Mosaic ageing: from organ-specific decline to the cause of death

Ageing is often framed as a systemic, uniform process. However, growing evidence shows that ageing occurs unevenly across cell types, tissues and organs, generating heterogeneous within-individual trajectories. This mosaic perspective highlights the myriad cross-tissue ageing patterns that emerge from interactions among development, the genome and environmental and lifestyle exposures. The way these uneven trajectories play out may determine the emergence of specific ageing-related diseases and ultimately the cause of death. Here, we combine insights from molecular biology, biogerontology and evolutionary ecophysiology to develop an integrative view of mosaic ageing. We first describe the proximate mechanisms underlying organ-specific ageing variation. These mechanisms are moulded through age-specific natural selection, embodying trade-offs between maintenance, function and fitness. We then review tools for quantifying organ-specific ageing, ranging from classical measures such as telomere dynamics to high-resolution approaches including epigenetic, proteomic and multi-omic clocks, single-cell atlases and longitudinal imaging. Finally, we discuss how combining these tools with causal inference methods can help identify drivers of context- and species-dependent senescence and life-history variation and enable organ-targeted biomedical interventions. Overall, this perspective calls for moving beyond systemic models of ageing towards an integrative framework that places heterogeneous organ-specific processes at the centre of ageing research. This article is part of the theme issue 'Developmental circuits in ageing'.