Epigenetic dynamics of aging and cancer development - current concepts from studies mapping aging and cancer epigenomes

Abstract

Purpose of review:

This review emphasizes the role of epigenetic processes as incidental changes occurring during aging, which, in turn, promote the development of cancer.

Recent Findings:

Aging is a complex biological process associated with the progressive deterioration of normal physiological functions, making age a significant risk factor for various disorders, including cancer. The increasing longevity of the population has made cancer a global burden, as the risk of developing most cancers increases with age due to the cumulative effect of exposure to environmental carcinogens and DNA replication errors. The classical "somatic mutation theory" of cancer etiology is being challenged by the observation that multiple normal cells harbor cancer driver mutations without resulting in cancer. In this review, we discuss the role of age-associated epigenetic alterations, including DNA methylation, which occur across all cell types and tissues with advancing age. There is an increasing body of evidence linking these changes with cancer risk and prognosis.

Summary:

A better understanding about the epigenetic changes acquired during aging is critical for comprehending the mechanisms leading to the age-associated increase in cancer and for developing novel therapeutic strategies for cancer treatment and prevention.

Introduction

Aging is a complex biological process marked by a gradual decline in normal bodily functions over time, significantly increasing the risk of various disorders, including cancer (1) (2,3). Aging and cancer share several biological processes which play critical roles in the increased incidence of cancer(4,5) (6). At a basic level, the risk of cancer development increases with age because of the cumulative effect of exposure to environmental carcinogens and random mistakes during normal DNA replication which increases with age (7). This classical “somatic mutation theory” of etiology of cancer is increasingly being challenged by observations that multiple normal cells in the human body harbor mutations, including what are considered as cancer driver mutations, without discernible cancer phenotypes (8,9). Simultaneously, emerging evidence underscores non-mutational processes during aging as crucial in driving tumor initiation, progression, and metastasis. This review will highlight key evolving concepts involving epigenetic changes during aging that are critical in tumorigenesis. Understanding these mechanisms is crucial in comprehending age-associated development of cancers, and for development of cancer treatments and preventive strategies.

Background on Epigenome

Epigenetic regulation of gene expression involves partly heritable gene activity programs without alterations in the DNA sequence, which is crucial for normal development and cellular functions. Broadly, epigenetic regulation involves any heritable molecular feature that does not affect DNA sequence, such as DNA methylation (DNAm), histone modification, chromatin remodeling, non-coding RNA regulation, and potentially RNA modifications. This review will focus on DNAm and histone modifications, and the resulting nuclear chromatin organization (10-12). DNAm modification of interest here involves the methyl group at the 5' position of cytosine residues, resulting in 5-methyl-cytosine. Majority of 5-methyl-cytosine in mammalian somatic cells post-development occurs in the context of 5’-cytosine-guanosine-3’ (CpG) dinucleotide (13). Histone modifications, on the other hand, alter DNA-protein complexes (chromatin) structure, influencing gene expression and the nuclear organization of chromatin (14,15), with important roles in cancers (16). These epigenetic mechanisms regulate chromatin structure, nuclear organization, thereby influencing gene expression (17).

Epigenetic patterns are pivotal for chromosomal organization and orchestrated gene expression critical for healthy physiology (17). Based on the DNAm and histone modification patterns, the genome is broadly organized into euchromatin and heterochromatin (Fig. 1). Euchromatin, less condensed and linked with active gene expression, is characterized by specific histone modifications like H3K4 di- or trimethylation, H3K36 trimethylation, and H3K9 acetylation. In contrast, heterochromatin is condensed, marked by H3K9 trimethylation and H4K20 trimethylation, and often linked to gene silencing (18-20). Transitioning between euchromatin and heterochromatin states is facultative heterochromatin, a dynamic and reversible form marked by H3K27 methylation, mediated by the Polycomb group (PcG) of proteins (21). Unlike the permanently condensed constitutive heterochromatin, typically consisting of repetitive sequences like centromeres and telomeres, facultative heterochromatin varies in its level of condensation and gene expression based on the cell's needs or developmental stage.

Figure 1: Chromatin and nuclear architecture of aging and cancer cells.

Somatic cells arising post-embryonic development, depicted on the left, have a highly ordered nuclear organization of DNA. This involves the major classes of chromatin domains based on epigenetic modifications and resulting transcriptional status. The overall structural organization of nuclear DNA undergoes similar alterations during aging and in cancers. Majority of the factors contributing to these changes are highly overlapping in aging and cancers. Although overall the nuclear structural organization, and the underlying mechanisms are similar, there are differences in the genomic regions involved, as discussed in the article, that endows tumor suppressive vs. oncogenic functionalities to the genomic organization. Normal age-associated changes lead to non-tumorigenic states. However, subpopulation of aging cells with an altered epigenome can potentially acquire tumor suppressive and oncogenic programs and may more readily undergo clonal expansion and further selection. These epigenetic processes can evolve, and may select for, cancer driving mutations.

Separation of the euchromatic and heterochromatic compartments is an universal feature of somatic cells with important roles in regulating gene expression and structural organization of DNA (Fig. 1). These chromatin compartments are radially organized in relation to other structural components, such as the nuclear envelope (lamin proteins) and nucleoli. Heterochromatin typically forms large domains that interact with the nuclear lamina, creating lamina-associated domains (LADs), while euchromatin occupies internal regions within the nucleus (22,23). The nature of chromatin compartments plays important roles in structural organization. Studies have demonstrated that the attraction between heterochromatin-marked chromatin and the nuclear lamina is critical in maintaining the nuclear organization of chromatin domains (24).

Epigenetic changes in aging and cancer

Over time, chromatin marks and DNAm patterns undergo alterations linked to aging-related processes and diseases (25,26). DNAm tends to decrease globally with age, a phenomenon known as global hypomethylation (27). However, certain regions of the genome, such as subsets of CpG islands (CGI), may become hypermethylated with age (27). This can result in the silencing of genes that should normally be active, contributing to age-related changes in cellular function.

Over the past decade, studies have unveiled numerous parallels in epigenetic changes during aging and in cancers. A major model system to study age-related changes to the epigenome has been senescent cells, a cellular state arising during aging mainly due to continuous cell division cycles and genotoxic stress. This is a metabolically active cellular state characterized by durable cell-cycle arrest. In parallel, aging also involves cells entering quiescent state, involving reversible proliferative arrest in which cells are not actively dividing but retain the capacity to reenter the cell cycle (28,29). This includes tissue-resident adult stem cells, such as hematopoietic, muscle, and neural stem cells, as well as differentiated cells like fibroblasts, hepatocytes, lymphocytes, and oocytes. Quiescent cells play crucial roles in tissue repair, immunity, and reproduction (30).

While most studies investigating epigenomic changes during aging focus on senescent and quiescent cells within non-epithelial lineages—like fibroblasts and muscle stem cells—epithelial cells contributing to over 80% of cancers (31) also undergo similar states during aging. Collectively, these studies suggest that aging induces epigenomic alterations, impacting various aspects of chromatin organization and gene expression. While these changes are primarily associated with tumor-suppressive roles, the same epigenomic states can foster the evolution of clonal expansions. In the context of key driver mutations and an aging tissue microenvironment, these states become conducive to tumorigenesis.

Age-related epigenetic changes primarily involve the loss of chromatin architecture in heterochromatin (Fig. 1). Notably, aging triggers a widespread reduction of core histone proteins across the genome, resulting in reconfiguration of heterochromatin (1,32). Several studies have extensively analyzed chromatin marks defining euchromatin, heterochromatin, interchromosomal interactions, chromatin domain organization, and interactions with nuclear lamin in aging, senescent, and quiescent cells (33,34). These studies have revealed a notable weakening of these chromatin demarcations in aged cells. Similarly, progressive loss of heterochromatin structures marked by decompaction, and enhanced formation of transcriptional hubs is characteristic of multiple cancer types (35,36). Disruption of chromatin patterns encompasses loss of constitutive and facultative heterochromatin components, triggered by loss of H3K9me3 and H3K27me3 marks, respectively (37). Concurrently, DNAm decreases within the heterochromatin, while promoter-CGI regions undergo increased DNAm (38-40). The decline in heterochromatin has been linked to the aging process and age-related disorders, contributing to cellular malfunctions and exacerbating the aging progression and evolution of cancer phenotypes (41,42).

The structural characteristics and spatial arrangement of heterochromatin are vital for maintaining nuclear architecture and coordinating gene expression. Changes to heterochromatin during aging and tumorigenesis are associated with large scale three-dimensional genome reorganization and aberrant transcription (37,43-45) , involving abnormal activation and silencing of genes by forming transcriptional and repressive hubs in aging (46,47) and in cancers (48-53) (Figure 1). In the aging context, the majority of gene expression changes potentially result from programmatic alterations in chromatin reorganization, however, these large-scale reorganizations can also lead to incidental gene expression changes. For example, both aging and cancer cells involve ectopic expression of genes that are normally silenced in somatic cells, such as extraembryonic antigens, cancer germline antigens (CGAs) and endogenous retroviruses (ERVs) (33,54). Additionally, in cancers chromatin alterations accompany formation of transcriptional hubs that meet the demand for high expression of oncogenic genes important for tumor progression, such as formation of super enhancer domains (55-58).

Programmed vs. Stochastic Epigenetic Changes During Aging and Tumorigenesis

Most of the epigenetic changes during aging appear to follow a program attaining a resultant transcriptome essential for the phenotype of aged cells, generally the state of halted cell division cycles. Chromatin architecture changes during senescence follow a defined program, with formation of senescence-associated heterochromatic foci (SAHF) associated with heterochromatic markers such as histone H3K9 and K27 trimethylation (H3K9me3 and H3K27me3), the histone H2A variant macroH2A, and high mobility group A (HMGA) proteins (59-61). SAHF foci are enriched in the DNA damage marker γH2AX, are devoid of active chromatin marks, and function in sequestering and silencing proliferation-promoting genes, including E2F target genes such as cyclin A (62). The quiescent state shares large-scale chromatin changes with senescent cells but maintains some compartmental organization seen in proliferating cells (46). SAHF is not associated with cells undergoing quiescence, indicating that SAHF formation is not linked to reversible cell cycle exit. Loss of heterochromatin structure in senescent cells creates open and accessible chromatin, likely facilitating the senescence-maintaining transcriptome, such as the senescence-associated secretory phenotype (SASP) which involves secretion of a range of pro-inflammatory cytokines, chemokines, and growth factors (59,63). In the aging process, senescence functions as a double-edged sword: while crucial for tissue repair in young individuals, its continued activation in aging causes tissue damage (64-66). The chromatin changes in quiescent cells mirror those in senescent cells, involving a loss of heterochromatin associated with nuclear lamin. In a liver model, these chromatin changes include global replacement of H3K9me3 domains with the facultative heterochromatin mark of H3K27me3 in broad domains. H3K27me3 is simultaneously lost from promoters of genes encoding developmental transcription factors leading to ectopic expression of non-hepatocyte markers. During regeneration, these alterations reverse as cells re-enter the cell cycle (67). Most of the aged cells in higher organisms tend towards this hyper-quiescent and non-dividing state, potentially conferring anti-tumor properties. Both senescent and quiescent cells exhibit increased cryptic transcription alongside these chromatin changes (45,68). Hence, epigenomic reorganizations in senescence and quiescence aim to sustain active tissue repair or regeneration. However, the negative outcomes, like cryptic transcription and misregulated, ectopic expression of non-specific genes, might result from the large-scale chromatin rearrangements demanded by aging processes.

DNA methylation and chromatin organization roles in cancers

Comparing DNAm alterations during in vitro senescence and transformation has revealed that transformation-associated methylation changes arise stochastically and independently of programmatic changes during senescence (40,69). Promoter hypermethylation events during transformation primarily affects genes involved in pro-survival and developmental regulation. Similar genes are affected by promoter hypermethylation in primary tumors. The programmatic methylation changes during senescence additionally targets biosynthetic processes early during the senescence progression, consistent with senescence-associated epigenetic reorganization promoting the shutting-down of cell cycle and biosynthetic processes (70,71). Interestingly, once the senescent-methylation state is established, these cells can be immortalized but are resistant to transformation.

Emerging evidence suggests that large-scale epigenetic changes, including the DNA hypomethylation accumulating during aging, are a resultant of continuous cell divisions and are tumor suppressive. By analyzing topological and DNAm changes in cancers, normal tissues and replicative senescence, it has been demonstrated that the majority of the compartmental reorganization of chromatin domains result from excessive cell divisions, an inseparable feature of aging (54). The compartmental reorganization in tumors involves the above-described loss of heterochromin (B-compartments) from the LADs at the nuclear periphery and intermixing with the euchromatic compartment (A-compartment) (Figure. 1). Broadly, this chromatin domain reorganization appears similar in senescent and tumor cells. Importantly, such chromatin reorganization in cells that have undergone numerous divisions leads to a tumor suppressive program, involving downregulation of genes associated with oncogenic functions, cell cycle, and Wnt signaling.

Consequently, most aged cells, encompassing quiescent and senescent cells, undergo tumor suppressive chromatin reorganization program. It is highly likely that from a pool of regenerative epithelial stem cells, the replicative divisions during aging processes also result in sufficient heterogeneity in epigenetic patterns, which may allow for clonal expansion of fitter clones. These fitter clones would then become fixed on an oncogenic trajectory in the presence of appropriate mutations. This model is supported by studies demonstrating an altered epigenome in ex vivo aged colon stem cells involving hypermethylation of CGI promoters of genes related to developmental processes, stem cell differentiation, and negative regulation of Wnt pathways (39). Within such background of epigenetic changes, induction of Braf-oncogene results in immediate transformation of colon stem cells. Supporting this notion, another recent study demonstrated that inducing Braf-oncogene in aged mice causes a ten-fold increase in neoplastic lesions compared to young animals (72). These lesions exhibit accelerated age-associated DNAm, particularly in Wnt pathway genes. In aged colon epithelial stem cells, promoter-methylation of Wnt and tumor suppressor genes, like Cdx2, Sfrp4, Sox17, and Cdkn2a, facilitates tumor initiation in the context of the Braf-oncogene (39).Thus, emerging models suggest that aging involves programmed chromatin reorganization, primarily tending towards tumor suppression. However, this process also results in an epigenome more malleable to adopting oncogenic programs and initiating tumors (Figure 1).

Drivers of epigenetic changes during aging and cancers

Some of the major mechanisms common to aging and cancers driving epigenome changes are:

DNA Damage:

There is mounting evidence supporting DNA damage as pivotal in driving age-related epigenetic alterations and associated physiological defects. Inducing DNA damage, without subsequent mutations, can sufficiently lead to the loss of epigenetic information and trigger the aging phenotype (73). These studies help understand aging as a process driven by erosion of epigenetic information rather than accumulation of genetic changes (73). Similarly, DNA damage play a role in inducing promoter methylation changes associated with cancer, and inhibiting this has anti-tumor effects (74). Similar to genomic mutations and transcriptional disruptions that increase with aging, DNAm aberrations and altered histone modifications also increase, fostering stochastic variations in gene expression (75). This increases the frequency of occurrence of spontaneous DNA lesions, prompting DNA damage response (DDR) to halt the cell cycle and enable DNA repair (76) (Figure 2). Excessive DDR causes cells to undergo apoptosis and senescence (the two basic hallmarks of aging) (77). Oxidative damage of nuclear DNA due to ROS induces formation and relocalization of silencing complexes consisting of key enzymes involved in chromatin and DNAm (Figure 2). This involves DNMT1 recruitment to complex(es) containing DNMT3B and members of the polycomb repressive complex 4 (PRC4) that causes de novo epigenetic changes and transcriptional silencing of targeted promoter regions.

Figure 2: Mitochondrial defects and its role in aging and cancer via modulation of epigenome.

Dysfunctional mitochondria can affect epigenome by causing oxidative stress as well as altering cellular metabolite pool. Mitochondrial ROS generation (due to mitochondrial metabolism) causes oxidative damage to the mitochondrial DNA (mtDNA) which can cause further mitochondrial dysregulation and ROS generation. Action of ROS on nuclear DNA influences epigenetic processes by inducing DNA damage related redistribution of epigenetic modifers such as DNMTs and PcG components. Mitochondrial ROS also catalyzes the activation of oncogenic signaling pathways in response to a DSB which is associated with H2AX phosphorylation and H4K16 acetylation. DSB activates the HATs followed by activation of the key components (BRD, SIRT1, EZH2, DNMT1, and DNMT3B) required for chromatin accessibility and thus, stimulates the repair pathway. This is further followed by decrease in H4K16 acetylation and increase in H3K27me because of the persistent localization of EZH2 and DNMT1 around the break site. The methylation mediated by H3K27 spreads along the gene promoter leading to aberrant gene silencing. Additionally, mitochondria is a source for critical metabolites such as, a-KG, SAM (S-Adenosyl methionine), which are cofactors and substrates for epigenetic modifiers. Mitochondrial dysfunction can alter the metabolite pools, thus impacting the epigenome.

One of the aspects driving DNA-damage related epigenetic changes is the high similarity of DNA repair enzymatic machinery with the DNA replication machinery, which includes epigenetic modifiers involved in catalyzing DNAm, histone depositions and subsequent histone modification at the newly synthesized/repaired DNA (78-80). This includes recruitment of silencing factors like HP1, polycomb group proteins (PRCs), histone deacetylases (HDACs, SIRT1), histone methyltransferases (SETDB1, SUV39H1/H2) and DNA methyltransferases (DNMT1, DNMT3B) at sites of DNA damage. Consequently, sites of DNA repair may harbor altered DNAm and histone modifications (74,80-82) (Figure 2). Importantly, acute DNA damage has been shown to cause a global redistribution of epigenetic modifiers at non-GC-rich to GC-rich areas, and cause methylation of CGI regions leading to gene silencing and involvement in tumor phenotypes (83). This redistribution is expected to change methylation not only at the DNA damage sites, but also at other chromatin regions. In a recent study, the introduction of ~20 damage sites in the mouse genome continuously for a short period of 3-weeks was enough to cause epigenetic alterations like those observed in aged cells, and aging phenotypes months after DNA damage (73). Thus, DNA damage-induced redistribution of epigenetic factors have roles in altering the epigenome during aging. Furthermore, coupling of DNA damage to epigenetic modulation is an evolutionarily conserved phenomenon. In yeast, aging is primarily associated with loss of epigenetic information primarily due to relocalization of chromatin modifiers to the site of DNA damage, involving chromatin modifiers including Sir2, Hst1, Rpd3, Gcn5, and Esa1 (84-86). DNA damage irregularities are a prominent feature of increased oncogenic signaling in cancers, which may thus further amplify epigenetic alterations during tumorigenesis.

Mitochondrial dysfunction:

Coupled to the DNA damage role in modulating the epigenome is the role for mitochondria, which is crucial in many cellular processes, including cellular metabolism and aging. Mitochondrial dysfunction and mitochondrial DNA (mtDNA) damage can influence epigenetic processes within cells (Figure 2). Several studies have identified mitochondrial dysfunction to impact epigenetic landscape of the nuclear genome (87,88). Mitochondrial dysfunction and mtDNA damage could induce reversible or irreversible changes in nuclear genomic DNAm profiles and thus, has important implication in the pathogenesis of aging, cancer and a wide range of mitochondrial diseases (89,90). Smiraglia et al. first reported that depletion of mtDNA induces DNAm in the nuclear genome, and that some of these nuclear changes can be reversed by reintroduction of the wild-type mitochondria (91). Dysfunctional mitochondria can lead to an increase in ROS production and thus, causes oxidative stress. Further, the elevated ROS levels due to mitochondrial dysfunction activates the NF-κB signaling pathway, thus, activating the inflammatory response (92). An inflammatory microenvironment has been independently linked to inducing epigenetic alterations by triggering alteration in expression of DNMT1 and inducing oxidative stress (93-98).

Emerging evidence shows that through its effects on ROS and energy metabolism, mitochondrial changes during aging can contribute to epigenetic changes (Figure 2). Mitochondrial activation of nicotinamide adenine dinucleotide phosphate (NADPH) oxidase (NOX) further facilitates mitochondrial ROS mediated activation of oncogenic signaling pathway. One such pathway is phosphoinositide 3-kinase (PI3K) signaling pathway, which is upregulated in several malignancies (99). As described earlier, oxidative damage from ROS can cause epigenetic changes via the DNA damage-related epigenetic processes. Through its role as central hub of metabolism, mitochondrial dysfunction can alter metabolite levels and impact epigenetic changes. Studying haplotypes of mtDNA within the same background of nuclear DNA has revealed that mtDNA-haplotypes influence chromosomal gene expression and DNAm patterns (100). These epigenetic changes may result from the differential production of α-ketoglutarate, a direct product of the TCA cycle, and a co-factor for the TET family of proteins involved in demethylating DNA. Another direct metabolite, linked to the mitochondrial metabolism via the TCA cycle and central to chromatin modifications, is acetate (101) which maintains acetyl coenzyme A (Ac-CoA) required for acetylation of histone proteins. Mitochondrial dysfunction can impact Ac-CoA levels through the inhibition of Ac-CoA production, acyl-CoA accumulation, and disruption of metabolic flexibility (102). Thus, mitochondrial metabolite generation is another key mechanism underlying epigenome modulation (103), and mitochondrial dysfunction during aging can potentially impact the epigenome in a gradual process. Increased mitochondrial dysfunction during tumorigenesis may further contribute to epigenetic changes by altering ROS and metabolite levels. The dynamics underlying these changes and the direct impact of oncogenic mutational changes in cancers need further work.

Telomere shortening and Senescence:

Telomere shortening plays a significant role in aging and is closely related to cancer development. Telomeres are protective caps consisting of repetitive DNA sequences in a nucleoprotein complex located at the ends of linear chromosomes (104). They are essential for maintaining genomic integrity, shielding chromosome ends from erosion during replication. However, telomere ends are shortened with each cell division, ultimately reaching lengths leading to DNA instability and triggering DDR and TP53-dependent checkpoint pathways (105,106) (Figure 3). These molecular checkpoints halt further cell divisions, and trigger senescence or programmed cell death (apoptosis) (107). In such capacity, telomere shortening is a tumor suppressive mechanism (108-110) where it leads to elimination of aged cells that are more likely to harbor genetic changes acquired during successive cell-division cycles.

Figure 3: Telomere shortening and DNA damage in aging and cancer.

During normal cell division cycle, the telomere shortening causes cellular senescence (replicative senescence). A fraction of cells which undergo genetic and epigenetic alterations, potentially progress to neoplastic transformation and forms cancer. Telomere shortening and environmental exposures causes double strand DNA damage which activates the TP53 dependent DDR to repair the damage which cause the cells to undergo senescence/apoptosis. Persistent DNA damage causes epigenetic alterations through various mechanisms as explained in the article. This leads to aging and cancer incidence.

However, continued DDR due to telomere shortening, and the ensuing senescence programs, have important roles in altering the epigenome. Damage induction causes widespread epigenetic changes, while shortened telomeres lead to the depletion of protective factors like SIRT1, rendering chromosomal ends susceptible to damage, fusions, and rearrangements (111). This loss of protective complexes prompts a shift of silencing mechanisms from chromosome ends to other areas of the genome, fostering epigenetic alterations and chromosomal instability that may trigger cancer development. Consequently, this redistribution of epigenetic modifiers can induce abnormal gene silencing (74,112).

Telomere shortening induced senescence is associated with multiple phenotypes involving progressive alterations to chromatin (Figure 3). One such alteration involves chromatin fragments detaching from the nucleus, forming cytoplasmic chromatin fragments that are subsequently degraded through phagocytosis. This process ultimately contributes to the loss of heterochromatin in senescent cells (113,114). SASP induction and the pro-inflammatory cytokine secretion triggers inflammatory microenvironment that positively feeds to the epigenetic alterations. The hypomethylation mediated transcriptional derepression of retrotransposable elements (such as L1) further activates a type-I interferon (IFN-I) response during later stages of senescence, which is critical for the SASP phenotype (115). Inhibitors targeting the L1 reverse transcriptase prevent this inflammation and can be a relevant target for cancer prevention. Senescence induction also links to mitochondrial dysfunction, thus leading to persistent and increased mitochondrial ROS (116). Mitochondrial ROS is required for SASP generation, and downstream effects of SASP, such as generation of cytoplasmic chromatin fragments (117-119).

Cancer cells circumvent telomere shortening and evade senescence by silencing key senescence checkpoints (such as p53 and CDKN2A) and by maintaining hTERT expression, an enzyme involved in telomere maintenance (120,121), or through the alternative lengthening of telomeres (ALT) pathway (122,123). hTERT activation triggers an epigenetic profile akin to aged and cancer cells, distinct from senescent cells (69). Thus, hTERT-mediated immortalization may contribute to escape from senescence-associated genome-wide epigenetic reprogramming, but still resulting in epigenetic changes due to constant cell divisions. These studies uncouple the age-related epigenetic changes from the tumor-suppressive senescence induced epigenetic changes. hTERT has roles other than telomere maintenance, such as efficient DNA repair and reducing mitochondrial oxidative stress (124). Thus, the process of immortalization per se is associated with age-related epigenetic changes by enabling continuous cell division cycles (66)(125). This process may involve constant DNA damage and oxidative stress during continuous cell division cycles. Thus, various aspects of the continuous cell division cycles involving the constant stress arising from telomere deprotection, DNA damage induced induction of senescence pathways, associated mitochondrial dysfunction forms a positive-feedback loop modulating large scale epigenetic changes in aging cells.

Conclusion:

Common molecular mechanisms driving epigenetic alterations but leading to different epigenomes in cancer and non-cancerous aged cells need further understanding, which is important to develop better therapeutic strategies, markers for early cancer detection and cancer-prevention approaches. Regarding the latter, recent developments in aging research have paved the way for the development of anti-aging strategies, such as diet restriction, senolytics and senomorphics, as potential interventions to address age-related disorders including cancer (126-129). These anti-aging approaches, aimed at targeting and mitigating multiple age-related processes like cellular senescence, inflammation and metabolic imbalance, hold promise to revolutionize therapy of age-related diseases. In parallel, epigenetic therapies have a long history of clinical development, with potent drugs able to reverse epigenetic changes discussed above (130,131). Further studies on the mechanism of aging and cancer epigenomes, and combined interaction of anti-aging and epigenetic drugs hold promise for targeting the epigenome for cancer therapeutic and prevention.

Key points:

1. Aging and cancer epigenomes have various commonalities due to similar mechanisms driving these changes.

2. Aging involves progressive epigenomic changes due to constant cell division cycles that promote tumor suppressive mechanisms but may also enable epigenetic states facilitating tumorigenesis.

3. Shared mechanisms involve non-mutational processes centrally linked to DNA damage pathways.