The protein family of sirtuins and FoXO1 transcription factor have been shown to play significant roles in the aging process. In this study we aimed to investigate the changes in the levels of SIRT2, NF kappa B and FoXO1 and oxidative parameters of colonic mucosa during aging, and the effects of exogenous melatonin (MLT). A total of twenty-four young (3-months-old) and aged (24 months old) male Wistar rats, divided into control [1 % ethanol-phosphate-buffered saline (PBS), s.c. for 21 days] and melatonin (10 mg kg(-1) MLT 1 % ethanol in PBS, s.c. for 21 days) were used in the study. The levels of malondialdehyde (MDA) as a parameter of lipid peroxidation, glutathione, NFkB pathway activation, SIRT2 expression, and FoXO1 transcription factor of colonic mucosa were assayed. The MDA levels and SIRT2 expression in the colonic mucosa were significantly increased in the aged group when compared to the younger group. However, the levels of FoXO1 transcription factor were significantly decreased in the aged group. Melatonin significantly decreased the MDA and SIRT2 expression levels of the colonic mucosa in the aged rats. In conclusion, our findings suggest a suppressive role of melatonin in the aging process of colonic tissue via decreasing SIRT2 expression.