Epigenetic Dynamics of Aging and Cancer Development (PDF)

REVIEW URRENT C OPINION Downloaded from http://journals.lww.com/co-oncology by BhDMf5ePHKav1zEoum1tQfN4a+kJLhEZgbsIHo4XMi0hC ywCX1AWnYQp/IlQrHD3i3D0OdRyi7TvSFl4Cf3VC1y0abggQZXdtwnfKZBYtws= on 03/07/2024 Epigenetic dynamics of aging and cancer development: current concepts from studies mapping aging and cancer epigenomes Shilpa Bisht, Yiqing Mao and Hariharan Easwaran 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 cause 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. Keywords aging, cancer, DNA damage response, DNA methylation, epigenetic mechanisms, gene silencing 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 [1–3]. Aging and cancer share several biological processes which play critical roles in the increased incidence of cancer [4–6]. 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. 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 nonmutational processes during aging as www.co-oncology.com 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. Cancer Genetics and Epigenetics, Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, CRB1, Baltimore, Maryland, USA Correspondence to Hariharan Easwaran, Cancer Genetics and Epigenetics, Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, CRB1 Rm530, 1650 Orleans Street, Baltimore, MD 21287, USA. Tel: +1 410 955 8506; fax: +1 410 614 9884; e-mail: [email protected] Curr Opin Oncol 2024, 36:82–92 DOI:10.1097/CCO.0000000000001020 Volume 36 Number 2 March 2024 Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved. Epigenetic dynamics of aging and cancer development Bisht et al. KEY POINTS Aging and cancer epigenomes have various commonalities due to similar mechanisms driving these changes. Downloaded from http://journals.lww.com/co-oncology by BhDMf5ePHKav1zEoum1tQfN4a+kJLhEZgbsIHo4XMi0hC ywCX1AWnYQp/IlQrHD3i3D0OdRyi7TvSFl4Cf3VC1y0abggQZXdtwnfKZBYtws= on 03/07/2024 Aging involves progressive epigenomic changes due to constant cell division cycles that promote tumor suppressive mechanisms but may also enable epigenetic states facilitating tumorigenesis. Shared mechanisms involve nonmutational processes centrally linked to DNA damage pathways. 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, noncoding 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 postdevelopment occurs in the context of 5’-cytosine-guanosine-3’ (CpG) dinucleotide. 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. These epigenetic mechanisms regulate chromatin structure, nuclear organization, thereby influencing gene expression. Epigenetic patterns are pivotal for chromosomal organization and orchestrated gene expression critical for healthy physiology. 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 FIGURE 1. Chromatin and nuclear architecture of aging and cancer cells. Young somatic cells have highly organized chromatin domains marked by different epigenetic modifications. The overall structural organization of nuclear DNA becomes compromised during aging and cancer development. While the mechanisms through which these changes occur are similar in aging and cancer, the different genomic regions involved distinguish oncogenic transformations from normal, nontumorigenic age-associated changes. Still, aged cells with altered epigenome could potentially acquire either tumor suppressive or oncogenic programs. The subpopulation of aged cells with cancer driving mutations and epigenetic alterations may have a selective advantage and undergo clonal expansion. 1040-8746 Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved. www.co-oncology.com Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved. 83 Cancer biology Downloaded from http://journals.lww.com/co-oncology by BhDMf5ePHKav1zEoum1tQfN4a+kJLhEZgbsIHo4XMi0hC ywCX1AWnYQp/IlQrHD3i3D0OdRyi7TvSFl4Cf3VC1y0abggQZXdtwnfKZBYtws= on 03/07/2024 euchromatin and heterochromatin states is facultative heterochromatin, a dynamic and reversible form marked by H3K27 methylation, mediated by the Polycomb group (PcG) of proteins. 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. Separation of the euchromatic and heterochromatic compartments is a 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. 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. However, certain regions of the genome, such as subsets of CpG islands (CGI), may become hypermethylated with age. 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, 84 www.co-oncology.com hepatocytes, lymphocytes, and oocytes. Quiescent cells play crucial roles in tissue repair, immunity, and reproduction. While most studies investigating epigenomic changes during aging focus on senescent and quiescent cells within nonepithelial lineages—like fibroblasts and muscle stem cells—epithelial cells contributing to over 80% of cancers 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. 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] (Fig. 1). In the aging context, the majority of gene expression changes potentially result from programmatic alterations in chromatin Volume 36 Number 2 March 2024 Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved. Epigenetic dynamics of aging and cancer development Bisht et al. Downloaded from http://journals.lww.com/co-oncology by BhDMf5ePHKav1zEoum1tQfN4a+kJLhEZgbsIHo4XMi0hC ywCX1AWnYQp/IlQrHD3i3D0OdRyi7TvSFl4Cf3VC1y0abggQZXdtwnfKZBYtws= on 03/07/2024 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 gH2AX, are devoid of active chromatin marks, and function in sequestering and silencing proliferation-promoting genes, including E2F target genes such as cyclin A. The quiescent state shares large-scale chromatin changes with senescent cells but maintains some compartmental organization seen in proliferating cells. 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 senescencemaintaining transcriptome, such as the senescenceassociated 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 nonhepatocyte 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 hyperquiescent and nondividing state, potentially conferring antitumor 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 nonspecific 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. The compartmental reorganization in tumors involves the abovedescribed loss of heterochromin (B-compartments) from the LADs at the nuclear periphery and intermixing with the euchromatic compartment (A-compartment) (Fig. 1). Broadly, this chromatin domain reorganization appears similar in senescent and tumor cells. Importantly, such chromatin reorganization in cells that have undergone numerous 1040-8746 Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved. www.co-oncology.com Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved. 85 Cancer biology Downloaded from http://journals.lww.com/co-oncology by BhDMf5ePHKav1zEoum1tQfN4a+kJLhEZgbsIHo4XMi0hC ywCX1AWnYQp/IlQrHD3i3D0OdRyi7TvSFl4Cf3VC1y0abggQZXdtwnfKZBYtws= on 03/07/2024 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. 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. 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 Brafoncogene. 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 (Fig. 1). DRIVERS OF EPIGENETIC CHANGES DURING AGING AND CANCERS Some of the major mechanisms common to aging and cancers driving epigenome changes are as follows. 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 && && 86 www.co-oncology.com methylation changes associated with cancer, and inhibiting this has antitumor effects. 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. This increases the frequency of occurrence of spontaneous DNA lesions, prompting DNA damage response (DDR) to halt the cell cycle and enable DNA repair (Fig. 2). Excessive DDR causes cells to undergo apoptosis and senescence (the two basic hallmarks of aging). Oxidative damage of nuclear DNA due to ROS induces formation and relocalization of silencing complexes consisting of key enzymes involved in chromatin and DNAm (Fig. 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. 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] (Fig. 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. This redistribution is expected to change methyl,ation not only at the DNA damage sites, but also at other chromatin regions. In a recent study, the introduction of nearly 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 && Volume 36 Number 2 March 2024 Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved. Epigenetic dynamics of aging and cancer development Bisht et al. Downloaded from http://journals.lww.com/co-oncology by BhDMf5ePHKav1zEoum1tQfN4a+kJLhEZgbsIHo4XMi0hC ywCX1AWnYQp/IlQrHD3i3D0OdRyi7TvSFl4Cf3VC1y0abggQZXdtwnfKZBYtws= on 03/07/2024 FIGURE 2. Mitochondrial defects and its role in aging and cancer via modulation of epigenome. Dysfunctional mitochondria can affect epigenome by causing oxidative stress and altering the cellular metabolite pool that contain critical cofactors and substrates for epigenetic modifiers. Mitochondrial metabolism generates ROS that leads to oxidative damage in both the mitochondrial DNA (mtDNA) and nuclear DNA. Damage to the mtDNA can cause further mitochondrial dysregulation and more ROS production. The impact of ROS on nuclear DNA is multifold: It can induce DNA damage related redistribution of epigenetic modifiers and catalyze the activation of oncogenic signaling pathways in response to a DSB. These processes will ultimately lead to aberrant gene silencing. 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 (Fig. 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. 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-kB signaling pathway, thus, activating the inflammatory response. An inflammatory microenvironment has been independently linked to inducing epigenetic alterations by triggering alteration in expression of DNMT1 and inducing oxidative stress [93–98]. 1040-8746 Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved. www.co-oncology.com Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved. 87 Cancer biology Downloaded from http://journals.lww.com/co-oncology by BhDMf5ePHKav1zEoum1tQfN4a+kJLhEZgbsIHo4XMi0hC ywCX1AWnYQp/IlQrHD3i3D0OdRyi7TvSFl4Cf3VC1y0abggQZXdtwnfKZBYtws= on 03/07/2024 Emerging evidence shows that through its effects on ROS and energy metabolism, mitochondrial changes during aging can contribute to epigenetic changes (Fig. 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. As described earlier, oxidative damage from ROS can cause epigenetic changes via the DNA damagerelated 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. These epigenetic changes may result from the differential production of a-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 , 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. Thus, mitochondrial metabolite generation is another key mechanism underlying epigenome modulation , 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. 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] (Fig. 3). These molecular checkpoints halt further 88 www.co-oncology.com cell divisions, and trigger senescence or programmed cell death (apoptosis). 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. 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. 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 (Fig. 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. 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. 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. Thus, hTERT-mediated immortalization may contribute to escape from senescenceassociated genome-wide epigenetic reprogramming, Volume 36 Number 2 March 2024 Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved. Epigenetic dynamics of aging and cancer development Bisht et al. Downloaded from http://journals.lww.com/co-oncology by BhDMf5ePHKav1zEoum1tQfN4a+kJLhEZgbsIHo4XMi0hC ywCX1AWnYQp/IlQrHD3i3D0OdRyi7TvSFl4Cf3VC1y0abggQZXdtwnfKZBYtws= on 03/07/2024 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. but still resulting in epigenetic changes due to constant cell divisions. These studies uncouple the agerelated 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. 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 positivefeedback loop modulating large scale epigenetic changes in aging cells. CONCLUSION Common molecular mechanisms driving epigenetic alterations but leading to different epigenomes in cancer and noncancerous 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 antiaging strategies, such as diet restriction, senolytics, and senomorphics, as potential interventions to address age-related disorders including cancer [126–129]. These antiaging 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 1040-8746 Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved. www.co-oncology.com Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved. 89 Cancer biology Downloaded from http://journals.lww.com/co-oncology by BhDMf5ePHKav1zEoum1tQfN4a+kJLhEZgbsIHo4XMi0hC ywCX1AWnYQp/IlQrHD3i3D0OdRyi7TvSFl4Cf3VC1y0abggQZXdtwnfKZBYtws= on 03/07/2024 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 antiaging and epigenetic drugs hold promise for targeting the epigenome for cancer therapeutic and prevention. Acknowledgements The authors thank NIH (grants AG066101, CA229240) and Samuel Waxman Cancer Research Foundation for their support. Financial support and sponsorship None. Conflicts of interest There are no conflicts of interest. REFERENCES AND RECOMMENDED READING Papers of particular interest, published within the annual period of review, have been highlighted as: & of special interest && of outstanding interest 1. Pal S, Tyler JK. Epigenetics and aging. Sci Adv 2016; 2:e1600584. 2. Li Z, Zhang Z, Ren Y, et al. Aging and age-related diseases: from mechanisms to therapeutic strategies. Biogerontology 2021; 22:165–187. 3. White MC, Holman DM, Boehm JE, et al. Age and cancer risk: a potentially modifiable relationship. Am J Prev Med 2014; 46(3 Suppl 1):S7–S15. 4. de Magalhães JP. How ageing processes influence cancer. Nat Rev Cancer 2013; 13:357–365. 5. Gavrilov LA, Gavrilova NS, Krut’ko VN. Historical evolution of old-age mortality and new approaches to mortality forecasting. Living 100 Monogr 2017; 1–27. 6. Berben L, Floris G, Wildiers H, Hatse S. Cancer and aging: two tightly interconnected biological processes. Cancers (Basel) 2021; 13:1400. 7. Tomasetti C, Li L, Vogelstein B. Stem cell divisions, somatic mutations, cancer etiology, and cancer prevention. Science 2017; 355:1330–1334. 8. Soto AM, Sonnenschein C. The somatic mutation theory of cancer: growing problems with the paradigm? Bioessays 2004; 26:1097–1107. 9. Porta-Pardo E, Valencia A, Godzik A. Understanding oncogenicity of cancer driver genes and mutations in the cancer genomics era. FEBS Lett 2020; 594:4233–4246. 10. Jaenisch R, Bird A. Epigenetic regulation of gene expression: how the genome integrates intrinsic and environmental signals. Nat Genet 2003; 33(Suppl):245–254. 11. Du W, Shi G, Shan CM, et al. Mechanisms of chromatin-based epigenetic inheritance. Sci China Life Sci 2022; 65:2162–2190. 12. Balaji AK, Saha S, Deshpande S, et al. Nuclear envelope, chromatin organizers, histones, and DNA: the many achilles heels exploited across cancers. Front Cell Dev Biol 2022; 10:1068347. 13. Unnikrishnan A, Freeman WM, Jackson J, et al. The role of DNA methylation in epigenetics of aging. Pharmacol Ther 2019; 195:172–185. 14. Strahl BD, Allis CD. The language of covalent histone modifications. Nature 2000; 403:41–45. 15. Jenuwein T, Allis CD. Translating the histone code. Science 2001; 293:1074–1080. 16. Zhao S, Allis CD, Wang GG. The language of chromatin modification in human cancers. Nat Rev Cancer 2021; 21:413–430. 17. Allis CD, Jenuwein T. The molecular hallmarks of epigenetic control. Nat Rev Genet 2016; 17:487–500. 18. Barski A, Cuddapah S, Cui K, et al. High-resolution profiling of histone methylations in the human genome. Cell 2007; 129:823–837. 19. Greer EL, Shi Y. Histone methylation: a dynamic mark in health, disease and inheritance. Nat Rev Genet 2012; 13:343–357. 20. Allshire RC, Madhani HD. Ten principles of heterochromatin formation and function. Nat Rev Mol Cell Biol 2018; 19:229–244. 21. Wiles ET, Selker EU. H3K27 methylation: a promiscuous repressive chromatin mark. Curr Opin Genet Dev 2017; 43:31–37. 90 www.co-oncology.com 22. Alagna NS, Thomas TI, Wilson KL, Reddy KL. Choreography of laminaassociated domains: structure meets dynamics. FEBS Lett 2023; 597:2806–2822. 23. van Steensel B, Belmont AS. Lamina-associated domains: links with chromosome architecture, heterochromatin, and gene repression. Cell 2017; 169:780–791. 24. Falk M, Feodorova Y, Naumova N, et al. Heterochromatin drives compartmentalization of inverted and conventional nuclei. Nature 2019; 570:395–399. 25. Easwaran H, Johnstone SE, Van Neste L, et al. A DNA hypermethylation module for the stem/progenitor cell signature of cancer. Genome Res 2012; 22:837–849. 26. Fernandez AF, Bayón GF, Urdinguio RG, et al. H3K4me1 marks DNA regions hypomethylated during aging in human stem and differentiated cells. Genome Res 2015; 25:27–40. 27. Wilson AS, Power BE, Molloy PL. DNA hypomethylation and human diseases. Biochim Biophys Acta 2007; 1775:138–162. 28. Marescal O, Cheeseman IM. Cellular mechanisms and regulation of quiescence. Dev Cell 2020; 55:259–271. 29. T€ umpel S, Rudolph KL. Quiescence: good and bad of stem cell aging. Trends Cell Biol 2019; 29:672–685. 30. Coller HA. Cell biology. The essence of quiescence. Science 2011; 334:1074–1075. 31. Holly JMP, Zeng L, Perks CM. Epithelial cancers in the postgenomic era: should we reconsider our lifestyle? Cancer Metastasis Rev 2013; 32:673–705. 32. Zhang W, Qu J, Liu GH, Belmonte JCI. The ageing epigenome and its rejuvenation. Nat Rev Mol Cell Biol 2020; 21:137–150. 33. Liu Z, Ji Q, Ren J, et al. Large-scale chromatin reorganization reactivates placenta-specific genes that drive cellular aging. Dev Cell 2022; 57:1347–1368; e12. 34. Lukasova E, Kovařík A, Kozubek S. Consequences of lamin B1 and lamin B receptor downregulation in senescence. Cells 2018; 7:11. 35. Barutcu AR, Lajoie BR, McCord RP, et al. Chromatin interaction analysis reveals changes in small chromosome and telomere clustering between epithelial and breast cancer cells. Genome Biol 2015; 16:214. 36. Xu J, Ma H, Ma H, et al. Super-resolution imaging reveals the evolution of higher-order chromatin folding in early carcinogenesis. Nat Commun 2020; 11:1899. 37. Zhang X, Liu X, Du Z, et al. The loss of heterochromatin is associated with multiscale three-dimensional genome reorganization and aberrant transcription during cellular senescence. Genome Res 2021; 31:1121–1135. 38. Cruickshanks HA, McBryan T, Nelson DM, et al. Senescent cells harbour features of the cancer epigenome. Nat Cell Biol 2013; 15:1495–1506. 39. Tao Y, Kang B, Petkovich DA, et al. Aging-like spontaneous epigenetic silencing facilitates Wnt activation, stemness, and BrafV600E-induced tumorigenesis. Cancer Cell 2019; 35:315–328; e6. 40. Xie W, Baylin SB, Easwaran H. DNA methylation in senescence, aging and cancer. Oncoscience 2019; 6:291–293. 41. Lee JH, Kim EW, Croteau DL, Bohr VA. Heterochromatin: an epigenetic point of view in aging. Exp Mol Med 2020; 52:1466–1474. 42. Carone DM, Lawrence JB. Heterochromatin instability in cancer: from the Barr body to satellites and the nuclear periphery. Semin Cancer Biol 2013; 23:99–108. 43. Peng A, Peng W, Wang R, et al. Regulation of 3D organization and its role in cancer biology. Front Cell Dev Biol 2022; 10:879465. 44. Sati S, Bonev B, Szabo Q, et al. 4D genome rewiring during oncogeneinduced and replicative senescence. Mol Cell 2020; 78:522–538; e9. 45. McCauley BS, Sun L, Yu R, et al. Altered chromatin states drive cryptic transcription in aging mammalian stem cells. Nat Aging 2021; 1:684–697. 46. Criscione SW, Teo YV, Neretti N. The chromatin landscape of cellular senescence. Trends Genet 2016; 32:751–761. 47. Shaban HA, Gasser SM. Dynamic 3D genome reorganization during senescence: defining cell states through chromatin. Cell Death Differ 2023; 1–7. 48. Yamaguchi K, Chen X, Oji A, et al. Large-scale chromatin rearrangements in cancer. Cancers (Basel) 2022; 14:2384. 49. Liu Y, Guo B, Aguilera-Jimenez E, et al. Chromatin looping shapes KLF5dependent transcriptional programs in human epithelial cancers. Cancer Res 2020; 80:5464–5477. 50. Petrovic J, Zhou Y, Fasolino M, et al. Oncogenic notch promotes long-range regulatory interactions within hyperconnected 3D cliques. Mol Cell 2019; 73:1174–1190; e12. 51. Gridina M, Fishman V. Multilevel view on chromatin architecture alterations in cancer. Front Genet 2022; 13:1059617. 52. Donaldson-Collier MC, Sungalee S, Zufferey M, et al. EZH2 oncogenic mutations drive epigenetic, transcriptional, and structural changes within chromatin domains. Nat Genet 2019; 51:517–528. 53. Cai Y, Zhang Y, Loh YP, et al. H3K27me3-rich genomic regions can function as silencers to repress gene expression via chromatin interactions. Nat Commun 2021; 12:719. 54. Johnstone SE, Reyes A, Qi Y, et al. Large-scale topological changes restrain malignant progression in colorectal cancer. Cell 2020; 182:1474–1489; e23. Volume 36 Number 2 March 2024 Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved. Epigenetic dynamics of aging and cancer development Bisht et al. Downloaded from http://journals.lww.com/co-oncology by BhDMf5ePHKav1zEoum1tQfN4a+kJLhEZgbsIHo4XMi0hC ywCX1AWnYQp/IlQrHD3i3D0OdRyi7TvSFl4Cf3VC1y0abggQZXdtwnfKZBYtws= on 03/07/2024 55. Di Giammartino DC, Polyzos A, Apostolou E. Transcription factors: building hubs in the 3D space. Cell Cycle 2020; 19:2395–2410. 56. Huang J, Li K, Cai W, et al. Dissecting super-enhancer hierarchy based on chromatin interactions. Nat Commun 2018; 9:943. 57. Tang SC, Vijayakumar U, Zhang Y, Fullwood MJ. Super-enhancers, phaseseparated condensates, and 3D genome organization in cancer. Cancers (Basel) 2022; 14:2866. 58. Deng S, Feng Y, Pauklin S. 3D chromatin architecture and transcription regulation in cancer. J Hematol Oncol 2022; 15:49. 59. Hao X, Wang C, Zhang R. Chromatin basis of the senescence-associated secretory phenotype. Trends Cell Biol 2022; 32:513–526. 60. Aird KM, Zhang R. Detection of senescence-associated heterochromatin foci (SAHF). Methods Mol Biol 2013; 965:185–196. 61. Olan I, Handa T, Narita M. Beyond SAHF: an integrative view of chromatin compartmentalization during senescence. Curr Opin Cell Biol 2023; 83:102206. 62. Narita M, Nũnez S, Heard E, et al. Rb-mediated heterochromatin formation and silencing of E2F target genes during cellular senescence. Cell 2003; 113:703–716. 63. Crouch J, Shvedova M, Thanapaul RJRS, et al. Epigenetic regulation of cellular senescence. Cells 2022; 11:672. 64. Demaria M, Ohtani N, Youssef SA, et al. An essential role for senescent cells in optimal wound healing through secretion of PDGF-AA. Dev Cell 2014; 31:722–733. 65. Ritschka B, Storer M, Mas A, et al. The senescence-associated secretory phenotype induces cellular plasticity and tissue regeneration. Genes Dev 2017; 31:172–183. 66. Shvedova M, Samdavid Thanapaul RJR, Thompson EL, et al. Cellular senescence in aging, tissue repair, and regeneration. Plast Reconstr Surg 2022; 150:4S–11S. 67. Yang N, Occean JR, Melters DP, et al. A hyper-quiescent chromatin state && formed during aging is reversed by regeneration. Mol Cell 2023; 83:1659–1676; e11. In this article, the authors used liver as a model organ to investigate chromatin changes in aging and found that H3K27me3 as a central regulator of the aging process and further suggested that regeneration mitigates age-related H3K27me3 patterns. 68. Sen P, Donahue G, Li C, et al. Spurious intragenic transcription is a feature of & mammalian cellular senescence and tissue aging. Nat Aging 2023; 3:402–417. The study shows that spurious transcription from inside genes is a pervasive feature of senescence and aging cells that accompanies chromatin changes. 69. Xie W, Kagiampakis I, Pan L, et al. DNA methylation patterns separate senescence from transformation potential and indicate cancer risk. Cancer Cell 2018; 33:309–321; e5. 70. Rocha A, Dalgarno A, Neretti N. The functional impact of nuclear reorganization in cellular senescence. Brief Funct Genomics 2022; 21:24–34. 71. Salama R, Sadaie M, Hoare M, Narita M. Cellular senescence and its effector programs. Genes Dev 2014; 28:99–114. 72. Fennell L, Kane A, Liu C, et al. Braf mutation induces rapid neoplastic transformation in the aged and aberrantly methylated intestinal epithelium. Gut 2022; 71:1127–1140. 73. Yang JH, Hayano M, Griffin PT, et al. Loss of epigenetic information as a && cause of mammalian aging. Cell 2023; 186:305–326; e27. In this study, the authors showed that nonmutagenic double strand repair causes the epigenetic landscape to erode and cells to drift into adjacent Waddington valleys, where they malfunction and thus cause aging. 74. O’Hagan HM, Wang W, Sen S, et al. Oxidative damage targets complexes containing DNA methyltransferases, SIRT1, and polycomb members to promoter CpG Islands. Cancer Cell 2011; 20:606–619. 75. Soto-Palma C, Niedernhofer LJ, Faulk CD, Dong X. Epigenetics, DNA damage, and aging. J Clin Invest 2022; 132:e158446. 76. Lans H, Hoeijmakers JHJ, Vermeulen W, Marteijn JA. The DNA damage response to transcription stress. Nat Rev Mol Cell Biol 2019; 20:766–784. 77. Ito T, Teo YV, Evans SA, et al. Regulation of cellular senescence by polycomb chromatin modifiers through distinct DNA damage- and histone methylationdependent pathways. Cell Rep 2018; 22:3480–3492. 78. Chagin VO, Reinhart B, Becker A, et al. Processive DNA synthesis is associated with localized decompaction of constitutive heterochromatin at the sites of DNA replication and repair. Nucleus 2019; 10:231–253. 79. Mortusewicz O, Rothbauer U, Cardoso MC, Leonhardt H. Differential recruitment of DNA Ligase I and III to DNA repair sites. Nucleic Acids Res 2006; 34:3523–3532. 80. Mortusewicz O, Schermelleh L, Walter J, et al. Recruitment of DNA methyltransferase I to DNA repair sites. Proc Natl Acad Sci U S A 2005; 102:8905–8909. 81. Alagoz M, Katsuki Y, Ogiwara H, et al. SETDB1, HP1 and SUV39 promote repositioning of 53BP1 to extend resection during homologous recombination in G2 cells. Nucleic Acids Res 2015; 43:7931–7944. 82. Dabin J, Fortuny A, Polo SE. Epigenome maintenance in response to DNA damage. Mol Cell 2016; 62:712–727. 83. Karakaidos P, Karagiannis D, Rampias T. Resolving DNA damage: epigenetic regulation of DNA repair. Molecules 2020; 25:2496. 84. Park PU, Defossez PA, Guarente L. Effects of mutations in DNA repair genes on formation of ribosomal DNA circles and life span in Saccharomyces cerevisiae. Mol Cell Biol 1999; 19:3848–3856. 85. Mills KD, Sinclair DA, Guarente L. MEC1-dependent redistribution of the Sir3 silencing protein from telomeres to DNA double-strand breaks. Cell 1999; 97:609–620. 86. Tamburini BA, Tyler JK. Localized histone acetylation and deacetylation triggered by the homologous recombination pathway of double-strand DNA repair. Mol Cell Biol 2005; 25:4903–4913. 87. Giulivi C, Zhang K, Arakawa H. Recent advances and new perspectives in mitochondrial dysfunction. Sci Rep 2023; 13:7977. 88. Behl T, Makkar R, Anwer MK, et al. Mitochondrial dysfunction: a cellular and molecular hub in pathology of metabolic diseases and infection. J Clin Med 2023; 12:2882. 89. Nadalutti CA, Ayala-Pe~ na S, Santos JH. Mitochondrial DNA damage as driver of cellular outcomes. Am J Physiol Cell Physiol 2022; 322:C136–C150. 90. San-Millan I. The key role of mitochondrial function in health and disease. Antioxidants (Basel) 2023; 12:782. 91. Smiraglia DJ, Kulawiec M, Bistulfi GL, et al. A novel role for mitochondria in regulating epigenetic modification in the nucleus. Cancer Biol Ther 2008; 7:1182–1190. 92. Ferrucci L, Fabbri E. Inflammageing: chronic inflammation in ageing, cardiovascular disease, and frailty. Nat Rev Cardiol 2018; 15:505–522. 93. DeStefano Shields CE, White JR, Chung L, et al. Bacterial-driven inflammation and mutant BRAF expression combine to promote murine colon tumorigenesis that is sensitive to immune checkpoint therapy. Cancer Discov 2021; 11:1792–1807. 94. Maeda M, Moro H, Ushijima T. Mechanisms for the induction of gastric cancer by Helicobacter pylori infection: aberrant DNA methylation pathway. Gastric Cancer 2017; 20(Suppl 1):8–15. 95. Katayama Y, Takahashi M, Kuwayama H. Helicobacter pylori causes runx3 gene methylation and its loss of expression in gastric epithelial cells, which is mediated by nitric oxide produced by macrophages. Biochem Biophys Res Commun 2009; 388:496–500. 96. Niwa T, Tsukamoto T, Toyoda T, et al. Inflammatory processes triggered by Helicobacter pylori infection cause aberrant DNA methylation in gastric epithelial cells. Cancer Res 2010; 70:1430–1440. 97. Matsusaka K, Funata S, Fukayama M, Kaneda A. DNA methylation in gastric cancer, related to Helicobacter pylori and Epstein-Barr virus. World J Gastroenterol 2014; 20:3916–3926. 98. Tan SYX, Zhang J, Tee WW. Epigenetic regulation of inflammatory signaling and inflammation-induced cancer. Front Cell Dev Biol 2022; 10:931493. 99. Akhiani AA, Martner A. Role of phosphoinositide 3-kinase in regulation of NOX-derived reactive oxygen species in cancer. Antioxidants (Basel) 2022; 12:67. 100. Lee WT, Sun X, Tsai TS, et al. Mitochondrial DNA haplotypes induce differential patterns of DNA methylation that result in differential chromosomal gene expression patterns. Cell Death Discov 2017; 3:17062. 101. Liu X, Cooper DE, Cluntun AA, et al. Acetate production from glucose and coupling to mitochondrial metabolism in mammals. Cell 2018; 175:502–513; e13. 102. Virmani MA, Cirulli M. The role of l-carnitine in mitochondria, prevention of metabolic inflexibility and disease initiation. Int J Mol Sci 2022; 23:2717. 103. Dai Z, Ramesh V, Locasale JW. The evolving metabolic landscape of chromatin biology and epigenetics. Nat Rev Genet 2020; 21:737–753. 104. Armanios M. The role of telomeres in human disease. Annu Rev Genomics Hum Genet 2022; 23:363–381. 105. Chin L, Artandi SE, Shen Q, et al. p53 deficiency rescues the adverse effects of telomere loss and cooperates with telomere dysfunction to accelerate carcinogenesis. Cell 1999; 97:527–538. 106. d’Adda di Fagagna F, Reaper PM, Clay-Farrace L, et al. A DNA damage checkpoint response in telomere-initiated senescence. Nature 2003; 426:194–198. 107. Cacchione S, Biroccio A, Rizzo A. Emerging roles of telomeric chromatin alterations in cancer. J Exp Clin Cancer Res 2019; 38:21. 108. Greenberg RA, Chin L, Femino A, et al. Short dysfunctional telomeres impair tumorigenesis in the INK4a(delta2/3) cancer-prone mouse. Cell 1999; 97:515–525. 109. Feldser DM, Greider CW. Short telomeres limit tumor progression in vivo by inducing senescence. Cancer Cell 2007; 11:461–469. 110. Rudolph KL, Millard M, Bosenberg MW, DePinho RA. Telomere dysfunction and evolution of intestinal carcinoma in mice and humans. Nat Genet 2001; 28:155–159. 111. Allsopp RC, Vaziri H, Patterson C, et al. Telomere length predicts replicative capacity of human fibroblasts. Proc Natl Acad Sci U S A 1992; 89:10114–10118. 112. Oberdoerffer P, Michan S, McVay M, et al. SIRT1 redistribution on chromatin promotes genomic stability but alters gene expression during aging. Cell 2008; 135:907–918. 113. Ivanov A, Pawlikowski J, Manoharan I, et al. Lysosome-mediated processing of chromatin in senescence. J Cell Biol 2013; 202:129–143. 114. Miller KN, Victorelli SG, Salmonowicz H, et al. Cytoplasmic DNA: sources, sensing, and role in aging and disease. Cell 2021; 184:5506–5526. 1040-8746 Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved. www.co-oncology.com Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved. 91 Cancer biology Downloaded from http://journals.lww.com/co-oncology by BhDMf5ePHKav1zEoum1tQfN4a+kJLhEZgbsIHo4XMi0hC ywCX1AWnYQp/IlQrHD3i3D0OdRyi7TvSFl4Cf3VC1y0abggQZXdtwnfKZBYtws= on 03/07/2024 115. De Cecco M, Ito T, Petrashen AP, et al. L1 drives IFN in senescent cells and promotes age-associated inflammation. Nature 2019; 566:73–78. 116. Chapman J, Fielder E, Passos JF. Mitochondrial dysfunction and cell senescence: deciphering a complex relationship. FEBS Lett 2019; 593:1566– 1579. 117. Martini H, Passos JF. Cellular senescence: all roads lead to mitochondria. FEBS J 2023; 290:1186–1202. 118. Correia-Melo C, Marques FDM, Anderson R, et al. Mitochondria are required for pro-ageing features of the senescent phenotype. EMBO J 2016; 35:724–742. 119. Vizioli MG, Liu T, Miller KN, et al. Mitochondria-to-nucleus retrograde signaling drives formation of cytoplasmic chromatin and inflammation in senescence. Genes Dev 2020; 34:428–445. 120. Okamoto K, Seimiya H. Revisiting telomere shortening in cancer. Cells 2019; 8:107. 121. Vaziri H, West MD, Allsopp RC, et al. ATM-dependent telomere loss in aging human diploid fibroblasts and DNA damage lead to the posttranslational activation of p53 protein involving poly(ADP-ribose) polymerase. EMBO J 1997; 16:6018–6033. 122. Lovejoy CA, Li W, Reisenweber S, et al. Loss of ATRX, genome instability, and an altered DNA damage response are hallmarks of the alternative lengthening of telomeres pathway. PLoS Genet 2012; 8:e1002772. 92 www.co-oncology.com 123. Mori JO, Keegan J, Flynn RL, Heaphy CM. Alternative lengthening of telomeres: mechanism and the pathogenesis of cancer. J Clin Pathol 2023; jcp-2023-209005. 124. Majerska J, Sýkorova E, Fajkus J. Nontelomeric activities of telomerase. Mol Biosyst 2011; 7:1013–1023. 125. Kabacik S, Horvath S, Cohen H, Raj K. Epigenetic ageing is distinct from senescence-mediated ageing and is not prevented by telomerase expression. Aging (Albany NY) 2018; 10:2800–2815. 126. Mont egut L, de Cabo R, Zitvogel L, Kroemer G. Science-driven nutritional interventions for the prevention and treatment of cancer. Cancer Discov 2022; 12:2258–2279. 127. Carpenter VJ, Saleh T, Gewirtz DA. Senolytics for cancer therapy: is all that glitters really gold? Cancers (Basel) 2021; 13:723. 128. Wang L, Lankhorst L, Bernards R. Exploiting senescence for the treatment of cancer. Nat Rev Cancer 2022; 22:340–355. 129. Mihaylova MM, Chaix A, Delibegovic M, et al. When a calorie is not just a calorie: diet quality and timing as mediators of metabolism and healthy aging. Cell Metab 2023; 35:1114–1131. 130. Bates SE. Epigenetic therapies for cancer. N Engl J Med 2020; 383:650–663. 131. Michalak EM, Burr ML, Bannister AJ, Dawson MA. The roles of DNA, RNA and histone methylation in ageing and cancer. Nat Rev Mol Cell Biol 2019; 20:573–589. Volume 36 Number 2 March 2024 Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.

Epigenetic Dynamics of Aging and Cancer Development (PDF)

Document Details

Tags

Related

Summary

Full Transcript

Upgrade to continue