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* Vitamins and Carcinogenesis Laboratory,
Vitamin Metabolism Laboratory,
** Mass Spectrometry Laboratory and
Comparative Biology Unit, Jean Mayer U.S. Department of Agriculture Human Nutrition Research Center on Aging at Tufts University, Boston, MA;
Divisions of Clinical Nutrition and Gastroenterology, Tufts University School of Medicine, Boston, MA;
School of Pharmacy, University at Buffalo, Buffalo, NY;
# Department of Clinical and Experimental Medicine, Policlinico G.B. Rossi, University of Verona, Verona, Italy
3To whom correspondence should be addressed. E-mail: sang.choi{at}tufts.edu.
ABSTRACT
Elder adulthood and diminished folate status are each associated with an enhanced risk of colorectal carcinogenesis. We therefore examined whether these two factors are mechanistically related. Weanling male Sprague-Dawley rats (n = 44) and 1-y-old rats (n = 44) were each divided into three groups and fed diets containing 0, 4.5 or 18 µmol folic acid/kg (deplete, replete and supplemented groups, respectively). Rats were killed at 0, 8 and 20 wk. The folate concentrations, the distribution of the different coenzymatic forms of folate, uracil incorporation into DNA and genomic DNA methylation were measured in the colonic mucosa. Folate-deplete and folate-replete elder rats had 30–45% lower colonic folate concentrations than young rats. Furthermore, 5-methyltetrahydrofolate was uniformly depleted in colons of the elder, folate-deplete rats, whereas this depletion occurred in only a minority of the younger rats. By the end of the experiment, the folate-deplete and folate-replete elder rats had 
50% more uracil incorporated into their colonic DNA than the corresponding young groups (P < 0.05). In elder rats, this uracil misincorporation was incremental across the three diet groups (P-test for trend < 0.05), whereas no excess uracil incorporation was observed in young rats. Neither age nor dietary folate affected genomic DNA methylation in the colon. In conclusion, the colon of elder rats is more susceptible to biochemical and molecular consequences of folate depletion than that of young rats. However, folate supplementation is as effective at sustaining adequate colonic folate status in elder rats as it is in the young.
KEY WORDS: • folate • colon cancer • aging • rats • uracil misincorporation
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