of particular cytosine residues at CpG dinucleotides to predict biological age, which may differ from chronological age.

Research indicates that DNA methylation levels typically increase during early life and subsequently decrease in late adulthood, a phenomenon referred to as "epigenetic drift." This drift is characterized by the accumulation of methylation errors that correlate with aging and can be used to predict age-related outcomes, including the risk of frailty and mortality [21][22]. For instance, a study on mouse intestinal stem cells revealed that age-related DNA methylation changes are not only evident in stem cells but also correlate with gene expression levels, impacting a significant number of detectable CpG sites [22].

A key finding in the literature is that while only a small fraction (approximately 2-3%) of CpG sites exhibit age-related methylation changes, this still represents millions of cytosines across the genome [23]. Furthermore, the changes in methylation patterns tend to be enriched in specific genomic contexts, with some studies noting that over 95% of age-related changes in DNA methylation are sexually divergent, indicating that aging impacts males and females differently [23].

Moreover, the association between aging and DNA methylation is further elucidated by the observation that local DNA sequence influences these methylation changes. In particular, low CpG density regions are more susceptible to age-associated alterations, exhibiting variability between individuals over the age of 65 [8]. This susceptibility contrasts with younger individuals, where these regions predominantly lose methylation [8].

The development of epigenetic clocks, which utilize specific sets of CpG sites, has provided powerful tools for estimating biological age. These clocks can accurately reflect an individual's biological state and have been shown to correlate with health-related characteristics and outcomes [24]. For example, epigenetic clocks based on DNA methylation have demonstrated the ability to predict chronological age with high accuracy and have been linked to health outcomes such as cancer risk [25].

Recent studies have also explored the potential for interventions to influence epigenetic aging. For instance, caloric restriction and certain treatments have been shown to reverse or slow down some of the age-related changes in DNA methylation [23]. This suggests that understanding the mechanisms of DNA methylation and its alterations with age could provide insights into potential therapeutic strategies aimed at extending healthspan and lifespan.

In summary, DNA methylation changes with aging are characterized by a complex interplay of genetic, environmental, and lifestyle factors. These changes are quantifiable through epigenetic clocks, which serve as valuable biomarkers for biological aging and related health outcomes. Continued research in this area is crucial for elucidating the underlying mechanisms and developing effective interventions against age-related decline.

5.2 Predictive Models of Biological Age ​

DNA methylation, a key epigenetic modification, undergoes significant changes throughout the aging process, serving as a critical biomarker for biological age. Research indicates that DNA methylation patterns evolve over an individual's lifespan, with specific CpG sites exhibiting either hypermethylation or hypomethylation as age progresses. Approximately 2% of CpG sites in the genome demonstrate age-related changes, translating to about 2 to 3 million cytosines that are influenced by aging [23]. These alterations in DNA methylation are not uniform; they vary across different tissues and cell types, and some studies suggest that age-related changes can be sexually divergent, particularly in the hippocampus [23].

The concept of epigenetic clocks has emerged as a pivotal tool in quantifying biological age based on DNA methylation. These clocks analyze the methylation status of specific CpG sites to accurately predict chronological age across various species, including humans. The development of multi-tissue predictors has shown that DNA methylation age correlates with biological processes and can serve as a measure of age acceleration, particularly in the context of diseases such as cancer [26].

Predictive models of biological age have been developed utilizing DNA methylation data from various tissues and body fluids. For instance, the VISAGE enhanced tool incorporates multiple DNA methylation markers to estimate age in blood, buccal cells, and bones, achieving mean absolute errors of approximately 3.2 to 3.7 years [27]. Such models highlight the applicability of DNA methylation-based age prediction in both clinical and forensic contexts, as they provide high accuracy in determining age from biological samples [28].

Furthermore, studies have explored the implications of DNA methylation changes on health outcomes. Higher DNA methylation age has been associated with increased risks of mortality, cancer, and cognitive impairment [29]. The responsiveness of DNA methylation age to environmental factors suggests its potential role as a mediator or modifier of health effects, emphasizing the need for further research to fully understand the interplay between environmental influences and DNA methylation in aging [29].

In summary, DNA methylation changes significantly with aging, serving as a robust biomarker for biological age. The development of predictive models based on these changes has advanced our understanding of aging and its associated health implications, positioning DNA methylation as a focal point for future research in aging and disease prevention.

6 Implications for Health and Disease ​

6.1 Age-Related Diseases and Methylation ​

DNA methylation is a crucial epigenetic modification that significantly changes with aging, influencing various biological processes and contributing to age-related diseases. As organisms age, the DNA methylation landscape undergoes substantial remodeling, which has been associated with an increased susceptibility to several diseases, including cancer and cardiovascular conditions.

Research indicates that DNA methylation patterns shift over time, characterized by a general trend towards global hypomethylation alongside specific hypermethylation at certain loci. For instance, a study noted that with aging, there is a gradient of DNA methylation changes, which can affect gene expression and cellular functions. These changes are not uniform across different tissues, suggesting that tissue-specific factors play a role in how aging impacts methylation patterns [30].

In the context of age-related diseases, aberrant DNA methylation profiles have been observed in conditions such as Hutchinson-Gilford Progeria and Werner syndrome, which are characterized by features of accelerated aging. In these disorders, mutations in specific genes (e.g., LMNA and WRN) are linked to significant alterations in DNA methylation, suggesting that epigenetic modifications may contribute to the pathophysiology of these conditions [30].

Moreover, aging is associated with the silencing of tumor suppressor genes and the activation of oncogenes through methylation changes, contributing to cancer development. Studies have shown that DNA methylation drift, characterized by both global hypomethylation and focal hypermethylation, plays a pivotal role in the emergence of age-related cancers [31]. The accumulation of methylation errors over time can lead to gene silencing and contribute to the malignant transformation of cells [31].

The interplay between aging and DNA methylation also has implications for other age-related diseases. For example, it has been established that DNA methylation alterations can influence neurodegenerative diseases and metabolic disorders. Changes in methylation levels have been linked to inflammatory responses and the regulation of genes involved in lipid metabolism, indicating that dietary interventions, such as calorie restriction, may mitigate age-related changes in DNA methylation and promote healthier aging [13].

Furthermore, longitudinal studies have documented that specific genes exhibit changes in methylation patterns over time in elderly populations, with some genes showing decreased methylation while others exhibit increased methylation. These findings suggest that DNA methylation may serve as a biomarker for biological aging and disease susceptibility [15].

In summary, the relationship between DNA methylation and aging is complex and multifaceted, with significant implications for health and disease. As aging progresses, alterations in DNA methylation contribute to the development of various age-related diseases, emphasizing the need for further research to understand the underlying mechanisms and potential therapeutic targets to mitigate these effects.

6.2 Potential Therapeutic Interventions ​

DNA methylation is a crucial epigenetic modification that plays a significant role in regulating gene expression and maintaining cellular identity. As individuals age, DNA methylation patterns undergo notable changes, which have profound implications for health and disease.

Aging is associated with a global trend of hypomethylation, particularly at repetitive elements, coupled with site-specific hypermethylation at certain gene promoters. This alteration in the methylation landscape can lead to the silencing of tumor suppressor genes and the activation of oncogenes, thereby contributing to the increased incidence of age-related diseases, including cancer [31]. For instance, studies have demonstrated that aberrant DNA methylation profiles are linked to premature aging disorders such as Hutchinson-Gilford Progeria and Werner syndrome, where significant changes in the DNA methylation landscape were observed in aging-related genes [30].

Moreover, specific gene methylation changes have been correlated with various age-related diseases. For example, research indicates that aging is significantly associated with decreased methylation of certain genes, such as GCR and iNOS, while others like IFNγ and F3 show increased methylation [15]. These gene-specific alterations suggest that DNA methylation can serve as a biomarker for biological aging and disease susceptibility.

The mechanisms driving these age-associated methylation changes remain a subject of investigation. Factors such as oxidative stress, inflammation, and dietary influences have been implicated in the modification of DNA methylation patterns [6]. Reactive oxygen species (ROS), for example, are thought to induce oxidative damage that affects DNA methylation, potentially leading to the dysregulation of genes involved in aging and disease [6].

Given the reversible nature of epigenetic modifications, DNA methylation presents a promising target for therapeutic interventions aimed at mitigating age-related diseases. Interventions such as dietary restriction have been shown to alter DNA methylation patterns, thereby delaying age-related changes and improving health outcomes [13]. Furthermore, the potential for developing DNA methylation-based biomarkers could enhance early detection and personalized treatment strategies for age-related diseases [32].

In summary, the changes in DNA methylation with aging are complex and have significant implications for health and disease. Understanding these alterations not only provides insights into the biological mechanisms of aging but also opens avenues for therapeutic interventions that could improve healthspan and lifespan. As research in this field continues to evolve, it is anticipated that new strategies will emerge to leverage DNA methylation modifications for disease prevention and treatment.

7 Conclusion ​

The intricate relationship between DNA methylation and aging reveals a complex interplay of global hypomethylation and localized hypermethylation, significantly impacting gene expression and contributing to age-related diseases. Current research indicates that as organisms age, there is a general decline in global DNA methylation levels, which can lead to a relaxation of gene regulation and abnormal gene expression patterns. However, specific genomic regions exhibit hypermethylation, particularly at gene promoters, which may silence essential genes and increase the risk of various age-related pathologies, including cancer and autoimmune disorders. The variability in DNA methylation changes across different tissues underscores the importance of understanding tissue-specific epigenetic dynamics in the context of aging. Future research should focus on elucidating the mechanisms driving these methylation changes and their biological implications, as well as exploring the potential of DNA methylation as a biomarker for biological age and a target for therapeutic interventions. The development of epigenetic clocks and predictive models of biological age highlights the relevance of DNA methylation in assessing individual health status and guiding personalized medicine approaches in aging and age-related diseases. Ultimately, advancing our understanding of the role of DNA methylation in aging may provide new avenues for interventions aimed at promoting healthy aging and mitigating the effects of age-related decline in health and function.

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