The roles of B vitamins in brain health
Nutrition plays a fundamental role in supporting the structural and functional development of the human brain from conception, throughout early infancy, and extending into later life.
Until now, recommendations for adequate nutrition could only be generalized, or at best specialized for target groups like children, sportsmen and -women or the elderly. In contrast, personalized nutrition aims to define dietary recommendations and possibly appropriate products for each individual based on their genetic and physiological characteristics. These recommendations would be designed to maintain health and avert the disease risks to which that individual might be predisposed. Micronutrients are involved in specific biochemical processes at all points in the metabolic process and play an important role in regulating health and in the onset of diseases. New analytical techniques make it possible to examine and describe the influence of micronutrients in health-preserving processes. This is usually done by analyzing a combination of biomarkers so as to provide the individual with a tailored micronutrient intake recommendation.
Several different molecular-diagnostic methods are used to uncover the complex interactions between hereditary disposition and nutrition as are the disciplines of nutrigenetics and nutrigenomics. These use a broad spectrum of methods to comprehensively describe individuals at the level of their genome and their metabolic status and attempt to establish causal relationships between genotype and phenotype. Data collected in this way primarily delivers biomarkers for the assessment of health status and/or disease risks. Once a specific genetic predisposition has been detected, biomarker analysis should provide the information needed to recommend a suitably adjusted diet. Alternatively, it should be possible to establish whether targeted consumption of micronutrients as dietary supplements is necessary and worthwhile as a preventive measure for a person with relevant family susceptibility.
Nutrigenetics analyzes genome variance. It defines the genetic heterogeneity of the human species and describes variants (polymorphisms) in metabolically relevant genes that can be associated with risks for specific diseases linked to nutrition. SNPs (single nucleotide polymorphisms) are “successful” point mutations that have survived in the genetic pool of a population. Variants of a nucleotide sequence on one and the same chromosome in the genome of a diploid individual are known as halotypes. Cells of the buccal mucosa or circulating blood cells are usually genotyped to identify SNPs. At present, DNA chips with molecular-biological detection systems are available which can identify up to 10 million SNPs simultaneously, but increasingly still more powerful sequencing techniques and equipment are being developed. These are needed to achieve the high throughput rates required. In genome-wide association studies, biomedical and epidemiological research is attempting to uncover genetic variants that lead to an increased risk of diseases like obesity, type 2 diabetes, hypertension, atherosclerosis or tumors (1). A number of candidate genes with SNPs have now been found for adiposity (2). For type 2 diabetes, around 40 candidate genes have also been identified that, based on their known or putative biological function, show significant linkage to the beta cell as the site of insulin secretion (3). Taken alone, each of these candidate genes increases the risk of disease by just a few percent, but when the detected variants of this gene occur en masse in an individual they can be fairly reliably linked to fasting blood sugar levels, for instance. Another well characterized example is genetic variants that lead to a loss of lactase activity in the intestine and are thus implicated in lactose intolerance (4).
SNPs have been extensively mapped and their significance characterized for vitamin metabolism, too. High blood levels of the amino acid homocysteine (hyperhomocysteinemia) are considered a risk factor for several diseases. Hyperhomocysteinemia (homocysteine levels above 100 micromol/L) can be caused by reduced breakdown of homocysteine due to a dietary deficiency of folate, vitamin B6 and vitamin B12, but it can also be caused by genetically determined enzyme defects. In the latter instance a genetic variation in the gene for the enzyme methylenetetrahydrofolate reductase (MTHFR), which plays an important part in the conversion of homocysteine to methionine, is present. This MTHFR mutation, which is associated with reduced enzymatic activity, is thought to be the most common cause of abnormally high homocysteine levels. An association between MTHFR gene mutation and folate deficiency and an increased risk for the incidence of cardiovascular diseases, diverse carcinomas and dementia has been demonstrated in many studies (5). At present, determination of the MTHFR genotype is recommended only for patients with plasma homocysteine concentrations over 50 micromol/L. The genetic defect itself, which is found in around 10% of the population, is not treatable, but targeted consumption of folate, vitamin B6 and vitamin B12 can help lower elevated homocysteine concentrations in the blood.
Apolipoproteins facilitate the transport and cellular uptake of lipids. Apolipoprotein E (apoE), a ligand for the LDL receptor, is produced primarily in the liver. It regulates the degradation of triglyceride and cholesterol -rich lipoproteins. Three variants of the gene for apoE exist (apoE2, apoE3, apoE4). These differ in respect of their binding affinity to the LDL receptor. Studies have shown that apoE4 is associated with an increased risk of developing cardiovascular and Alzheimer’s disease (6). In Alzheimer’s patients the apoE4 variant is about four times more common than in control groups. Moreover, carriers of the apoE4 gene appear to have a limited ability to store vitamin E in peripheral tissue. The genetically determined significantly lower vitamin E tissue levels could be compensated by increasing the intake of this nutrient.
Vitamin A is existentially important for normal growth and development, the immune system, vision and other functions of the human body. Since the human body cannot synthesize vitamin A for itself, it has to ingest pre-formed vitamin A or provitamin A carotenoids (especially beta-carotene) from the diet. Provitamin A carotenoids are immediately converted to vitamin A in the human organism by the enzyme beta-carotene 15,15’-monoxygenase (BCMO1) (7). Recent research has shown that two frequently occurring polymorphisms (SNPs) within the BCMO1 coding gene sequence reduce the catalytic activity of the enzyme by as much as 59% (8). Research results indicated that around 45% of all Europeans show one of these genetic mutations. The genetic variations could therefore contribute to a significant restriction in the utilization of beta-carotene and hence make higher intakes of this carotenoid necessary for a sufficient provision of vitamin A to the body.
In contrast to nutrigenetics, nutrigenomics deals with gene products, i.e., blood levels of messenger RNA (mRNA – carries the code for synthesis of a specific protein), proteins and metabolites (intermediate stages in metabolic processes). Its methodology includes all molecular levels, from control of gene expression to metabolic events in the whole organism (9). Whilst transcriptomatics analyzes mRNA levels for all or selected genes, proteomics examines proteins as a whole and metabolomics determines and quantifies metabolites of very diverse substance classes in the metabolic pathways. Hence the “omics” allow us to draw up molecular profiles that are typical for each individual and their current metabolic status. Extensive studies thus generate profiles for people with specific medical conditions in order to identify characteristic differences as compared with healthy people. Nutrition studies use the same methods to detect profile changes after consumption of specific nutrients and/or specific dietary regimes. If characteristic biomarkers in the profile can be linked to specific diseases, conversely their occurrence can be viewed as an indication of disease risk. This facilitates predictions based on statistical probabilities, although it does not represent a link between cause and effect, but only identifies statistically reliable associations or correlations between the occurrence of a marker and a metabolic condition; the physiological function of the marker still has to be determined.
Studies into the activities of selected food ingredients on the full complement of genes transcribed at a specific time (transcriptome) in cells or organs (especially in cell cultures or model organisms) can detect many effects. Targeted intake of omega-3 fatty acids was found to lead to reduced expression of genes involved in inflammatory processes and processes contributing to atherosclerosis (10). Other research provided evidence of a positive influence of folic acid on gene expression in patients with type 1 diabetes and of vitamin E on patients with prostate cancer. Changes in the transcriptome were also investigated in tissue biopsies or circulating blood cells from healthy persons and overweight patients or metabolic syndrome. Although there are great inter-individual differences in the transcriptome, within an individual there is little variation. This means that the transcriptome is especially suitable for studying individual food-induced effects and disease-specific changes.
Analyses of the full complement of proteins present in cells and tissues at a specific point in time (the proteome) are still in the pilot study phase. Their goal is usually to understand the physiological response of single food components in healthy persons or to find new biomarkers for specific pathological metabolic conditions (10). They are already being used in clinical diagnosis, especially the diagnosis of tumors (11). Concomitant analysis of a large number of different proteins in proteomics places great demands on the resolution and sensitivity of the applied methodology. Currently, almost 2500 individual gene products and 4900 protein units have been identified in blood plasma (12). These include 360 classic plasma proteins – i.e., primarily those originating in the liver – and around 350 proteins related to the circulatory system. As cytokines or adhesion molecules, over 100 of the detectable proteins and peptides are closely linked to inflammatory processes.
Metabolite-profiling analyses identify and quantify nutrients and metabolites such as organic acids, lipids and carbohydrates in a biological sample. The chemical heterogeneity of these substances makes the analytical procedure highly complex. Further, it is not known how many of these metabolites exist. There are thought to be around 10,000 substances which are produced in the body (endogenous substances) and another 100 to 1000 times more substances that are consumed in the diet (exogenous substances). The human metabolome (the full complement of metabolites) would therefore be ten times bigger than the human genome, with around 23,000 genes, or the human proteome with its estimated 100,000 proteins. Metabolome samples are often prepared from blood plasma or urine, although other bodily fluids like saliva and tears can also be used. The information value of different fluids varies greatly and they have other advantages and disadvantages. In blood plasma, for example, substances biosynthesized in the body or produced in the process of metabolism have a much greater effect on the pattern than exogenous substances ingested in the diet.
The biological data collected in nutrigenetics and nutrigenomics therefore primarily deliver signatures and biomarkers intended to enable the assessment of health or disease risks. If a person is known to have a particular genetic predisposition and their biomarkers are analyzed it should be possible to recommend a diet tailored to their needs or, in the case of a person with relevant family susceptibilities, it might be possible to establish whether changing their diet as a preventive measure is necessary and useful. Further, the success of dietetic measures or lifestyle interventions could be constantly monitored via nutrigenomic profiling. A careful assessment leading to a personalized recommendation would have to include the conventional physical parameters such as height, weight and waist measurement, as well as vital bodily functions like blood pressure and blood glucose, cholesterol and hormones. It would also have to include measurement of personal fitness and the influence of any medication being taken. Evaluation of all these data would make it possible to generate particular metabolic scenarios and estimations of risks, which could then be translated into personalized dietary recommendations. Nutritional consultants could formulate recommendations on the consumption of specific foodstuffs, offer on-line personal purchasing support, recipes and instructions on proper food preparation, all taking into account the individual’s personal preferences and habits.
Personalized micronutrient supply
In principle, recommendations by nutrition experts to eat a balanced diet with for instance five portions of fruit and vegetables a day are perfectly correct, but they are very general and not always easy to adhere to in daily life. Several nutrition surveys have shown, for example, that it is always a minority of people surveyed who consume the recommended amount of fruit and vegetables daily. But a sufficient supply of micronutrients, which are involved in almost all metabolic processes, is essential to maintain a balance between optimal health and the premature occurrence of nutrition-dependent diseases (13). Even a slight deficiency, an imbalance or chronic excess of a micronutrient can give rise to a functional decline which may be directly related to health problems. Moreover, environmental stresses, medications, general stress and genetic factors can all significantly increase the individual requirements for micronutrients. Additionally, in 30% of over-70s intestinal absorption is reduced and dietary habits change, which can lead to a manifest deficiency profile (14). However, as yet the relevant professional organizations have published reference values only for the vitamin and mineral intakes of healthy people and for prevention of deficiency diseases caused by lack of specific nutrients. Requirements for vitamins and minerals to achieve optimal metabolic activity and concentrations adequate for disease prevention are much more individual than previously thought. For this reason, advice on targeted micronutrient requirements should not rely solely on generalized recommendations for healthy persons, but should be guided by the individual requirements in specific life situations (sickness, old age, medication). Individual predispositions and differences in lifestyle should lead to differentiated nutritional recommendations (15).
New analytical techniques make it possible to investigate and describe the influence of micronutrients on health-maintaining processes. Usually a combination of markers is analyzed with the objective of providing a personalized recommendation for micronutrient intake. This not only examines known markers for nutritional status, like blood levels of the micronutrients themselves, but includes the functioning of metabolic pathways that are micronutrient-dependent, or markers that indicate health status in terms of micronutrients. Biomarkers are measurable laboratory values determined from blood samples and other bodily fluids or cell components. Markers that indicate pathological processes can be drawn on too. Importantly, the primary focus is no longer on the measurement of blood concentrations of one micronutrient, which only ever allows a statistical interpretation. Instead, the effects of that micronutrient on health and on health-preserving processes, which differ in each individual, are examined.
Overall micronutrient requirements can now be determined using a number of established biomarkers. Compared to the measurement of single micronutrients, this has the added advantage that biomarkers can directly indicate bioavailability and effect on risk factors, as well as nutritional status. Hence elevated homocysteine levels (an independent risk factor for cardiovascular diseases and Alzheimer’s disease) correlate with low plasma status for vitamin B6, vitamin B12 and folic acid (16, 17). Dietary supplementation with these B vitamins leads to a dose-dependent drop in homocysteine levels which is related to genotype. Biomarkers for increased oxidative stress and its related diseases include hydroperoxide (HPO), a lipid peroxidation metabolite, and the enzymes glutathione peroxidase (GPx) and superoxide dismutase (SOD) (18, 19). The activity of these substances depends in turn on intakes of selenium (GPx) and zinc, manganese and copper (SOD). High-sensitivity C-reactive protein (hs-CRP) and oxidized LDL (ox- LDL) are today considered to be reliable independent predicators of atherosclerosis and cardiovascular risk (20, 21). Many of these markers can be determined by rapid testing at a pharmacy using capillary blood.
The data collected through analysis can then be integrated into a system that is capable of preparing personalized, tailored micronutrient intake recommendations. Today, “personalized supplementation” is already commercially available. This recommends, for instance, supplementation with “personalized” vitamin mixtures based on genotyping. To date no studies to provide prospective evidence of a preventive or therapeutic effect of dietary recommendations for people with similar genetic risk profiles have been conducted. Statistical risks that have been calculated retrospectively from large trial groups cannot be directly applied to individuals. Studies to substantiate these new methodological approaches are complex and expensive, requiring large numbers of participants and long periods of observation, as well as adequate biomarkers.
Nutrition plays a fundamental role in supporting the structural and functional development of the human brain from conception, throughout early infancy, and extending into later life.