Previous reports revealed immune dysfunction, chromosomal abnormalities, cytokine deregulation, and telomere length dynamics following prolonged spaceflight. However, the stress of space on hematopoietic stem and progenitor cells (HSPCs) that maintain lifelong hematopoiesis and immune responses was not studied. We performed HSPC functionally organized multi-omics aging (HSPC-FOMA) analyses in 7 astronauts before, during, and after short-duration ISS missions. Specifically, whole genome sequencing with telomere length, mitochondrial and clonal mutational profiling; whole transcriptome sequencing with RNA editing and retrotransposon analyses; single-cell RNA sequencing; cytokine arrays; and FACS-analyses were performed to assess HSPC and immune subpopulation survival dynamics. Overall, the observed space-associated stem cell hallmarks of aging, including spaceflight-dependent alterations in HSPC survival and self-renewal, adenosine deaminase associated with RNA1 (ADAR1), telomere maintenance, mobilization and cell cycle gene expression combined with space-associated clonal hematopoietic mutations, apolipoprotein B mRNA editing catalytic polypeptide-like (APOBEC3C) activation and retrotransposon deregulation warrant countermeasure development to enable long-duration spaceflight.

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2025
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