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Persistent activation of the unfolded protein response (UPR), particularly under chronic endoplasmic reticulum (ER) stress, has been implicated in age\u2010related liver vulnerability even in the absence of metabolic disease. This study evaluated the effects of time\u2010restricted feeding (TRF), either alone or in combination with exercise training, on age\u2010associated hepatic alterations in adult (6\u2010month\u2010old) and aged (24\u2010month\u2010old) male C57BL\/6\u2009J mice maintained on a standard diet. TRF consisted of a 12\u2010h fasting\/feeding cycle applied 5 days per week for 8 weeks, and exercise comprised alternating aerobic and resistance sessions (1\u2009h\/day). Aged mice exhibited sustained activation of PERK\u2010associated ER stress signaling, particularly along the PERK\u2013CHOP axis, accompanied by mild inflammatory cell infiltration, increased collagen deposition, and elevated MASLD score, despite the absence of increased adiposity or impaired glucose tolerance. TRF alone partially attenuated PERK\u2010associated ER stress signaling and histological alterations; however, only the combined intervention significantly reduced upstream PERK phosphorylation. Persistent elevation of CHOP across aged groups suggests that downstream PERK\u2010associated stress signaling were not fully reversible. Collectively, these findings demonstrate that hepatic aging under non\u2010obesogenic conditions is characterized by sustained PERK\u2010associated ER stress signaling accompanied by mild inflammatory cell infiltration and increased collagen deposition, and that coordinated nutritional and exercise strategies can modulate stress\u2010responsive pathways associated with hepatic resilience during aging.<\/jats:p>","DOI":"10.1002\/cbf.70272","type":"journal-article","created":{"date-parts":[[2026,7,20]],"date-time":"2026-07-20T07:57:24Z","timestamp":1784534244000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Combined Time\u2010Restricted Feeding and Physical Exercise Attenuate ER Stress and Improve Liver Inflammation and Collagen Deposition in Aged Mice"],"prefix":"10.1002","volume":"44","author":[{"ORCID":"https:\/\/orcid.org\/0009-0001-6342-3380","authenticated-orcid":false,"given":"Guilherme Correia 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Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9679-8357","authenticated-orcid":false,"given":"Adelino Sanchez Ramos da","family":"Silva","sequence":"additional","affiliation":[{"name":"Postgraduate Programs in Rehabilitation and Functional Performance and Physical Education and Sport University of S\u00e3o Paulo (USP) Ribeir\u00e3o Preto Brazil"},{"name":"National Institutes of Science Technology and Innovation (INCT) S\u00e3o Paulo Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1655-9557","authenticated-orcid":false,"given":"Eduardo Rochete","family":"Ropelle","sequence":"additional","affiliation":[{"name":"Laboratory of Molecular Biology of Exercise University of Campinas (UNICAMP) Limeira S\u00e3o Paulo Brazil"},{"name":"OCRC \u2010 Obesity and Comorbidities Research Center University of Campinas (UNICAMP) Campinas S\u00e3o Paulo Brazil"},{"name":"Nutrigenomics and Lipids 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