{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,10]],"date-time":"2026-10-10T06:59:26Z","timestamp":1791615566047,"version":"4.3.4"},"reference-count":137,"publisher":"MDPI AG","issue":"10","license":[{"start":{"date-parts":[[2025,10,17]],"date-time":"2025-10-17T00:00:00Z","timestamp":1760659200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Biology"],"abstract":"<jats:p>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.<\/jats:p>","DOI":"10.3390\/biology14101434","type":"journal-article","created":{"date-parts":[[2025,10,17]],"date-time":"2025-10-17T14:29:17Z","timestamp":1760711357000},"page":"1434","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":6,"title":["The Brown Bear and Hibernating Mammals as a Translational Model for Human Resilience: Insights for Space Medicine, Critical Care, and Austere Environments"],"prefix":"10.3390","volume":"14","author":[{"ORCID":"https:\/\/orcid.org\/0009-0004-3088-7543","authenticated-orcid":false,"given":"Jainam","family":"Shah","sequence":"first","affiliation":[{"name":"Albert Einstein College of Medicine, Bronx, NY 10461, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8365-5672","authenticated-orcid":false,"given":"Ryung","family":"Lee","sequence":"additional","affiliation":[{"name":"Department of Medicine, Jacob\u2019s School of Medicine and Biomedical Sciences, Buffalo, NY 14203, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sachin","family":"Pathuri","sequence":"additional","affiliation":[{"name":"Creighton University School of Medicine, Phoenix Regional Campus, Phoenix, AZ 85012, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0002-2702-3934","authenticated-orcid":false,"given":"Jason","family":"Zheng","sequence":"additional","affiliation":[{"name":"California University of Science and Medicine, Colton, CA 92324, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4860-827X","authenticated-orcid":false,"given":"Joshua","family":"Ong","sequence":"additional","affiliation":[{"name":"Department of Ophthalmology and Visual Sciences, University of Michigan Kellogg Eye Center, Ann Arbor, MI 48105, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0005-7241-0994","authenticated-orcid":false,"given":"Alex","family":"Suh","sequence":"additional","affiliation":[{"name":"Department of Ophthalmology, USC Roski Eye Institute, Keck School of Medicine, University of Southern California, Los Angeles, CA 90333, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0004-4245-0226","authenticated-orcid":false,"given":"Kimia","family":"Rezaei","sequence":"additional","affiliation":[{"name":"University of California Riverside School of Medicine, Riverside, CA 92507, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gagandeep","family":"Mudhar","sequence":"additional","affiliation":[{"name":"Albert Einstein College of Medicine, Bronx, NY 10461, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andrew D.","family":"Parsons","sequence":"additional","affiliation":[{"name":"Albert Einstein College of Medicine, Bronx, NY 10461, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jaewoo","family":"Park","sequence":"additional","affiliation":[{"name":"Albert Einstein College of Medicine, Bronx, NY 10461, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2473-299X","authenticated-orcid":false,"given":"Andrew G.","family":"Lee","sequence":"additional","affiliation":[{"name":"Department of Ophthalmology, Blanton Eye Institute, Houston Methodist Hospital, Houston, TX 77030, USA"},{"name":"Department of Ophthalmology, Baylor College of Medicine and the Center for Space Medicine, Houston, TX 77030, USA"},{"name":"The Houston Methodist Research Institute, Houston Methodist Hospital, Houston, TX 77030, USA"},{"name":"Departments of Ophthalmology, Neurology, and Neurosurgery, Weill Cornell Medicine, New York, NY 10065, USA"},{"name":"Department of Ophthalmology, University of Texas Medical Branch, Galveston, TX 77555, USA"},{"name":"University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA"},{"name":"Texas A&M College of Medicine, Bryan, TX 77807, USA"},{"name":"Department of Ophthalmology, The University of Iowa Hospitals and Clinics, Iowa City, IA 52242, USA"},{"name":"Department of Ophthalmology, University of Buffalo, Buffalo, NY 14214, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,10,17]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","unstructured":"Demontis, G.C., Germani, M.M., Caiani, E.G., Barravecchia, I., Passino, C., and Angeloni, D. 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