The "young-to-aged" paradigm: fantasy or feasible strategy for cardiovascular and systemic rejuvenation?

The “young-to-aged” paradigm represents a long existing postulation that rejuvenation in aged individuals can be achieved by replacing components such as cells, tissues, or organs with young counterparts. While highly publicized human plasma exchange trials show conflicting results, preclinical studies in mice demonstrate promising yet partial functional rejuvenation, including enhanced mitochondrial metabolism, reduced neurodegeneration, and revitalized stem cells via transfer of young biological components (e.g., plasma and microbiota). Importantly, certain critical studies have demonstrated that the “young-to-aged” paradigm could achieve partial cardiovascular rejuvenation in murine models. For instance, exposure to young plasma represses cardiac hypertrophy, while exposure to young microbiota alleviates vascular dysfunction and systemic inflammation. However, significant challenges still persist, including ethical concerns, the irreversibility of aging beyond certain thresholds, and senescence propagation of young donor transplants due to aged recipient environments. This paradigm faces immense scientific and ethical hurdles, raising profound questions about feasibility and identity. © The Author(s) 2025.