Light-dark shift promotes colon carcinogenesis through accelerated colon aging

Colorectal cancer (CRC) is the third most common cancer worldwide, with rising prevalence among younger adults. Several lifestyle factors, particularly disruptions in circadian rhythms by light-dark (LD) shifts, are known to increase CRC risk. Epidemiological studies previously showed LD-shifts are associated with increased risk of CRC. To explore the mechanisms and interactions between LD-shift and intestinal aging, we investigated how the combination of LD-shifts and aging impacts colon carcinogenesis development. Our data showed that LD-shifts and aging increased colon tumorigenesis. Notably, LD-shift accelerated intestinal aging by altering aging-related pathways, such as intestinal barrier damage, accompanied by dysbiotic changes in the intestinal microbiota that negatively impacts barrier stability. The increased carcinogenesis and intestinal aging were preceded by enrichment in host-microbiome features that are strongly regulated by the circadian clock. Overall, our results suggest that LD-shifts, increasingly prevalent among young adults, contribute to both intestinal aging and the development of colon carcinogenesis.