Aging enhances G(1) phase in the colonic mucosa of rats

Although in Fischer-344 rats, aging has been shown to be associated with increased crypt cell production in the colonic mucosa, no information is available about the responsible intracellular mechanisms for the age-related rise in colonic mucosal cell proliferation. To determine whether cell cycling events are affected by aging, the present investigation examines the age-related changes in Cdk2 activity and the regulation of this process in the colonic mucosa. Colonic mucosae from 4-, 13- and 24-month-old Fischer-344 rats were assayed for Cdk2 activity and protein expression of Cdk2, cyclin D1 and E, as well as p21(Waf1/Cip1) (total and the fraction bound to Cdk2), p53 and phosphorylated Rb. Kinase activity and protein levels of Cdk2, as well as cyclin D1 concentration in the colonic mucosa, rose steadily with advancing age. However, the levels of cyclin E in the colonic mucosa were found to be higher in 24-month-old than 13-month-old rats, compared to their 4-month-old counterparts. On the other hand, levels of mucosal p21(Waf1/Cip1) (total and the fraction bound to Cdk2), one of the universal inhibitors of Cdks, were found to be lower in aged than in young rats. This was accompanied by a parallel decrease in mucosal p53, a tumor suppressor protein that is known to regulate p21(Waf1/Cip1). Additionally, we observed that the levels of phosphorylated Rb protein, a form which is involved in regulating progression of cells through the S phase, are increased in the colonic mucosa of 24-month-old rats, but not in 13-month-old animals, when compared with their 4-month-old counterparts. Our data suggest that, G(1) to S phase transition, as well as progression through the S phase of the cell cycle are accelerated in the colonic mucosa of aged rats.