////Omega-3 Supplementation Affects Epigenetics in Patients with Alzheimer’s Disease

Omega-3 Supplementation Affects Epigenetics in Patients with Alzheimer’s Disease

  • Omega-3 fatty acids, eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) alter inflammation through several mechanisms including gene expression.

  • Epigenetics is the study of heritable changes in gene function that don’t involve changes in DNA sequence. DNA methylation is an epigenetic mechanism that involves adding a methyl group to a DNA molecule DNA methylation usually represses the activity of a DNA segment and occurs during development, disease and aging. Research has suggested DNA methylation plays an important role in the regulation of long-term memory.

  • Previous research has not fully investigated the effect of long-term EPA and DHA treatment on epigenetics.

  • The Omega AD Study investigated the effect of omega-3 supplementation on DNA methylation in blood cells of patients with Alzheimer’s Disease.

  • At 6 months, the group who received the omega-3 supplement had increased EPA and DHA blood levels and decreased DNA methylation in 2 of the 4 DNA regions assessed.

  • This study is important for the research of the effects of omega-3 fatty acids, especially the effects on gene expression.

Omega-3 fatty acids, especially EPA and DHA have been shown to improve the symptoms of many inflammatory conditions1-3. These fatty acids use several mechanisms such as transcription factors, G-proteins, ion pumps and surface receptor modulation to alter processes in the human body.

Omega-3 can also exert its effects by altering gene expression. Concentration of messenger RNA can be used as a measurement of this change in gene expression1,2,4,5. Previous research has shown the omega-3 fatty acids EPA and DHA can up- or down-regulate the activity of genes involved in inflammation and chronic neurodegenerative disorders6-8. These changes in gene activity may be due to epigenetic factors such as DNA methylation9,10. For example, decreased DNA methylation in the CpG regions of genes can enhance gene expression. The hypo – or hypermethylation caused by omega-3 may be the cause of its beneficial effects.

High fish consumption and omega-3 supplementation is linked to a decreased risk of developing Alzheimer’s Disease (AD) and delayed cognitive decline11-14. The OmegaAD study aimed to investigate if DHA-rich omega-3 supplementation can reduce cognitive impairment in Alzheimer’s Disease patients. The study also investigated if omega-3 supplementation alters DNA methylation to explain previously reported gene expression changes6.

As part of The OmegaAD Study, patients consumed a supplement containing 1.7g DHA and 0.6g EPA or a placebo daily for 6 months. Of the 63 AD patients, 30 received the omega-3 supplement and 33 received a placebo. The study investigated the effect of omega-3 supplementation on DNA methylation in blood cells of patients with Alzheimer’s Disease. DNA methylation in peripheral blood mononucleotide cells (PBMCs) was analysed as The OmegaAD Study previously assessed gene expression in PBMCs6,15. Four CpG regions of DNA from 63 AD patients were assessed as an estimate of global methylation of blood cells. After 6 months of supplementation, researchers measured blood levels of EPA and DHA and compared these levels with occurrence of DNA methylation16.

After the 6 months, total omega-3 levels decreased in placebo group, while blood levels of EPA and DHA significantly increased in the omega-3 supplemented group16. EPA levels increased 3.5-fold and DHA levels increased 2.6-fold. The omega-3 group had significant reductions in methylation at CpG1 and CpG4. Methylation scores for CpG2, CpG3 and CpG4 were also significantly lower in omega-3 group than the placebo group16. EPA and DHA were seen to have opposite effects on methylation scores at the CpG regions. There was a significant negative correlation for CpG2 and CpG4 methylation scores compared to changes in blood EPA concentration16. This means as blood levels of EPA increased, hypomethylation at CpG2 and CpG4 sites increased. There was a significant positive correlation for CpG1 and CpG3 methylation scores compared with change in DHA blood levels, meaning patients with increased DHA levels had higher methylation scores at CpG1 and CpG316.

These results are important findings for the research on the role of omega-3 fatty acids in gene expression. The changes in methylation caused by omega-3 supplementation may affect inflammation and other processes that play a role in the development and progression of Alzheimer’s Disease. This study also suggests that specific hypomethylating agents, such as omega-3 fatty acids may be used in the future to treat Alzheimer’s Disease.

  1. Serhan CN. Pro-resolving lipid mediators are leads for resolution physiology. Nature. 2014;510(7503):92-101.
  2. Calder PC. Marine omega-3 fatty acids and inflammatory processes: Effects, mechanisms and clinical relevance. Biochim Biophys Acta. 2015;1851(4):469-484.
  3. Del Gobbo LC, Imamura F, Aslibekyan S, et al. ω-3 Polyunsaturated Fatty Acid Biomarkers and Coronary Heart Disease: Pooling Project of 19 Cohort Studies. JAMA Intern Med. 2016;176(8):1155-1166.
  4. Tsunoda F, Lamon-Fava S, Asztalos BF, Iyer LK, Richardson K, Schaefer EJ. Effects of oral eicosapentaenoic acid versus docosahexaenoic acid on human peripheral blood mononuclear cell gene expression. Atherosclerosis. 2015;241(2):400-408.
  5. Ulven SM, Myhrstad MC, Holven KB. Marine n-3 Fatty Acids and Gene Expression in Peripheral Blood Mononuclear Cells. Curr Cardiovasc Risk Rep. 2014;8(11):412.
  6. Vedin I, Cederholm T, Freund-Levi Y, et al. Effects of DHA-rich n-3 fatty acid supplementation on gene expression in blood mononuclear leukocytes: the OmegAD study. PLoS One. 2012;7(4):e35425.
  7. Bouwens M, van de Rest O, Dellschaft N, et al. Fish-oil supplementation induces antiinflammatory gene expression profiles in human blood mononuclear cells. Am J Clin Nutr. 2009;90(2):415-424.
  8. Myhrstad MC, Ulven SM, Günther CC, et al. Fish oil supplementation induces expression of genes related to cell cycle, endoplasmic reticulum stress and apoptosis in peripheral blood mononuclear cells: a transcriptomic approach. J Intern Med. 2014;276(5):498-511.
  9. Ma Y, Follis JL, Smith CE, et al. Interaction of methylation-related genetic variants with circulating fatty acids on plasma lipids: a meta-analysis of 7 studies and methylation analysis of 3 studies in the Cohorts for Heart and Aging Research in Genomic Epidemiology consortium. Am J Clin Nutr. 2016;103(2):567-578.
  10. Lee HS, Barraza-Villarreal A, Biessy C, et al. Dietary supplementation with polyunsaturated fatty acid during pregnancy modulates DNA methylation at IGF2/H19 imprinted genes and growth of infants. Physiol Genomics. 2014;46(23):851-857.
  11. Solfrizzi V, Colacicco AM, D’Introno A, et al. Dietary intake of unsaturated fatty acids and age-related cognitive decline: a 8.5-year follow-up of the Italian Longitudinal Study on Aging. Neurobiol Aging. 2006;27(11):1694-1704.
  12. Zhang Y, Chen J, Qiu J, Li Y, Wang J, Jiao J. Intakes of fish and polyunsaturated fatty acids and mild-to-severe cognitive impairment risks: a dose-response meta-analysis of 21 cohort studies. Am J Clin Nutr. 2016;103(2):330-340.
  13. Cederholm T. Fish consumption and omega-3 fatty acid supplementation for prevention or treatment of cognitive decline, dementia or Alzheimer’s disease in older adults – any news? Curr Opin Clin Nutr Metab Care. 2017;20(2):104-109.
  14. Freund-Levi Y, Eriksdotter-Jönhagen M, Cederholm T, et al. Omega-3 fatty acid treatment in 174 patients with mild to moderate Alzheimer disease: OmegAD study: a randomized double-blind trial. Arch Neurol. 2006;63(10):1402-1408.
  15. Vedin I, Cederholm T, Freund Levi Y, et al. Effects of docosahexaenoic acid-rich n-3 fatty acid supplementation on cytokine release from blood mononuclear leukocytes: the OmegAD study. Am J Clin Nutr. 2008;87(6):1616-1622.
  16. Karimi M, Vedin I, Freund Levi Y, et al. DHA-rich n-3 fatty acid supplementation decreases DNA methylation in blood leukocytes: the OmegAD study. Am J Clin Nutr. 2017;106(4):1157-1165.
2018-03-20T13:00:26+00:00March 20th, 2018|Categories: Benefits, Brain Health|
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