Dec. 4, 2003 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."
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