Background: Colorectal cancer (CRC) is the third most common cancer worldwide. The opening of the TCGA and GEO databases has promoted the progress of CRC prognostic assessment, while the aging-related risk signature has never been mentioned.

Methods: R software packages, GSEA software, Venn diagram, Metascape, STRING, Cytoscape, cBioPortal, TIMER and GeneMANIA website were used in this study.

Results: Aging-related gene sets, GO_AGING, GO_CELL_AGING and GO_CELLULAR_SENESCENCE, were activated significantly in CRC tissues. We constructed an aging-related risk signature using LASSO COX regression in training group TCGA and validated in testing group GSE39582. The risk score was significantly associated with the overall survival of CRC patients, whose stability was clarified by stratified survival analysis and accuracy was demonstrated using the ROC curve. The risk score was significantly increased in the advanced stage, T3-4, N1-3 and M1 and positively correlated with the richness of immune cell infiltration in the tumor microenvironment. We further investigated the molecular characteristics of 15 hub genes at the DNA and protein levels and performed GSEA between high- and low-risk groups.

Conclusions: The aging-related signature is a reliable prognostic analysis model and can predict the severity and immune cell infiltration of CRC patients.