<p>As Earth’s magnetic field weakens, space radiation begins to pose a significant threat to the health of not only space travelers, but the world’s population. Space radiation, comprising high-energy and high-charge ions, creates distinct clusters of DNA damage and dense macromolecular damage that result in the accumulation of senescent cells (SnCs) known to play a critical role in promoting multimorbidity. Here, we demonstrate that human fibroblasts exposed to different forms of space radiation acquire senescence-associated phenotypes including morphological alterations and the accumulation of SA-ß-gal⁺ cells to a greater extent than what is observed following γ-irradiation. Bulk and single cell RNA (scRNAseq) sequencing analysis revealed that space irradiated human fibroblasts up-regulated senescent-like phenotypes to a greater extent compared to γ-irradiation and enriched pathways associated with chronic activation and adaptation of the integrated stress response and NADPH-coupled redox metabolism. Healthy cells treated with conditioned media from irradiated SnCs manifested pro-inflammatory transcriptional profiles dependent on both radiation and cell type. Finally, treatment with known senotherapeutics demonstrated radiation-specific effects in primary dermal fibroblasts. Our data demonstrate that space radiation differentially induces senescent phenotypes in human cells compared to γ-irradiation, which may play a key role in the pathogenic effects of space travel.</p>