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Methylation is an integral, enzymatic process that occurs billions of times per second in every cell of the body, governing a vast array of physiological functions. A plethora of research demonstrates the significance of efficient methylation to the health and functioning of our cells, and moreover mood.
Reactions of the methylation cycle involve the donation of methyl groups requiring various enzymes and nutrients as cofactors. In addition to exerting neuroprotective functions, micronutrients serve as methyl donors in methylation pathways, altering gene expression and phenotype.
Folate obtained from the diet has a key role in methylation and is converted to tetrahydrofolate (THF), requiring various steps, enzymes and vitamin B3 as a cofactor. THF is then converted to 5,10 methyl-THF with the help of an enzyme and vitamin B6 as a coenzyme. Following this reaction, the reduction of 5,10 methyl-THF to 5-methyl-THF occurs via the enzyme, methylenetetrahydrofolate reductase (MTHFR) with B2 as a coenzyme.
At the conclusion of this cycle, 5-methyl THF is converted back to THF, utilizing vitamin B2 as a coenzyme. Homocysteine is converted to methionine which describes a further pathway of methylation including the conversion of methionine. This amino acid is also obtained from the diet and converted into S-adenosylmethionine (SAM), the body’s primary methyl donor. Following donation of its methyl group, SAM is then converted into S-adenosylhomocysteine (SAH). SAH is either converted back to methionine for SAM production, or homocysteine, depending on the availability of nutrients warranted for this enzymatic reaction. Remethylation of homocysteine to methionine depends on vitamin B12 and zinc, where it can move the methylation cycle along, or it can accumulate within the system, impeding upon a number of processes.
The primary pathway of methylation involves bioactive forms of B12 (methylcobalamin) and folate (methyl folate, 5-MTH), as well as zinc as cofactors. Biologically active forms of these nutrients are significant in adequate amounts for the synthesis of neurotransmitters— serotonin, dopamine, melatonin, epinephrine and norepinephrine —having vast implications for mood health.
A subsequent methylation pathway includes the conversion of choline– significant for cellular membrane repair into acetylcholine, a neurotransmitter integral for cholinergic signaling. Choline can also be oxidized to betaine, contributing to the formation of SAM. Zinc is also a cofactor for these reactions. Transsulfuration, is the final methylation pathway involving remethylation of homocysteine, requiring adequate concentrations of SAM and glutathione, a major antioxidant in the body. This pathway is activated in response to oxidative stress.
Cycles of methylation include the interplay among folate and methionine metabolism, as well as homocysteine transsulfuration. As noted, these are dependent on amino acids, B vitamins, and minerals for cofactors. Genetic variants (SNPs) may exist for a number of methylation and transsulfuration enzymes, which can either speed up or slow down these reactions. Nutritional deficiencies can further compound these processes, as well as oxidative stress induced in the body.
Methylation is integral in unraveling the intricate mechanisms of how our genes interact with our lifestyle and environment. Epigenetics refers to cellular mechanisms that modulate the expression of genes, independent of alterations to the underlying DNA sequence. The methylome refers to the full set of DNA methylation modifications within a cell. Methylation (DNAm) is an example of an epigenetic process that plays a key role in cellular and mental health.
The mechanisms in which methylation supports these processes include DNA epigenetic modification, hormone detoxification, neurotransmitter production, nitric oxide (NO) synthesis and immune function. Efficient methylation is also significant for supporting a healthy inflammatory process, improving cellular functioning, and turning genes on and off to promote health. Disruptions in methylation, therefore, can alter genetic expression, and impede cellular function and mood.
A 2018 review published in The Journal of Nutrition Neuroscience, highlights the importance of this epigenetic mechanism in underlying the interplay among biology, nutrition, lifestyle, mental health and the methylome. Disruptions in methylation may manifest in clinical concerns. Findings of a 2023 systematic review and meta-analysis in The Journal of Affective Disorders demonstrated that hypermethylation of BDNF and NR2C1 were associated with depression, as well as increased risk of depression.
Further findings of a 2022 meta-analysis published in Frontiers of Psychology demonstrated that variants in MTHFR increased the risk of depression due to their reduced MTHFR activity. Epigenetic alterations of the brain-derived neurotrophic factor (BDNF) gene have also been implicated in mental health conditions. A 2020 study demonstrated an association of higher BDNF methylation with higher amygdala reactivity. These findings provide evidence that epigenetic modifications of BDNF can result in anxiety and mood disorders.
Efficient methylation is essential for cellular health, as well as for the integrity and functioning of DNA, thereby healthy cellular regeneration, as evidenced in a 2021 study demonstrating how nutrients can support methylation.
Nutrition and lifestyle factors promote restoration of more youthful methylation patterns. In fact, a study provides evidence for this, suggesting that cellular health and aging are malleable. Researchers in this study found that participants who followed an 8-week intervention comprised of a plant-centered diet, regular sleep and exercise, observed a reduction in epigenetic age by 3.33 years.
Methylation supports biological processes underlying mood health. Emerging research continues to support interrelationships between microbiota, immune, and nervous system functioning in influencing neurotransmitter synthesis and neuroplasticity. Diversity and quality of microbiota is significant, as is having sufficient stomach acid for efficient digestion and absorption capabilities of nutrients necessary for methylation, such as folate, B12 and zinc.
Reductions in epigenetic information can influence aging, resulting in mitochondrial dysfunction, compromised cellular rejuvenation, a suboptimal inflammatory response and cellular senescence—associated with changes in cell functioning structure. Accumulation of senescent cells affects the inflammatory process and induces reactive oxygen species (ROS), further impeding cellular functioning. This often results in aging and related conditions as referenced in a 2023 study published in The Journal of Aging.
Findings of a 2023 review published in the Journal of Biological Psychiatry, demonstrate a connection between mental health, methylation and cellular health– suggesting that individuals with mental health conditions may be at increased risk of age-related diseases as evidenced by epigenetic clocks–further highlighting the connection between impeded cellular health and DNA methylation levels.
In sum, these studies underscore the interconnectedness of the body, and the significance of methylation for improved cellular and mood health.
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