February 21, 2003
Aged Blood Stem Cells Indicator For Cardiovascular Disease Risk

The levels of a type of adult stem cells called endothelial progenitor cells are inversely correlated with cardiovascular disease risk.

Levels of a type of adult stem cell in the bloodstream may indicate a person's risk of developing cardiovascular disease, according to a study supported by the National Heart, Lung, and Blood Institute (NHLBI), part of the National Institutes of Health in Bethesda, MD.

The study looked at the blood level of endothelial progenitor cells, which are made in the bone marrow and may help the body repair damage to blood vessels. Scientists from NHLBI and Emory University Hospital in Atlanta, GA, found that cardiovascular disease risk was higher in persons with fewer endothelial progenitor cells. The cells of those at higher risk also aged faster than those at lower risk, as determined by the Framingham Heart Study risk factor score, a standard measurement of cardiovascular risk. Additionally, the study found that blood vessels were much less likely to dilate and relax appropriately in persons with low levels of the cells.

Results of the study, which involved 45 healthy men aged 21 and older, some of whom had standard cardiovascular risk factors, appear in the February 13, 2003, issue of The New England Journal of Medicine. The two main forms of cardiovascular disease are heart disease and stroke. Standard heart disease risk factors are age, family history of early heart disease, smoking, high blood pressure, high blood cholesterol, overweight/obesity, physical inactivity, and diabetes.

"Past research on cardiovascular disease has often focused on what causes the damage to the blood vessels," said Dr. Toren Finkel, chief of NHLBI's Cardiology Branch and coauthor of the study. "We looked at the other part of the equation: How does the body repair damaged blood vessels? What does that tell us about the cause of the disease?

"We believe that these endothelial progenitor cells patch damaged sites in blood vessel walls," he continued. "When the cells start to run out, cardiovascular disease worsens. We don't yet know what causes their depletion but it may be related to the fact that the risk of cardiovascular disease increases as people age. For instance, the cells may be used up repairing damage done by other risk factors or those risk factors could directly affect the survival of the endothelial cells themselves.

"Much more research needs to be done to better understand this finding," Finkel added. "But it's possible that, some day, doctors may be able to test a person's risk of cardiovascular disease by taking a blood sample and measuring these cells. If the level is too low, an injection of endothelial cells might boost the body's ability to repair itself and prevent more blood vessel damage."

The decline in endothelial progenitor cells may be due an aging process that has left those stem cells less able to divide and make new cells for blood vessel repair.

In order to test their hypothesis that endothelial progenitor cells age prematurely in individuals with higher cardiovascular risk factors, the investigators studied endothelial progenitor cells from subjects with either high or low Framingham risk scores. After seven days in culture, a significantly higher number of cells from the high-risk subjects had characteristics of senescence, or aging.

"Cardiovascular health is dependent on the ability of the blood vessels to continually repair themselves," says Arshed Quyyumi, MD, professor of medicine at Emory University School of Medicine, formerly of the NHLBI, and a member of the research team. "Evidence has shown that cardiovascular risk factors ultimately lead to damage to the endothelial layer of blood vessels. We can now speculate that continuing exposure to cardiovascular risk factors not only damages the endothelial layer, but may also lead to the depletion of circulating endothelial progenitor cells. Thus, the net damage to blood vessels and hence the risk of developing atherosclerosis depends not only on the exposure to risk factors, but also on the ability of the bone marrow-derived stem cells of endothelial origin to repair the damage.

"We will need larger studies to determine a definite cause and effect relationship between a decrease in these cells and adverse cardiovascular events. Our study did demonstrate, however, a correlation between endothelial progenitor cells, cardiovascular risk factors, increased senescence of endothelial progenitor cells, or stem cells, and vascular function. We are hopeful that further research will show that endothelial progenitor cells are a useful marker for cardiovascular disease risk."

Here's part of what might be going on here: in someone who has cardiovascular risk factors the endothelial progenitor cells (which are a type of non-embryonic stem cell) may need to divide at a faster rate in order to repair the damage being done to cells in the endothelial layer of blood vessels. The need to divide at a faster rate basically may be causing the endothelial progenitor cells to age more rapidly.

If the endothelial progenitor cells divide more rapidly in response to damage caused by cardiovascular risk factors then the telomeres on their chromosomes shrink more rapidly and the cells will lose the ability to divide sooner. Short telomeres are a marker for increased risk of mortality. This latest result suggests one reason why: blood vessels can not be repaired as well and this will increases the risk of heart disease and stroke.

Another reason why some people have lower levels of endothelial progenitor cells may be because they started life with shorter telomeres. Whether the telomeres are shrinking more rapidly or starting out shorter it is likely that short telomeres are at least one of the causes of the senescence of endothelial progenitor cells. It would be very interesting to test the cells of those with lower and higher Framingham heart disease risk scores and see if those with higher risk scores have shorter telomeres in their endothelial progenitor cells and in other blood cell types.

What can be done about this? A direct approach would be to remove stem cells, lengthen their telomeres, and then return those cells into the body. This approach might increase the risk of cancer unless accompanied with other techniques to assure that the cells so treated do not have any mutational damage that makes them prone to become cancerous. Another approach would be to use stem cells from embryos to replace host blood stem cells. But that approach elicits strong ethical objections from some quarters. Its not clear that therapeutic cloning or the harvesting of stem cells from aborted embryos will ever be allowed i the United States.

This latest result is further evidence for the idea that reseeding non-embryonic stem cell reservoirs with more youthful stem cells will be an essential technique for reversing aging.

Update: Statins may provide part of their benefit by boosting endothelial progenitor cells.

Quyyumi noted a class of drugs called statins, used to lower high cholesterol levels and reduce the risk of developing heart disease, have been shown to triple the levels of these stem cells.

This is an interesting twist. If telomere shortening was causing the stem cells to become senescent then one wouldn't expect a drug that lowers cholesterol to boost the levels of these cells.

Share |      Randall Parker, 2003 February 21 07:37 PM  Aging Reversal


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