Researchers at Kobe Gakuin University have reported that sesaminol, a natural lignan found in sesame seeds, significantly attenuates alcohol-induced cellular senescence in the colons of middle-aged mice. Published in the journal GeroScience, the study provides new evidence that this dietary compound may help preserve intestinal barrier integrity and modulate inflammatory responses associated with chronic alcohol exposure in aging animals. The findings suggest that sesaminol could serve as a potential dietary strategy to mitigate the accelerated biological aging of the gut caused by long-term alcohol consumption, although the study was conducted exclusively in a murine model.
The research team, led by Daiki Oikawa and Toru Nakayama, adopted a geroscience-centered perspective to investigate how chronic alcohol intake affects the intestinal homeostasis of middle-aged mice. Previous studies by the same group established that alcohol triggers oxidative stress and inflammation in the gut of young mice, leading to chronic colitis and dysbiosis. However, the specific effects of alcohol on senescence-related changes in middle-aged animals, and the potential protective role of sesaminol in this context, remained unclear. The study aimed to determine whether chronic alcohol administration alters aryl hydrocarbon receptor (AhR) and nuclear factor erythroid 2-related factor 2 (Nrf2) signaling, and whether sesaminol supplementation is associated with an amelioration of these effects.
To address these questions, the researchers utilized male C57BL/6NCr mice, dividing them into young controls (10 weeks old) and middle-aged experimental groups (50 weeks old at the start of intervention). The middle-aged mice were randomly allocated to four groups: a control group, an alcohol-only group, an alcohol plus sesaminol group, and a sesaminol-only group. For 10 weeks, the alcohol groups were fed an ad libitum liquid diet containing 2.5% ethanol, while the sesaminol groups received a daily oral gavage of 1.2 mg of sesaminol. This dosage was calculated to be approximately 25 mg/kg based on the initial mean body mass of the mice. The experimental design allowed the researchers to distinguish between the effects of aging, alcohol exposure, and sesaminol supplementation on intestinal health.
The results indicated that chronic alcohol consumption induced significant hepatotoxicity in the middle-aged mice, characterized by hepatomegaly and elevated plasma activities of alanine aminotransferase and aspartate aminotransferase. More critically, the alcohol group exhibited marked features of colonic senescence and inflammation. The researchers observed a significant increase in the concentration of 4-hydroxynonenal, a lipid peroxidation product and hallmark of oxidative damage, in the colonic tissue of the alcohol-treated mice. Concurrently, the activity of Nrf2, a master transcription factor involved in cellular antioxidant responses, was significantly lower in the alcohol group compared to both young and aged controls. Sesaminol co-administration significantly attenuated the alcohol-induced increase in oxidative stress markers and restored Nrf2 activity to levels comparable to those of the aged controls.
In addition to oxidative stress, the alcohol group displayed higher protein levels of senescence-associated secretory phenotype (SASP) biomarkers, including tumor necrosis factor-alpha, interleukin-6, and monocyte chemoattractant protein-1. These proinflammatory mediators were significantly reduced in the group that received both alcohol and sesaminol, indicating a robust anti-inflammatory effect of the compound. The study also assessed markers of cellular senescence, such as senescence-associated beta-galactosidase activity and the expression of cyclin-dependent kinase inhibitors p21 and p16. The alcohol group showed an expansion of p21-positive cells and increased p16 mRNA expression, both of which were mitigated by sesaminol supplementation. These findings suggest that sesaminol may help mitigate the cellular stress and tissue responses associated with chronic alcohol exposure.
The integrity of the intestinal barrier was another key focus of the study. Chronic alcohol exposure was associated with a depletion of the mucus barrier, evidenced by fewer PAS-positive goblet cells and reduced MUC2 immunoreactivity. Furthermore, the protein levels of key tight junction proteins, including ZO-1, occludin, and claudin-1, were significantly lower in the alcohol group. Sesaminol co-administration restored these proteins to control levels and normalized plasma lipopolysaccharide concentrations, which are indicative of gut leakiness. These results demonstrate that sesaminol helps preserve the structural and functional integrity of the intestinal barrier during chronic alcohol exposure.
Microbiome analyses revealed distinct shifts in the gut microbial community composition. Chronic alcohol administration was associated with dysbiosis, characterized by a depletion of the Muribaculaceae family and an enrichment of Bacteroidaceae, Lachnospiraceae, and Streptococcaceae. In contrast, sesaminol supplementation was associated with greater abundance of Lactobacillaceae, Rikenellaceae, and Muribaculaceae. The researchers also measured fecal short-chain fatty acid (SCFA) concentrations and found that sesaminol supplementation was associated with significantly higher levels of butyrate and lactate. The enrichment of Rikenellaceae is of particular interest because members of this family have been associated with longevity and a healthy metabolic profile in previous studies.
The study also investigated the role of the AhR-Nrf2 signaling axis in the response to alcohol and sesaminol. The AhR is a ligand-activated transcription factor that plays a pivotal role in maintaining intestinal mucosal immunity and barrier function. The researchers found that AhR protein levels were significantly lower in the alcohol group but were restored by sesaminol supplementation. Similarly, the levels of CYP1A1 and IL-22, which serve as functional indicators of AhR transcriptional activity, were suppressed by alcohol exposure and restored by sesaminol. These findings suggest that sesaminol preserves colonic homeostasis, at least in part, by sustaining AhR signaling in the presence of chronic alcohol-induced stress.
Despite these promising findings, the authors highlight several limitations of the study. The experiments were not capable of differentiating direct effects on senescent cells from the attenuation of senescence-associated responses to alcohol-induced tissue stress. Additionally, while the changes in gut microbial composition and fecal metabolite content imply a potential lactate-butyrate metabolic relay, microbial cross-feeding and metabolic fluxes were not directly assessed. The study also did not involve selective manipulation of AhR or Nrf2 signaling in vivo, nor did it directly assess epigenetic mechanisms such as histone acetylation. Therefore, the causal relationships among these interconnected responses remain to be fully established.
The findings should be interpreted in the context of alcohol-associated acceleration of intestinal aging rather than physiological aging itself. The researchers did not directly assess whether sesaminol affects normal age-associated intestinal senescence in the absence of alcohol exposure. Moreover, the exposure of mice to alcohol does not fully reproduce the heterogeneous patterns of alcohol consumption by humans, and the pharmacokinetics and bioavailability of sesaminol have not been characterized in humans. Further studies involving various age groups and experimental models are needed to establish the broader biological and translational relevance of these findings, including the evaluation of additional hallmarks of aging and the effects of sesaminol in humans.
Subject of Research: Effects of sesaminol on alcohol-induced colonic senescence and intestinal homeostasis in middle-aged mice
Article Title: Sesaminol attenuates alcohol-induced colonic senescence in middle-aged mice: potential involvement of the AhR–Nrf2 axis
Article References: Oikawa, D., Ohira, H., Omura, A., Kiyomoto, K., Nakagawa-Tsutsui, W., Mamoto, R., Fujioka, Y., & Nakayama, T. (2026). Sesaminol attenuates alcohol-induced colonic senescence in middle-aged mice: potential involvement of the AhR–Nrf2 axis. GeroScience. https://doi.org/10.1007/s11357-026-02622-z
Image Credits: AI Generated
DOI: 10.1007/s11357-026-02622-z
Keywords: sesaminol, colonic senescence, alcohol exposure, gut microbiota, AhR-Nrf2 signaling, intestinal barrier, geroscience, middle-aged mice, short-chain fatty acids, oxidative stress, attenuates, alcohol-induced
News Source: Beatrice Stafford. (November 10, 2026). Sesame Compound Counteracts Alcohol-Driven Aging in Mouse Colon. Scienmag.
