When genomes burn: how DNA damage ignites inflammation and fuels ageing.

Abstract

Ageing is accompanied by a progressive loss of homeostasis driven by inter connected molecular stress responses. Two central hallmarks, genome instability and chronic low-grade inflammation (inflammaging), are increasingly recognized as mechanistically inseparable. Persistent DNA damage, defective repair and transcriptional stress activate inflammatory signalling not only through canonical DNA damage response (DDR) pathways, but also via innate immune sensing of mislocalized self-nucleic acids. In turn, inflammatory mediators, metabolic stress and reactive oxygen and nitrogen species inflict new genomic damage and compromise repair, establishing a self-reinforcing feedback loop. Evidence from human DNA repair syndromes and genetically engineered mouse models reveals that chronic DDR engagement rewires metabolism, endocrine signalling, mitochondrial function and immune surveillance well before overt tissue degeneration. Recent work further highlights extra-nuclear DDR programmes, RNA-based danger signals and organelle dysfunction as key amplifiers linking genome instability to inflammation. Here, we synthesize insights from genome maintenance, innate immunity and metabolism to propose a unified framework in which ageing emerges from the chronic persistence of stress circuits originally evolved for transient repair and host defence. We discuss evolutionary implications, disease relevance and emerging therapeutic strategies aimed at disrupting this damage-inflammation axis to restore tissue homeostasis. This article is part of the theme issue 'Developmental circuits in ageing'.