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Systemic epigenetic dysregulation as a driver of ageing and a therapeutic target

Nature Reviews Molecular Cell Biology (2026)Cite this article

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Abstract

Although epigenetic changes during ageing are well documented, we lack an integrated framework to systematically explain their mechanistic relationships. In this Review, we present a systems-level framework that demonstrates how epigenetic regulation controls ageing. We discuss four interdependent processes through which epigenetic fidelity — the capacity of chromatin regulatory systems to maintain precise gene expression states — progressively fails: deterioration of nuclear architecture, including breakdown of lamina-associated domains; dysregulation of epigenetic memory through chromatin-modifying complexes such as Polycomb repressive complex 2 (PRC2); nucleosome alterations involving replication-independent accumulation of the histone variant H3.3; and transcription reprogramming driven by transcription factors. These processes interact through cross-regulatory feedback, producing cascading failures in gene expression and cell-state maintenance. This framework reveals why therapeutics targeting epigenetic systems have consistent effects across multiple model systems and ageing phenotypes. The interconnected organization of chromatin regulation mechanisms creates concrete therapeutic targets to restore regulatory coherence. By providing mechanistic clarity on how epigenetic dysregulation drives ageing phenotypes, we aim to enable rational design of therapeutics that target the epigenetic systems that fail during ageing, rather than individual molecular defects.

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Fig. 1: The four pillars of epigenetic ageing.
Fig. 2: Progressive deterioration of nuclear architecture during ageing.
Fig. 3: Disruption of epigenetic memory and loss of transcriptional fidelity.
Fig. 4: Histone variant replacement during ageing.
Fig. 5: Transcription reprogramming and AP-1-mediated enhancer hijacking.

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Acknowledgements

The authors thank K. Hochedlinger, C. Petty, T. Duffield and the members of the Gladyshev lab for constructive feedback on the manuscript, as well as A. Molière for extensive discussions of the topics addressed herein. The authors were supported by grants from the National Institute on Aging and from the Hevolution Foundation.

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Authors and Affiliations

  1. Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, USA

    A. Doğa Yücel & Vadim N. Gladyshev

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  1. A. Doğa Yücel
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  2. Vadim N. Gladyshev
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Contributions

A.D.Y. researched data for the article. Both authors contributed substantially to discussion of the content, wrote the article and reviewed and/or edited the manuscript before submission.

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Correspondence to Vadim N. Gladyshev.

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Nature Reviews Molecular Cell Biology thanks Berenice Benayoun, who coreviewed with Victor Ansere; Oliver Bischof, who coreviewed with Yacine Djabali; and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.

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Supplementary information

Glossary

Bistability

Co-existence in a chromatin region of two stable epigenetic states, with transitions between states requiring crossing an energy barrier.

Bivalent

Refers to chromatin domains that simultaneously carry gene-activating and gene-repressing histone modifications.

Enhancer–promoter loops

Physical interactions between distant enhancer elements and gene promoters that enable gene activation.

Epigenetic drift

The progressive accumulation of both random and directional changes in chromatin states during ageing that disrupts gene regulation.

Epigenetic memory

The maintenance of gene expression states through cell divisions without changes in DNA sequence.

Intermediate genomic compartment

A compartment formed at the interface of genomic A and B compartments and that holds an intermediate spatial position.

Lamina-associated domains

(LADs). Large chromatin regions associated with the nuclear lamina that are typically gene-poor and transcriptionally repressed.

Nuclear lamina

The protein meshwork lining the inner nuclear membrane; supports nuclear structure and helps organize chromatin.

Pioneer transcription factors

Transcription factors capable of binding to condensed chromatin and initiating its opening.

Polycomb repressive complex 2

(PRC2). A chromatin modifier that trimethylates histone H3 Lys27 (H3K27me3) to maintain gene silencing and cellular identity.

Positional memory

The capacity of chromatin-modifying complexes to maintain their genomic localization following cell division, typically through self-reinforcing biochemical feedback such as recognition of their own catalytic products.

Radial disorder

Increased cell-to-cell variability in the radial positioning of genomic loci within the nucleus.

Recruitment logic

The rules governing how chromatin-modifying complexes are recruited to specific genomic loci, including DNA sequence motifs, pre-existing histone modifications, transcription factor interactions and noncoding RNA binding.

Senescence-associated secretory phenotype

(SASP). The secretion of inflammatory cytokines and other factors by senescent cells.

Shannon entropy

An information-theory measure of disorder in a distribution.

Substrate drift

In this context, age-associated changes in histone variant landscapes.

Topologically associating domains

(TADs). Three-dimensional chromatin domains that group genes with their regulatory elements and insulate them from neighbouring regions.

Waddington landscape

A metaphor for how gene regulation modulates cell fate, visualizing development as marbles rolling down a landscape of valleys.

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Yücel, A.D., Gladyshev, V.N. Systemic epigenetic dysregulation as a driver of ageing and a therapeutic target. Nat Rev Mol Cell Biol (2026). https://doi.org/10.1038/s41580-026-00958-0

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