Folate and Age-Related Disease

Aging is associated with increased risk of cardiovascular and neurodegenerative disorders and an increase in their risk factors, such as decreased concentrations of folate and increased concentrations of homocysteine. The association of folate and homocysteine with age-related disease and, most importantly, the causality needs to be assessed for effective public health policy. The pathogenic mechanisms, which link these risk factors to age-related diseases may include non-specific disease mechanisms such as inflammation. We investigated the association of folate and homocysteine with cardiovascular disease risk, cognitive performance on a battery of neuropsychological tests and hearing thresholds in middle-aged and elderly men and post-menopausal women using cross-sectional data obtained from the baseline measurements of the FACIT trial. FACIT is an acronym for Folic Acid and Carotid Intima-media Thickness. The FACIT trial investigates the effects of daily folic acid supplementation (0.8 mg/d) for three years on age-related parameters, carotid artery wall thickness and arterial stiffness, cognitive performance and hearing. Furthermore, we investigated whether supplementation with folic acid after one year will lead to a reduction in plasma concentrations of inflammation markers in the final 530 participants of the FACIT trial. Low folate status and high concentrations of homocysteine were associated with increased carotid intima-media thickness, a marker of cardiovascular disease risk. However, the relationships were explained to a great part by conventional risk factors (mean difference between first vs. fourth quartile of erythrocyte folate 0.03 mm, 95% confidence interval -0.002 to 0.06 mm). Neither folate nor homocysteine were associated with carotid distension, a measure of arterial stiffness. Decreased concentrations of erythrocyte folate and increased concentrations of homocysteine were independently associated with poor cognitive performance. The cognitive domains with the greatest variability with age, like memory and speed-related functions, were also the domains with the strongest relation with low folate levels. Unexpectedly, folate, not homocysteine, was directly associated with hearing impairment; however, this association was confined to subjects with the 5,10-methylenetetrahydrofolate reductase (MTHFR) 677C allele. Subjects with the MTHFR 677TT genotype had better cognitive performance and hearing levels than subjects with the CC or CT genotype. Finally, inflammation markers did not respond to one-year folic acid supplementation, despite a 25% decrease in homocysteine concentrations. Conclusions and implications; mso-ansi-language:EN-US;font-style:normal'>Increased concentrations of folate, independent of its role in homocysteine-lowering, are weakly associated with decreased risk of cardiovascular disease and better cognitive function, but not with hearing acuity. Further research is required to establish whether these relationships are causal and the mechanism responsible for disease. If faced with the decision whether to fortify the national food chain with folic acid, public health policy makers should wait for the large trials to report their findings on the effects of folic acid—alone or in combination with other B vitamins—on cardiovascular disease and dementia.