Replacement-Based Ageing Interventions for Systemic Rejuvenation: Shaping Longevity Science and Clinical Directions.

Biological and synthetic replacement-based ageing interventions hold substantial potential to reverse many forms of age-related damage simultaneously and extend healthy lifespan beyond what can be achieved with conventional therapeutics. In this Perspective, we discuss recent insights, unmet needs, and emerging trajectories that are catalysing research and clinical development of replacement-based treatments and synergistic strategies for multi-targeted damage removal and export at the molecular, organellar, and cellular levels. The first workshop dedicated to replacement as an ageing intervention at the Aging Research & Drug Discovery 2025 conference helped prioritise key challenges, opportunities, and future directions to address the need for preventive replacement and bioengineering technologies capable of inducing systemic and sustained rejuvenation across cells, tissues, and regulatory networks. We propose a roadmap to guide research and innovation integrating replacement and next-generation damage-removal therapeutics to modulate the ageing process in the whole body, restore biological function, and extend healthy lifespan.