Naringin Mitigates Synergistic Brain Aging Model Induced by D‐Galactose and Gamma Radiation via Targeting Oxidative Stress, Inflammation and Senescence

ABSTRACT Brain aging is a multifactorial process driven by oxidative stress, chronic inflammation, and cellular senescence, culminating in neurodegeneration and cognitive decline. In this study, we established a robust aging model by synergistically combining d ‐galactose and acute gamma‐irradiation (6 Gy), intensified senescence‐associated phenotypes in rat brain tissue. Rats were divided into four groups: Group I: negative control; group II (naringin‐treated): rats were given naringin (50 mg/kg; p.o.) for 1 week; group III (Rad+ D ‐galactose): rats were exposed to whole‐body gamma radiation (6 Gy) and then received D ‐galactose (300 mg/kg b. wt. i.p.) for 7 days; group IV (Rad+ D ‐galactose+ naringin): as in group III, then naringin (50 mg/kg b. wt. p.o.) for 1 week. This model exhibited elevated levels in IL‐6, TNF‐α, p16 INK4A , p21 CIP1 and retinoblastoma protein (Rb) levels, as well as upregulated NF‐κBp65 protein expression in brain tissue. Remarkably, naringin supplementation reversed the pathological signatures, restoring antioxidant balance, suppressing inflammatory mediators, and modulating apoptotic pathways. Histological hallmarks such as gliosis, neurophagia, and pyknosis, as well as immunohistological staining of caspase‐3 and p53 expression, confirmed the aforementioned consequences. Collectively, these findings highlight naringin's therapeutic potential in mitigating brain aging by targeting oxidative stress, inflammation, and apoptosis. This study offers a robust experimental framework for investigating senescence and supports naringin as a promising candidate for intervention in age‐related neurodegenerative disorders.