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

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.