Combined Time‐Restricted Feeding and Physical Exercise Attenuate ER Stress and Improve Liver Inflammation and Collagen Deposition in Aged Mice

Aging is associated with progressive impairment of hepatic adaptive capacity, including mitochondrial dysfunction, oxidative stress, and disruption of proteostasis. Persistent activation of the unfolded protein response (UPR), particularly under chronic endoplasmic reticulum (ER) stress, has been implicated in age-related liver vulnerability even in the absence of metabolic disease. This study evaluated the effects of time-restricted feeding (TRF), either alone or in combination with exercise training, on age-associated hepatic alterations in adult (6-month-old) and aged (24-month-old) male C57BL/6 J mice maintained on a standard diet. TRF consisted of a 12-h fasting/feeding cycle applied 5 days per week for 8 weeks, and exercise comprised alternating aerobic and resistance sessions (1 h/day). Aged mice exhibited sustained activation of PERK-associated ER stress signaling, particularly along the PERK-CHOP 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-associated 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-associated stress signaling were not fully reversible. Collectively, these findings demonstrate that hepatic aging under non-obesogenic conditions is characterized by sustained PERK-associated ER stress signaling accompanied by mild inflammatory cell infiltration and increased collagen deposition, and that coordinated nutritional and exercise strategies can modulate stress-responsive pathways associated with hepatic resilience during aging.