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DURHAM, N.C. -- The exceptions have always fascinated Duke
University Medical Center cardiologist Pascal Goldschmidt, M.D.
In the case of atherosclerosis, these exceptions --
specifically how some people's bodies can repair arterial
damage better than others -- might hold a key to a new way of
looking at the link between aging and the disease process in
general.

He cites as examples those individuals who smoke all their
lives but do not get cardiovascular disease, or those who have
always eaten an unhealthy diet but still make it to old age
with clear arteries.

Goldschmidt, chairman of the department of medicine, and
fellow cardiologist Eric Peterson, M.D., Duke Clinical Research
Institute, believe that medicine has spent so much time
investigating the risk factors for disease that they have
neglected to appreciate the other half of the equation -- the
body's innate ability to protect and repair itself.

"It is this relationship between the body's ability to keep
up with the cumulative damage it suffers over time that could
be the key to who gets sick and who stays healthy into old
age," Goldschmidt explained. "We believe that the key resides
in the bone marrow, which produces cells that can repair damage
to the body, and it is not until this restorative ability is
exhausted or overwhelmed that the disease process takes its
toll."

The researchers published their theory on the online
"Science of Aging Knowledge Environment" (SAGE KE),
(http://sageke.sciencemag.org/), a joint effort of the journal
Science and its publisher, the American Association for the
Advancement of Science (AAAS).

Said Peterson, "Age has always been considered a risk factor
for heart disease, but we haven't really understood why. Why do
some of us age faster than others? Why aren't the effects of
aging consistent from individual to individual? It may have to
do with the delicate balance between physical insults of daily
life and the ability to repair them.

"On one side of the equation are the factors that damage
blood vessels, like smoking, hypertension or high cholesterol,"
Peterson continued. "On the other side is the ability to repair
that damage -- people who can repair with a high degree of
success can withstand more damage and live longer."

Earlier this year (Circulation, July 29, 2003), Duke
researchers discovered that a major outcome of aging is an
unexpected failure of the bone marrow to produce progenitor
cells needed to repair and rejuvenate arteries exposed to a
genetically induced risk of high blood pressure in the mouse.
Stem cells are immature cells produced in the bone marrow that
have the potential to mature into a variety of different cells.
The researchers demonstrated that an age-related loss of these
particular stem cells – which reside in the marrow but are also
designed to repair arteries -- is critical to determining the
onset and progression of atherosclerosis, which causes arteries
to clog and become less elastic.

Goldschmidt and Peterson believe that it might ultimately be
possible to forestall or even prevent the development of
atherosclerosis by injecting these cells into patients: or to
retrain the patient's own stem cells to differentiate into
progenitor cells capable of arterial repair.

"Our studies indicate that the inability of bone marrow to
produce progenitor cells which repair and rejuvenate the lining
of the arteries drives the process of atherosclerosis and the
formation of plaques in the arteries," said Goldschmidt. "For a
long time we've known that aging is an important risk factor
for coronary artery disease, and we've also known that this
disease can be triggered by smoking, bad diet, diabetes, high
blood pressure, lack of exercise and other factors.

"However, if you compare the chance of having a heart attack
between someone who is over 60 with someone who is 20 with the
same risk factors, there is obviously something else going on
as well," he continued. "The possibility that stem cells may be
involved is a completely new piece of the puzzle that had not
been anticipated or appreciated before. These findings could be
the clue to help us explain why atherosclerosis complications
like heart attacks and strokes are almost exclusively diseases
of older people."

Once the repair cells from the marrow become deficient, the
inflammatory process that destroys arteries is no longer held
in check, said Goldschmidt.

"Over time, the damaged tissue is not repaired, so it
continues to send out biochemical signals to continue the
inflammatory response," he said. "It becomes a vicious cycle
with a deadly end."

The researchers believe that living organisms, including
humans, are born with a finite capacity for stem-cell-mediated
repair of damaged tissues -- capacity that is perhaps
determined by the genetic makeup of the individual. A reduction
in the consumption of these cells may represent an important
benefit of efficient preventative maneuvers such as diet and
exercise, the researchers said. While they have proven the role
of stem cells in repairing damaged arteries, they believe the
same situation could also hold true for other organ systems in
the body.

"A chronic problem in one organ system could divert cells
from another," Goldschmidt explained. "We know for example that
rheumatoid arthritis is a risk factor for cardiovascular
disease, so it may be the two are intimately related. The
chronic process of joint disease could consume stem cells that
could otherwise be used for the repair of the cardiovascular
system at a later time."

While the direct use of stem cells as a treatment might be
many years off, the researchers said it is likely that
strategies currently used to reduce the risks for heart disease
-- such as lifestyle modifications and/or different medications
-- preserve these rejuvenating stem cells for a longer period
of time, which delays the onset of atherosclerosis.

"For those people whose repair system is weak or
inefficient, it would be very important to minimize their risk
factors at a very early age," Peterson said.

"Our newly developing insight into the role of stem cells in
the disease process should write new chapters in our
understanding of the disease process," he said. "We really
don't truly understand repair and rejuvenation, yet they are
important factors in determining who is at risk for disease and
our ability to treat it."