02428nas a2200277   4500000000100000008004100001260001500042100002000057700001700077700002100094700002200115700001500137700001500152700002100167700001600188700002600204700002100230700002200251700001500273245011300288856007200401300001100473490000600484520164600490022001402136       2026                            d  c2026-03-011 aAmi Mehta-Doshi1 aBlake L. Tsu1 aConsuelo Sauceda1 aStefanie N. Kairs1 aJustin Liu1 aJeslyn Rai1 aThomas Whisenant1 aRoman Sasik1 aChristopher A. Barnes1 aDeependra K. Ban1 aDavid J. Gonzalez1 aKiana Aran00aAge-dependent neuroinflammatory effects of red blood cells and their exosomes in a human brain-on-chip model  uhttps://www.sciencedirect.com/science/article/pii/S3050598425000447  a1000440 v23 aThe systemic blood milieu profoundly influences the cellular function across tissues, acting as a key driver of age-related cognitive decline. Therapeutic plasma exchange and heterochronic parabiosis have widely explored the role of plasma and blood age on various tissues. However, the role of red blood cells (RBCs) remains largely unexplored. In this study, we investigated the impact of RBCs and their exosomal cargo from young (aged 20-40 years) and old (aged 50-70 years) donors on human brain cells using a human brain microphysiological system (hB-MPS). The RBCs and their exosomes from the donors were circulated in the vascular channel of the hB-MPS device. Compared with that obtained from young donors, RBCs and their exosomes from old donors exhibited elevated levels of the inflammatory marker CD68 and increased the accumulation of heme in the brain cells. Molecular profiling of the RBC-derived exosomes using proteomics and microRNA sequencing analysis revealed age-associated differences in cargo, including downregulation of proteins linked to neuroprotective pathways and upregulation of those involved in inflammation and synaptic dysregulation. Proteomic analysis of the brain cells in response to the RBC-derived exosomes from older donors altered brain cell homeostasis by modulating key signaling pathways directly correlated to neurobiological processes such as cytokine signaling, neurotrophin signaling, metabolic activity, and DNA repair. This highlights a novel role for RBCs in brain aging and neuroinflammation and points toward RBCs and their exosomal profiling as a biomarker for age-associated pathologies.  a3050-5984