PLMI Blog

Mounting research findings demonstrate the importance of DNA methylation as a robust indicator of biological health, influencing body and brain functions. Methylation, the addition of a methyl group (CH3) to DNA, modulates genetic expression and cellular health and occurs billions of times per second in every cell (1). Disruptions in this integral process result from an interplay of genetic and lifestyle factors, including nutritional deficiencies, stress, and environmental exposures.

The Genome, Epigenome & Methylation

The genome contains an individual’s complete set of genetic material, while the epigenome regulates gene expression through modifications to DNA, or its associated proteins, without altering the DNA sequence. DNA methylation is a pivotal tool for understanding how lifestyle and environmental factors influence genetic expression and cellular function. Healthy methylation levels are essential for modulating DNA synthesis and repair, aging, metabolism, detoxification, and hormonal, immune, and neurological health while reducing oxidative stress and inflammation.

Methylation patterns shift over time, revealing important and distinct measures of cellular function, biological age, and chronic disease. Methylation has further been linked to individual responses to medications, substance use risk, and a range of health conditions. Using DNA methylation as a biomarker enhances understanding of the mechanisms underlying these conditions, allowing for more precise preventive and therapeutic strategies customized to one’s bio-individual makeup (1-2).

Modifications in the Epigenome

Environmental factors, including chronic stress and lead exposure, have been found to induce changes in methylation patterns (3-4). In addition to having adverse interactions with epigenetic mechanisms, lead exposure has been shown to also inhibit DNA repair. Prolonged stress can further accelerate aging by compromising cellular health.

The aging process is critical for understanding the genetic, epigenetic, molecular, and environmental factors that influence and underlie biological health. Research reveals connections between epigenomic alterations and markers of aging, including changes in DNA methylation, histone modifications, and genomic instability (5-6). The role of epigenetic mechanisms in these processes underscores the widespread effects of altered methylation, increasing the risk for chronic health conditions.

Methylation: A “Biochemical Bridge” Between Environment & Epigenetic Changes

One-carbon (1C) metabolism describes the set of biochemical pathways involved in methylation, necessary for governing these important cellular functions related to health. 1C is driven by folate and methionine cycles, requiring nutrients to generate methyl donors necessary to modulate DNA and RNA synthesis and methylation reactions. S-adenosylmethionine (SAM) is the principal methyl donor for these pathways, linking metabolic processes to epigenetic modulation. Research underscores the significance of these pathways, referring to them as a “biochemical bridge” between our environment and epigenetic changes. Genetic variations in 1C-related genes have been shown to contribute to individual variability in epigenetic regulation, influencing gene expression and susceptibility to chronic health conditions (12).

Altered Methylation Patterns and Systemic and Mental Health

Obesity – A 2023 study investigated the role of DNA methylation variations in obesity, combining epigenome-wide association and genomics to explore their impact on adipocyte function. Researchers identified over 860 obesity-associated DNA methylation alterations across subcutaneous and visceral adipocytes in 190 samples. Methylation variations were related to genetic expression alterations at more than 500 genes and potential interactions with transcription factors. Further methylation variations revealed distinct underlying regulatory cellular metabolic effects. These findings underscore DNA methylation as a key factor in obesity and provide insights into how altered methylation affects metabolic disturbances (7).

Inflammation & Cardiometabolic Health – A 2022 study examined the DNA methylation pattern associated with chronic low-grade inflammation, indicated by increased levels of C-reactive protein (CRP). Researchers identified 1,511 differentially methylated loci linked to CRP, with significant implications for cardiometabolic health. Smoking further compounded these epigenetic alterations (8).

Immunity – T cells, integral to immune function, have been demonstrated to adapt metabolic pathways based on their activation status — essential for epigenetic functions — as evidenced by a 2023 study. Metabolic alterations were observed to induce epigenetic changes, including DNA methylation and histone modifications. These findings provide novel therapeutic insights for compromised immune health (9).

Autoimmune Diseases – Oxidative stress plays a central role in the pathophysiology of Crohn’s disease (CD), a chronic autoimmune condition. A 2023 study integrating multi-omics data found that oxidative stress genes, modulated by DNA methylation and host-microbiota interactions, contribute to CD susceptibility. Genes including BAD, SHC1, and STAT3 were identified as key regulators of oxidative stress in CD. These findings underscore the role of epigenetic mechanisms underlying inflammatory conditions and support the development of targeted bio-individual approaches (10).

Multiple sclerosis (MS), an autoimmune disease of the central nervous system (CNS), is influenced by both genetic susceptibility and environmental risk factors. Epigenetic mechanisms, particularly DNA methylation, are involved in MS pathophysiology, including immune response, blood-brain barrier breakdown, and neurodegeneration. A recent study published in The Journal of Neuroinflammation demonstrated these connections (11).

Post Traumatic Stress Disorder (PTSD) – Early life stressors, including parental stress and trauma, have been suggested to have long-term adverse health effects, increasing risk of mental health conditions through altered DNA methylation. A 2024 study revealed this relationship, noting compromised neurobehavioral health and heightened stress reactivity (13). These findings underscore the profound role stress has on our biology, particularly early in life, and its influence on increasing susceptibility to mental health conditions. Research demonstrates distinct methylation signatures associated with PTSD, including differentially methylated regions, underscoring the role stress plays in epigenetics (14).

Neurological Health – A recent review published in The Journal of Psychiatry Research, explored the role of DNA methylation in governing gene expression within the CNS. Disturbances in DNA methylation patterns were found in major depressive disorder, schizophrenia, autism spectrum disorder, bipolar disorder, and attention-deficit hyperactivity disorder (ADHD). This 2021 study also revealed the mechanisms and functions of DNA methylation and its relationship with the etiology of these conditions, highlighting the role of altered methylation in neurological health (15).

Increased methylation levels have also been associated with anxiety, affecting genes related to generalized anxiety disorder and brain-derived neurotrophic factor (BDNF), influencing neurotransmitter synthesis and regulation, particularly relative to GABA (11). Hypermethylation of NR2C1 and BDNF have been linked with depression. Compellingly, 105 altered methylation markers across 120 genes have been identified in alcohol use disorder (AUD), as evidenced in a 2024 study (16). Distinct methylation signatures across the genome have also been observed in habitual smokers (17).

Schizophrenia – A robust 2024 meta-analysis revealed significant variability in DNA methylation in individuals with schizophrenia, which was found to contribute to individual differences in presenting symptoms, cognitive deficits, and overall treatment response. Variations in methylation were associated with brain-enriched genes and have been suggested to influence the onset and severity of this disorder. GAD1 has been shown to be hypomethylated in schizophrenia — whereas hypermethylation of COMT and aberrant methylation of BDNF have been shown to confer increased risk. These findings highlight the potential of DNA methylation variance as a factor in personalized treatment approaches for schizophrenia, yielding better outcomes for this debilitating condition (18).

Obsessive Compulsive Disorder (OCD) – Research explored the role of epigenetic alterations in the transcriptional modulation of BDNF in individuals with obsessive-compulsive disorder (OCD). Researchers focused on DNA methylation at specific gene promoters in peripheral blood mononuclear cells from OCD patients and matched controls. Findings demonstrated a significant increase in BDNF gene expression correlated with epigenetic changes, suggesting a connection between altered methylation, BDNF levels, and OCD (19).

A further study examined genome-wide DNA methylation in blood samples from 65 patients with OCD and 96 healthy controls. Researchers identified 8,417 differentially methylated probes corresponding to 2,190 unique genes between the two groups. Genes associated with OCD (BCYRN1, BCOR, FGF13, HLA-DRB1, and ARX) were among those with altered methylation. Pathway analysis revealed that processes including actin cytoskeleton regulation, cell adhesion, and transcription regulation were related to increased susceptibility to OCD. These findings further underscore that differential DNA methylation plays a significant role in the etiology of OCD (20).

A Robust Biomarker of Health

Methylation serves as a pivotal biomarker of health, with patterns influencing genetic expression and serving as indicators of disease risk, offering novel insights into the underlying biological aspects of chronic health conditions. Identification of distinct DNA methylation markers associated with these conditions allows for more precise, targeted interventions in modifying epigenetic patterns with nutrition and lifestyle, as with medication efficiency.

This growing body of research underscores the significance of DNA methylation for developing personalized treatments to improve health (21). For example, variants in MTHFR C677T (a gene important for folate metabolism) can compromise methylation cycles and increase risk for a number of health conditions by raising homocysteine levels, warranting thoughtful nutrition and lifestyle protocols (22).

Lifestyle & Personalized Nutrition

DNA methylation is highly responsive to external factors such as nutrition, environmental influences, and lifestyle choices. Sleep, circadian rhythms, and mindfulness can positively modulate methylation, while chronic stress, oxidative stress, and genotoxic stress accelerate epigenetic changes that increase aging and disease risk (23). Conversely, exercise, intermittent fasting, and stress reduction support healthy methylation patterns.

Advances in nutrition, particularly gene-nutrient interactions, support personalized plans tailored to an individual’s genetic makeup, improving health by optimizing DNA methylation pathways (24). Proper nutrition is critical for maintaining efficient and balanced methylation cycles, with nutrients B6, folate, B12, zinc, betaine, methionine, and choline playing important roles. Additionally, supporting the gut microbiome with consumption of fermented and probiotic-rich foods is important, as the gut microbiome contains 3.3 million genes, offering vast potential for improving genetic expression (25).

Methylation can also shed light on which medications individuals are responsive to, potentially improving treatment outcomes for metabolic and mental health conditions (26-27).

The Future of DNA Methylation as a Biomarker

DNA methylation is a sensitive and robust biomarker of health, holding promise for enhancing understanding of chronic disease risk, prevention, and treatment. By actively supporting DNA methylation through diet, lifestyle, and environment, we can restore healthy epigenetic patterns, promoting health and longevity.

Join us for this free, one of a kind online event: Updates on DNAm: What works to reverse aging from 75 treatments and why a single test might replace the need for all others occurring on November 19th from 5-7 pm. Renowned experts Dr. Mike Stone, Dr. Mathew Dawson, and Jeff Bland, PhD, will delve further into advances in methylation research. Novel clinical insights will be revealed, underscoring the profound impact this epigenetic mechanism has on cellular health. Specific epigenetic DNA signatures and biomarkers will be presented, supporting thoughtful and precise bio-individual treatment protocols.

References

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