As they age, older adults are increasingly susceptible to health decline associated with excessive alcohol consumption, which can accelerate biological aging through cellular stress, senescence-associated responses, and inflammaging. Although sesaminol, a sesame-derived lignan, protects against alcohol-induced colitis in young animals, its effects on alcohol-associated intestinal dysfunction and senescence-related changes in middle-aged animals remain unclear. In this study, middle-aged mice (50 weeks old at the start of intervention) were fed an ad libitum 2.5% (v/v) ethanol-containing liquid diet for 10 weeks and administered 1.2 mg sesaminol or vehicle daily by gavage, with young mice (10 weeks old at the start) serving as controls.　We evaluated the colonic senescence-associated secretory phenotype, the expression of markers of senescence, the gut microbiota, fecal short-chain fatty acid concentrations, intestinal barrier integrity, and aryl hydrocarbon receptor (AhR)/nuclear factor erythroid 2-related factor 2 (Nrf2)-related signaling. Chronic alcohol intake was associated with dysbiosis, more marked features of colonic senescence and inflammation, impairment in AhR/Nrf2 signaling, and the depletion of tight junction proteins. Sesaminol supplementation attenuated these alterations and was associated with greater abundance of the Lactobacillaceae, Rikenellaceae, and Muribaculaceae, together with higher fecal butyrate content. These effects were accompanied by an improvement in intestinal barrier integrity and changes in AhR- and Nrf2-related signaling. Taken together, these findings suggest that sesaminol may ameliorate the interconnected microbial, metabolic, epithelial, and redox-related responses to chronic alcohol exposure, thereby attenuating alcohol-associated intestinal dysfunction and senescence-related changes in middle-aged mice.
