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National Laboratory for help with the irradiations."},{"name":"DOI","value":"10.26030/4kkv-z246"},{"name":"Data Source Accession","value":"GSE297560"},{"name":"Data Source Link","value":"https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE297560"},{"name":"Experiment Platform","value":""},{"name":"Flight Program","value":""},{"name":"Funding","value":"Funding for this research was provided by grants from NASA 80NSSC20K0732 (SB) and NIH R01 CA246807 (SB), R01 AG069819 (PDR), P01 AG043376 (PDR), U19 AG056278 (PDR), P01 AG062413 (PDR, JLK, NKL), U54 AG079754 (PDR), U54 AG076041 (PDR), R37AG013925 (JLK), R33AG061456 (JLK) and T32AG029796 (LEP)."},{"name":"Identifiers","value":""},{"name":"Managing NASA Center","value":""},{"name":"Mission End","value":""},{"name":"Mission Link","value":""},{"name":"Mission Name","value":""},{"name":"Mission Start","value":""},{"name":"Project Identifier","value":"Gamma_Irradiation, Heavy_Ion_HZE_Irradiation, Proton_Irradiation, Multiple_Radiation_Types, 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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-beta-gal+ cells to a greater extent than what is observed following gamma-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 gamma-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 gamma-irradiation, which may play a key role in the pathogenic effects of space travel. 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