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ARS Home » Northeast Area » Boston, Massachusetts » Jean Mayer Human Nutrition Research Center On Aging » Research » Publications at this Location » Publication #203684
Title: Older age and dietary folate are determinants of genomic and p16-specific DNA methylation in mouse colon

Author
item KEYES, MARY - HNRCA AT TUFTS
item JANG, HYERAN - HNRCA AT TUFTS
item Mason, Joel
item LIU, ZHENHUA - HNRCA AT TUFTS
item CROTT, JIMMY WALTER - HNRCA AT TUFTS
item Smith, Donald
item FRISO, SIMONETTA - UNIVERSITY OF VERONA
item Choi, Sang-Woon

Submitted to: Journal of Nutrition
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 5/1/2007
Publication Date: 7/1/2007
Citation: Keyes, M.K., Jang, H., Mason, J.B., Liu, Z., Crott, J., Smith, D., Friso, S., Choi, S. 2007. Older age and dietary folate are determinants of genomic and p16-specific DNA methylation in mouse colon. Journal of Nutrition. 131(7):1713-1717.

Interpretive Summary: Both aging and dietary folate, a water soluble B-vitamin, are important risk factors for colon cancer development. Since most of colon cancer developed in the elderly, we investigated the synergistic effect of aging and folate depletion on DNA methylation in the colon using a young and old mice model. DNA methylation is a reversible DNA change which can regulate gene expression and integrity, and it is also highly associated with cancer development. Compared with young mice, old mice significantly affects DNA methylation in the colon according to the dietary folate levels, indicating that aging and dietary folate synergistically affect DNA methylation and provide an environment to develop cancer.

Technical Abstract: Elder age and inadequate folate intake are strongly implicated as important risk factors for colon cancer, and each is associated with altered DNA methylation. This study was designed to determine the effect of aging and dietary folate on select features of DNA methylation in the colon that are relevant to carcinogenesis. Old (18 mo, n=34) and young (4 mo, n=32) male C57BL/6 mice were divided into three groups, and fed diets containing 0, 2, or 8mg folate/kg (deplete, replete, and supplemented groups, respectively) for 20 weeks. Genomic DNA methylation and p16 promoter methylation in the colonic mucosa were analyzed by LC/ESI/MS and methylation specific PCR, respectively. p16 gene expression was determined by real-time RT-PCR. Old mice had significantly lower genomic DNA methylation compared with young mice at each level of dietary folate (4.5+/-0.2, 4.8+/-0.1, and 4.9+/-0.1 vs 6.0+/-0.1, 5.3+/-0.2, and 5.9+/-0.2%, in folate-deplete, -replete and -supplemented groups, respectively, p<0.05), as well as markedly higher p16 promoter methylation (61.0+/-2.7, 69.7+/-6.9 and 87.1+/-13.4 vs 10.8+/-3.6, 8.4+/-1.8 and 4.9+/-1.7%, respectively, p<0.05). Genomic and p16 promoter DNA methylation each increased in a manner that was directly dependent on dietary folate, but only in the old mice (p for trend=0.009). Age-related enhancement of p16 expression was present in folate-replete (p=0.001) and folate-supplemented groups (p=0.041) but not evident in the folate-deplete group. Aging decreases genomic DNA methylation and increases promoter methylation and expression of p16 in the mouse colon, and this effect is affected by dietary folate intake.