|Choi, Sang-Woon - HNRCA|
|Friso, Simonetta - HNRCA|
|Dolnikowski, Gregory - HNRCA|
|Bagley, Pamela - HNRCA|
|Edmonson, Antoinette - ALBERT EINSTEIN COLL OF M|
|Nadeau, Marie - HNRCA|
|Smith, Donald - HNRCA|
|Mason, Joel - HNRCA|
Submitted to: Journal of Nutrition
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: December 24, 2002
Publication Date: April 1, 2003
Citation: CHOI, S., FRISO, S., DOLNIKOWSKI, G.G., BAGLEY, P.J., EDMONSON, A.N., NADEAU, M.R., SMITH, D.E., MASON, J.B. BIOCHEMICAL AND MOLECULAR INDICATIONS THAT THE ELDER RAT COLON IS PARTICULARLY SUSCEPTIBLE TO FOLTE DEPLETION. JOURNAL OF NUTRITION. 2003.133(4):1206-12. Interpretive Summary: Cancer of the large bowel is the second most common cause of cancer death in the United States and in most of the developed world. Although exact cause of this cancer is not known yet, the most important risk factors is aging, which has been attributed partly to the cumulative exposure to carcinogens over time and to the multiple molecular 'hits' required for cancer to proceed. The risk of developing colorectal cancer begins to increase slightly at age 40 and more sharply at age 50, doubling with each decade and reaching a maximum at age 75. Diet is also one of the most important environmental factors implicated in colorectal cancer: it has been estimated that up to 90% of colorectal cancer in the United States may be avoidable through alterations in the diet. Folate are among the most important dietary factors. Folate depletion appears to enhance the development of cancer whereas folate supplementation above what is presently considered to be the basal requirement appears to convey a protective effect. We investigate the effect of aging and folate status on the development of colorectal cancer using an animal model of folate depletion and aging. Biochemical and molecular results suggest that elder rats were more sensitive to folate depletion than young rats, but folate supplementation was as effective at sustaining adequate folate status in elder animals as it is in the young. This study will extend our understanding of the mechanisms by which aging and folate status modulates cancer development.
Technical Abstract: Aging and diminished folate status have independently been associated with an enhanced risk of colorectal carcinogenesis. We therefore examined in a rodent model whether these two factors are mechanistically related. Forty-four weanling male Sprague-Dawley rats and 44 one year old animals were each divided into three groups and fed diets containing 0, 2, or 8 mg folic acid/kg (deplete, replete, and supplemented groups, respectively). Rats were killed at 0, 8 and 20 wks. The folate concentrations and the distribution of the different co-enzymatic forms of folate were measured in pertinent tissues. Uracil misincorporation into DNA and genomic DNA methylation were measured in colonic mucosa as well. By 20 weeks the mean colonic folate concentrations of the elder, folate-deplete and -replete rats were significantly lower compared to the corresponding young animals (p<0.05). Furthermore, the folate-deplete elder rats uniformly demonstrated nearly a total disappearance of methyltetrahydrofolate with chronic depletion (p<0.001). By 20 weeks, the folate-deplete and folate-replete elder rats developed a significant increase in the uracil incorporated in colonic DNA compared to corresponding young group (p<0.05). In elder rats the effect was incremental across the three diet groups (p-test for trend <0.05). No age related differences existed among animals receiving supplemental levels of dietary folate. Elder rats are more sensitive to folate depletion than young rats. However, folate supplementation is as effective at sustaining adequate folate status in old animals as it is in the young.