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 analyzed 686 small RNA samples of mice from 13 solid organs at 3 and 8 months of age, after at least 3 weeks on the ISS and compared them to earth-bound controls. We observed 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 involved tissue remodeling through MIR-8, MIR-154 and MIR-15 families in MAT, pancreas, and diaphragm. Our findings provide evidence on how spaceflight regulates mammalian gene expression in preparation for interplanetary spaceflight. We sequenced 686 samples across 13 organs of young (3 months) and middle-aged (8 months) mice that were sent to the ISS (Flight). We compared them against mice living in standard conditions (Vivarium Ground Control) and mice living in an environment matched to ISS conditions (Habitat Ground Control). We euthanized mice at two time-points (matching timelines for controls and flight mice), one before returning to earth (TERM) and one after (LAR) in order to distinguish spaceflight-induced effects from the reentry-induced stress.