1 Introduction
B12 is essential for brain health, and physiologically active in the body in the forms of Methylcobalamin and adenosylcobalamin , while cyanocobalamin is the main commercially available synthetic form. Adenosylcobalamin (AdoB12) is cofactor for methylmalonic coenzyme A mutase (MMCoAM) and methylcobalamin (MetB12) is a cofactor for 5-methyltetrahydrofolate-homocysteine methyltransferase (MTR) (Hathout and El-Saden, 2011). B12 deficiency has been associated with an increased prevalence of neurodevelopmental disorders and psychiatric disorders such as Alzheimer’s Disease, schizophrenia, autism, depression and epileptic conditions (Venkatramanan et al., 2016).
2. B12 in Neurodevelopment in utero and in Childhood
B12 plays a vital part in myelination and synaptogenesis. Both are stimulated in the third trimester of pregnancy and influence infant neuronal growth and development during the early years and functioning over the lifespan (Venkatramanan et al., 2016). Observational studies of children’s B12 status and cognitive outcomes showed higher levels were associated with improved academic performance and developmental indexes (Duong et al., 2015; Strand et al., 2013; Kvestad et al., 2015) whilst supplementation in deficient infants normalised B12 levels and improved general health and neurodevelopmental outcomes in the majority of cases (Mütze et al., 2021).
3. B12 deficiency
3.1 Clinical vs subclinical Vitamin B12 Deficiency
Most cases of B12 deficiency fall under the category of subclinical cobalamin deficiency (SCCD) – distinguished by lack of clinical symptoms or haematological abnormalities (anaemia) and only mild/minimal alterations in methylmalonic acid (MMA) and homocysteine (HCY) concentrations. Food bound cobalamin deficiency may be a factor in up to 50% cases (Moll and Davis, 2017). Clinical cobalamin deficiency occurs in <0.1% of adults and 1-2% of elderly and is a serious disease requiring medical intervention. It is caused by severe malabsorption due to ileal dysfunction in >95% cases (Moll and Davis, 2017; McCaddon, 2013).
3.2 B12 deficiency and the elderly
Although physiological decrease of B12 with age is unlikely, pathologically low serum B12 does increase in the elderly, with a prevalence of approx. 40% in certain populations, often lacking clinical symptoms of deficiency. Food sources of B12 may be an important determinant of plasma concentrations in the elderly, however one causative factor behind low B12 serum levels is prevalence of atrophic gastritis and associated hypochlorhydria/ achlorhydria in this cohort, varying from 20-50%. Certain prescribed drugs may also contribute to low levels in the elderly (PPIs, H2 antagonists and metformin) (McCaddon, 2013).
Poor B12 status is believed to be at least partly responsible for cognitive decline in some elderly patients, although in patients with low status supplemented with B12, positive alterations were only seen in those with mild cognitive impairment when supplemented early in disease development (McCaddon, 2013).
In epidemiological studies, adherence to dietary patterns such as the Mediterranean-type diet is consistently associated with a lower risk of Alzheimer’s disease (AD). In a small study of at-risk cognitively individuals, higher intake of B12, vitamin D and Omega-3 was associated with reduced Aβ deposition in Alzheimer’s regions of the brain and researchers found that this nutrient combination was associated with consumption of a Mediterranean-type dietary pattern. Interestingly, these associations were notably stronger when nutrients were derived from food sources. (Mosconi et al., 2014)
4. Mechanisms
4.1 5-Methyltetrahydrofolate-homocysteine methyltransferase (MTR) or Methionine Synthase
As methylcobalamin, B12 acts as coenzyme in the methylation of homocysteine to methionine (via Methionine Synthase) (See diagram 1). In this reaction, folate (N5-methyltetrahydrofolate) acts as methyl donor and results in regeneration of tetrahydrofolate (THF) and formation of methionine. B12 deficiency in this scenario can therefore reduce methionine synthesis, concomitantly increase homocysteine levels and impair the regeneration of THF resulting in impaired DNA synthesis and affecting cells that undergo rapid turnover, such as blood cells (Moll and Davis, 2017; Hathout and El-Saden, 2011).
4.2 Methylmalonic coenzyme A mutase (MMCoAM)
The final step of the pathway that metabolises propionyl CoA, requires 5′-deoxyadenosyl cobalamin B12 as coenzyme in the conversion of methylmalonyl coenzyme A into Succinyl CoA, via the enzyme methylmalonic coenzyme A mutase (MMCoAM) (See Diagram 2). Succinyl CoA then enters the citric acid/Krebs cycle to be converted into energy (ATP). In B12 deficiency, this final reaction is impaired, which can lead to a build up of plasma HCY and MMA (Moll and Davis, 2017; Hathout and El-Saden, 2011).
4.3 B12, senescence and oxidative stress (OS)
As humans age, their capacity to reduce thiol groups diminishes, and resulting OS reduces B12 availability. In the frontal cortex, MS gene expression is reduced >400 fold in normal humans through the lifespan and methylcobalamin levels decrease by over 10 fold, suggesting that reduced B12 function may contribute to cognitive and neurodegenerative disorders of senescence (Offringa et al., 2021). Since OS has been associated with AD, Offringa et al (2021) suggest that supraphysiological doses of B12 may be a possible treatment to combat OS stress-related diseases e.g. AD due to B12’s O2 scavenging action (Offringa et al., 2021).
4.4 B12’s role as redox compound and modulator of OS
The B12 in MS acts as a sensor of redox status, inactivating the enzyme and controlling methionine synthesis during OS and it is via this B12-dependent enzyme that HCY is largely metabolised in the brain. MS is reactivated using SAM as methyl donor, generating SAH and HCY in the process – ultimately resulting in increased HCY (See Diagram 3). Excess homocysteine is diverted via the trans-sulfuration pathway to synthesise glutathione, thereby counteracting OS. Hence, the SAM-supported methylation reactions are also linked to redox status of B12 (Offringa et al., 2021; McCaddon, 2013).
OS-induced deficit of reduced cobalamin also limits the availability of succinyl-CoA for Krebs (see above), thereby inhibiting supply of energy substrates. Succinyl-CoA is involved in glycogen storage and synthesis of heme, implicating the OS-related redox balance of B12 with development of some common B12 deficiency associated symptoms – fatigue, anaemia and neuropathy (Offringa et al., 2021).
4.5 Protective effect of B12 on MS
Results from experiments on C. elegans nematodes fed strains of E. coli suggested that proteotoxicity relating to Aβ accumulation in AD may be modified by B12 supplementation, which impacted upon the function of MS, and also protected against mitochondrial fragmentation, ROS and ATP crises and Aβ induced paralysis observed in these animals. Similar results were observed in other neurological diseases (amyotrophic lateral sclerosis and Huntington’s disease) (Lam, Kervin and Tanis, 2021).
4.6 Effect of B12 and folate supplementation on neuronal gene expression
There is an age-dependent reduction in the phosphorylation of CREB, a marker of synaptic plasticity and transcription factor for many other synaptic plasticity genes, including neuronal immediate early genes (nIEGs). Barman et al. (2021) observed that old mice showed enhanced neuroplasticity and improved recognition memory compared to controls, with altered expression of these nIEGs after a B12-folic acid supplementation regimen. The authors suggested that the regulatory mechanism controlling nIEG expression was differential DNA methylation at the promoter sites of nIEGs and CREB phosphorylation, following supplementation (Barman, Kushwaha and Thakur, 2021).
5. Summary
Researcher: Elisa Sciandro BSc Nutritional Science (CNELM in Conjunction with Middlesex University)
References
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