New Insights into Folate–Vitamin B12 Interactions

Folate and vitamin B 12 (B12) are essential cofactors in folate-mediated one-carbon metabolism (FOCM). FOCM includes a series of methyl transfer reactions for methionine regeneration and de novo synthesis of nucleotides, including thymidylate. Deficiency in either folate or B12 can result in negative health outcomes including megaloblastic anemia, with additional neurocognitive impairments observed as a result of B12 deficiency. While folate deficiency is not common in the United States due to mandatory folic acid fortification, B12 deficiency is observed more frequently, particularly in certain subpopulations such as vegetarians/vegans and older adults. Fortification of the food supply with folic acid has been effective to increase folate status and reduce the incidence of birth defects. However, consumption of fortified foods and use of dietary supplements containing folic acid have led to an increase in the proportion of individuals exceeding the tolerable upper intake level of folic acid. Although the interaction between folate and B12 has been appreciated for decades in relation to megaloblastic anemia, it has been recently proposed that elevated serum folate may worsen neurocognitive effects and other metabolic impairments (altered glucose homeostasis, type 2 diabetes in offspring) associated with B12 deficiency. This review highlights molecular mechanisms that may explain the biology underlying these associations with a focus on findings from studies in model systems.