Alternate-Day Fasting Modulates Endoplasmic Reticulum Stress and Lipid Metabolism in Young and Middle-Aged Rats

Abstract Background This study aimed to investigate the effects of alternate-day fasting (ADF) on body weight (BW), fat distribution, and key molecular markers related to endoplasmic reticulum stress (ERS) and sterol regulatory element-binding protein-1(SREBP-1) in young (3-month-old) and middle-aged (16-month-old) rats. Methods Thirty-two male Wistar rats were divided into four groups: Group1 (ad libitum(AL)-fed young rats), Group2 (ADF-young rats), Group3 (AL-fed middle-aged rats), and Group4 (ADF-middle-aged rats). ADF was implemented as a 24 h feeding period followed by 24 h of fasting for 28 days. Serum and liver samples were analyzed via ELISA for SREBP-1, protein kinase RNA-like ER kinase (PERK), activating transcription factor-6 (ATF6), and glucose-regulated protein 78 (GRP78) levels. Results Compared with Group-1, Group-3 had significantly greater BW and retroperitoneal fat content ( p = 0.001). ADF reduced BW in young rats (Group-2 vs. Group-1, p = 0.015) but not in middle-aged rats (Group-4 vs. Group-3, p = 0.073). ADF significantly reduced fat accumulation in middle-aged rats (Group-4 vs . Group-3 p = 0.001), although fat accumulation was greater in middle-aged rats than in young rats ( p = 0.001). Serum and liver PERK,GRP78,ATF6, and SREBP-1 levels were significantly greater in AL-fed middle-aged rats (Group-3 vs . Group-1, p < 0.05), indicating that ERS and lipid dysregulation increase with age. ADF significantly reduced these markers in middle-aged rats (Group-4 vs . Group-3, p < 0.05), suggesting a protective effect. Additionally, ADF lowered serum and liver SREBP-1 levels in young rats (Group-2 vs . Group-1, p = 0.003), highlighting its role in lipid metabolism regulation. Conclusions ADF appears to be a promising nonpharmacological approach for mitigating age-related metabolic and molecular disturbances. Further research is warranted to explore its long-term effects and translational potential in human aging. Graphical Abstract