Although aging is shown to be associated with decreased apoptosis and increased survival of cells in the colonic mucosa of Fischer-344 rats, the regulatory mechanisms are poorly understood. The current investigation examines the involvement of phosphotidylinositol 3-kinase (PI3K)/Akt signaling pathway in mediating the events of colonic mucosal cell survival during aging. We have observed that aging is associated with activation of PI3K/Akt signaling, as evidenced by the higher levels of phosphorylated forms of p85, the regulatory subunit of PI3K and of Akt in the proximal and distal colonic mucosa of aged (21-23 months) than in young (4-7 months) rats. These increases are accompanied by a concomitant rise in phosphorylation of proapoptotic protein Bad, which is sequestered by 14-3-3 family of proteins following phosphorylation by Akt resulting in reduction in non-phosphorylated Bad. The amount of anti-apoptotic Bcl-_XL bound to non-phosporylated Bad in the colonic mucosa is found to be substantially lower in aged than in young rats, resulting in a marked rise in unbound/ free form of Bcl-_XL in the aging colon. The age-related activation of PI3K and the reduction in caspase-3 activity could be reversed by Wortmannin, a specific inhibitor of PI3K. Increased levels of Bcl-_XL and phosphorylated forms of Akt and Bad and reduction in caspase-3 activity were observed throughout the entire length of the colonic crypt of aged rats. We conclude that the constitutive activation of PI3K/Akt signaling pathway is partly responsible for the age-related increase in colonic mucosal cell survival. This is evident throughout the entire length of the colonic cryp