MiRNAs shape mouse age-independent tissue adaptation to spaceflight via ECM and developmental pathways.

As human space exploration accelerates, understanding the organism-wide molecular effects of longer spaceflight in mammals becomes increasingly critical. Non-coding RNAs like miRNAs are key to regulating this landscape. We thus analyze 686 small RNA samples of female mice from 13 solid organs at 3 and 8 months of age, after at least 3 weeks on the International Space Station and compare them to earth-bound controls. We observe significant spaceflight effects in systemic tissue remodeling pathways along the Fat-Liver-Pancreas axis and in heart, brain, spleen and thymus. The MIR-17/92 and MIR-1/133 families drive distinct molecular changes through specific gene targeting. Age-dependent changes, smaller in magnitude compared to age-independent changes, primarily involve tissue remodeling through MIR-8, MIR-154 and MIR-15 families in mesenteric adipose tissue, pancreas, and diaphragm. Our findings provide evidence on how spaceflight regulates mammalian gene expression in preparation for interplanetary spaceflight.