The Brown Bear and Hibernating Mammals as a Translational Model for Human Resilience: Insights for Space Medicine, Critical Care, and Austere Environments.

Long-term spaceflight induces multisystem stress, including cardiovascular deconditioning, skeletal muscle atrophy, immune suppression, and neuro-ocular syndromes. Current countermeasures reduce symptoms but cannot replicate the synergistic resilience needed for extended missions or critical illness. Hibernating animals, specifically brown bears (Ursus arctos), survive prolonged immobility, starvation, and bradycardia without resultant pathology. This review incorporates adaptations observed in bears and certain torpid species, including reversible insulin resistance, suppression of muscle atrophy genes MuRF1 and Atrogin-1, and maintenance of the heart despite seasonal production decline. The thirteen-lined ground squirrels (Ictidomys tridecemlineatus) maintain retinal structure and synaptic stability throughout torpor, avoiding neuro-ocular complications despite prolonged inactivity. Mechanisms span from RBM3-dependent synaptic maintenance, titin isoform remodeling under the control of RBM20, mTOR and FOXO pathway regulation, remodeled hydrogen sulfide metabolism, and microbiome-mediated nitrogen salvage. These adaptations are different from human adaptation to microgravity and disuse and offer translational candidates for synthetic torpor, probiotic engineering, neuroprotection, and protein-sparing therapy. Hibernators are not passive stress subjects; they perform coordinated anticipatory responses in multiple organs. Comparing these systems in large and small hibernators, we aim to uncover a biologically realistic path to human resilience. These findings guide a shift from reactive, pharmacological measures for preserving human health during space flight, intensive care, and extreme environments towards proactive, biologically initiated measures.