Epigenetic Alterations Module

Aging Module epigenetic_alterations 3 disorders Pathograph 8

A conserved mechanism module for the hallmark of aging (Lopez-Otin et al.) termed epigenetic alterations: the progressive, partly stochastic remodeling of the epigenome with age. Aging is accompanied by drift in DNA-methylation patterns, chromatin reorganization, and altered histone modifications, which together perturb the epigenetic regulation of gene expression. The DNA-methylation changes are regular enough to build accurate multi-tissue "epigenetic clocks" that estimate biological age and reveal age acceleration in disease and cancer. Because these marks are, in principle, reversible, the epigenetic hallmark is a distinctive source of "druggable" targets against age-related decline - the basis of epigenetic-clock biomarkers and emerging epigenetic-reprogramming interventions. Individual disorder entries declare conformance via conforms_to on their pathophysiology nodes, substituting the disease-specific epigenetic lesion (e.g. a chromatin-modifier mutation, a methylation-clock acceleration, or an aging-associated transcriptional shift) while preserving the conserved drift -> altered-expression -> cellular-decline chain.

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Pathophysiology Nodes

3 shared nodes are defined in this module.

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Cell Types

No cell types are annotated for this module.

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Biological Processes

Notes

This is a mechanism module, not a specific disease. Disorder entries reference individual nodes via conforms_to (e.g., "epigenetic_alterations#Altered Epigenetic Regulation of Gene Expression"). Conforming nodes in disorder files should include the corresponding biological processes and causal edges, specialized to their disease context. The module captures the conserved epigenetic-drift chain and its biomarker (epigenetic-clock) and reversibility angles, but deliberately does NOT embed specific clock coefficients or contested reprogramming-rejuvenation claims; those belong on the relevant disorder or method entry. Worked conformers: Hutchinson-Gilford Progeria Syndrome (heterochromatin loss, attaching at the "Age-Associated Epigenetic Drift" node), plus the chromatin/DNA-methylation-machinery Mendelian disorder that attaches at the central node - Heyn-Sproul-Jackson syndrome (DNMT3A gain-of-function hypermethylation recapitulating age-related DNAme gains). Scope boundary against the germline chromatinopathies. Wiedemann-Steiner syndrome (KMT2A) and Bainbridge-Ropers syndrome (ASXL3/PR-DUB) previously conformed here for want of a better target. They now conform to `epigenetic_machinery_neurodevelopmental_dysregulation` instead, which models the Mendelian disorders of the epigenetic machinery. The distinction is the explanandum: this module is about age-associated, partly stochastic drift of a normally-established epigenome, whereas those disorders begin with a germline lesion in a machinery component and disrupt neurodevelopment from the outset. A germline chromatinopathy should conform there, not here. Heyn-Sproul-Jackson is retained because its DNMT3A gain-of-function hypermethylation is curated specifically as recapitulating age-related methylation gains - the drift phenotype this module models - rather than only as a machinery lesion. Note the GO "DNA methylation" term is obsolete, so methylation drift is bound via "epigenetic regulation of gene expression" and "chromatin organization" and described in prose. Key conformance target: "epigenetic_alterations#Altered Epigenetic Regulation of Gene Expression".

Discussions and Knowledge Gaps

How should dismech represent an epigenetic clock, given that no ontology term names one and a clock is an estimator rather than an analyte?

KNOWLEDGE GAP OPEN knowledge_gap_no_ontology_term_for_epigenetic_clock

Attached to: DNAm PhenoAge epigenetic clock estimate Age-Associated Epigenetic Drift

Two problems compound here. The ontology problem is that NCIT, the vocabulary dismech binds biomarkers to, has no term for an epigenetic clock or for biological age, so the single most important class of aging biomarker cannot be bound to what it actually is. The interim binding used here names the assay and carries the clock in free text, which validates but does not make the concept queryable. The representational problem is deeper: a clock is a penalized regression over hundreds of CpG sites whose output is an age estimate in years. Nothing about that is an analyte, and the same objection applies to the frailty index, to composite biomarker panels, and to the multimorbidity count. dismech represents mechanisms and analytes well and represents estimators over them not at all. Deciding this properly means either extending the schema or accepting that clocks live in computational_models with a link back to the mechanism node. It is filed in the decision register as "Computed indices and composite endpoints in aging biology" (docs/explanation/design-decisions.md section 12), which separates the computed-index problem from the composite-endpoint one and lists three candidate shapes; consult it rather than settling this ad hoc when adding the next clock.

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Animal Models

Aging turquoise killifish epigenome (Nothobranchius furzeri) Naturally short-lived vertebrate aging model

Two complementary studies cover both halves of this module in killifish. On the DNA methylation side, the full DNMT/TET machinery was identified and profiled across the life cycle, and global 5-methylcytosine falls with age in a tissue-specific manner, most steeply in skeletal muscle, alongside declining methyltransferase transcripts. On the chromatin side, aged skeletal muscle becomes less accessible and more condensed, accumulating H3K27me3 and heterochromatic foci while losing euchromatic marks, with a transcriptional output shifted away from repair and toward inflammation and senescence.

Species

Turquoise killifish (Nothobranchius furzeri)

Genotype

Wild type

Background

Whole-lifecycle sampling from embryogenesis into late adulthood for the DNA methylation arm (brain, liver, skeletal muscle), and young versus old skeletal muscle for the chromatin arm.

Publication

PMID:34222326

Pathograph links

Age-Associated Epigenetic Drift recapitulates fidelity: moderate Both the methylation and the chromatin arms of drift are measurable in this model: global 5mC declines with age in liver and muscle, and aged muscle chromatin shifts toward a condensed, heterochromatin-rich state with loss of euchromatic marks.

Limitations: Global 5mC quantification is not a CpG-resolution methylation clock, so this supports directional drift rather than the site-specific clock behavior used in humans and mice. The chromatin findings are from a single tissue. The teleost genome carries multiple de novo methyltransferase paralogs absent in mammals, so machinery-level inferences transfer only in part.

Readouts

Global 5-methylcytosine content across age

Global 5mC quantified in brain, liver, and muscle across the killifish lifespan, validated against methylated and hydroxymethylated oligonucleotide standards.

Direction: DECREASED

Interpretation: A significant negative correlation of 5mC with age is the direct measurement supporting methylation drift in this model.

Evidence: 1

DNA methyltransferase transcript levels in aging muscle

Transcript levels of maintenance and de novo DNA methyltransferases in skeletal muscle across age, read against the global 5mC decline in the same tissue.

Direction: DECREASED

Interpretation: Coordinated loss of methyltransferase expression is the machinery-level correlate of the hypomethylation, tying drift to a mechanism rather than leaving it as an observation.

Evidence: 1

Heterochromatin content and H3K27me3 in aged skeletal muscle

Chromatin accessibility and histone mark profiling in young versus old killifish skeletal muscle.

Direction: INCREASED

Interpretation: Accumulating repressive marks and heterochromatic foci are the chromatin half of drift, distinct from and complementary to the methylation loss.

Evidence: 1

Euchromatic histone marks in aged skeletal muscle

Levels of activating histone marks including H3K9ac in old versus young killifish skeletal muscle.

Direction: DECREASED

Interpretation: Loss of activating marks in the same tissue that gains repressive ones is what makes this a directional shift rather than a general increase in histone modification.

Evidence: 1

Altered Epigenetic Regulation of Gene Expression recapitulates fidelity: moderate The chromatin shift in aged killifish muscle has a measured transcriptional consequence: integrated RNA-seq and ChIP-seq show cell cycle, differentiation, and DNA repair genes turned down while inflammation and senescence genes are turned up.

Limitations: The association between the mark changes and the expression changes is correlative within one tissue; no mark was manipulated to test whether it drives the expression shift. The authors themselves state that more work is needed on the mechanism.

Readouts

Repair, cell cycle, inflammation, and senescence gene expression

Integrated transcriptome and chromatin profiling of killifish skeletal muscle at different ages.

Direction: ALTERED

Interpretation: A coordinated, directional shift in gene classes is what turns the chromatin observation into an altered-regulation claim.

Evidence: 1

Curated as part of a tranche adding turquoise killifish models across the hallmarks-of-aging modules. Note that these are global and tissue-level measurements, not a CpG-resolution epigenetic clock; a killifish methylation clock is a separate and later line of work and is not what this entry supports.

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Computational Models

Horvath Multi-Tissue DNA Methylation Age Predictor MACHINE_LEARNING

Penalized-regression predictor of chronological age from DNA methylation levels at 353 CpG sites, trained across a large panel of human tissues and cell types. Its cross-tissue applicability is the key property: the same clock reads age in tissues with very different cell-division histories, which is why the drift it measures is treated as a systemic ageing signal rather than a proliferation counter.

PMID:24138928

Pathograph links

Age-Associated Epigenetic Drift measures fidelity: high Quantifies the drift directly in human tissue as a single scalar, and defines epigenetic age acceleration as its residual against chronological age.

Limitations: A predictive model, not a mechanistic one: it identifies which CpGs track age but asserts nothing about what drives their methylation change, so it cannot distinguish causal drift from a downstream correlate.

The reason this module's first node is measurable at all in humans. Treat clock output as a readout of the node, never as evidence for a mechanism.

DNAm GrimAge Mortality Predictor MACHINE_LEARNING

Second-generation methylation clock trained not on chronological age but on surrogate DNA-methylation estimators of plasma proteins and smoking pack-years, composited against time-to-death. It predicts lifespan and healthspan, including time to coronary heart disease and cancer, more strongly than chronological-age-trained clocks.

PMID:30669119

Pathograph links

Age-Associated Epigenetic Drift measures fidelity: high Measures the drift, but weights it toward the components that carry mortality risk rather than those that merely track time.

Epigenetically Driven Cellular Decline partially recapitulates fidelity: moderate Links the methylation state to downstream morbidity and mortality outcomes, supporting the claim that the drift is consequential rather than incidental.

Limitations: Association with outcomes, not demonstration of cellular decline; its predictive power partly reflects smoking and plasma-protein surrogates rather than an autonomous epigenetic mechanism.

Przybilla2014 Multiscale Model of Epigenetic Drift in Aging Stem Cells AGENT_BASED

Individual cell-based model of a stem cell population combined with a model of epigenetic regulation of transcription, simulating age-related changes in H3K4 trimethylation and DNA methylation and the resulting expression changes that induce age-related cellular phenotypes. Drift originates in the limited capacity of cells to inherit epigenetic information faithfully through division. The model contrasts quiescent niche-resident stem cells with proliferating cells and varies the activity of the epigenetic modifiers.

PMID:24428552

Pathograph links

Age-Associated Epigenetic Drift recapitulates fidelity: moderate Derives drift mechanistically from imperfect inheritance of histone marks across division, rather than treating it as an unexplained age correlate.

Altered Epigenetic Regulation of Gene Expression recapitulates fidelity: moderate Propagates the H3K4me3 and DNA-methylation changes into transcription through an explicit cis-regulatory network, producing age-related phenotypes.

Epigenetically Driven Cellular Decline partially recapitulates fidelity: low Shows epigenetic ageing strongly increasing cell-to-cell heterogeneity within the population.

Limitations: Uses an artificial genome and a synthetic regulatory network rather than measured human loci, so the mechanism is demonstrated in principle rather than for specific genes.

The mechanistic counterpart to the clocks above - it proposes why drift happens, where the clocks only measure that it does. Also the shared model with stem_cell_exhaustion, where the same simulation drives the functional decline.

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Module Collections

Hallmarks of Aging as Epigenetic alterations

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Used By Disorder Entries

Ependymoma via EZHIP Overexpression → Altered Epigenetic Regulation of Gene Expression , PRC2 Catalytic Inhibition → Altered Epigenetic Regulation of Gene Expression , Global H3K27me3 Loss → Altered Epigenetic Regulation of Gene Expression , CpG Island Methylator Phenotype Silencing → Altered Epigenetic Regulation of Gene Expression

Heyn-Sproul-Jackson syndrome via DNMT3A-mediated DNA hypermethylation → Altered Epigenetic Regulation of Gene Expression

Hutchinson-Gilford Progeria Syndrome via Heterochromatin loss and epigenetic dysregulation → Age-Associated Epigenetic Drift

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Pathograph

Use the checkboxes to hide or show graph categories. Hover nodes for evidence-backed metadata.

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Pathophysiology

Age-Associated Epigenetic Drift

trigger

With age the epigenome drifts: DNA-methylation patterns change (global hypomethylation with focal hypermethylation), chromatin is reorganized, and histone modifications shift. This progressive, partly stochastic remodeling of chromatin is the initiating alteration of the hallmark and is a consistent correlate of aging across species and tissues.

Chromatin Organization GO:0006325 ⚠ ABNORMAL

Used by disorders

Hutchinson-Gilford Progeria Syndrome as Heterochromatin loss and epigenetic dysregulation

Downstream

Altered Epigenetic Regulation of Gene Expression

Show evidence (4 references)

PMID:27518561 SUPPORT Other

"Accumulating evidence links aging to genetic and epigenetic alterations."

Establishes the link between aging and epigenetic alterations, the initiating drift modeled here. Evidence source is OTHER because this is a review.

PMID:36599349 SUPPORT Other

"We propose the following twelve hallmarks of aging: genomic instability, telomere attrition, epigenetic alterations, loss of proteostasis, disabled macroautophagy, deregulated nutrient-sensing, mitochondrial dysfunction, cellular senescence, stem cell exhaustion, altered intercellular..."

Enumerates epigenetic alterations as a hallmark of aging, framing this module. Evidence source is OTHER because this is a review.

PMID:42362890 SUPPORT Human Clinical

"Epigenetic changes, in particular DNA methylation, accumulate with age across different tissues"

A 2026 meta-analysis of more than 15,000 human methylation profiles across 17 tissues directly evidences the age-associated DNA-methylation drift modeled by this trigger node as a pan-tissue phenomenon. Evidence source is HUMAN_CLINICAL (large multi-tissue human methylation meta-analysis).

+ 1 more reference

Altered Epigenetic Regulation of Gene Expression

central effector

Epigenetic drift perturbs the epigenetic control of transcription: genes are aberrantly silenced or de-repressed and cell-identity programs erode. The regularity of the underlying DNA-methylation changes is sufficient to build accurate multi-tissue epigenetic clocks that estimate biological age, and disease and cancer tissues show measurable epigenetic age acceleration. This is the conserved central node that disease-specific epigenetic lesions converge upon.

Epigenetic Regulation of Gene Expression GO:0040029 ⚠ ABNORMAL

Used by disorders

Ependymoma as CpG Island Methylator Phenotype Silencing

Ependymoma as EZHIP Overexpression

Ependymoma as Global H3K27me3 Loss

Ependymoma as PRC2 Catalytic Inhibition

Heyn-Sproul-Jackson syndrome as DNMT3A-mediated DNA hypermethylation

Downstream

Epigenetically Driven Cellular Decline

Show evidence (5 references)

PMID:24138928 SUPPORT Other

"I developed a multi-tissue predictor of age that allows one to estimate the DNA methylation age of most tissues and cell types."

Establishes the multi-tissue DNA-methylation epigenetic clock that quantifies the altered methylation landscape modeled here. Evidence source is OTHER because this is a methodological/analytical study of methylation arrays rather than a disease cohort.

PMID:24138928 SUPPORT Other

"Analysis of 6,000 cancer samples from 32 datasets showed that all of the considered 20 cancer types exhibit significant age acceleration, with an average of 36 years."

Documents epigenetic age acceleration across cancer types, evidence that the altered methylation landscape tracks pathological states. Evidence source is OTHER because this is an array-based analytical study.

PMID:40462948 SUPPORT Model Organism

"We then created a novel, gene-specific, transcriptional aging clock, which demonstrated that sulforaphane-treated individuals exhibited a "transcriptional age" that was approximately four days younger than age-matched controls, representing a nearly 20% reduction in biological age."

Shows an aging clock responding to a pharmacological intervention rather than only tracking chronological age, supporting clock-type measures as readouts of modifiable biological aging. Two limits a curator must carry forward: this clock is transcriptional, so unlike the DNA-methylation clocks cited above it measures the gene-expression output of this node and not the epigenetic marks themselves; and the source is a bioRxiv preprint (2025.05.11.653363) that was not peer-reviewed at time of curation. The paper attributes the dominant response to detoxification pathways and reads the dose-response shape as hormetic, so the effect is not evidence of direct epigenetic remodeling. Evidence source is MODEL_ORGANISM (C. elegans).

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Epigenetically Driven Cellular Decline

consequence

Aberrant epigenetic gene regulation degrades cellular function - loss of cell-identity fidelity, transcriptional dysregulation, and reduced resilience - contributing to age-related tissue decline and disease. Because epigenetic marks are reversible, this node is also the conserved entry point for epigenetic-clock biomarkers and reprogramming-based interventions aimed at countering age-related decline.

Show evidence (3 references)

PMID:27518561 SUPPORT Other

"Given the reversible nature of epigenetic mechanisms, these pathways provide promising avenues for therapeutics against age-related decline and disease."

States that the reversibility of epigenetic mechanisms makes them therapeutic avenues against age-related decline, the consequence and intervention angle modeled here. Evidence source is OTHER because this is a review.

PMID:27518561 SUPPORT Other

"We establish links between common operative aging pathways and hallmark chromatin signatures that can be used to identify "druggable" targets to counter human aging and age-related disease."

Links aging pathways to chromatin signatures as druggable targets, supporting the reversibility/intervention framing of this outcome node. Evidence source is OTHER because this is a review.

PMID:42362890 SUPPORT Human Clinical

"a more modifiable cluster linked to NAD+ metabolism, supporting NAD+ as a potential therapeutic target in aging"

Supports the reversibility/intervention angle of this consequence node: within the aging co-methylation networks most modules resisted beneficial modulation, but a modifiable NAD+-metabolism cluster stood out, nominating NAD+ as a druggable node against epigenetically driven age-related decline. Evidence source is HUMAN_CLINICAL.