Homocysteine is an intermediate compound produced when methionine is metabolized in the liver to obtain cysteine. This process depends on adequate levels of Vitamins B6, B9, and B12.

Increased plasma homocysteine is linked to an increase in total and cardiovascular mortality; it presents as inflammation, promoting clot formation and endothelial cell alteration, with a risk of cardiovascular pathologies, arteriosclerosis, and neurological diseases.

Almost two-thirds of the prevalence of high homocysteine is attributable to a low status or intake of vitamins B6, B9, and B12, which participate in the methionine methylation process. Smoking, low-protein diets, certain pathologies, and other lifestyle factors also play a role.

The "problem" of high homocysteine levels emerged in early studies due to the observation that increased fasting plasma levels of this amino acid were an independent predictor of cardiovascular disease as well as loss of cognitive function, including dementia and Alzheimer's.

The mechanisms by which homocysteine is postulated to have these detrimental effects on brain function include increased oxidative stress, inhibition of methylation reactions, increased DNA damage and dysregulation of its repair, and direct and indirect neurotoxicity leading to cell death and apoptosis. It is suggested that these processes lead to general effects such as brain tissue atrophy and impairment of cerebrovascular circulation.

There are 3 enzymes that play a fundamental role in the balance of methionine and homocysteine. These are: methylenetetrahydrofolate reductase (MTHFR), methionine synthase (MTR), and methionine synthase reductase (MTRR); furthermore, they participate in the regulation of folate or vitamin B9 metabolism.

Genetic variations in these enzymes affect the biochemistry of vitamins and physiological processes in our body. For this reason, they have been associated with various diseases, including cardiovascular diseases, certain types of cancer, inflammatory conditions, diabetes, and vascular disorders.

It is believed that genetic variation of MTHFR is the most common cause of elevated homocysteine levels, which, as we have already reviewed, is considered an independent risk factor for cardiovascular disease.

This MTHFR gene mutation is more common than people think and therefore translates into a higher risk of B vitamin deficiency, especially Cobalamin and Folate.

People who present with this polymorphism or genetic variation also have impaired conversion of B vitamins into their active form, that is, a form in which they can be absorbed and used by the body; this is why they can have a deficiency even while following an adequate diet and supplementation.

It is a vital process for cellular function, which consists of the addition of a small chemical group called a methyl group (composed of one carbon atom and three hydrogen atoms, CH3) to various molecules, such as DNA, proteins, and other substances. They are like molecular switches that, when attached to a molecule, can turn it on, turn it off, or modify its function.

Methylation helps regulate gene expression, which means it maintains the proper functioning of all the cells in our body. It suppresses the expression of harmful DNA fragments that have infiltrated human DNA over time, such as endogenous retroviruses and mutations.

In humans, between 60% and 90% of DNA needs to be methylated.

Methylation is a key pathway in the body's detoxification processes, especially in the liver. It is also crucial for the production and recycling of glutathione, the body's main antioxidant, which protects cells from damage.

Genetic variations of MTHFR prevent the addition of methyl groups to B vitamins; for this reason, the incorporation of vitamins through diet or even supplementation is inefficient, as they require a long process to be bioavailable if they are not previously "methylated".

For example, folates from food or supplements must be activated by the MTHFR enzyme to convert from folate to "Methyl Folate"; in this way, this vitamin manages to reach the cells and cross the blood-brain barrier. The same happens with cobalamin, which must be activated to "Methyl Cobalamin".

In addition to genetic variations, stress, metabolic alterations, or digestive problems, among others, also play a role. That is why our recommendation is that you always choose vitamins in their active form, ready to act and be absorbed.

Although genetics cannot be changed, it can be compensated for by taking an already methylated supplement, such as methylfolate or methylcobalamin.

1. Non-methylated vitamins: These are the most common forms found in many supplements and fortified foods. For the body to be able to use them, they must first go through a biochemical conversion process. This process, which often involves methylation (the addition of a methyl group), transforms them into their active or "coenzymated" form. If this conversion process is not efficient, the body cannot utilize the vitamin optimally.
2. Methylated vitamins: These vitamins are already in their active, biologically available form. That is, they already have that methyl group incorporated into their structure. This means the body can use them directly, without needing to go through the conversion step. This is especially crucial for people whose bodies might have difficulty efficiently methylating vitamins due to genetic factors (such as variations in the MTHFR gene mentioned earlier), nutrient deficiencies, or oxidative stress.

They are fundamental nutrients for the proper functioning of our body; however, we do not produce them, so we must incorporate them through diet and/or supplementation.

Vitamins can be classified by their role, similarity in chemical structure, or by the interrelated functions they perform, but in general, they are grouped according to their solubility. In this way, we have fat-soluble vitamins called liposoluble (vitamins A, D, E, K) and water-soluble vitamins, which, as their name indicates, are soluble in water (vitamin C and B-complex).

Known as Thiamine (B1), Riboflavin (B2), Niacin (B3), Pantothenic acid (B5), Pyridoxine (B6), Folate (B9), and Cobalamin (B12). Their functions as a group or complex are essential in numerous aspects of brain function, including energy production, DNA/RNA synthesis and/or repair, genomic and non-genomic methylation, and the creation of numerous neurochemicals and signaling molecules.

This vitamin complex is produced by plants, where they perform the same cellular functions that they perform in our body or in other animals. The exception to the rule is Cobalamin or Vitamin B12, which is manufactured by microbiota bacteria in some quantity and is commonly obtained by our body from foods of animal origin. In the case of vegetarians, vegans, or even omnivores with a low consumption of animal-based foods, it is not possible to reliably determine how much B12 their microbiota produces; therefore, obtaining vitamin B12 is recommended through supplements, preferably methylated.

Our inability to synthesize B vitamins is due to the loss of one or more of the necessary genes that express the enzymes required for the synthesis of these vitamins, especially vitamins B6 and B9. As an alternative, our body adapted to integrate them externally through the diet.

• Enzymatic function: Among its functions, we can highlight the coenzyme role that this vitamin group carries out, in a significant proportion and of vital importance for several physiological processes at the cellular level. In general, the large number of functions that B vitamins perform can be subdivided into their functions in catabolic metabolism, which leads to energy generation, and anabolic metabolism, which results in the construction and transformation of bioactive molecules.

• Brain health: The brain is by far the most metabolically active organ in our body; although it represents only 2% of total body weight, it is responsible for more than 20% of total energy expenditure. This explains why the general metabolic functions of B vitamins, along with their roles in neurochemical synthesis, have such a significant impact on brain function. B vitamins can cross the blood-brain barrier and/or the choroid plexus, and once they are in the brain tissues, specific cellular uptake mechanisms are created that establish the distribution of the vitamins. Even though all B vitamins are present in high concentrations, their levels are closely regulated by multiple homeostatic mechanisms in the brain. This ensures that there are much higher concentrations of vitamins in the brain versus the concentrations observed in blood plasma. The relevance of all B vitamins for brain function is demonstrated by the neurological and psychiatric symptoms commonly associated with a deficiency of any of the vitamins in this complex.

• Development and prevention of neural tube defects: Vitamin B9 or Folate is crucial for the formation of new cells and DNA; its most well-known role is to prevent serious birth defects such as spina bifida or anencephaly. It is especially important before and during pregnancy for the proper development of the neural tube in the developing embryo.

These are mainly neurological; for example, vitamin B6 deficiency can manifest as depression, cognitive impairment, dementia, and autonomic dysfunction. In the case of vitamin B12 deficiency, it can manifest neurological symptoms as well as anemia (there is a specific anemia called megaloblastic anemia, which, unlike iron-deficiency anemia, is not due to a lack of iron, but rather B12). However, it generally manifests as neurological symptoms before the appearance of hematological changes. Studies show that while approximately one-third of people suffering from vitamin B9 or vitamin B12 deficiency present only with anemia, a similar proportion presents only with neuropsychiatric symptoms. In fact, it has been found that more than one-third of psychiatric patient admissions suffer from folate (B9) or cobalamin (B12) deficiencies.

As we have seen, vitamin B12 deficiency can not only be associated with fatigue or low energy but can also manifest as megaloblastic anemia and, in many cases, appear first with neurological symptoms before hematological ones. For this reason, ensuring effective and bioavailable supplementation is fundamental.

At Ortomolecular, we offer Liposomal Vitamin B12 with D-Ribose in its active form of methylcobalamin, which allows for better absorption and direct action in the body. Thanks to its liposomal technology, it promotes the delivery of the vitamin at the cellular level, supporting cognitive, cardiovascular, and metabolic health.

B-complex vitamins participate in a series of vital functions, most notably pyridoxine (B6), folate (B9), and cobalamin or methylcobalamin (B12), as they are cofactors necessary for the synthesis of various cerebral and metabolic functions.

A decrease in the levels of these vitamins is associated with elevated homocysteine levels, and consequently a greater risk of cognitive impairment, cardiovascular issues, and depression.

Genetic variations or polymorphisms highlight the need to incorporate these vitamins in their active or methylated form to prevent risks and deficiencies.

To conclude this article, we summarize the most important points regarding the relationship between homocysteine, methylation, and the importance of choosing methylated B-complex vitamins.

• High homocysteine is a risk factor for cardiovascular, neurological, and metabolic health.

• Deficiency of vitamins B6, B9, and B12, along with genetic factors such as the MTHFR mutation, hinders their regulation.

• Methylation is key for proper cellular functioning, DNA protection, and detoxification.

• Methylated vitamins, being in their active form, offer better absorption and efficacy, even in people with genetic variations.

• Supplementing with methylated B-complex is a safe and effective strategy to maintain health and prevent deficiencies.

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Javier Colomer, Todo lo que necesitas saber sobre las vitaminas metiladas. https://www.hsnstore.com/blog/nutricion/vitaminas/metiladas/?srsltid=AfmBOorksZYrFMtxIbUyERUSaa9SQoV_e0sOFA4RDG17sX-tkX0gLjj5