Age-dependent decreases in DNA methyltransferase levels and low transmethylation micronutrient levels synergize to promote overexpression of genes implicated in autoimmunity and acute coronary syndromes
| Autor: | Faith M. Strickland, YePeng Li, Bruce Richardson, Ying Liu |
|---|---|
| Rok vydání: | 2010 |
| Předmět: |
Adult
DNA (Cytosine-5-)-Methyltransferase 1 Male Aging medicine.medical_specialty Homocysteine T-Lymphocytes Biology Biochemistry DNA methyltransferase Article Autoimmune Diseases chemistry.chemical_compound Folic Acid Methionine Endocrinology CD28 Antigens Receptors KIR Internal medicine Genetics medicine Humans DNA (Cytosine-5-)-Methyltransferases Micronutrients Epigenetics Acute Coronary Syndrome DNA Modification Methylases Molecular Biology Cells Cultured Aged Aged 80 and over Cell Biology DNA Methylation Middle Aged DNA demethylation Gene Expression Regulation chemistry Immunology DNA methylation DNMT1 Female Transmethylation CD27 Ligand |
| Zdroj: | Experimental Gerontology. 45:312-322 |
| ISSN: | 0531-5565 |
| DOI: | 10.1016/j.exger.2009.12.008 |
| Popis: | T cell DNA methylation levels decline with age, activating genes such as KIR and TNFSF7 (CD70), implicated in lupus-like autoimmunity and acute coronary syndromes. The mechanisms causing age-dependent DNA demethylation are unclear. Maintenance of DNA methylation depends on DNA methyltransferase 1 (Dnmt1) and intracellular S-adenosylmethionine (SAM) levels, and is inhibited by S-adenosylhomocysteine (SAH). SAM levels depend on dietary micronutrients including folate and methionine. SAH levels depend on serum homocysteine concentrations. T cell Dnmt1 levels also decline with age. We hypothesized that age-dependent Dnmt1 decreases synergize with low folate, low methionine or high homocysteine levels to demethylate and activate methylation-sensitive genes. T cells from healthy adults ages 22-81, stimulated and cultured with low folate, low methionine, or high homocysteine concentrations showed demethylation and overexpression of KIR and CD70 beginning at age approximately 50 and increased further with age. The effects were reproduced by Dnmt1 knockdowns in T cells from young subjects. These results indicate that maintenance of T cell DNA methylation patterns is more sensitive to low folate and methionine levels in older than younger individuals, due to low Dnmt1 levels, and that homocysteine further increases aberrant gene expression. Thus, attention to proper nutrition may be particularly important in the elderly. |
| Databáze: | OpenAIRE |
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