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Is folic acid good for everyone?^1,2

¹ From the Oxford Project to Investigate Memory and Ageing (OPTIMA), Department of Physiology, Anatomy & Genetics, University of Oxford, Oxford, United Kingdom (ADS and HR); the Departments of Medicine and Nutritional Sciences, University of Toronto, Division of Gastroenterology, St Michael's Hospital, Toronto, Canada (Y-IK); and the Institute of Basic Medical Sciences, Department of Nutrition, University of Oslo, Oslo, Norway (HR)

Fortification of food with folic acid to reduce the number of neural tube defects was introduced 10 y ago in North America. Many countries are considering whether to adopt this policy. When fortification is introduced, several hundred thousand people are exposed to an increased intake of folic acid for each neural tube defect pregnancy that is prevented. Are the benefits to the few outweighed by possible harm to some of the many exposed? In animals, a folic acid–rich diet can influence DNA and histone methylation, which leads to phenotypic changes in subsequent generations. In humans, increased folic acid intake leads to elevated blood concentrations of naturally occurring folates and of unmetabolized folic acid. High blood concentrations of folic acid may be related to decreased natural killer cell cytotoxicity, and high folate status may reduce the response to antifolate drugs used against malaria, rheumatoid arthritis, psoriasis, and cancer. In the elderly, a combination of high folate levels and low vitamin B-12 status may be associated with an increased risk of cognitive impairment and anemia and, in pregnant women, with an increased risk of insulin resistance and obesity in their children. Folate has a dual effect on cancer, protecting against cancer initiation but facilitating progression and growth of preneoplastic cells and subclinical cancers, which are common in the population. Thus, a high folic acid intake may be harmful for some people. Nations considering fortification should be cautious and stimulate further research to identify the effects, good and bad, caused by a high intake of folic acid from fortified food or dietary supplements. Only then can authorities develop the right strategies for the population as a whole.

Key Words: Folate • folic acid • vitamin B-12 • fortification • supplements • cancer • antifolates • cognition • epigenetics • public health