ANTIOXIDANT STATUS AND METHYLATION IN THE BRAIN
TOPIC: Vitamin B12 in human brain
PROJECT: Clinical evaluation of a brain-targeted nutraceutical formulation of vitamin B12 in autism and mild cognitive impairment (early Alzheimer’s disease)
To further explore the role of methylation in human brain we measured vitamin B12 levels in postmortem brain samples of subjects from fetal to 80 yrs of age. Total B12 levels decreased more than 10-fold across the lifespan, mainly after 50 yrs of age and mainly reflecting a decrease in the methylB12 species, which is needed for methylation activity. Such a decrease is not observed in blood measurements of B12, further indicating the brain-specific importance of methylation and epigenetic regulation. Autistic subjects and subjects with schizophrenia had brain B12 levels that were only one-third of control subjects of the same age. This work suggests that augmenting brain B12 levels might have therapeutic benefit. Consistent with this finding, clinical studies from a number of other investigators have reported encouraging effects of vitamin B12, folic acid and vitamin B6 supplementation in decreasing the rate of progression of early Alzheimer’s disease. Accordingly, we have undertaken development of a novel multi-component nutraceutical formulation to provide improved effectiveness in preventing Alzheimer’s disease and/or slowing its progression.
TOPIC: Oxidative metabolism and brain disorders
PROJECT: Analysis of antioxidant and methylation metabolite status in different brain regions of subjects with autism, schizophrenia, major depression and Alzheimer’s disease.
All cells depend upon energy-producing metabolic pathways, including aerobic and non-aerobic sources, and they must have adequate antioxidant capacity to avoid damage, especially from aerobic metabolism by mitochondria. While the human brain develops and functions within a unique metabolic environment that is optimized for its cognitive and memory functions, this unique metabolic environment also brings risk. Most important among these factors is the extraordinarily high level of aerobic metabolism in the brain, which consumes oxygen at a 10-fold higher rate than other tissues. At the same time, however, the available level of antioxidant resources in the brain is the lowest of any tissue. This precarious metabolic balance assures that the level of neural firing activity will strongly impact antioxidant levels, setting into motion changes in gene expression which constitute a form of learning and memory. During a person’s early years these activity-dependent changes in gene expression serve to incorporate experience into the developing neural networks, but if antioxidant resources fall short there can be neurodevelopmental consequences. Similarly, the occurrence of oxidative stress later in life can contribute to functional brain disorders such as schizophrenia and depression, while in older age it can lead to neurodegenerative disorders such as Alzheimer’s disease. Our studies of postmortem human brain were the first to demonstrate dynamic age-dependent changes in the vitamin B12 and folate-dependent enzyme (methionine synthase) across the lifespan. Recognition of the crucial importance of oxidative stress in brain disorders across the lifespan provides a guide for basic and clinical research while also opening the way to novel metabolism-based treatment strategies.
TOPIC: Epigenetic regulation
PROJECT: Evaluation of gene-specific DNA methylation patterns for antioxidant and methylation pathway enzymes in subjects with autism, schizophrenia, major depression and Alzheimer’s disease.
Over the past 15 years there has been an explosion of knowledge about how gene expression is regulated, revealing the central role of epigenetic mechanisms involving methylation of DNA and histone proteins. Since methylation reactions are very sensitive to antioxidant status, the energy demand associated with high rates of neuronal firing leads to changes in DNA and histone methylation and gene expression which can last for a lifetime, or even be transmitted across generations. The metabolic pathways which support methylation and antioxidant production are therefore essential for normal learning and memory capabilities, which involve epigenetic mechanisms. Moreover, our recent research has provided evidence that antioxidant-dependent epigenetic regulation appears to be fundamental for the overall program of development, including neural stem cell differentiation.
TOPIC: Environmental exposures affect the brain
PROJECT: Evaluate the dose-dependent impact of selected environmental toxins on antioxidant and methylation pathway metabolites in brain regions of laboratory animals.
There is increasing concern about the health impact of toxic chemical exposures, for example those arising from the environment, food ingredients, dental amalgams, vaccines, prescribed and illicit drugs etc. Almost all toxic exposures deplete antioxidant levels, which is in fact their mechanism of toxicity, and it is not surprising, therefore, that neurodevelopment and ongoing brain function are highly sensitive to toxic exposures. We have previously characterized the potent inhibitory effects of toxins such as lead, mercury, aluminum and arsenic on both antioxidant status and methylation activity. We further demonstrated that alcohol and morphine impair the production of glutathione (GSH) the principal antioxidant in all cells, as well as interfering with methylation and epigenetic regulation. Recognition of these relationships leads to metabolic treatment strategies capable of preventing and reversing the impact of environmental exposures.
To further explore the role of methylation in human brain we measured vitamin B12 levels in postmortem brain samples of subjects from fetal to 80 yrs of age. Total B12 levels decreased more than 10-fold across the lifespan, mainly after 50 yrs of age and mainly reflecting a decrease in the methylB12 species, which is needed for methylation activity. Such a decrease is not observed in blood measurements of B12, further indicating the brain-specific importance of methylation and epigenetic regulation. Autistic subjects and subjects with schizophrenia had brain B12 levels that were only one-third of control subjects of the same age. This work suggests that augmenting brain B12 levels might have therapeutic benefit in autism and schizophrenia, consistent with several clinical studies from other investigators.
TOPIC: Gluten and casein intolerance
PROJECT: Influence of dietary casein and gluten on brain antioxidant levels across the lifespan.
An increasing number of people appear to be intolerant of gluten and casein-containing foods such as wheat and milk products, and a gluten-free/casein-free (GF/CF) diet has been reported to be beneficial in autism, schizophrenia, chronic fatigue syndrome and other disorders. In 2014 we published studies showing that opiate peptides released from both gluten and casein restrict transport of the amino acid cysteine, limiting antioxidant availability. Thus a GF/CF diet can help to increase antioxidant levels, which is especially important for individuals with low levels. Notably, the opiate peptide is not released from cow milk containing only the a2-type casein, resulting in higher antioxidant levels. These finding also has important implications for early development when breast milk or infant formula are the primary source of nutrition, illustrating that efficient absorption of macro- and micronutrients, in concert with a healthy microbiome, is essential for postnatal brain development.
TOPIC: Epigenetics and addiction
PROJECT: Evaluation of redox and gene-specific epigenetic changes in addiction-related brain regions after acute and chronic administration of morphine
Addiction is associated with epigenetic-related changes in gene expression and a number of drugs with addictive potential have effects on neuronal antioxidant metabolic pathways (e.g. opiates, alcohol, amphetamines, caffeine and nicotine). Consequently, we proposed that addiction reflects a state of epigenetic adaptation to the sustained presence of drugs which potently interfere with the relationship between antioxidant status and methylation. In other words, addictive drugs hijack the molecular mechanisms that provide for attention, learning and memory, allowing drug exposures to induce neurochemical changes in gene expression that substitute for normal experience. The current “opiate epidemic” emphasizes the importance of exploring the molecular mechanisms of addiction for the purpose of identifying more effective treatments.
TOPIC: Nutritional interventions
PROJECT: Clinical assessment of nutraceutical and nutrition-based interventions to augment brain redox and methylation status.
Recognition of the critical role of antioxidant and methylation status in autism and other brain disorders opens the way to treating and/or preventing these conditions with metabolic interventions, including nutritional supplements. Building upon insights gained from our previous studies, we have initiated development of novel nutraceuticals specifically designed to augment brain levels of vitamin B12. In addition, we have established commercial collaborations to evaluate the efficacy of nutrition-based products to improve redox and methylation status in the brain.