• Nutrition Research and Practice
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• v.17 no.4
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• pp.597-615
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• 2023

Healthy aging can be defined as an extended lifespan and health span. Nutrition has been regarded as an important factor in healthy aging, because nutrients, bioactive food components, and diets have demonstrated beneficial effects on aging hallmarks such as oxidative stress, mitochondrial function, apoptosis and autophagy, genomic stability, and immune function. Nutrition also plays a role in epigenetic regulation of gene expression, and DNA methylation is the most extensively investigated epigenetic phenomenon in aging. Interestingly, age-associated DNA methylation can be modulated by one-carbon metabolism or inhibition of DNA methyltransferases. One-carbon metabolism ultimately controls the balance between the universal methyl donor S-adenosylmethionine and the methyltransferase inhibitor S-adenosylhomocysteine. Water-soluble B-vitamins such as folate, vitamin B6, and vitamin B12 serve as coenzymes for multiple steps in one-carbon metabolism, whereas methionine, choline, betaine, and serine act as methyl donors. Thus, these one-carbon nutrients can modify age-associated DNA methylation and subsequently alter the age-associated physiologic and pathologic processes. We cannot elude aging per se but we may at least change age-associated DNA methylation, which could mitigate age-associated diseases and disorders.

• Preventive Nutrition and Food Science
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• v.6 no.1
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• pp.73-78
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• 2001

The elevation of total plasmahomocysteine is now an established risk factor for cardiovascular disease. Plasma folate and vitamin {TEX}$B_{12}${/TEX} influence Hcy metabolism as cofactors. In this study, we studied the relationship of major risk factors for cardovascular disease, including advanced age, male gender, obesity, hypertension, hyperglycemia, and dislipidemia and plasma homocyteine, folate and vitamin {TEX}$B_{12}${/TEX} levels in Koreans. A total of 195 adult Koreans participated. The subjects were divided into three groups according to how many major conventional risk factors of cardiovascular disease they had: no risk, low risk (1~3 risk factors) and high risk (>3 risk factors) groups. As the number of risk factors increased, the plasma homocysteine levels significantly increase, while the plasma folate levels significantly decreased. The plasma homocysteine levels re higher in males than in females. The subjects with hyperglycemia had higher plasma homocysteine levels than the subjects without the risk factor. Also the subjects with dislipidemia had higher plasma homocysteine levels than the subjects without the risk factor. The plasma folate and vitamin {TEX}$B_{12}${/TEX} levels were significantly lower in males tan females. However, there were no significant differences in plasma folate and vitamin {TEX}$B_{12}${/TEX} levels between the subjects with or without other risk factors. These results indicate that plasma homocysteine levels were positively related with risk factors for cardiovascular disease and plasma folate levels were negatively related with the risk factors for cardiovascular disease. Also, we conclude that plasmahomocysteine levels might be related to the combination of risk factors, rather than an individual risk factor.

• Proceedings of the Korean Society of Life Science Conference
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• 2008.10a
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• pp.79.1-79.1
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• 2008

• Asian Pacific Journal of Cancer Prevention
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• v.15 no.21
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• pp.9313-9317
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• 2014

Fragile histidine triad (FHIT) is a suppressor gene related to cervical cancer through CpG island hypermethylation. Folate is a water-soluble B-vitamin and an important cofactor in one-carbon metabolism. It may play an essential role in cervical lesions through effects on DNA methylation. The purpose of this study was to observe effects of folate and FHIT methylation and HPV 16 on cervical cancer progression. In this study, DNA methylation of FHIT, serum folate level and HPV16 status were measured using methylation-specific polymerase chain reaction (MSP), radioimmunoassay (RIA) and polymerase chain reaction (PCR), respectively, in 310 women with a diagnosis of normal cervix (NC, n=109), cervical intraepithelial neoplasia (CIN, n=101) and squamous cell carcinoma of the cervix (SCC, n=101). There were significant differences in HPV16 status (${\chi}^2=36.64$, P<0.001), CpG island methylation of FHIT (${\chi}^2=71.31$, P<0.001) and serum folate level (F=4.57, P=0.011) across the cervical histologic groups. Interaction analysis showed that the ORs only with FHIT methylation (OR=11.47) or only with HPV 16 positive (OR=4.63) or with serum folate level lower than 3.19ng/ml (OR=1.68) in SCC group were all higher than the control status of HPV 16 negative and FHIT unmethylation and serum folate level more than 3.19ng/ml (OR=1). The ORs only with HPV 16 positive (OR=2.58) or with serum folate level lower than 3.19ng/ml (OR=1.28) in CIN group were all higher than the control status, but the OR only with FHIT methylation (OR=0.53) in CIN group was lower than the control status. HPV 16 positivity was associated with a 7.60-fold increased risk of SCC with folate deficiency and with a 1.84-fold increased risk of CIN. The patients with FHIT methylation and folate deficiency or with FHIT methylation and HPV 16 positive were SCC or CIN, and the patients with HPV 16 positive and FHIT methylation and folate deficiency were all SCC. In conclusion, HPV 16 infection, FHIT methylation and folate deficiency might promote cervical cancer progression. This suggests that FHIT may be an effective target for prevention and treatment of cervical cancer.

• Journal of Nutrition and Health
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• v.36 no.8
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• pp.801-810
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• 2003

Chronic alcoholism is considered a common cause of malnutrition. Especially, micronutrient deficiency may playa critical role in the incidence of alcoholic liver diseases. This study was conducted to investigate the effect of folate deficiency and ethanol consumption on cholesterol metabolism and the antioxidative system in rats. Plasma concentration of total cholesterol was increased by ethanol administration in folate-fed rats. HDL-cholesterol tended to be higher in the folate-fed group, but it was not significant. The plasma and hepatic levels of malondialdehyde were increased after chronic ethanol feeding, but dietary folate depressed the plasma malondialdehyde content of rats. Ethanol or folate feeding did not significantly change alcohol dehydrogenase activity. But folate feeding increased catalase activity in ethanol-fed rats. There was no significant change in superoxide dismutase activity among the experimental groups. Glutathione peroxidase activity tended to decrease by chronic ethanol feeding, but dietary folate did not affectthe glutathione peroxidase activity of chronic ethanol-fed rats. Glutathionine-S-transferase activity was not affected by ethanol feeding or folate deficiency. The plasma and hepatic levels of retinol decreased after chronic ethanol feeding. The hepatic level of retinol significantly decreased in ethanol-fed rats by folate deficiency. The plasma level of $\alpha$-tocopherol tended to be low in the folate deficient group with ethanol feeding, but there was no difference among the experimental groups in the hepatic level of $\alpha$-tocopherol. These results demonstrate that chronic ethanol consumption changes the plasma cholesterol metabolism and antioxidative system of rats, and optimal folate feeding in ethanol-fed rats exerts protective effects to some extent.

• Asian Pacific Journal of Cancer Prevention
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• v.14 no.11
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• pp.6249-6256
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• 2013

One-carbon metabolism plays an important role in colorectal carcinogenesis. Meta-analyses have suggested protective associations of folate and vitamin $B_6$ intakes with colorectal cancer primarily based on studies in Caucasians, and genetic polymorphisms pertaining to the folate metabolism have been a matter of interest. Less investigated are the roles of methionine synthase (MTR) and thymidylate synthetase (TS) polymorphisms in colorectal carcinogenesis. In a study of 816 cases and 815 community controls in Japan, we investigated associations of dietary intakes of folate, methionine, vitamin $B_2$, vitamin $B_6$, and vitamin $B_{12}$ with colorectal cancer risk. The associations with MTR 2756A>G, MTRR 66A>G, and TSER repeat polymorphism were examined in 685 cases and 778 controls. Methionine and vitamin $B_{12}$ intakes were inversely associated with colorectal cancer risk, but the associations were totally confounded by dietary calcium and n-3 fatty acids. The other nutrients showed no association with the risk even without adjustment for calcium and n-3 fatty acids. The TSER 2R allele was dose-dependently associated with an increased risk. The MTR and MTRR polymorphisms were unrelated to colorectal cancer risk. There was no measurable gene-gene or gene-nutrient interaction, but increased risk associated with the TSER 2R allele seemed to be confined to individuals with high folate status. This study does not support protective associations for folate and vitamin $B_6$. The TSER 2R allele may confer an increased risk of colorectal cancer. The role of the TSER polymorphism in colorectal carcinogenesis may differ by ethnicity.

• Journal of Nutrition and Health
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• v.42 no.5
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• pp.423-433
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• 2009

Folate and vitamin $B_{12}$ are essential cofactors for homocysteine (Hcy) metabolism. Homocysteinemia has been related with cardiovascular and neurodegenerative disease. We examined the effect of folate and/or vitamin $B_{12}$ deficiency on biomarkers of one carbon metabolism in blood, liver and brain, and analyzed the correlation between vitamin biomarkers in mild and moderate homocysteinemia. In this study, Sprague-Dawley male rats (5 groups, n = 10) were fed folatesufficient diet (FS), folate-deficient diet (FD) with 0 or 3 g homocystine (FSH and FDH), and folate-/vitamin $B_{12}$-deficient diet with 3 g homocystine (FDHCD) for 8 weeks. The FDH diet induced mild homocysteinemia (plasma Hcy 17.41 ${\pm}$ 1.94 nmol/mL) and the FDHCD diet induced moderate homocysteinemia (plasma Hcy 44.13 ${\pm}$ 2.65 nmol/mL), respectively. Although liver and brain folate levels were significantly lower compared with those values of rats fed FS or FSH (p < 0.001, p < 0.01 respectively), there were no significant differences in folate levels in liver and brain among the rats fed FD, FDH and FDHCD diet. However, rats fed FDHCD showed higher plasma folate levels (126.5 ${\pm}$ 9.6 nmol/L) compared with rats fed FD and FDH (21.1 ${\pm}$ 1.4 nmol/L, 22.0 ${\pm}$ 2.2 nmol/L)(p < 0.001), which is the feature of "ethyl-folate trap"by vitamin $B_{12}$ deficiency. Plasma Hcy was correlated with hepatic folate (r = -0.641, p < 0.01) but not with plasma folate or brain folate in this experimental condition. However, as we eliminated FDHCD group during correlation test, plasma Hcy was correlated with plasma folate (r = -0.581, p < 0.01), hepatic folate (r = -0.684, p < 0.01) and brain folate (r = -0.321, p < 0.05). Hepatic S-adenosylmethionine (SAM) level was lower in rats fed FD, FDH and FDHCD than in rats fed FS and FSH (p < 0.001, p < 0.001 respectively) and hepatic S-adenosylhomocysteine (SAH) level was significantly higher in those groups. The SAH level in brain was also significantly increased in rats fed FDHCD (p < 0.05). However, brain SAM level was not affected by folate and/or vitamin $B_{12}$ deficiency. This result suggests that dietary folate- and vitamin B12-deficiency may inhibit methylation in brain by increasing SAH rather than decreasing SAM level, which may be closely associated with impaired cognitive function in nutritional homocysteinemia.

• Journal of Preventive Medicine and Public Health
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• v.42 no.6
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• pp.360-370
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• 2009

Genetic factors clearly play a role in carcinogenesis, but migrant studies provide unequivocal evidence that environmental factors are critical in defining cancer risk. Therefore, one may expect that the lower availability of substrate for biochemical reactions leads to more genetic changes in enzyme function; for example, most studies have indicated the variant MTHFR genotype 677TT is related to biomarkers, such as homocysteine concentrations or global DNA methylation particularly in a low folate diet. The modification of a phenotype related to a genotype, particularly by dietary habits, could support the notion that some of inconsistencies in findings from molecular epidemiologic studies could be due to differences in the populations studied and unaccounted underlying characteristics mediating the relationship between genetic polymorphisms and the actual phenotypes. Given the evidence that diet can modify cancer risk, gene-diet interactions in cancer etiology would be anticipated. However, much of the evidence in this area comes from observational epidemiology, which limits the causal inference. Thus, the investigation of these interactions is essential to gain a full understanding of the impact of genetic variation on health outcomes. This report reviews current approaches to gene-diet interactions in epidemiological studies. Characteristics of gene and dietary factors are divided into four categories: one carbon metabolism-related gene polymorphisms and dietary factors including folate, vitamin B group and methionines; oxidative stress-related gene polymorphisms and antioxidant nutrients including vegetable and fruit intake; carcinogen-metabolizing gene polymorphisms and meat intake including heterocyclic amins and polycyclic aromatic hydrocarbon; and other gene-diet interactive effect on cancer.

• Journal of Society of Preventive Korean Medicine
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• v.11 no.1
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• pp.45-53
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• 2007

Homocysteine is a sulfur amino-acid produced during the metabolism of the essential amino acid methionine. Moderately increased plasma total homocysteine concentration have been implicated as a risk factor for occlusive vascular disease. Smoking is known to be one of the most significant factors leading to elevated plasma homocysteine concentration. However, the main component of a cigarette, nicotine has been not studied whether it is linked directly to the increase of homocysteine concentration in blood. The metabolism of homocysteine is closely linked to that of its cofactors, folate. Here, the effects of nicotine and folic acid on amount of plasma homocysteine were studied. The concentration of homocysteine was increased by about 70% in rat plasma after nicotine treatment for one month. This increased concentration of homocysteine was reduced by about 60% at 6 hours later after folate treatment. Thus, nicotine should be directly involved in increasing the concentration of plasma homocysteine. Also it is suggested that these results can be and applied and used for controlling withdrawal symptoms after stopping smoking as one of oriental medicine formulas.

• Clinical Psychopharmacology and Neuroscience
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• v.16 no.4
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• pp.383-390
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• 2018

Objective: Autism spectrum disorder (ASD) is a complex neurodevelopmental syndrome with an increasingly prevalent etiology, yet not fully understood. It has been thought that vitamin D, complex B vitamin levels and homocysteine are associated with environmental factors and are important in ASD. The aim of this study was to examine serum vitamin D, vitamin D receptor (VDR), homocysteine, vitamin B6, vitamin B12 and folate levels in ASD. Methods: In this study, serum vitamin D and VDR, homocysteine, vitamins B6, B12 and folate levels were determined in 60 patients with ASD (aged 3 to 12 years) and in 45 age-gender matched healthy controls. In addition, calcium, phosphorus and alkaline phosphatase, which are associated with vitamin D metabolism, were measured from serum in both groups. ASD severity was evaluted by the Childhood Autism Rating Scale (CARS). Results: Serum vitamin D and VDR were substantially reduced in patients with ASD in comparision to control group. However, homocysteine level was significantly higher and vitamin B6, vitamin B12 and folate were also reduced in patients with ASD. Total CARS score showed a positive association with homocysteine and a negative correlation with vitamins D,B6, B12, folate and VDR. Conclusion: This comprehensive study, which examines many parameters has shown that low serum levels of vitamins D, B6, B12, folate and VDR as well as high homocysteine are important in the etiopathogenesis of ASD. However, further studies are required to define the precise mechanism(s) of these parameters and their contributions to the etiology and treatment of ASD.