Single-cell analysis reveals inter-organ endothelial crosstalk in aging and obesity

Background Cellular senescence safeguards against tumorigenesis, yet its hyper-activation deteriorates tissue function. Aging- and obesity-driven metabolic stress is systemic, whereas vascular pathology progresses in an organ-specific manner for reasons that remain obscure. We therefore interrogated vascular endothelial cells, the arbiters of organ identity. Methods Endothelial cells were purified from adipose tissue, heart, skeletal muscle, and liver of mice exposed to natural aging or diet–induced obesity. Single-cell RNA-seq defined differentially expressed genes, which were integrated with pathway and transcription-factor analyses. Ligand–receptor crosstalk was inferred by computational cell–cell communication analysis, and spatial localization was verified by spatial transcriptomics. Results Aging triggered organ-specific transcriptional shifts yet uniformly upregulated interferon (IFN) signaling driven by IRF family factors. Obesity elicited divergent activation of PPARg-centered lipid-metabolic and inflammatory programs across organs. Computational inference of cell–cell communication identified TNF signals from an adipose macrophage subset to endothelial cells that initiated endothelial IFN activation. Spatial maps showed TNF effects radiated beyond immediate proximity, while IFN-high endothelial cells formed clustered niches in every organ that attracted leukocytes. In heart and skeletal muscle, these endothelial clusters promoted anti-inflammatory macrophage polarization, reshaping local immune homeostasis; notably, we found that IFN-induced downstream ligands from endothelial cells drove anti-inflammatory differentiation of monocytes. Collectively, the data quantitatively link organ-specific transcriptional networks to systemic inflammatory cues and implicate their feed-forward activation in vascular aging. Conclusions Metabolic and aging stress converge on adipose-derived TNF to synchronize a bodywide endothelial IFN response while forging organ-specific cytokine circuits that govern the plasticity of vascular lesions and the immune microenvironment.