A decade ago, only a handful of laboratories worldwide were studying
homocysteine. Now this amino acid is rivaling the reputation of elevated
blood cholesterol as a major contributor to heart disease and strokeand
to other maladies as well. Early studies at the Jean Mayer USDA Human
Nutrition Research Center on Aging (HNRCA) at Tufts University in Boston
have greatly contributed to bringing homocysteine research into the
"Our work on the role of nutrition in regulating homocysteine
had a big impact," says Paul F. Jacques, who heads nutritional
epidemiology studies at the center, which is funded by ARS.
Before 1993, most cases of high circulating homocysteine were thought
to be of genetic origin.
Then Jacques, together with Jacob Selhub, who heads the center's vitamin
metabolism research laboratory, center director Irwin Rosenberg, and
others, reported that most cases of mildly elevated homocysteine in
an elderly population were linked to low vitamin B status. They had
looked for an association with B vitamins because the body requires
folate, vitamin B6, and vitamin B12
to convert homocysteine to other amino acids that aren't toxic to the
lining of blood vessels. Blood folate levels appeared to have the most
influence on homocysteine levels.
Earlier this year, Jacques, Selhub, and colleagues with the Framingham
(Massachusetts) Offspring Study reported on other diet and lifestyle
factors that appear to contribute to elevated homocysteine. Their results
supported findings by other researchers that high homocysteine concentrations
were related to low vitamin B6 and riboflavin (B2)
intake, to high alcohol and caffeine intake, and to smoking and hypertension.
"Smoking was one of the most noteworthy findings," says Jacques,
"because it was so strongly associated with high homocysteine concentrations."
He says the study was important because it established that other factors
besides low folate influence blood homocysteine concentrations. Since
1998, virtually all grain products sold in the United States have been
fortified with folate to prevent spinal abnormalities in fetuses. That
has dramatically improved folate status in the U.S. population and halved
the prevalence of high homocysteine, Jacques notes. He and colleagues
reported this impact of folate fortification in 1999 after analyzing
data from the Framingham Offspring Study.
Hard on the Heart and Brain
Meanwhile, evidence had been steadily growing that elevated circulating
homocysteine increases the risk of vascular diseases, especially heart
attack and stroke. But a few studies hadn't found an association. So
nutritional epidemiologist Martha S. Morris joined HNRCA to look for
a link among the vast amount of data collected in the third National
Health and Nutrition Examination Survey, NHANES III. She and Selhub's
laboratory collaborated with the Centers for Disease Control and Prevention.
The researchers excluded all participants whose medical condition or
use of nutritional supplements or estrogen might directly influence
homocysteine levels. And they adjusted the analysis to account for differences
in age, race, smoking, blood pressure, and other risk factors for vascular
disease among participants aged 40 years and over.
The result: Men and women who had blood homocysteine levels over 12
micromoles per liter were more than twice as likely to have experienced
a heart attack or stroke.
"The new finding," says Morris, "was that blood homocysteine
concentrations were not related to heart attack or stroke in women who
had not reached menopause, whereas the relationship was strong in men
of the same age group." Conversely, the relationship faded among
the older men and surfaced among postmenopausal women, Jacques adds.
This may explain why some studies found no association. It may differ
depending on gender and age.
"The findings support the idea that women may be protected from
heart attack and stroke by their high estrogen status," says Morris.
The Helpful Hormone
There was already evidence that estrogen helps keep blood homocysteine
concentrations down. Premenopausal women, those who use oral contraceptives,
and pregnant women all have lower blood homocysteine than men and postmenopausal
womenexcept those who take estrogen replacement. But Morris, Jacques,
and their HNRCA colleagues wanted to confirm the thesis by again using
data from NHANES III.
"The data provides a unique opportunity to explore the variation
of homocysteine concentration with estrogen status in a large, representative
sample of the U.S. population," Morris says. She noted that previous
studies compared old and young women, so age alone could have accounted
for their homocysteine differences.
The researchers analyzed data from nearly 8,400 people ranging in age
from 17 to over 70 years. Last year, they reported that higher estrogen
status is associated with a decreased mean serum homocysteine concentrationindependent
of nutritional status or muscle mass. Muscle mass is a possible contributor
because homocysteine is created during production of a substance that
aids energy flow in muscle tissue.
"It's a dramatic demonstration of the relationship between estrogen
status and homocysteine concentrations," says Morris. "Estrogen
may explain the previously reported differences in homocysteine concentrations
between males and females." (See "A
Snapshot of Blood Homocysteine Levels," Agricultural Research,
March 1999, p. 25.)
Brain Function and Folate
Morris, Jacques, and colleagues again turned to NHANES III data on
the over-60 participants to tease out a possible association between
elevated homocysteine and memory loss. The amino acid increases risk
of stroke, which is a major player in the loss of cognitive function.
But the researchers wanted to see if homocysteine or B vitamin status
had a more subtle influence on memory.
The B vitamins are involved in the synthesis of chemicals crucial to
brain function, explains Morris. Or homocysteine itself might be toxic
to nerve cells. Fortunately, the NHANES III included a sensitive test
of recall after a short delayone that can identify individuals
with a mild loss of recall.
She says others had found evidence that elevated homocysteine was related
to Alzheimer's disease, as well as to poor cognitive function in elderly
both with and without dementia. The difference, she explains, is that
"people without dementia sometimes can't remember where they left
their keys; people with dementia can't remember what keys are for."
Perhaps 75 percent of dementia is due to stroke or Alzheimer's diseasewhich
is now thought to develop from minor strokes, Morris says. So the researchers
excluded data from people who had reported having a stroke.
While they did find an association between memory loss and elevated
homocysteine levels, the survey subjects in the upper half for blood
folate levels appeared to be protected from memory loss even if their
homocysteine levels were high.
"The take-home message," says Morris, "is to keep your
folate levels up." And that's easy to do now that grain products
are being fortified with the vitamin.By Judy McBride, formerly
This research is part of Human Nutrition, an ARS National Program
(#107) described on the World Wide Web at http://www.nps.ars.usda.gov.
Paul F. Jacques and Martha
Savaria Morris are at the Jean Mayer USDA Human
Nutrition Research Center on Aging at Tufts University, 711 Washington
St., Boston, MA 02111; phone (617) 556-3322 [Jacques], (617) 556-3302
[Morris], fax (617) 556-3344.