Folic acid: a supplementary question

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The results of a randomised clinical trial, published in The Lancet in January 2007, provide intriguing evidence that folic acid supplementation can help to ward off the seemingly inescapable cognitive decline that accompanies advancing age. Individuals from ages 50–70 years who received folic acid supplementation over the course of 3 years did significantly better on measures of memory, information processing speed, and sensorimotor speed than those taking placebo. On the surface, this seems like encouraging news for our growing ageing population, and adds to the evidence that an increased dietary intake of folic acid would be beneficial. But should we advocate folic acid supplementation—or even fortification—given that our knowledge of the potential adverse consequences on many aspects of health and in much of the population remains scarce? Since 1998, flour and other grain products in the USA have been fortified with folic acid, and many other countries, including Canada, much of South America, some Middle Eastern countries, and Indonesia, have followed suit. Although no European or Australasian countries have so far introduced fortification, there is ongoing debate, and in December 2006, the UK Food Standards Agency launched a consultation process to reconsider mandatory fortification versus alternative options to increase folate intake. The aim of fortification is to reduce the incidence of neural tube defects, and epidemiological studies in countries that have mandated fortification suggest that this has been a successful endeavour. However, fortification exposes many sections of the population beyond the original target group, women of childbearing age, to high levels of folic acid. Critics of fortification argue that increased folic acid levels might mask or even exacerbate deficiencies in vitamin B12. Such deficiencies are most prevalent in the elderly as our capacity to absorb B12 declines with age, making this section of the population particularly vulnerable to the adverse effects of increases in folic acid. Anaemia is a common symptom of vitamin B12 deficiency, and if untreated, can result in irreversible nerve damage. Some disturbing consequences of the interaction between folate and vitamin B12 for cognitive function have also been reported. Studies have shown that cognitive function declines steeply in individuals who have a high folate status and low levels of vitamin B12, whereas those with normal levels of vitamin B12 are protected against cognitive decline. Importantly, individuals with a vitamin B12 deficiency were excluded from the study reported in The Lancet. Moreover, the study participants had high baseline plasma total homocysteine levels, indicative of low folate status, and so these findings cannot be generalised to other sections of the population. Increasing dietary intake of folic acid raises further causes for concern. It had been hoped that the introduction of folic acid fortification would help to reduce the incidence of cardiovascular disease and stroke through a reduction in homocysteine levels, but this initial optimism has been dampened with some trials showing only a minimal effect or no effect at all. Nevertheless, studies are ongoing and there are some indications that we should remain hopeful. Epidemiological studies generally indicate that folate has a protective effect against some types of cancer. However, there are some suggestions that high levels of folic acid increase the risk of breast cancer and accelerate tumour growth in colorectal cancer. Recently, it has been reported that high levels of unmetabolised folic acid were linked to impaired immune function in women aged 60 and over. Studies of the consequences—both negative and positive—of folic acid supplementation and fortification remain to be validated with long-term, large-scale clinical trials that shed light on the effects on multiple health outcomes. It would be important to understand the influences of potential sources of variation in response to folic acid, such as age, vitamin status, genetic factors, medical conditions, and drugs. A greater appreciation of the interactions between folate and vitamin B12, disruptions to this tight partnership, and the underlying cause of the harmful events (unmetabolised folic acid, for example) could point us towards further causes for concern that require investigation. The potentially adverse consequences of increased folic acid intake give us reason to be cautious about uncontrolled population-wide interventions. Moreover, recent studies of women of childbearing age in the USA have found reduced blood levels of folates, despite the fortification programme, emphasising the need for additional or alternative solutions. Instead, we should step up our efforts to encourage targeted supplementation and promote healthy diets that are rich in a variety of folates, and not just folic acid, in those groups who would benefit most.