Homocysteine, a sulphur containing compound within the methionine cycle, is explored here in this comprehensive review conducted by Tracey-Anne Hipkiss, MSc.
Introduction
The purpose of this review is to consider correlations between homocysteine and disease risk that have been identified by other researchers, including risk factors for elevation of homocysteine concentration in blood (hyperhomocysteinemia). The aim of this work is to identify dietary components that may support maintenance of a healthy homocysteine concentration in the body. This study is important because hyperhomocysteinemia has been identified as a potential marker for a variety of neurovascular and psychological conditions across lifespan.
There are many questions yet to be answered regarding the role of diet in relation to homocysteine and the role of homocysteine in health and disease. Nevertheless, learning about how dietary adjustment may have an effect on homocysteinemia for an individual is noteworthy because research suggests that homocysteine is linked to many diverse cellular mechanisms such as glutamate receptor neurotoxicity (Deep et al, 2019); N-methyl-D aspartate (NMDA) receptor agonist exerting a neurotoxic effect on dopaminergic neurons (Bhatia and Singh, 2015); reduction of microcirculation in the brain (Hassan et al, 2004); and increasing oxidative stress by stimulating NADPH oxidase (Alber et al., 2021).
Undoubtedly, the importance of homocysteine as a biological marker in health and disease is due to its significant position at the intersection of two distinct pathways: Firstly, the remethylation of homocysteine as part of the methionine cycle which is essential for methionine availability; Secondly, the transsulfuration pathway that utilises homocysteine to provide the body with cysteine.
To help with explanations, a brief summary of the methionine cycle, transsulfuration pathway, and connections to the folate cycle and Betaine (GB) pathway is provided in the next paragraph, and a schematic representation in figure 1.
Methionine forms S-adenosyl-methionine (SAM) following activation by ATP, SAM serves as a key donor of methyl groups for cells and S-adenosyl-homocysteine (SAH) is formed when SAM is demethylated. SAH is converted to homocysteine and adenosine via hydrolysis. In the transulfation pathway, homocysteine is condensed in the presence of enzyme cystathione β-synthase (CBS) with serine and a vitamin B6 cofactor to form cystathionine, which then may be converted to cysteine via enzyme cystathione 𝝲-lyase (CSE) and cofactor vitamin B6 or converted back to homocysteine via enzyme cystathione β-lyase (CBL). The transsulfuration pathway is irreversible from cysteine and is reported to only occur in instances when levels of methionine are biologically dispensable but is also regulated by the availability of CSE and a biological need for cysteine (Homocysteine metabolism is reviewed in depth by Azzini et al, 2020). The folate cycle provides methyl groups for the subsequent remethylation of homocysteine to methionine. Folic acid enters the cycle as tetrahydrofolate whereas dietary derived folate enters the cycle as 5-methyl tetrahydrofolate. There is an alternative methyl-donation process involving Glycine Betaine (GB) in conjunction with the zinc requiring enzyme Betaine-homocysteine S-methyltransferase (BHMT).
As suggested above and in figure 1, the methionine cycle and the transsulfuration pathway influence homocysteine concentration and for this reason they are important research targets: The formation of methionine from homocysteine is essential to reduce the risk of homocysteine toxicity, conserve methionine as a substrate for protein synthesis, and produce a principle methylating agent in the form of SAM; Meanwhile, the transsulfuration pathway is based on demand for cysteine and its products (Coenzyme A, hydrogen sulphide, cystine, glutathione (GSH) and the selenoproteins) rather than a route for the disposal of methionine and homocysteine.
The normal function of the methionine cycle and adjoining pathways are collectively dependent on many factors, not least the regular provision of dietary components such as: protein; folate; vitamins B2, B6 and B12; zinc; choline and/or betaine. With this in mind, dietary and lifestyle adjustments have the potential to aid regulation of homocysteine in humans.
Figure 1
Homocysteine and brain health: Implications for preconception / Intrauterine
Periconception & Neonatal Brain Development
A study of 256 Dutch children aged between 6 and 8 years old reports that higher than normal maternal prenatal homocysteine level (>9.1 μmol/L) may predict poorer visuospatial and language development in children when measured at age between 6 and 8 years old (Ars et al, 2019). However, there is no evidence that maternal homocysteine is a causative factor in neonatal brain development but measurement of maternal homocysteine concentration may provide an insight into the efficiency of the methionine cycle and provision of methyl groups (one carbon metabolism) during pregnancy.
Excessive availability or deficiency of methyl groups, either periconceptional or during pregnancy, is biologically relevant in terms of genetic programming of the foetus but this area is currently under researched (McGee et al, 2018). Studies are required to ascertain if homocysteine is a useful biomarker to steer a personalised supplement intervention or dietary intervention for positive health outcomes for mother and child.
Down Syndrome (DS)
A small case-controlled study comparing 52 DS cases to 52 control cases noted that average maternal serum homocysteine concentration was slightly higher in mothers giving birth to children with DS but this difference was not statistically significant (Mohanty et al 2012).
Importantly, the availability of the enzyme cystathionine β-synthase (CBS) goes some way to regulating the methionine cycle (see figure 1). This is clearly demonstrated in people living with DS, where the overexpression of CBS is a genetic consequence that causes a significant reduction of serum homocysteine concentration leading to less available methionine within the methionine cycle. Overexpression of CBS also has the downstream effect of increasing cysteine availability and the potential for a functional folic acid deficiency known as ‘the folate trap’ in DS individuals (Pogribna et al, 2001).
Pre-natal alcohol exposure (PAE) and Fetal Alcohol Spectrum Disorders (FASD)
There are extensive reviews indicating that chronic or binge consumption of alcohol by pregnant women can significantly lower the availability of important micronutrients such as folate and choline at a time when the developing brain of the fetus is vulnerable to environmental changes (Ernst et al, 2022; Naik et al, 2022). There is a lack of available FASD human research that measures homocysteine.
Childhood & Adolescence
A cross sectional study of 483 children (male and female participants aged between 7-15 years) identified biological correlations with risk of raised serum homocysteine as follows: male; aged older than 12 years; high blood pressure; low HDL-c levels; high triglyceride levels; overweight; diet (low intake of dark green vegetables, whole grains, legumes and citrus fruit) (Farias Costa et al, cited in Azzini et al 2020).
Autism Spectrum Disorder (ASD)
Yektaş et al (2019) identified that the young people in their study living with ASD diagnosis have a tendency to low vitamin B12 status and high serum homocysteine when compared to aged-matched controls. Although this is an interesting correlation, the investigators state that their results do not suggest causality since the difference may be due to many factors such as the avoidance of specific foods in the ASD group. As reviewed in Azzini et al (2020), an intervention study by Sun et al demonstrated that supplementation of 800μg/day of folic acid improved autism symptoms and reduced homocysteine plasma levels. A study by Hamlin et al (2013) concluded that children living with ASD had low dietary intake of betaine and choline and this translated into significantly lower serum concentrations compared to age matched controls.
More studies are justified to investigate the relationship between homocysteine with important dietary factors and improvements to behavioural symptoms and health outcomes for individuals living with ASD.
Importantly, although folic acid supplementation is encouraged at specific windows of neural development for the developing foetus, there is a risk of over supplementation of folic acid and vitamin B12 by expectant mothers. As previously mentioned, the availability of methyl groups is important for genetic programming of the foetus.
A review by Murray et al (2018) highlights a potential connection between increased risk of ASD in offspring following over supplementation of folic acid and vitamin B12 in mothers. A positive association (increased risk) has been identified between maternal environmental arsenic exposure during pregnancy and offspring affected by ASD and ADHD (Skogheim et al, 2021). Clearly, this is an area of health that is deserving of closer scientific attention and better education directed at the general population about how to limit exposure to environmental toxins is essential. The potential relationship between heavy metal exposure and homocysteine is discussed later in this report.
Attention-Deficit/Hyperactivity Disorder (ADHD)
Studies investigating the role of homocysteine in ADHD aetiology have yielded different results. Altun et al. (2018) conducted a study that included 30 children with ADHD and 30 age and sex matched controls without ADHD. Results demonstrated that children with ADHD had lower serum levels of B6, B12 and folate, and also lower levels of homocysteine. The authors posited in this instance that low levels of homocysteine may be a risk factor for ADHD development in children. Importantly, low plasma levels of homocysteine will lead to a reduction in cysteine and a limited capacity of individuals to respond to oxidative stress.
A subsequent cross-sectional study by Yektaş et al. (2019) included 48 children diagnosed with ADHD and investigated homocysteine, folate and B12 status. In this sample, children with ADHD were observed to exhibit higher levels of homocysteine and lower levels of vitamin B12, compared with controls (without ADHD). Furthermore, a correlation was observed between homocysteine and B12 levels and hyperactivity. No significant results were observed with relation to serum folate levels in this study.
De la Torre-Turbe et al (2022) further investigated the role of homocysteine in mechanisms involved in ADHD in an animal study. In this study, Sprague-Dawley rats were administered with homocysteine neonatally from postnatal day 2 and then monitored until adulthood. Brain activity was assessed before puberty and then again at adulthood. Results indicated that limbic areas of the brain involved in attention, memory and learning were observed to exhibit changes similar to those seen in the brains of individuals affected by ADHD. Due to ethical reasons, it would be impossible to repeat this study in humans. However, further studies to measure homocysteine in relation to methylation capabilities and cysteine availability of children with a ADHD diagnosis would help to clarify this area.
Homocysteine and brain health: Implications for midlife and older adults
Menopause
Postmenopausal women are at risk of increased homocysteine levels. This may be due to alterations in oestrogen levels affecting methylation processes. Furthermore, risk of deficiencies of key nutrients that are essential cofactors, such as folate and B12, for methylation and conversion of homocysteine may increase in prevalence postmenopausally, in response to disruptions to oestrogen levels (Vasquez-Lorenete et al., 2022). In addition, low oestrogen status may reduce endogenous conversion of phosphatidycholine to choline (as reviewed by Derbyshire, 2019) suggesting that the menopause is a time when women experience a rapid change to the enzymatic control of endogenous choline production.
Cardiovascular disease & neurodegeneration
Homocysteine concentration in plasma has a tendency to rise with advancing age (Ganji and Kafai, 2006). Significantly elevated homocysteine has been observed in people suffering with cardiovascular disease, stroke, neurodegeneration (Nelson et al, 2016) and frailty in old age (Guaita et al, 2021) and elevated homocysteine is associated with a reduced blood flow to the small vessels in the brain (reduced microcirculation) (Hassan et al, 2004) which is an important connection because a reduced microcirculation may increase the risk of developing Alzheimer’s disease, amyotrophic lateral sclerosis (ALS) or Parkinson’s disease (Erdener and Dalkara, 2019). Homocysteine may therefore be a useful biomarker to identify people at a higher risk of developing Alzheimer’s or vascular dementia (Wang et al, 2021).
A study by Xiao et al (2013) clearly associated people aged between 40-85 years old following long-term diets high in animal proteins (a rich source of methionine) with a higher risk of hyperhomocysteinemia, the reverse being true for diets that include a high consumption of plant foods (Xiao et al, 2013). In line with these findings, a lower risk of stroke is associated with a dietary pattern that provides a good supply of dietary cysteine (Larsson et al, 2015) which may be easily satisfied by healthy and balanced plant based diets. Furthermore, folic acid (the pharmaceutical form of folate) has been shown to improve the function of the layer of cells lining the blood vessels (Antoniades et al, 2006). Any improvement of function to these cells will be beneficial for microcirculation in the ageing brain. There are numerous ongoing studies investigating protein metabolism in the hope that these studies may inform preventative medicine and dietary change guidance in the future to support healthy ageing.
Benefits of dietary folate sufficiency, to reducing cardiovascular risk and stroke, may be demonstrated by the accelerated decline in the numbers of cardiovascular risk and stroke victims in the population of United States and Canada following the fortification of folic acid to commonly consumed food in the US, compared to the statistics from the UK population (Yang et al, cited in Debreceni and Debreceni, 2011) where a requirement for folic acid fortification of white bread flour commenced from autumn 2021 (Department of Health and Social Care, 2021).
Depression
A twin study by Bremner et al (2021) suggested that individuals with higher serum levels of homocysteine exhibited increased self reported symptoms of depression, the study concluded that homocysteine may be correlated but not causative in the aetiology of depression.
Although elevated homocysteine has the potential to be neurotoxic to dopaminergic neurons which in turn may cause depressive symptoms (Bhatia and Singh, 2015) the overall effect of lowering homocysteine over the course of two years by supplementation with vitamin B12, folate and vitamin D3 was not seen to make a significant difference to the reduction of depressive symptoms in a randomised control trial with older adult participants (De Koning et al, 2016).
Risk Factors Across the Lifespan
Genetic Variations & genetic susceptibility
Nutrigenomics is an emerging area that considers genetic individuality with regards to nutrient requirements. Research has indicated that genetic variations to the T allele of the C677T MTHFR gene have been associated with increased risk of hyperhomocysteinemia. Further research in this area is of merit, to determine the impact and requirements for B vitamins and other nutrients that support methylation in individuals with this specific genetic polymorphism (Cirilo et al., 2021).
A study by Garcia-Minguillan et al (2014) suggests that optimisation of vitamin B2 may be an important strategy for lowering homocysteine in individuals that have the genetic polymorphism MTHFR 677C>T, dual optimisation of vitamin B2 and vitamin B12 may reduce homocysteine concentration for individuals with the genetic polymorphism MTRR 66A>G, and optimal vitamin B12 status may be especially important for individuals with MTRR 524C>T.
A polymorphism in the Arsenic (+3 oxidation state) MethylTransferase (AS3MT) gene is a strong determinant of arsenic methylation capacity and closely related to health conditions that are correlated to raised homocysteine, covered in reviews by Abuawad et al (2021) and Thomas (2021).
Coeliac disease and dietary restriction of gluten
Interestingly, a small study of 20 adults with newly diagnosed coeliac disease identified that most were hyperhomocysteinemic. Gluten abstinence for 6-8 months failed to improve this parameter (Marchi et al, 2013) but conflicting results on this topic are reported in a narrative review conducted by Kreutz et al (2020).
Any diet restriction requires careful consideration to ensure the appropriate supply of essential nutrients. There may be a higher risk of nutritional imbalance from regular consumption of products aimed at a gluten-free diet (Miranda et al, 2014) and avoidance of cereal products such as wheat will reduce the opportunity for dietary betaine; Eggs, beef, fish, chicken and nuts represent dietary sources of choline (Derbyshire, 2019), individuals on a gluten-free or vegan restricted diet may also wish to consider pseudocereals amaranth, buckwheat and quinoa as alternative dietary sources for betaine (Ross et al, 2014). Children who are post coeliac disease diagnosis and gluten-free diet compliant may be at risk of declining vitamin B6 levels and this should be monitored (McGrogan et al, 2021). A declining vitamin B6 status and a concurrent lower dietary intake of choline/betaine suggests a perfect storm leading to raised homocysteine and a higher inflammatory profile due in part to inadequate supply of methyl donors to the methionine cycle.
Caffeine & Catechins
Research indicates that folate status may correlate with serum homocysteine concentration. The catechin content of green tea may act to reduce circulating folate (Shiraishi et al, 2013). Indeed, a negative association between caffeine and tannins with serum folate levels has been reported in a study of pregnant Japanese women consuming caffeinated beverages such as coffee and/or green/oolong teas (Otake et al, 2018).
Catechins including epigallocatechin-3-O-gallate (EGCG) and epigallocatechin (EGC) may be found in high concentrations in green tea. Whilst green tea is perceived as beneficial to health at low levels, high intake of green tea (containing more than approximately 300mg EGCG per day) may impede liver function for some people (EFSA, 2018). A study by Maeda-Yamamoto et al (2018) indicates that consumption of green teas containing approximately 320mg EGCG per day and 400mg per day EGC correlated with elevation of homocysteine, blood pressure and blood lipids in the study group compared to the control group.
Brewed teas may also contain significant amounts of heavy metal contamination (Schwalfenberg et al, 2013), this may account for some of the effects noted in the above stated studies . Exposure to environmental toxins in relation to homocysteine status is discussed later in this report.
Coffee
Moderate consumption of filtered coffee (1-3 cups per day) may be linked to a reduced chance of developing hyperhomocysteinemia, as reported by a cross-sectional study population of 557 adults with an average age of 45 years that included 58% non-smokers, 78% with low activity levels and 74% non-obese, from south-eastern Brazil (Miranda et al, 2017). In the study, a cup of coffee measured 50ml and included only caffeinated coffee. The investigators ascertained that moderate consumption provides between 101-337mg per day polyphenols (especially hydroxycinnamic acids, alkylmethoxyphenols and others including catechol and phenol) and made an attempt to consolidate the polyphenol intake per day from coffee with the same polyphenols from the diet. When adjusted for confounders and adjusted for folate, vitamin B6 and vitamin B12 intake, the odds ratio (OR) for moderate coffee consumption in relation to hyperhomocysteinemia was reported as OR=0.29; 95% confidence interval (CI) 0.11, 0.78). Interestingly, filtered coffee was more likely to be linked to lower homocysteine than unfiltered coffee and, on average, approximately 150ml of coffee per day was more advantageous than higher consumption or no coffee consumption. A study by Tverdal et al (2020) concurs that moderate intake of filtered coffee is also correlated with a lower all-cause mortality rate, when compared to regular consumption of either unfiltered brew or no coffee consumption.
A study by Correa et al (2013) concludes that approximately 450ml per day paper-filtered coffee consumption (taken as 3 -4 cups per day with 15g beans of medium or medium-light roast prepared per 150ml cup over 4 weeks) makes no difference to total homocysteine, glycemic biomarkers or blood pressure in healthy participants but increases were observed for total cholesterol and other cardiovascular markers. Whereas three or more cups per day of unfiltered Turkish-style prepared coffee for four weeks correlated with raised homocysteine in a study conducted by Eren and Besler (2019) and ‘dark roast’ correlated to increased cholesterol levels and serum lipids in healthy participants.
On balance, any improvements in plasma homocysteine from moderate coffee consumption (approximately 150ml per day of the filtered preparation) may be due to a synergy of the beneficial polyphenols ingested at optimal dietary levels acting on biochemical pathways that are yet to be elucidated. Coffee is also a source of choline and may therefore support the GB pathway.
Alcohol
Scientific studies conducted with people living with alcoholism suggest that ethanol is a hyperhomocysteinemic substance. Although cellular mechanisms remain elusive, we may speculate that the effect of alcohol on homocysteine levels for any individual may be closely linked to folate status.
Intervention trials with folic acid have consistently shown a reduction in plasma homocysteine in humans, and it is well reported that alcohol is a known adversary of folate concentration in the human body. Therefore, an extrapolation of the available research suggests that alcohol intake and dietary folate (or folic acid supplementation) may have an opposing effect on homocysteine in the human body. Indeed, a review by Kamat et al (2016) concludes that alcohol intake, coupled with a low folate diet, may lead to higher total homocysteine concentration for an individual. However, in the case of low folate intake and high alcohol consumption, the GB pathway supplying methyl groups via dietary choline may play an important supportive role to reduce homocysteine concentrations in the individual (Chiuve et al, 2007).
Interestingly, a small study investigating moderate/high alcohol consumption of 375ml white wine per day (42g alcohol) for 1 month reported that alcohol consumption did not increase the average baseline homocysteine concentration but a very high level of folic acid supplementation along with alcohol ingestion was effective at lowering homocysteine ( Rajdl et al, 2016).
The influencing factors of mild to moderate alcohol intake on homocysteine concentration appear to be rather complex. Whilst some studies report a positive correlation between regular alcohol intake and raised homocysteine levels, others do not reach the same conclusion. This demonstrates the difficulties of comparing different studies with different experimental protocols involving different populations consuming different diets. One should also bear in mind that the focus of this report is homocysteine: the influence of alcohol reaches many other metabolic and neuronal pathways.
Exposure to toxic heavy metals
Lead
The concentration of lead in blood was found to be positively correlated with homocysteine in healthy reproductive-age women except for those in the upper quartile for dietary intake of vitamin B12, B6 and folate (Pollack et al, 2017).
Arsenic
Research suggests that an indirect link between arsenic exposure and raised homocysteine may occur due to modulation of several significant upstream and downstream pathways of the methionine cycle. Inorganic arsenic exposure from the environment will place extra demand on total methylation capacity for an individual because removal of arsenic from the body is reliant on SAM and other methyltransferases. Indeed, polymorphism in the Arsenic (+3 oxidation state) MethylTransferase (AS3MT) gene has been demonstrated to be a strong determinant of arsenic methylation capacity and related health outcomes as covered in reviews by Abuawad et al (2021) and Thomas (2021). It should also be noted that arsenic is documented as an inhibitor of glutathione reductase and the seleno-enzymes glutathione peroxidase and thioredoxin reductase; arsenic contributes to an imbalance between necessary and harmful levels of intracellular hydrogen peroxide as discussed in a review by Nurchi et al (2020). Nurchi et al (2020) also focus on the sources of human exposure to environmental arsenic such as drinking water, food and occupational exposure.
A review of human studies suggests that methionine, choline, folic acid, vitamin B2, B6, B12 and zinc may be essential to increase arsenic metabolism and reduce toxicity of arsenic within the human body (Sijko and Kozlowska, 2021). Moreover, folic acid supplementation lowered homocysteine and improved arsenic methylation capacity among environmentally arsenic-exposed Bangladeshi adults who presented initially with low betaine and choline status (Bozack et al, 2020).
Homocysteine & brain health: key nutrients, lifestyle & dietary strategies
Reduce environmental arsenic exposure
The World Health Organisation has documented the risks of arsenic and the sources of arsenic exposure (WHO, 2022). It goes without saying that heeding this advice, and taking steps to reduce individual exposure to arsenic, is prudent. The BBC have a useful article in their archive that explains how to reduce potential individual exposure to arsenic from contaminated rice (BBC, 2022).
Research is underway to examine how nutritional support targeted at one-carbon metabolism may be helpful for safe excretion of arsenic metabolites from the human body: Folate, betaine and choline sufficiency may have a positive influence where timely methylation and safer excretion of arsenic metabolites are key (Bozack et al, 2020; Saxena et al, 2019).
A healthy balanced diet & B Vitamins
Vitamins B2 (riboflavin), B6, B9 (folate) & B12 are interconnected in the folate cycle, the remethylation pathway and in the glutathione cycle.
Whilst it is impossible for investigators to consider all the factors at play within the ‘package’ of whole diet, especially when comparing plant and animal derived proteins (Richter et al, 2015), studies consistently report that achieving adequate folate (vitamin B9) status is an important factor to mitigate the risk of homocysteine accumulation (Selhub et al, 2000; Xiao et al, 2013). Furthermore, folic acid has been shown to improve the function of the layer of cells lining the blood vessels (Antoniades et al, 2006).
The enzyme Methionine Synthase (MS) has an important role in the remethylation of homocysteine to methionine. Vitamin B12 status is important for the function of MS. Vitamin B2 is also an important consideration because the enzyme methionine synthase reductase (MTRR) is dependent on vitamin B2 to reactivate MS. Vitamin B6 is required for serine hydroxymethyltransferase (SHMT) function in the folate cycle and also in the conversion of homocysteine to cysteine in the transsulfuration pathway. Vitamin B12, and vitamin B2 are also important to the function of MTHFR in the folate cycle (Garcia-Minguillan et al, 2014) along with folate.
A study by Hankey et al (2013) reports that supplementation of vitamins B6, folic acid, and vitamin B12 taken together for approximately 2.5 years significantly reduced homocysteine by approximately 4 μmol/L in a study of participants having previously experienced stroke or ischemic attack. Similarly, a randomised control trial in older adults with median age 73 years reported that supplementation of 500 mcg vitamin B12, 400 mcg folic acid and 15 mcg vitamin D3 for two years resulted in an average reduction of homocysteine by approximately -4.2 micro mol/L compared to the placebo group (De Koning et al, 2016).
As previously noted, there is some emerging evidence that optimisation of vitamin B2 may be an important strategy for lowering homocysteine in individuals that have the genetic polymorphism MTHFR 677C>T; B2 and vitamin B12 may influence homocysteine concentration for individuals with the genetic polymorphism MTRR 66A>G; optimal vitamin B12 status may be especially important for individuals with MTRR 524C>T (Garcia-Minguillan et al, 2014).
An interesting pilot investigation by Lindschinger et al (2019) suggests that bioavailability of B vitamins (vitamin B1, B2, B6, B9 and B12) from food sources is similar to that provided by the same level of supplementation, with the exception of folate/folic acid where supplementation dramatically increased serum B9 level compared to folate from diet. Boosting vitamin B intake in this study of thirty healthy participants reduced serum homocysteine by an average of 13% overall after 6 weeks. Good dietary sources of B vitamins (Gov.UK, 2022):
Vitamin C & Vitamin D
Hyperhomocysteinaemia may have an effect on vitamin D levels, due to the upregulation of Fgf23 (fibroblast growth factor 23) gene expression and subsequent increased synthesis of ROS (reactive oxygen species) and oxidative stress. However, the antioxidant activity of vitamin C has been observed to mitigate this mechanism in an in vitro study (Alber et al., 2021). Ensuring vitamin C and vitamin D adequacy, but not excess, for an individual is important for overall good health and to minimise oxidative stress in the body.
Zinc
Recent research has highlighted the key role of zinc in modulating concentrations of homocysteine. Proposed mechanisms via which zinc functions in this capacity are with relation to its synergistic relationship with folate and B12. In a randomised control trial 51 postmenopausal women were stratified into either a zinc (50mg/daily) intervention or a placebo group for 8 weeks. Nutrient intake was measured using a 72 hour food recall, and zinc levels were analysed. Results indicated that women in the zinc group had significantly higher levels of folate and significantly lower homocysteine levels. Further, a specific correlation was observed between higher serum levels of B12, folate and homocysteine levels in the zinc group (Vasquez-Lorente et al., 2022). We may speculate that this study provides an insight into how zinc sufficiency is important for BHMT functionality, since BHMT is a zinc dependent enzyme that catalyses the transmethylation of homocysteine to methionine in the presence of the methyl group donor betaine.
Betaine & choline
A human retrospective cross-sectional analysis of 1477 women suggests that adequacy of dietary choline/betaine may be important for individuals with a lower folate intake or where the folate cycle is reduced due to SNPs or high alcohol consumption (lowering folate status) because the betaine-remethylation pathway of homocysteine is able to go someway to compensate for the folate re-methylation pathway (Chiuve et al, 2007). The interconnected relationship between the folate cycle and GB pathway as methyl donors with the potential to reduce homocysteine concentration is shown in figure 1.
The most widely distributed form of betaine occurring in nature is glycine betaine (GB). The inclusion of dietary sources in regular diet plays a decisive role in the betaine content of the body but betaine can also be synthesised from choline derivatives. Betaine is rapidly absorbed from the duodenum in animals and can be freely filtered in the kidney and reabsorbed into circulation. Betaine is utilised in most tissues as an osmoproctectant in addition to its primary role as a methyl group donor in liver metabolism (reviewed by Zhao et al, 2018).
A study by Knight et al (2017) confirms that betaine is actively accumulated in hippocampal slices in a time, dose and osomolarity dependent manner; Betaine is implicated in hippocampal neurophysiology and neuroprotection.
A meta analysis to investigate the effect of betaine supplementation on plasma homocysteine concentration in healthy adults concludes that supplementation of at least 4g/day of betaine for a minimum of 6 weeks may lower plasma homocysteine. The pooled analysis estimates a statistically significant reduction of approximately 1.23 μmol/L (McRae, 2013).
Betaine supplementation has been used for over 40 years to support individuals with genetic defects of folate dependent remethylation because betaine is known to increase methionine concentration and aid homocysteine reduction. However, it should be noted that supplementation of betaine in individuals with CBS deficiency, without sufficient dietary methionine restriction, leads to methionine excess with severe clinical consequences (Schwahn et al, 2019). See figure 1 for the schematic relationship between CBS function and methyl donors.
Dietary sources of betaine are wholegrain cereals such as wheat bran and wheat germ, spinach, beetroot and quinoa (Ross et al, 2014). Dietary sources of choline include milk, chicken, beef, eggs, soybeans, fish, broccoli, peas (NIH, 2022). Individuals following dietary restriction such as veganism or gluten-free diet may wish to seek professional help to identify appropriate sources of dietary choline and betaine.
Methionine & cysteine
When considering the potential metabolic pathways that lead to hyperhomocysteinemia it is important to note that the amino acid methionine, but not the amino acid cysteine, is the dietary precursor of homocysteine (Stipanuk et al, cited in Xiao et al, 2013). There is some evidence that a sufficient daily dietary intake of cysteine may reduce the requirement for methionine (Di Buono et al, 2001). By simple extrapolation this suggests that dietary protein sufficiency, and not excess, may go some way to reduce the metabolic pressures that influence raised homocysteine in the body.
Worryingly, synthetic methionine has been entering the food chain at an alarming rate to meet the increasing human demand for meat (especially chicken). An imbalance or excess of methionine compared with other amino acids in food may have serious implications to human health and healthy ageing as discussed in a personal view from Neubauer and Landecker (2021). Indeed, a small study by Gao et al (2019), involving 6 human participants, reported that a lowered dietary methionine intake may lead to a significant reduction of circulating homocysteine along with reductions in L-cysteine, N-acetyl cysteine, glutathione and a significant increase in circulating riboflavin (vitamin B2) after 3 weeks. Interestingly, methionine restriction in relation to the extension of lifespan in different experimental animal species is a growing area of research.
Conclusion
Homocysteine is inextricably linked to the methionine cycle and degenerative diseases and is a useful biomarker to check the efficiency of one-carbon metabolism for an individual. Measuring homocysteine may help to identify ‘bottlenecks’ in the methionine cycle and related pathways, informing the use of appropriate, targeted and personalised interventions to alleviate restricted function for an individual; A strategy that is essential to the success of preventative healthcare practice.
A balanced diet and the ability to absorb specific nutrients such as vitamins B2, B6, Folate and B12, C, D, zinc, choline, betaine, methionine and cysteine are important to the healthy function of the methionine cycle, but this list is not exhaustive. In addition, human studies indicate that the combinatory effects of diet, health of the digestive system, ageing, genetics and environmental inputs can all influence homocysteine concentration for an individual; Personalised information will enable individuals to take responsibility for lifestyle and dietary changes that may help them to optimise their future health.
Whilst compensatory mechanisms have evolved to defend against short-term perturbations of the methionine cycle (the choline/Betaine pathway and the folate cycle work together to provide methyl groups for the re-methylation of homocysteine to methionine) they can do so only if the biological mechanisms are able to draw on necessary enzymatic cofactors and raw ingredients provided from the diet. Unfortunately, a modern ‘western-type’ diet and exposure to environmental toxicities may put a strain on these important biological pathways from an early age.
It is important to identify individuals at risk of hyperhomocysteinemia because there is sufficient research to suggest that a personalised diet, or a considered vitamin, mineral and/or protein supplementation, may be helpful to adjust homocysteine status toward a more normal level. By considering how nutrition interventions may be able to improve homocysteine status, a healthcare professional may be able to provide early and simple interventions to improve quality of life for an individual with the potential to reduce the strain on healthcare services in the future.
References
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