Systemic factors from young human serum rejuvenate human skin in vitro using a microphysiological system featuring BM-derived blood cells

Aging is a multifaceted systemic process that contributes to the onset of age-related diseases. Despite advances, few comprehensive anti-aging strategies have successfully reversed the adverse effects of aging. Heterochronic parabiosis studies have highlighted the potential of systemic rejuvenation through blood-borne factors, yet the precise drivers of aging and rejuvenation, along with their mechanisms, remain largely elusive. Furthermore, translating these findings to humans has been challenging. In this study, we achieved human skin rejuvenation through systemic factors using a microphysiological system comprising a 3D skin model and a 3D bone marrow model, which simulates the niche for progenitor and blood cells. Treatment with young human serum, compared to aged human serum, enhanced cell proliferation and reduced the biological age of skin tissue, as determined by methylation-based age clocks. Notably, these effects required the presence of bone marrow-derived cells in the system. Further analysis of the bone marrow model revealed serum-dependent changes in cell population composition and aging markers. Proteome profiling identified 55 potential systemic rejuvenating proteins secreted by bone marrow-derived cells. Among these, seven proteins were validated to have rejuvenating effects on human skin cells through hallmark aging assays, underscoring their role as key systemic factors in reversing skin aging.