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Vitamins and Carcinogenesis Laboratory, Jean Mayer U.S. Department of Agriculture Human Nutrition Research Center on Aging at Tufts University, Boston, MA 02111
4To whom correspondence should be addressed. E-mail: sang.choi{at}tufts.edu.
ABSTRACT
Folate is among the most strongly implicated dietary components to convey protection against colon cancer, and diminished folate status is associated with an enhanced risk of colon cancer. Age is also regarded as one of the most important risk factors for colonic carcinogenesis. It is therefore of considerable interest to determine whether the process of aging influences folate metabolism in the colon and whether folate supplementation might prevent the procarcinogenic effects associated with aging. Recent studies in our laboratory demonstrated that the colonic mucosa of elder rats is more susceptible to folate depletion than that of young rats. Depletion of folate results in a shift in the forms of folate in the colon as well as increased uracil incorporation into DNA, a purported mechanism for colonic carcinogenesis. However, modest folate supplementation eliminates evidence of inadequate folate status in the colons of elder rats, suggesting that the relation between age and folate status in the colon might be one mechanism by which aging modulates colorectal cancer risk. Interactions between folate and aging also affect a spectrum of epigenetic and genetic phenomena such as uracil misincorporation, DNA methylation, protein methylation, mitochondrial deletion, and critical gene expression, which could be related to carcinogenesis. Aging and inadequate dietary folate may interact and collectively induce derangements in folate metabolism, thereby provoking subsequent molecular aberrations, which may enhance carcinogenesis. However, folate supplementation appears to reverse these adverse effects of aging, which is potentially of substantial import because the latter is an unmodifiable risk factor.
KEY WORDS: • folate • aging • 1-carbon metabolism • DNA methylation • uracil misincorporation
Inadequate folate status is associated with an increased risk of several chronic diseases that commonly afflict the aging population, such as cardiovascular disease and cancer. Folate is an important factor for a number of metabolic pathways in the cell that involve the transfer of 1-carbon groups. Among them are nucleotide synthesis and biological methylation reactions, both of which have been regarded as critical mechanisms for folate-related carcinogenesis.
Aging is accompanied by an accumulation of a variety of genetic and epigenetic alterations in the genome, some of which may alter the expression of genes related to carcinogenesis. Although aging itself is an unmodifiable factor, evidence is emerging that folate, when provided in supplemental quantities, may be effective in preventing some of these age-induced molecular events linked to carcinogenesis (1–4).
In this review, we address currently available information regarding the genetic and epigenetic interactions between folate and aging and how these interactions affect 1-carbon metabolism and carcinogenesis.
Folate and cancer
The body of evidence that has accumulated over the past 15 y suggests that folate may play a significant role in determining the risk of developing several malignancies, including cancers of the colorectum, lung, pancreas, esophagus, stomach, cervix, and breast, as well as neuroblastoma and leukemia (5). These observations collectively suggest an inverse association between folate status, assessed either by dietary folate intake or by the measurement of blood and/or tissue folate levels, and the risk of these malignancies (6). The mechanisms by which folate deficiency enhances and supplementation suppresses carcinogenesis have not yet been clearly elucidated. However, several potential mechanisms related to the disruption of known biochemical functions of folate have been proposed and investigated (7,8).
Folate and 1-carbon metabolism
One-carbon metabolism is a network of interrelated biochemical reactions in which a 1-carbon unit is transferred to tetrahydrofolate for subsequent reduction or oxidation. The transfer of this 1-carbon moiety into biochemical pathways is essential for DNA synthesis (thymidylate and purine synthesis) and biological methylation, including DNA methylation (9) (Fig. 1).
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Biological methylation. Methylenetetrahydrofolate reductase (MTHFR)5 is a critical enzyme in folate metabolism. MTHFR catalyzes the chemical reduction of 5,10-methylenetetrahydrofolate to 5-methyltetrahydrofolate, the primary methyl donor for the remethylation of homocysteine to methionine (17). 5-Methyltetrahydrofolate, the predominant form of folate in plasma, provides the methyl group for methionine synthesis and S-adenosylmethionine (SAdoMet), the universal methyl donor of biological methylation. SAdoMet donates its labile methyl group to >80 methylation reactions involving DNA, RNA, proteins (including histones), and phospholipids. After transfer of the methyl group, SAdoMet is converted to S-adenosylhomocysteine (SAdoHcy), which has high affinity for methyltransferases and thereby acts as a potent inhibitor of most SAdoMet-dependent methyltransferases (18). Therefore, the efficiency of methylation reactions depends on effective product removal of SAdoHcy. The remethylation pathway allows reutilization of the homocysteine backbone as a carrier of methyl groups derived primarily from serine. An alternative mechanism for the regeneration of methionine that does not require folate also exists—the methylation of homocysteine by betaine—although the latter reaction seems to be operative only in the liver and kidney (19). Through the transsulfuration pathway, homocysteine also condenses with serine to form cystathionine in an irreversible reaction catalyzed by cystathionine-ß-synthase; vitamin B-6 serves as a cofactor in this reaction (20).
DNA methylation and cancer. DNA methylation is essential for normal development (21), X-chromosome inactivation (22), imprinting (23), and the suppression of parasitic DNA sequences (24). Aberrant methylation of cytosine residues at cytosine-guanine-sequence (CpG) dinucleotides in DNA is a common epigenetic phenomenon early in carcinogenesis, and accumulating evidence indicates that it is integral in the genesis of neoplastic transformation. The extent of genomic DNA methylation decreases progressively through the stages of neoplasia, from benign proliferation to invasive cancer (25). DNA hypomethylation has been observed to produce elevated mutation rates due to mitotic recombination-related deletions or loss of entire chromosomes (26). In addition, hypomethylation of malignant cell DNA can reactivate intragenomic parasitic DNA, such as long interspersed nuclear elements and Alu repeats (24,27). Imprinted genes can also be affected by the loss of methyl groups and thereby lose their imprinting. This loss-of-imprinting phenomenon is a newly highlighted pathway in carcinogenesis (28).
Despite genome-wide DNA hypomethylation in tumor cells, select areas within the genome develop an increase in DNA methylation, whereas others become hypomethylated (29,30). CpG islands located in the promoter region of certain tumor-suppressor genes undergo hypermethylation in cancer cells, and in some instances this has produced gene silencing. The most extensively documented among these is the cell cycle inhibitor p16, which is hypermethylated in a variety of human primary tumors and cell lines (31–33).
Effect of aging on 1-carbon metabolism
Aging, which is one of the strongest determinants of colon cancer and many other types of common cancers, has profound effects on 1-carbon metabolism, manifested by hyperhomocysteinemia and genomic DNA hypomethylation, and on the DNA repair system.
Aging and hyperhomocysteinemia. Hyperhomocysteinemia in older adults can be explained by an interaction of a variety of factors. The most important age-related conditions are suboptimal folate, vitamin B-12, or vitamin B-6 status; impaired renal function; and dietary insufficiencies. An increased number of chronic conditions, such as malignancies and rheumatic diseases, among older adults may also contribute to impairment of 1-carbon metabolism (34).
Plasma and intracellular homocysteine levels increase with aging independent of vitamin B status (35,36). Animal studies demonstrated that aging reduces methionine synthase activity and increases the activities of glycine N-methyltransferase and cystathionine ß-synthase in rat liver, suggesting that aging decreases the transmethylation pathway and enhances the transsulfuration pathway (37,38). Interestingly, Ingenbleek and Young (39) recently reported that conditions that can decrease total body nitrogen, such as reduced nitrogen intake or excessive nitrogen loss, suppress the homocysteine transsulfuration pathway by inhibiting cystathionine ß-synthase to preserve methionine homeostasis. Thus, hyperhomocysteinemia can arise from the contraction of endogenous nitrogen pools. One might speculate that aging-related decrements in total body nitrogen account for a portion of age-associated hyperhomocysteinemia that cannot be solely explained by B-vitamin deficiencies or decreased renal function (40).
Aging and DNA methylation. DNA methylation is an important epigenetic determinant of gene expression, maintenance of DNA integrity and stability, chromosomal modifications, and development of mutations (41). In general, genome-wide DNA methylation decreases during aging (42,43), and the rate of decrease appears to be inversely proportional to the maximum life-span potential (44). However, the response of DNA methylation to aging is quite tissue specific; in rats, most tissues, such as brain, liver, small intestine mucosa, heart, and spleen, undergo genomic DNA hypomethylation with aging, whereas kidney shows hypermethylation and lung shows no changes (43).
Distinct from the global decrease in DNA methylation, methylation levels increase in specific genes. Age-related gene-specific methylation was observed in the study of the estrogen receptor gene in human colorectal tissues (45). The change in methylation was directly related to the age of the individuals: it was absent in young individuals and progressively more pronounced with age. Increased methylation and inactivation of estrogen receptor is also observed in cardiovascular tissue with increasing age (46). Aberrant methylation of CpG islands in the promoter region may contribute to the progressive inactivation of tumor-suppressor genes during aging, resulting in the survival of particular clones of cells with a growth advantage.
Aging and DNA repair. The repair of damaged DNA is a critical function in all organisms and is required to maintain the integrity of genetic information. Age-related alterations of DNA repair could be involved in the accumulation of genetic damage with age. An age-dependent decline was observed in cultured cells in regard to the activity of glycosylases that remove aberrant bases (47). Szczesny et al. (48) demonstrated an age-dependent decline in the mitochondrial import of uracil-DNA glycosylase for DNA repair in mice. As a result, a large fraction of mitochondrial uracil-DNA glycosylase is stuck to the mitochondrial outer membrane in the precursor form and cannot be translocated to the mitochondrial matrix in the liver in old mice.
Interactions between folate and aging for carcinogenesis
Alterations in cellular biology with aging may reduce folate availability in certain tissues and thereby disturb 1-carbon metabolism, resulting in impairment of nucleotide synthesis and biological DNA methylation (Fig. 2). Recent observations of select genetic and epigenetic phenomena support this hypothesis.
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Mitochondrial DNA instability and repair. It is becoming evident that the integrity of the mitochondrial genome is also related to age and the availability of folate. This is highly relevant because emerging evidence suggests that deletions in mitochondrial DNA may also play a role in carcinogenesis (49,50). Recently, Crott et al. (4) observed that elder rats have significantly more random hepatic mitochondrial DNA deletions than young rats (64 and 3.2% of samples, respectively, P < 0.0001). In addition, dietary folate reduced the frequency of the common mitochondrial deletion, with replete and supplemented rats having 2.2- and 3.2-fold fewer deletions, respectively, than the depleted rats. These observations suggest that interactions between folate and aging can also affect mitochondrial DNA stability.
Protein methylation. The formation of isoaspartyl residues from aspartic acid in proteins is generally viewed as a deleterious event associated with protein senescence (51). Protein-L-isoaspartyl methyltransferase (PIMT)-dependent methylation of isoaspartyl sites apparently serves to either repair the damaged sites or tag the damaged proteins for degradation (52,53), and this is among many protein methylation reactions mediated by 1-carbon metabolism. One study showed that the amount of L-isoaspartyl residues in hepatic proteins is greatly increased by folate deficiency among young rats but is uniformly very high among elder rats regardless of folate status (54). The functional importance of preventing excess L-isoaspartyl residues from accumulating is underscored in PIMT-knockout mice, in which L-isoaspartyl residues within histone H2B accumulate at a rate of 1%/d, and are thought to disrupt normal gene regulation and contribute to reduced life span (55).
Gene expression.
A limited number of studies examined the effect of folate status on gene expression. Cell culture studies showed that folate depletion causes an upregulation of folate-metabolizing genes, such as folate-receptor-
(56) and folate-binding protein (57). Kim et al. (58) observed that p53 expression in the rat colon is reduced by dietary folate depletion and increased above basal levels with supplementation. Steady-state levels of p53 transcript were significantly correlated with folate status and p53 integrity within exons 5 to 8 (P < 0.002). Using gene expression microarrays, Jhaveri et al. (59) reported that folate depletion in human nasopharyngeal epidermoid carcinoma cells led to the upregulation of 5 genes and downregulation of 3 genes. Although folate depletion produced global DNA hypomethylation, it also produced hypermethylation of the 5' CpG island and consequent downregulation of the H-cadherin gene (59). This is presumed to be a compensatory response. Recently Crott et al. (3) investigated the effects of dietary folate status in combination with aging on in vivo gene expression in the colon in rats, using oligonucleotide probe arrays. Both age and folate status had marked effects on gene expression. In the comparison of folate intakes, 84 genes were downregulated and 52 genes were upregulated in response to depletion in young rats, whereas 21 genes were downregulated and 41 were upregulated in old rats; thus, the younger adult appears to possess a broader response to the presence of folate depletion. In folate-depleted rats, aging induced the downregulation of several immune-related genes, urokinase, p53, insulin-like growth factor binding protein-3, and vav-1 oncogene. In folate-supplemented rats, the downregulation of p53 and insulin-like growth factor binding protein-3 that accompanied aging was spared. Thus, higher levels of folate intake may reduce the risk of age-associated cancers by preventing deleterious changes in the expression of critical genes that occur with aging.
Histone modification and gene expression. DNA exists in vivo in the context of chromatin: segments of DNA wrapped around a nucleosome that is composed of 2 molecules each of histones H2A, H2B, H3, and H4. DNA methylation; histone modifications such as acetylation, phosphorylation, methylation, and ubiquitination; methyl-CpG binding proteins; and chromatin-remodeling proteins all influence interactions with transcription machinery and, consequently, gene expression (60). Notably, modifications of the tails of histones H3 and H4 appear to determine the accessibility to DNA methyltransferases, methyl-CpG–binding proteins, chromatin-remodeling proteins, and transcription factors (60). In particular, methylation of lysine residues in the histone tails of H3 and H4 appears to provide an additional layer of control over the chromatin structure and subsequently over gene expression (60). Histone lysine methylation is catalyzed by a group of enzymes called histone methyltransferases; these enzymes use SAdoMet as the methyl donor (61) and can be inhibited by SAdoHcy (62), providing yet another regulatory forum for interactions between aging and folate status.
A strong correlation between DNA hypermethylation in the promoter region, transcriptional silencing, and tightly compacted chromatin structure was established in many different systems (63,64). Among many modifications at histone tails, methylation of lysine residues in the histone H3 tail seems to be connected to the DNA methylation status of the particular chromatin region in which it occurs (60). The mechanistic understanding of how folate and aging are involved in DNA methylation and chromatin structure may further clarify the insights of the regulation of gene expression.
Conclusion
Folate availability plays a very large role in determining the integrity of 1-carbon metabolism, derangements of which result in genetic and epigenetic changes related to carcinogenesis. In many contexts it is now evident that aging magnifies the effects of folate inadequacy, including its downstream molecular consequences. However, there is evidence that modest folate supplementation may overcome these adverse effects of aging. Thus, sustaining normal 1-carbon metabolism in older adults with folate supplementation may prove to be important in preventing certain age-related cancers. A mechanistic understanding of how aging and folate deficiency interact in carcinogenesis may strengthen the case for a causal role for folate and provide important insights into the possible cancer chemopreventive roles of folate in aging.
FOOTNOTES
1 Published in a supplement to The Journal of Nutrition. Presented as part of the International Research Conference on Food, Nutrition, and Cancer held in Washington, DC, July 14–15, 2005. This conference was organized by the American Institute for Cancer Research and the World Cancer Research Fund International and sponsored by (in alphabetical order) California Avocado Commission; California Walnut Commission; Campbell Soup Company; The Cranberry Institute; Danisco USA, Inc.; The Hormel Institute; National Fisheries Institute; The Solae Company; and United Soybean Board. Guest editors for this symposium were Vay Liang W. Go, Ritva R. Butrum, and Helen A. Norman. Guest Editor Disclosure: R. R. Butrum and H. Norman are employed by conference sponsor American Institute for Cancer Research; V.L.W. Go, no relationships to disclose. 
2 Author Disclosure: No relationships to disclose.
3 This material is based on work supported by the U.S. Department of Agriculture, under Agreement No. 581950-9-001. Any opinions, findings, conclusions or recommendations expressed in this publication are those of the authors and do not necessarily reflect the view of the U.S. Department of Agriculture. Also supported in part by the following grants from the National Cancer Institute: K05 CA100048 and U54 CA100971 (JBM).
5 Abbreviations used: CpG, cytosine-guanine sequence; MTHFR, methylenetetrahydrofolate reductase; PIMT, protein-L-isoaspartyl methyltransferase; SAdoHcy, S-adenosylhomocysteine; SAdoMet, S-adenosylmethionine.
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