A compound called alagebrium, which is very similar to
another used in anti-wrinkle creams, may be useful in
reducing the deleterious effects of arterial aging in the
majority of elderly Americans with systolic hypertension, a
new study from researchers at Johns Hopkins shows.
Systolic hypertension refers to higher than normal
levels of the "upper" number in a blood pressure reading,
or with a lower than normal "bottom" number, in this case a
pressure of 140 millimeters of mercury or greater and/or a
diastolic pressure of less than 90 millimeters of mercury.
Hypertension of this sort indicates stiffening of the
"This is the first demonstration that this class of
drugs, known as collagen-crosslink breakers, can turn back
the clock and make old arteries behave like young ones,"
said senior study investigator and geriatric cardiologist
Susan Zieman, an assistant professor at the
School of Medicine and its
Heart Institute. "There are many medications for
routine hypertension, and coronary artery disease or
atherosclerosis, which can lead to heart attack and heart
failure, but none that help counteract the aging of cells
inside the arterial walls that often precedes symptoms of
According to the American Heart Association, more than
65 million Americans have high blood pressure, most of it
of the systolic kind. In systolic hypertension, the
pressure or force of blood flow through the arteries is too
strong as blood is pumped by the heart's ventricles
(systole) to the rest of the body. Diastolic pressure, on
the other hand, is a measure of the pressure against
arterial walls when the heart is resting and refilling
The Johns Hopkins researchers found that alagebrium
reduced stiffening in the vessel wall in the carotid
artery, the main artery of the neck, by as much as 37
percent. The drug also improved endothelial function, the
ability of the vessels' inner lining to relax and dilate in
response to increased stress from blood flow, by 102
Chemically, alagebrium is a so-called crosslink
breaker, responsible for destroying the rigid chemical
bonds known as advanced glycation endproducts, or AGE for
short, that form between body proteins and sugars over
time. According to Zieman, both stiffening and reduced
capacity of the arteries to expand in response to stress
are common effects of aging that occur when the crosslinks
form in the body's key structural proteins, such as
collagen, or when AGEs interact directly with enzymes that
regulate blood flow.
Crosslinking effectively carmelizes the collagen
— found in all parts of the body, especially in the
skin, eyes, blood vessels and nerves — leading to
tissue "wrinkles" and cataracts, as well as stiffening and
increased speed and force of blood flow. These processes
are accelerated in diabetics whose blood sugar content is
As hypertension becomes chronic, aging blood vessels
lose their ability to stretch and relax between heartbeats.
The anti-wrinkle effects of a crosslink-breaker treatment
occur on facial skin because the compound similarly lets
collagen there relax, giving the skin a plumper, smoother
The Johns Hopkins findings, presented Nov. 15 at the
American Heart Association's Scientific Sessions 2005 in
Dallas, also suggest that the cellular effects of aging
caused by AGE are potent targets for new therapies.
In the study, 13 elderly men and women with systolic
hypertension took either daily doses of alagebrium (210
milligrams) for eight weeks or a placebo containing no
active drug. AGE and collagen levels were monitored through
blood tests. Stiffness was measured using a small
pressure-sensor device called a tonometer.
Ultrasound readings, taken before and after drug
therapy, were made as a blood pressure cuff was inflated
for five minutes and deflated. This allowed researchers to
calculate endothelial function based on how much the blood
vessel lining relaxed as a percentage increase of how much
the blood vessel could expand.
After treatment with alagebrium, neck arteries became
less stiff, as shown by tonometer readings and decreased
levels of collagen in the blood as AGE crosslinks were
broken down. Analysis of additional pressure-wave readings
also showed flatter patterns more closely resembling
younger arteries than older, stiffer ones, which have wave
patterns with higher peaks.
While the results did not explain why endothelial
function improved, the researchers believe it has to do
with the drug's effects on AGE and cell function. Their
theory, Zieman said, is that one chemical reaction, the
breakdown of AGE crosslinks, both reduces the structural
causes of arterial stiffness in the artery wall and
alleviates the detrimental effects of AGE on other enzymes
or related proteins, possibly nitric oxide and other
chemicals causing vessel inflammation, which are essential
to regulating heart and blood vessel function.
"These results confirm that this drug does have
important effects on the aging process in the arteries, but
we still have to prove that there's some benefit to
patients in terms of reducing cardiovascular disease,"
Zieman said. "Our next step will be a study, expected to
begin in late 2006, of the drug's potential benefit at
preventing or reversing heart failure in the elderly."
Alagebrium has been under investigational study since
1999, originally as a treatment for hypertension. While
clinical studies have demonstrated the drug's ability to
loosen up stiff arteries, two larger studies in older
people with hypertension have not shown significant results
in lowering blood pressure.
Funding for this study, which took one year to
complete, was provided by the National Heart, Lung and
Blood Institute, a member of the National Institutes of
Health. Medication was supplied free of charge by the
drug's manufacturer, Alteon of Parsippany, N.J.
Others participating in the study, in addition to
Zieman, were Vojtech Melenovsky, Lia Clattenburg, Mary
Corretti, Patricia Fitzgerald, Anne Capriotti, Gary
Gerstenblith and David Kass.