Characterization of Age- and Sex-Specific Metabolic Pathway Alterations in the Colon Associated with CRC Development

Abstract

Both age and sex are important factors influencing metabolic processes, impacting energy production, immune regulation, and lipid metabolism. Metabolic efficiency usually declines with age, leading to dysregulation of key metabolic pathways, which could lead to different health issues such as chronic inflammation and cancer. These age-related changes are affected in both sexes differently, with males and females experiencing distinct metabolic shift patterns due to their biological differences, such as sex hormones. Investigating these variations could help clarify how age- and sex-specific metabolic shifts elevate health risks. Therefore, a proteomic analysis was used to filter proteins from C57BL/6J mice of different ages and sexes based on their involvement in metabolic processes, and then through statistical analysis, significantly up-regulated or down-regulated proteins were identified. STRING network analysis was employed to identify key metabolic pathways enriched in these regulated proteins. Notably, pathways related to lipid metabolism, such as fatty acid oxidation and lipid transport, were highly enriched in up-regulated protein, particularly in older male mice, suggesting an age-related shift toward lipid utilisation. Down-regulated proteins were primarily associated with amino acid metabolism across sexes, though with distinct patterns. Among the proteins involved in enriched pathways, four proteins were observed in multiple enriched pathways. CD36, FABP4, HMGCS2, and KYAT3. These metabolic shifts are closely tied to the development and progression of colorectal cancer (CRC). CRC incidence increases with age, and men are generally at higher risk than women. Metabolic dysregulation, including lipid accumulation, impaired energy metabolism, and a weakened immune response, has been strongly linked to CRC. These processes not only facilitate the growth and proliferation of cancer cells but also create a tumour-friendly environment in an ageing colon. Therefore, monitoring these metabolic alterations could provide insights into potential biomarkers for early CRC detection.