Colorectal cancer remains the second most common cause of cancer mortality in both the United States and in much of the developed world. The risk of developing colorectal cancer appears to be strongly linked to several environmental factors, the most notable of which is dietary patterns, and in this regard there is considerable data from many different types of studies indicating that the risk of the cancer is inversely related to habitual dietary intake of folate. Age is also a very strong determinant of colorectal cancer risk; past the age of 40 the risk doubles with each passing decade. Preliminary animal studies in our laboratory have indicated a mechanistic link between advancing age and diminished integrity of folate metabolism in the colon; thereby suggesting that the impact of age on colorectal cancer risk may be mediated, at least in part, through changes in folate metabolism. This application outlines studies in a laboratory rodent model which are designed to clearly define the relationship between the aging process and folate metabolism in the target tissue of interest, the colonic mucosa. We propose to determine whether elder age alters quantitative and qualitative aspects of folate metabolism in the colon in such a way as to make it more susceptible to folate depletion and to examine whether the elder animal therefore requires a higher level of dietary folate to maintain adequate levels of cellular folate in the colonic mucosa. In addition, several molecular aberrations of DNA which are implicated as mechanisms of carcinogenesis have been previously identified as consequences of folate depletion and we will therefore determine the inter-relationships between age, folate status and the evolution of these molecular anomalies.
