Aging is a complex process that significantly contributes to age-related diseases and poses significant challenges for effective interventions, with few holistic anti-aging approaches successfully reversing its signs. Heterochronic parabiosis studies illuminated the potential for rejuvenation through blood-borne factors, yet the specific drivers including underlying mechanisms remain largely unknown and until today insights have not been successfully translated to humans. In this study, we were able to recreate rejuvenation of the human skin via systemic factors using a microphysiological system including a 3D skin model and a 3D bone marrow model. Addition of young human serum in comparison to aged human serum resulted in an improvement of proliferation and a reduction of the biological age as measured by methylation-based age clocks in the skin tissue. Interestingly, this effect was only visible in the presence of bone marrow-derived cells. Further investigation of the bone marrow model revealed changes in the cell population in response to young versus aged human serum treatment. Using proteome analysis, we identified 55 potential systemic rejuvenating proteins produced by bone marrow-derived cells. For seven of these proteins, we were able to verify a rejuvenating effect on human skin cells using hallmarks of aging assays, supporting their role as systemic factors rejuvenating human skin tissue.