Cellular parabioisis as a senotherapeutic approach

Abstract

Beyond cell death and differentiation, cell senescence is profoundly influenced by the social nature of cells, which is intricately linked to cell communication as a fundamental aspect of biological systems shaping both individual and collective cellular behaviors. As demonstrated by cellular parabiosis, sophisticated communication plays a critical role in maintaining tissue health and delaying age-related diseases. It is now widely accepted that signaling crosstalk, through both direct cell-to-cell interactions and indirect mechanisms, drives cell heterogeneity and cell state transitions, and that increasing cell heterogeneity with age significantly contributes to the development of age-related diseases. Aging is also associated with increased stem cell heterogeneity, leading to functional decline and decreased regenerative capacity. Heterochronic parabiosis and stem cell transplantation studies have indicated that impaired regeneration observed in aging organisms can be reversed by a youthful systemic environment that restores balanced signaling and rejuvenates aged cells. Multiple reports on autologous and allogeneic transplantation have confirmed the rejuvenative potential of hematopoietic stem cell and various tissue-derived mesenchymal stem cell transplants, providing insights into the potential of integrating cellular parabiosis-like approaches into regenerative medicine to combat aging and its associated pathologies. Scientific advances in these areas are now progressing to clinical trials. In this chapter, we first summarize the current knowledge of cellular parabiosis as a complex physiological process and emphasize heterogeneity in senescent cells. Subsequently, it reviews therapeutic approaches for treating aging-induced stem cell dysfunction as innovative solutions for addressing this issue. Finally, the chapter discusses future directions and challenges for senotherapeutic applications, highlighting their potential to advance the field of regenerative medicine. © 2025