Folic acid and homocysteine in age-related disease.

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.