Choi Sang-Woon, Friso Simonetta, Dolnikowski Gregory G, Bagley Pamela J, Edmondson Antoinette N, Smith Donald E, Mason Joel B
Vitamins and Carcinogenesis Laboratory, Jean Mayer U.S. Department of Agriculture Human Nutrition Research Center on Aging at Tufts University, Boston, MA, USA.
J Nutr. 2003 Apr;133(4):1206-12. doi: 10.1093/jn/133.4.1206.
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 micro mol 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 approximately 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.
老年期和叶酸水平降低均与结直肠癌发生风险增加有关。因此，我们研究了这两个因素在机制上是否相关。将断乳雄性Sprague-Dawley大鼠（n = 44）和1岁大鼠（n = 44）各分为三组，分别饲喂含0、4.5或18 μmol叶酸/kg的饲料（分别为缺乏组、充足组和补充组）。在0、8和20周时处死大鼠。测定结肠黏膜中的叶酸浓度、不同辅酶形式叶酸的分布、尿嘧啶掺入DNA的情况以及基因组DNA甲基化水平。叶酸缺乏和充足的老年大鼠结肠叶酸浓度比年轻大鼠低30 - 45%。此外，5-甲基四氢叶酸在叶酸缺乏的老年大鼠结肠中均匀耗竭，而这种耗竭仅发生在少数年轻大鼠中。到实验结束时，叶酸缺乏和充足的老年大鼠结肠DNA中掺入的尿嘧啶比相应的年轻组多约50%（P < 0.05）。在老年大鼠中，三个饮食组的尿嘧啶错掺入呈递增趋势（趋势P检验 < 0.05），而在年轻大鼠中未观察到尿嘧啶掺入过量。年龄和饮食叶酸均未影响结肠中的基因组DNA甲基化。总之，老年大鼠的结肠比年轻大鼠更容易受到叶酸缺乏的生化和分子影响。然而，叶酸补充在维持老年大鼠结肠叶酸充足状态方面与年轻大鼠一样有效。
