Space radiation and microgravity as models of accelerated aging: modulation of hepatic miRNA-TGF-β networks associated with senescence and fibrosis

Hayslip et al., GeroScience, 2026 asked whether the two defining stressors of deep space, ionizing radiation and weightlessness, push the liver toward the molecular state of an aging organ, and whether inhibiting a small set of microRNAs can hold that shift back. Female 15-week-old C57BL/6J mice spent 14 days in hindlimb unloading to simulate microgravity, then received 0.5 Gy of simulated galactic cosmic radiation or 1.0 Gy of simulated solar particle event radiation at the NASA Space Radiation Laboratory. Livers were taken 24 hours after irradiation and read by RT-PCR for 8 microRNAs and 15 messenger RNAs in the TGF-beta pathway. Hindlimb unloading alone raised miR-16-5p, miR-125b-5p, miR-21-5p, miR-27a-3p and miR-148a-3p, and both radiation types raised the senescence transcript p21.

The intervention arm used AUMantagomir oligonucleotides against miR-16-5p, miR-125b-5p and let-7a-5p, built with full complementarity to the mature microRNA sequences and given by intraperitoneal injection at 10 mg/kg each, 30 mg/kg in total, every 3 days from 1 day before unloading until 1 day before irradiation. The oligonucleotides reached their targets in the liver: all three fell under both radiation types compared with the untreated sham group, and miR-125b-5p and let-7a-5p fell in the non-irradiated normally loaded and hindlimb unloaded animals as well. The transcripts downstream moved with them. Tgfb1, which solar particle irradiation combined with microgravity had pushed down, returned to baseline, as did the aging-associated transcript mtor under both radiation types, and the anti-inflammatory Il10 rose in all radiation groups.

The authors report the fibrotic result against themselves. Col1a1 and Col4a1 rose further with treatment under galactic cosmic radiation, moving from slightly upregulated to significantly upregulated, and they note the study included no scrambled antagomir control group and measured no protein or histological endpoint. Against human data the direction of change matched: in the NASA Twins Study and the Inspiration4 mission, both flown in low Earth orbit at far lower doses of 14.634 cGy and 0.472 cGy, TGF-beta pathway genes in circulating blood cells were downregulated during and shortly after flight and recovered with further time on Earth.