Fucoxanthin Attenuates Hepatic Damage in a d ‐Galactose‐Induced Accelerated Aging Mouse Model: Insight Into Underlying Mechanisms

ABSTRACT The global population is aging rapidly, and aging‐related hepatic damage poses a significant public health challenge. This study aimed to investigate the protective effects and mechanisms of fucoxanthin (Fx), a marine carotenoid, against hepatic damage in a d ‐galactose ( d ‐gal)‐induced accelerated aging mouse model. Accelerated aging was induced by daily intraperitoneal injection of 400 mg/kg d ‐gal for 12 weeks, during which the Fx groups received daily gavage of Fx at 50 and 100 mg/kg. The results demonstrated that Fx treatment significantly attenuated d ‐gal‐induced hepatic damage, as evidenced by reduced serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) activities, improved liver histopathology, and decreased DNA damage. Furthermore, Fx treatment delayed the hepatic aging‐like phenotype by down‐regulating the protein expression of senescence markers, such as p53, p21, p16, and β‐galactosidase. Mechanistically, Fx treatment alleviated hepatic oxidative stress by reducing levels of intracellular reactive oxygen species, malondialdehyde, and protein carbonyls, as well as restored the activities of antioxidant enzymes, such as catalase (CAT), superoxide dismutase (SOD), and glutathione peroxidase (GSH‐Px). Additionally, Fx treatment appeared to suppress d ‐gal‐induced hepatic inflammation by inhibiting the nuclear factor kappa B (NF‐κB) signaling pathway, as reflected by decreased phosphorylation of inhibitor of kappa B kinase beta (IκKβ), inhibitor of nuclear factor kappa B alpha (IκBα), and NF‐κB p65, along with reduced protein levels of pro‐inflammatory mediators, including inducible nitric oxide synthase (iNOS), tumor necrosis factor‐alpha (TNF‐α), interleukin‐6 (IL‐6), interleukin‐1beta (IL‐1β), and interleukin‐18 (IL‐18). Importantly, Fx treatment inhibited d ‐gal‐induced activation of multiple programmed cell death pathways in the liver, including the intrinsic apoptosis pathway, the receptor‐interacting protein kinase 1 (RIPK1)/receptor‐interacting protein kinase 3 (RIPK3)/mixed lineage kinase domain‐like protein (MLKL) necroptotic signaling cascade, and the NOD‐like receptor family pyrin domain containing 3 (NLRP3)/caspase‐1/gasdermin D (GSDMD) pyroptotic signaling cascade. These findings suggest that Fx has potential as a nutraceutical ingredient for supporting liver health during aging.