Modulation of DNA methylation by one-carbon metabolism: a milestone for healthy aging

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.

Iron Supplementation Reverses the Reduction of Hydroxymethylcytosine in Hepatic DNA Associated With Chronic Alcohol Consumption in Rats

BACKGROUND: Alcohol is known to affect two epigenetic phenomena, DNA methylation and DNA hydroxymethylation, and iron is a cofactor of ten-eleven translocation (TET) enzymes that catalyze the conversion from methylcytosine to hydroxymethylcytosine. In the present study we aimed to determine the effects of alcohol on DNA hydroxymethylation and further effects of iron on alcohol associated epigenetic changes. METHODS: Twenty-four male Sprague-Dawley rats were fed either Lieber-DeCarli alcohol diet (36% calories from ethanol) or Lieber-DeCarli control diet along with or without iron supplementation (0.6% carbonyl iron) for 8 weeks. Hepatic non-heme iron concentrations were measured by colorimetric assays. Protein levels of hepatic ferritin and transferrin receptor were determined by Western blotting. Methylcytosine, hydroxymethylcytosine and unmodified cytosine in DNA were simultaneously measured by liquid chromatography/mass spectrometry method. RESULTS: Iron supplementation significantly increased hepatic non-heme iron contents (P < 0.05) but alcohol alone did not. However, both alcohol and iron significantly increased hepatic ferritin levels and decreased hepatic transferrin receptor levels (P < 0.05). Alcohol reduced hepatic DNA hydroxymethylation (0.21% ± 0.04% vs. 0.33% ± 0.04%, P = 0.01) compared to control, while iron supplementation to alcohol diet did not change DNA hydroxymethylation. There was no significant difference in methylcytosine levels, while unmodified cytosine levels were significantly increased in alcohol-fed groups compared to control (95.61% ± 0.08% vs. 95.26% ± 0.12%, P = 0.03), suggesting that alcohol further increases the conversion from hydroxymethylcytosine to unmodified cytosine. CONCLUSIONS: Chronic alcohol consumption alters global DNA hydroxymethylation in the liver but iron supplementation reverses the epigenetic effect of alcohol.

A lifelong exposure to a Western-style diet, but not aging, alters global DNA methylation in mouse colon

BACKGROUND/OBJECTIVES: Previous studies have indicated that when compared to young mice, old mice have lower global DNA methylation and higher p16 promoter methylation in colonic mucosa, which is a common finding in colon cancer. It is also known that a Western-style diet (WSD) high in fat and calories, and low in calcium, vitamin D, fiber, methionine and choline (based on the AIN 76A diet) is tumorigenic in colons of mice. Because DNA methylation is modifiable by diet, we investigate whether a WSD disrupts DNA methylation patterns, creating a tumorigenic environment. SUBJECTVIES/METHODS: We investigated the effects of a WSD and aging on global and p16 promoter DNA methylation in the colon. Two month old male C57BL/6 mice were fed either a WSD or a control diet (AIN76A) for 6, 12 or 17 months. Global DNA methylation, p16 promoter methylation and p16 expression were determined by LC/MS, methyl-specific PCR and real time RT-PCR, respectively. RESULTS: The WSD group demonstrated significantly decreased global DNA methylation compared with the control at 17 months (4.05 vs 4.31%, P = 0.019). While both diets did not change global DNA methylation over time, mice fed the WSD had lower global methylation relative to controls when comparing all animals (4.13 vs 4.30%, P = 0.0005). There was an increase in p16 promoter methylation from 6 to 17 months in both diet groups (P < 0.05) but no differences were observed between diet groups. Expression of p16 increased with age in both control and WSD groups. CONCLUSIONS: In this model a WSD reduces global DNA methylation, whereas aging itself has no affect. Although the epigenetic effect of aging was not strong enough to alter global DNA methylation, changes in promoter-specific methylation and gene expression occurred with aging regardless of diet, demonstrating the complexity of epigenetic patterns.