Combating ageing beyond the cell: Emerging roles of extracellular proteostasis

Proteostasis, the maintenance of a healthy proteome, is a fundamental pillar of cellular and organismal health that declines with age. While the intracellular proteostasis network (PN) is well-characterised, proteostasis mechanisms acting in the extracellular space remain understudied. Yet, these mechanisms face unique challenges and are critical for ensuring functional systemic signalling, immune surveillance and structural integrity. In contrast to the cytosol, extracellular environments lack ATP-activated chaperones and a comprehensive ubiquitin-proteasome system and instead rely on specialised secreted chaperones, extracellular proteases and receptor-mediated clearance mechanisms. This review examines the emerging landscape of the extracellular proteostasis network (exPN) and its challenges with age. We discuss how age-related remodelling of the extracellular proteome, shifts in extracellular physicochemical properties and disrupted fluid dynamics collectively create a permissive environment for protein misfolding and aggregation. We evaluate current experimental models of extracellular protein damage and examine how exPN factors target specific stages of the aggregation process to cooperatively safeguard extracellular proteome integrity. Analysis of recent human proteomic data spanning the life course uncovers an unexpected upregulation of exPN components with age. We further explore the role of extracellular proteostasis in inflammageing, a defining hallmark of ageing. Finally, we highlight strategies that bolster extracellular proteostasis as a promising frontier for extending healthspan, limiting age-associated protein aggregation and restoring extracellular matrix homeostasis. By adopting an ageing-centred perspective, we move beyond the disease context to present a holistic overview of extracellular proteostasis in organismal health, thereby positioning the exPN as a critical yet under-exploited target for biomedical intervention.