X-Message-Number: 22204
Date: Tue, 15 Jul 2003 20:19:55 -0700 (PDT)
From: Doug Skrecky <>
Subject: breakthrough in understanding aging of the arteries (long)

Age-related Stem Cell Loss Prevents Artery Repair And Leads To Atherosclerosis

DURHAM, N.C. - Aging has long been recognized as the worst risk factor
for chronic ailments like atherosclerosis, which clogs arteries and leads
to heart attacks and stroke. Yet, the mechanism by which aging promotes
the clogging of arteries has remained an enigma.
 Scientists at Duke University Medical Center have discovered that a major
problem with aging is an unexpected failure of the bone marrow to produce
progenitor cells that are needed to repair and rejuvenate arteries
exposed to such environmental risks as smoking or caloric abuse.
 The researchers demonstrated that an age-related loss of particular stem
cells that continually repair blood vessel damage is critical to
determining the onset and progression of atherosclerosis, which causes
arteries to clog and become less elastic. When atherosclerosis affects
arteries supplying the heart with oxygen and nutrients, it causes coronary
artery disease and puts patients at a much higher risk for a heart
attack.
 The researchers' novel view of atherosclerosis, based on experiments in
mice, constitutes a potential new avenue in the treatment of one of the
leading causes of death and illness in the U.S., they said. Just as
importantly, they continued, this loss of rejuvenating cells could be
implicated in a broad range of age-related disorders, ranging from
rheumatoid arthritis to chronic liver disease.
 The results of the Duke research were posted early (July 14, 2003) on the
website of the journal Circulation. The study will appear in the July 29,
2003, issue of the journal.
 At issue is the role of stem cells, which are immature cells produced in
the bone marrow that have the potential to mature into a variety of
different cells. The Duke team examined specific stem cells known as
"bone-marrow-derived vascular progenitor cells" (VPCs).
 The researchers believe that it might ultimately be possible to
forestall or even prevent the development of atherosclerosis by injecting
these cells into patients, or to induce 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 Duke cardiologist Pascal Goldschmidt, M.D., chairman of
the Department of Medicine. "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 and other factors. "But if you compare 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."
In their experiments, the Duke team used mice specially bred to develop
severe atherosclerosis and high cholesterol levels. The researchers
injected bone marrow cells from normal mice into these
atherosclerosis-prone mice numerous times over a 14-week period. As a
control, an equal of number of the same kind of atherosclerosis-prone mice
went untreated.
 After 14 weeks, the mice treated with the bone marrow cells had
significantly fewer lesions in the aorta, despite no differences in
cholesterol levels. Specifically, the researchers detected a 40-60
percent decrease in the number of lesions in the aorta, the main artery
carrying blood from the heart.
 Using specific staining techniques on the aortas, the researchers were
able to determine that the donor bone marrow cells "homed in" on areas
where atherosclerotic lesions are most common, especially where smaller
vessel branches take off from larger vessels. These areas tend to
experience "turbulence" of blood.
 When the researchers examined the vessels under a microscope, it appeared
that the bone marrow cells not only migrated to where they were needed
most, but that they differentiated into the proper cell types. Some
turned into endothelial cells lining the arteries, while others turned
into the smooth muscle cells beneath the endothelium that help strengthen
the arteries.
 To further prove that the donor bone marrow cells were responsible for
rejuvenating arteries, the scientists measured in the endothelial cells
the lengths of structures known as telomeres at the end of chromosomes.
They found that the telomeres in the endothelial cells were longer in the
treated mice than the untreated mice. Over time, telomeres are known to
shorten as the organism ages.
 The researchers also injected these atherosclerotic mice with donor cells
from older mice as well as from younger, pre-atherosclerotic mice.
"We found that the bone marrow cells from the young mice had a nearly
intact ability to prevent atherosclerosis, while the cells from the older
mice did not," Goldschmidt explained. "This finding suggests that with
aging, cells capable of preventing atherosclerosis that are normally
present in the bone marrow became deficient in the older mice that had
developed atherosclerosis."
 Once the repair cells from the marrow become deficient, inflammation
develops and leads to increase in inflammation markers (such as CRP). By
providing competent bone marrow cells, the investigators were able to
suppress the inflammation and its blood markers.
 While the direct use of stem cells as a treatment may 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 the collection of these
rejuvenating stem cells for a longer period of time, which delays the
onset of atherosclerosis.
 For Goldschmidt, a major question is whether researchers can somehow use
these cells to restore the integrity of the circulatory system of
patients who already have a lifetime of atheroslerosis. "We need to look
at the possibility of re-training stem cells that would otherwise be
targeted to a different organ system to help repair the cardiovascular
system," he said. "Another interesting question is whether rheumatoid
arthritis, as an example of chronic inflammatory disorders, causes stem
cell loss, since such arthritis is a risk factor for coronary artery
disease. The chronic process of joint disease could consume stem cells
that could otherwise be used for the repair of the cardiovascular system.
We are just beginning to appreciate the links between stem cells and
cardiovascular disease."

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