A review published last week confirmed that there is clearer evidence to support a role for folate and other B vitamins in slowing the progression of cognitive decline and possibly reducing the risk of depression in ageing. People with low B vitamin status are likely to benefit the most from increasing levels of certain B vitamins.
B vitamins are needed in the brain for energy production, methylation and homocysteine reduction. Raised homocysteine is a strong independent risk factor for dementia and in observation studies, patients with Alzheimer’s had higher serum concentrations of homocysteine. In this week’s blog, we discuss the amino acid homocysteine, its role in the body and causes and consequences of high levels.
What is Homocysteine?
Homocysteine is a naturally occurring amino acid produced as part of the body’s methylation process; levels are an important indicator of methylation status. Thus, homocysteine is not obtained from the diet – its role is to serve as an intermediate in methionine metabolism. Methionine is an essential amino acid that is obtained from the diet, especially from animal foods.
Homocysteine itself is located at a branch-point of metabolic pathways, where it is either irreversibly degraded via the trans-sulfuration pathway to cysteine (which is then synthesised into a number of other products including the important antioxidant glutathione) or it is remethylated back to methionine.
The Methylation Cycle & Methionine Metabolism
The methylation cycle is one of the body’s most important chemical processes – methylation reactions occur more than a billion times per second. It is a vital metabolic process that occurs in every cell in the body and in many pathways – it is used to switch genes on and turn genes off; for synthesis and metabolism of neurotransmitters, DNA/RNA, hormones, cell membrane structures, immune cells; and for neurological development and lack of methylation can cause irreversible neurological damage such as that seen with folate and/or B12 deficiency. So poor methylation has the potential to affect every bodily system and lead to a wide variety of symptoms and conditions including poor brain health.
Methylation involves the donation of a methyl group to a substance. A methyl group is a chemical fragment consisting of one carbon and three hydrogen atoms (CH3).
The main intermediates or chemicals involved in the methylation cycle include methionine, S-adenosylmethionine (SAM or SAMe), S-adenosylhomocysteine (SAH) and homocysteine. The purpose of the cycle being to produce SAMe, the universal methyl donor.
Homocysteine is produced as a consequence of this cycle and is regenerated back to methionine, with the help of Vitamin B12 (specifically the methyl version of Vitamin B12, methylcobalamin) and 5-methyltetrahydrofolate (or L-methylfolate, which is produced in the folate cycle). The main steps are:
Step I: This involves the conversion of methionine to SAMe. SAMe is the primary source of methyl groups for most other biochemical reactions including methylation of DNA, RNA, proteins, creatine etc. Studies have shown that it influences brain chemicals by helping to convert noradrenaline to adrenaline and serotonin to melatonin. Lack of SAMe is linked to nerve damage, depression, cognitive decline, and dementia.
Step II: SAMe, once it donates its methyl group to various reactions, gets converted to SAH.
Step III: SAH in turn is metabolised to homocysteine by the enzyme S-adenosylhomocysteinehydrogenase (SAHH). This reaction also generates a chemical called adenosine.
Step IV: Homocysteine can then be metabolised in 3 ways.
a) Trans-sulfuration Pathway: This pathway involves the irreversible conversion of homocysteine into cystathione in the presence of vitamin B6 as cofactor. Cystathione is in turn converted to cysteine. Other important downstream products of this pathway include glutathione and taurine.
b) Regenerated to methionine. This process is mediated by the enzyme methionine synthase with the aid of methylcobalamin (Vitamin B12 that has a methyl group as part of its structure). Essentially cobalamin accepts a methyl group from 5-methyltetrahydrofolate (which is produced in the folate cycle) and becomes methylcobalamin. Methylcobalamin in turn donates the methyl group to homocysteine and this converts homocysteine back to methionine. Effectively, homocysteine is being re-methylated to methionine.
c) Finally, there is another reaction that can convert homocysteine into methionine. The enzyme involved here is the zinc dependent betainehomocysteinemethyltransferase (BHMT). This pathway does not involve B12 or folate. Methionine is regenerated from homocysteine by the transfer of a methyl group from betaine (TMG or trimethylglycine) to homocysteine. In the process TMG is converted to dimethylglycine (DMG).
Causes and Consequences of High Homocysteine
As noted above, the complex metabolism of homocysteine within the body is highly dependent on vitamin derived cofactors, and deficiencies in vitamin B12, folate (folic acid) and vitamin B6 may be associated with raised homocysteine levels. Blood levels of homocysteine tend to be highest in people who eat a large amount of animal protein and consume very little leafy green vegetables and fruits, which provide the folate and other B vitamins that help the body recycle homocysteine.
Certain drugs such as methotrexate and anticonvulsants, can also cause high homocysteine and elevations can also occur in illnesses such as chronic kidney disease or hypothyroidism.
Other factors which are known to raise levels are sedentary lifestyle, stress, smoking, excess coffee, alcohol, heavy metals, or certain genetic methylation cycle mutations, for example mutations on the well-known gene MTHFR (which codes for the enzyme involved in the final stage of the folic acid cycle, producing 5-methyltetrahydrofolate).
Elevated levels of blood homocysteine are being recognised as a risk factor for a number of diseases and conditions such as cardiovascular disease, dementia (including Alzheimer’s), declining memory, poor concentration and judgement, fatigue, migraines and lowered mood. In addition, women with high homocysteine levels find it harder to conceive and are at risk from repeated early miscarriage. Conditions such as diabetes and osteoporosis may also be associated with raised homocysteine levels.
In the brain, raised homocysteine is associated with increased oxidative stress and inflammation, white matter damage, brain atrophy and neurofibrillary tau tangles.
Results from a study in 2013 showed that B-vitamin supplementation slowed the atrophy of specific brain regions that are a key component of the Alzheimer’s disease process and that are associated with cognitive decline. They recommended that further B-vitamin supplementation trials focussing on elderly subjects with high homocysteine levels are warranted to see if progression to dementia can be prevented.
Other research has determined that supplementation with homocysteine-lowering B vitamins can slow the rate of brain atrophy in elderly with mild cognitive impairment.
Some studies have not shown such positive results viz using B vitamins to lower homocysteine, but a review last year suggests that this is because most homocysteine-lowering trials, with folate and vitamins B6 and/or B12 (tested as protective agents against cognitive decline), were poorly designed.
As discussed in (c) above, a parallel pathway exists for regeneration of homocysteine to methionine, in which choline, by way of betaine, is the methyl donor. A study carried out in 2005 confirmed that choline deficiency may also result in decreased methylation capacity.
Diet and Homocysteine
Eating a high protein diet increases our need for homocysteine-neutralising nutrients like vitamins B6, B12, folate, and choline.
Conversely, increased levels of these vitamins in the blood stream result in a reduction of homocysteine levels.
Elevated levels of homocysteine are commonly caused when insufficient levels of ‘methyl group’ foods are consumed.
Foods to Limit/Avoid
- Too many animal products, especially conventionally raised meats.
- Processed meat
- Caffeine – no more that 2-3 cups a day
Foods to recommend
- Folate-rich – dark leafy greens, asparagus, broccoli, liver, beans, chickpeas, lentils
- Betaine-rich foods such as quinoa, beetroot (not in vinegar!), spinach, turkey, rye
- Vitamin B12 – beef liver, sardines, grass-fed beef, cottage cheese, lamb, eggs, salmon
- Vitamin B6 – turkey breast, grass-fed beef, pistachio nuts, pinto beans, avocado, chicken breast, sunflower seeds, sesame seeds
Something else to consider is the health of your digestive tract. This is crucial when it comes to levels of B12 and other B vitamins both because malabsorption can lead to low levels and because the gut is actually able to produce some B vitamins. You may also want to consider consuming probiotic-rich foods to increase your levels of vitamin B12.
Other factors to consider in lowering homocysteine
‘Methylation blocks’ which can hinder the methionine cycle should also be identified and removed. These include high levels of stress and other factors which may deplete B vitamins (see also our recent blog on B12), high oxidative stress/ inflammation; certain medications; environmental toxicity (heavy metals can block enzymes); and acetaldehyde – a product from the breakdown of alcohol (it is also produced by Candida).
If you have any questions regarding the topics that have been raised, or any other health matters please do contact me (Clare) by phone or email at any time.
firstname.lastname@example.org, 01684 310099
The Cytoplan editorial team: Clare Daley, Jackie Tarling and Joseph Forsyth.
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