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However, the processes involved, particularly the response of senescence markers and cell fitness status in the context of Alzheimer\u2019s disease (AD) pathology, remain unclear. We analyzed male and female 5XFAD transgenic AD mice subjected to 6 months of voluntary wheel running using molecular and behavioral techniques. Levels of mRNA of selected genes, mitochondrial complex proteins, and proteasomal function, were analyzed in the cerebral cortex or hippocampus. In an exploratory translational approach, proteasomal dynamics- and senescence-related genes were analyzed in peripheral blood from middle-aged amateur sportsmen. Physical exercise increased expression of antioxidant genes and modulated epigenetic genes in 5XFAD male and female mice. An increase in protein levels of hippocampal mitochondrial complexes CIII and CV was also induced in males. Both exercised 5XFAD mice and veteran sportsmen showed improved proteasomal status and decreased expression of senescence genes. Exercised mice showed memory and behavior preservation, as well as increases in brain metabolic fitness and gene modulation. These changes may contribute to the neuroprotective effect of physical exercise.<\/jats:p>","DOI":"10.3390\/antiox15060698","type":"journal-article","created":{"date-parts":[[2026,6,3]],"date-time":"2026-06-03T09:33:14Z","timestamp":1780479194000},"page":"698","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Translational Insights into Exercise-Induced Protective Adaptations in 5XFAD Mice and Middle-Aged Amateur Sportsmen"],"prefix":"10.3390","volume":"15","author":[{"ORCID":"https:\/\/orcid.org\/0009-0009-6784-8114","authenticated-orcid":false,"given":"Pau","family":"Garcia-Baucells","sequence":"first","affiliation":[{"name":"Departament de Neuroci\u00e8ncies i Terap\u00e8utica Experimental, Institut d\u2019Investigacions Biom\u00e8diques de Barcelona (IIBB), CSIC, 08036 Barcelona, Spain"},{"name":"Institut Hospital del Mar d\u2019Investigacions M\u00e8diques (IMIM), 08003 Barcelona, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7426-0751","authenticated-orcid":false,"given":"Clara","family":"Bartra","sequence":"additional","affiliation":[{"name":"Departament de Neuroci\u00e8ncies i Terap\u00e8utica Experimental, Institut d\u2019Investigacions Biom\u00e8diques de Barcelona (IIBB), CSIC, 08036 Barcelona, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sara","family":"Sarroca","sequence":"additional","affiliation":[{"name":"Departament de Neuroci\u00e8ncies i Terap\u00e8utica Experimental, Institut d\u2019Investigacions Biom\u00e8diques de Barcelona (IIBB), CSIC, 08036 Barcelona, Spain"},{"name":"Independent Researcher, 08015 Barcelona, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Filipa","family":"Reinoite","sequence":"additional","affiliation":[{"name":"Departament de Neuroci\u00e8ncies i Terap\u00e8utica Experimental, Institut d\u2019Investigacions Biom\u00e8diques de Barcelona (IIBB), CSIC, 08036 Barcelona, Spain"},{"name":"ITQB NOVA, NOVA University of Lisbon, 2780-157 Lisbon, Portugal"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6518-2456","authenticated-orcid":false,"given":"J\u00falia","family":"Senserrich","sequence":"additional","affiliation":[{"name":"Departament de Neuroci\u00e8ncies i Terap\u00e8utica Experimental, Institut d\u2019Investigacions Biom\u00e8diques de Barcelona (IIBB), CSIC, 08036 Barcelona, Spain"},{"name":"Instituto de Biomedicina y Biotecnolog\u00eda de Cantabria (IBBTEC, UC-CSIC), Centro de Investigaci\u00f3n Biom\u00e9dica en Red de Salud Mental (CIBERSAM), 39011 Santander, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rub\u00e9n","family":"Corpas","sequence":"additional","affiliation":[{"name":"Departament de Neuroci\u00e8ncies i Terap\u00e8utica Experimental, Institut d\u2019Investigacions Biom\u00e8diques de Barcelona (IIBB), CSIC, 08036 Barcelona, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5424-9130","authenticated-orcid":false,"given":"Christian","family":"Gri\u00f1\u00e1n-Ferr\u00e9","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, Toxicology and Therapeutic Chemistry, University of Barcelona, Av. Joan XXIII, 27-31, 08028 Barcelona, Spain"},{"name":"Institute of Neurosciences of the University of Barcelona, 08035 Barcelona, Spain"},{"name":"Centro de Investigaci\u00f3n en Red, Enfermedades Neurodegenerativas (CIBERNED), Instituto de Salud Carlos III, 28029 Madrid, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9004-1206","authenticated-orcid":false,"given":"Coral","family":"Sanfeliu","sequence":"additional","affiliation":[{"name":"Departament de Neuroci\u00e8ncies i Terap\u00e8utica Experimental, Institut d\u2019Investigacions Biom\u00e8diques de Barcelona (IIBB), CSIC, 08036 Barcelona, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,5,31]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"417","DOI":"10.1146\/annurev-clinpsy-072720-014213","article-title":"Cognitive Aging and the Promise of Physical Activity","volume":"18","author":"Erickson","year":"2022","journal-title":"Annu. 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