Dietary folic acid intake differentially affects methionine metabolism markers and hippocampus morphology in aged rats

Eur J Nutr. 2013 Apr;52(3):1157-67. doi: 10.1007/s00394-012-0426-1. Epub 2012 Jul 26.


Purpose: Folic acid (FA) is an emerging nutritional factor in the pathogenesis of diverse neurodegenerative disorders by still unknown mechanisms. The hippocampus is altered during the loss of cognitive abilities in humans and selectively affected when homocysteine increases. The aim was to evaluate the potential protective role of folic acid in the maintenance of biochemical markers related to the methionine cycle, as well as the integrity of the hippocampus as part of the brain in aged rats.

Methods: Male Sprague-Dawley rats (18 months old) were assigned to four different folic acid groups (0 mg FA/kg diet, deficient; 2 mg FA/kg diet, control; 8 mg FA/kg diet, moderate supplementation; 40 mg FA/kg diet, extra supplementation) for 30 days. We evaluated several parameters related to the methionine cycle. In addition, hippocampus areas were immunostained for specific neuronal markers and astrocytes.

Results: Serum folate levels increased according to FA dietary level (p < 0.01). There was a significant increase in the serum homocysteine concentrations in the folic acid-deficient diet group (p < 0.01). However, brain S-adenosylmethionine and S-adenosylhomocysteine did not differ significantly between the folic acid groups. Consequently, the methylation ratio was also unchanged. The morphometric analysis did not show any differences in the number of neurons and astrocytes between groups, except when comparing the folic acid-deficient diet versus folic acid-supplemented diet in the striatum of the hippocampus.

Conclusions: Clearly, the dietary FA deficiency negatively affects the methionine metabolism biomarkers, while excessive supplementation seems to be unnecessary for optimal maintenance of the methylation cycle and hippocampus integrity.

Publication types

  • Comparative Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aging*
  • Animals
  • Astrocytes / metabolism
  • Astrocytes / pathology
  • Biomarkers / metabolism
  • Cognitive Dysfunction / etiology
  • Cognitive Dysfunction / metabolism
  • Cognitive Dysfunction / pathology
  • Cognitive Dysfunction / prevention & control*
  • Diet* / adverse effects
  • Dietary Supplements
  • Folic Acid / administration & dosage
  • Folic Acid / blood
  • Folic Acid / metabolism
  • Folic Acid / therapeutic use*
  • Folic Acid Deficiency / diet therapy
  • Folic Acid Deficiency / etiology
  • Folic Acid Deficiency / physiopathology
  • Hippocampus / metabolism*
  • Hippocampus / pathology
  • Hyperhomocysteinemia / etiology
  • Hyperhomocysteinemia / physiopathology
  • Hyperhomocysteinemia / prevention & control
  • Male
  • Methionine / metabolism*
  • Methylation
  • Neurons / metabolism
  • Neurons / pathology
  • Neuroprotective Agents / administration & dosage
  • Neuroprotective Agents / blood
  • Neuroprotective Agents / metabolism
  • Neuroprotective Agents / therapeutic use*
  • Random Allocation
  • Rats
  • Rats, Sprague-Dawley
  • S-Adenosylhomocysteine / metabolism
  • S-Adenosylmethionine / metabolism


  • Biomarkers
  • Neuroprotective Agents
  • S-Adenosylmethionine
  • Folic Acid
  • S-Adenosylhomocysteine
  • Methionine