FOLIC ACID

Ageing Res Rev 2002 Feb;1(1):95-111
Folic acid and homocysteine in age-related disease
Mattson MP, Kruman II, Duan W
Laboratory of Neurosciences, Gerontology Research Center, National Institute on Aging, 5600 Nathan Shock Drive, Baltimore, MD 21224, USA. mattsonm@grc.nia.nih.gov

It has been known for decades that babies born to women that have a dietary deficiency in folic acid (folate) are at increased risk for birth defects, and that the nervous system is particularly susceptible to such defects. Folate deficiency in adults can increase risk of coronary artery disease, stroke, several types of cancer, and possibly Alzheimer's and Parkinson's diseases. Recent findings have begun to reveal the cellular and molecular mechanisms whereby folate counteracts age-related disease. An increase in homocysteine levels is a major consequence of folate deficiency that may have adverse effects on multiple organ systems during aging. Humans with inherited defects in enzymes involved in homocysteine metabolism, including cystathionine beta-synthase and 5,10-methylenetetrahydrofolate reductase, exhibit features of accelerated aging and a marked propensity for several age-related diseases. Homocysteine enhances accumulation of DNA damage by inducing a methyl donor deficiency state and impairing DNA repair. In mitotic cells such DNA damage can lead to cancer, while in postmitotic cells such as neurons it promotes cell death. The emerging data strongly suggest that elevated homocysteine levels increase the risk of multiple age-related diseases, and point to dietary supplementation with folate as a primary means of normalizing homocysteine levels and increasing healthspan.

Cancer Detect Prev. 2005;29(1):46-53. Epub 2004 Nov 11.
The role of folates in squamous cell carcinoma of the head and neck.
Kane MA.
Division of Medical Oncology, University of Colorado Health Sciences Center and the Denver Veterans Affairs Medical Center, Denver VA Medical Center (111F), 1055 Clermont Street, Denver, CO 80220, USA.

The primary objective of this review is to explore the hypothesis that folate insufficiency may be important in the pathogenesis of squamous cell carcinomas of the head and neck (SCCHN) and that folate repletion may be an effective component of chemoprevention. The main results are that folate insufficiency disrupts DNA global and specific gene methylation patterns such that the activity of certain tumor suppressor genes such as p16 and possibly p53 may be lost. Folate pool imbalance and impaired repair mechanisms may contribute to DNA instability and strand breaks. Sensitive methods exist for identification of individuals with folate insufficiency in contrast to the relatively insensitive conventional serum or red cell folate assays with broad "normal" ranges. The impact of folate supplementation can thus be quantified. Folate imbalance may result from alterations in folate cellular uptake by the reduced folate carrier (RFC) and/or the folate receptor (FR) and polymorphisms in enzymes important in folate retention such as folylpolyglutamate synthetase and in folate modification such as methylene tetrahydrofolate reductase (MTHFR). Known predisposing factors for SCCHN such as alcohol and tobacco carcinogens may influence folate balance. Folate supplementation may reduce primary or secondary risk of cancer. Formal studies of folate sufficiency in persons at risk for or diagnosed and treated for SCCHN are needed to define the role of folate supplementation in the prevention of these cancers.

Folate is an essential vitamin that is also known as folic acid and folacin. The synthetic form of the vitamin (folic acid), pteroylglutamic acid, is seldom found naturally in food. The folates found in nature contain the core chemical structure of pteroylglutamic acid but vary in their state of reduction, the single carbon moiety they bear and/or the length of the glutamate chain attached. At least 50% of whole body folate is stored in the liver.
The metabolic role of folate is as an acceptor and donor of one-carbon units in a variety of reactions involved in amino acid and nucleotide metabolism. The carbon can be carried as a methyl, methylene, formyl, formimino or methenyl group. The coenzyme form of the vitamin is typically fully reduced and poly-glutamylated. In the adult, folate is absorbed primarily in the proximal one-third of the small intestine. It is also conceivable that a portion of the large depot of bacterially synthesized folate in the large intestine may be absorbed. A large portion of folate delivered to the liver is secreted into bile and redistributed to peripheral tissues. Polyglutamylation (addition of glutamic acids) of folate is believed necessary to concentrate and store folates in tissues.

Deficiencies: Given the role that folate coenzymes play in the synthesis of RNA, DNA and protein, it is not surprising that the folate requirement and, consequently, the risk of deficiency is elevated during periods of rapid growth and/or enhanced metabolic activity (e.g. pregnancy, lactation). Overt symptoms of severe folate deficiency such as depapillation of the tongue are uncommon. Megaloblastic anemia, indistinguishable from megaloblastic anemia secondary to vitamin B12 deficiency, is a more frequently cited functional outcome. Less than optimal maternal folate status has been implicated in a number of negative maternal and fetal outcomes, including low infant birthweight, abruptio placenta, cervical dysplasia and neural tube defects. Low folate intakes also are correlated with high levels of serum homocysteine which are associated with an increased risk of atherosclerosis and several forms of vascular disease. However, it is unclear currently whether supplemental folate lowers risk.

Clinical Uses: Recent public policy recommendations suggest that women of child-bearing potential consume 400 µg/d of folate to reduce the number of pregnancies affected by a neural tube defect. Consumption of large amounts of folate may interfere with the diagnosis of pernicious anemia, a condition not uncommon in the elderly which may produce neurologic defects. Very high doses of folic acid may counteract certain antiepileptic drugs. Because of the importance of folate in the synthesis of nucleotides, which are required for cell multiplication, antifolate drugs such as methotrexate are important in cancer therapy. When methotrexate is used in arthritis therapy, folate supplements often are used to lessen side effects.

Diet Recommendations: The Dietary Reference Intakes (DRIs) for folate each day are 400 µg Dietary Folate Equivalents (DFE) for adults and teenagers. Pregnant women need a greater amount, 600 µg DFE, for building red blood cells; lactating women require 500 µg. For children, DRIs are 65 µg for infants 0-0.5 yr. and 80 µg for infants 0.5-1 yr.; and 150 µg for ages 1-3 yr., 200 µg for ages 4-8 yr., and 300 µg for ages 9 - 13 yr.

Food Sources: The folate content of foods is inherently variable and a large fraction of the folate consumed each day comes from foods that are frequently ingested, but not particularly concentrated, sources of the vitamin. Excellent food sources of folate (>55 µg/d) include fortified cereals, citrus fruits and juices, asparagus, Brussels sprouts, spinach, baked beans, chickpeas, kidney beans or lentils.

Many cereal-grain foods (flour, rice, pasta, cornmeal) constitute important sources because they are fortified with folic acid. Folate bioavailability varies with food type and overall diet composition. In general, added folic acid in fortified foods is absorbed more efficiently than many forms of naturally-occurring folate.

Toxicity: Most reports of folate toxicity have involved massive (nonphysiological) doses given by injection. Such massive doses have produced evidence of neuro- and nephrotoxicity. The main concern of large doses of dietary folate intakes and commonly available supplements is that a large intake might mask a B12 deficiency by allowing some synthesis of blood cells by temporarily relieving the block of nucleotide synthesis. This possibility should be continually evaluated in populations at risk, including the elderly individuals. Under conditions of typical intake in the US population, the beneficial effects of improved folate status currently outweigh this small potential risk.

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