Both injury and aging of the central nervous system reportedly produce profound changes in gene expression. Therefore, aging may interfere with the success of therapeutic interventions which were tailored for young patients. Using genome-scale transcriptional profiling, we identified distinct age-dependent expression profiles in rat sensorimotor cortex during acute, subacute and chronic phases of spinal cord injury (SCI). Aging affects the cortical transcriptomes triggered by transection of the corticospinal tract as there was only a small overlap between the significantly lesion-regulated genes in both age groups. Over-representation analysis of the lesion-regulated genes revealed that, in addition to biological processes in common, such as lipid metabolism, others, such as activation of complement cascade, were specific for aged animals. When a recently developed treatment to suppress fibrotic scarring (anti-scarring treatment AST) was applied to the injured spinal cord of aged (22 months) and young (2 months) rats, we found that the cortical gene expression in old rats was modulated to resemble regeneration-associated profiles of young animals including the up-regulation of known repair promoting growth and transcription factors at 35 dpo. In combination with recent immunohistochemical findings demonstrating regenerative axon growth upon AST in aged animals, the present investigation on the level of gene expression strongly supports the feasibility of a successful AST therapy in elderly patients.