Health for life

Researchers at the Linda Crnic Institute for Down Syndrome and the University of Colorado School of Medicine have found that a single mechanism may underlie the damaging effect of cholesterol on the brain and on blood vessels.

High levels of blood cholesterol increase the risk of both Alzheimers disease and heart disease, but it has been unclear exactly how cholesterol damages the brain to promote Alzheimers disease and blood vessels to promote atherosclerosis.

Using insights gained from studying two much rarer disorders, Down Syndrome and Niemann Pick-C disease, researchers at the Linda Crnic Institute for Down Syndrome and the Department of Neurology of the University of Colorado School of Medicine found that cholesterol wreaks havoc on the orderly process of cell division, leading to defective daughter cells throughout the body.

In the new study published this week in the on-line journal PLOS ONE, Antoneta Granic, PhD, and Huntington Potter, PhD, show that cholesterol, particularly in the LDL form, called bad cholesterol, causes cells in both humans and mice to divide incorrectly and distribute their already-duplicated chromosomes unequally to the next generation. The result is an accumulation of defective daughter cells with the wrong number of chromosomes and theore the wrong number of genes. Instead of the correct two copies of each chromosome, and thus two copies of each gene, some cells acquired three copies and some only one.

Granic and Potters study of the effects of cholesterol on cell division included a prominent finding of cells carrying three copies of the chromosome (#21 in humans and #16 in mice) that encodes the amyloid peptide that is the key component of the neurotoxic amyloid filaments that accumulate in the brains of Alzheimer patients.

Human trisomy 21 cells are significant because people with Down syndrome have trisomy 21 in all of their cells from the moment of conception, and they all develop the brain pathology and many develop the dementia of Alzheimers disease by age 50. Earlier studies by Granic, Potter and others have shown that as many as 10% of cells in an Alzheimer patient, including neurons in the brain, have three copies of chromosome 21 instead of the usual two. Thus, Alzheimers disease is, in some ways, a form of acquired Down syndrome. Furthermore, mutant genes that cause inherited Alzheimers disease cause the same defect in chromosome segregation as does cholesterol, thus indicating the presence of a common cell division problem in both familial and sporadic (non-familial) Alzheimers disease.

The new research also found trisomy 21 neurons in the brains of children with what, until now, was thought to be an unrelated neurodegenerative disease (Niemann Pick type C), caused by a mutation affecting cholesterol physiology. This result suggests that neurodegeneration itself might be linked to chromosome missegregation.

Such a model is supported by the finding of Thomas Arendt, MD, and colleagues at the University of Leipzig that 90% of the neuronal cell death observed at autopsy in Alzheimer patients is due to the creation and selective loss of neurons with the wrong number of chromosomes.

Identifying the specific problem caused by cholesterol will lead to completely new approaches to therapy for many human diseases, including Alzheimers disease, atherosclerosis and possibly cancer, all of which show signs of defective cell division. Granic and Potter already have found a potentially simple approach to preventing cholesterol from causing cells to distribute their chromosomes unequally into their new daughter cells. Specifically, when cells in culture were first treated with ethanol, the subsequent exposure to bad cholesterol was without effect on cell division: Each daughter cell received the correct number of chromosomes.

Researchers publishing in the journal Nutrition show that Omega-3 fatty acids found in fish and natural foods including nuts and seeds can lower levels of dangerous homocysteine, an amino acid linked with increased risk of cardiovascular disease and dementia. Reviewing data from eleven trials including more than 720 study participants, scientists found that introducing Omega-3 fats from dietary or supplemental sources were associated with significantly lowered levels of plasma homocysteine.

Study shows clear benefits of a healthy diet, exercise, maintaining normal weight and not smoking

A large, multi-center study led by Johns Hopkins researchers has found a significant link between lifestyle factors and heart health, adding even more evidence in support of regular exercise, eating a Mediterranean-style diet, keeping a normal weight and, most importantly, not smoking.

The researchers found that adopting those four lifestyle behaviors protected against coronary heart disease as well as the early buildup of calcium deposits in heart arteries, and reduced the chance of death from all causes by 80 percent over an eight-year period. Results of the study, "Low-Risk Lifestyle, Coronary Calcium, Cardiovascular Events, and Mortality: Results from the Multi-Ethnic Study of Atherosclerosis," are described in an online article posted June 3, 2013 by the American Journal of Epidemiology.

"To our knowledge, this is the first study to find a protective association between low-risk lifestyle factors and early signs of vascular disease, coronary heart disease and death, in a single longitudinal evaluation," says Haitham Ahmed, M.D., M.P.H., the lead author who is an internal medicine resident with the Ciccarone Center for the Prevention of Heart Disease at Johns Hopkins.

"We evaluated data on more than 6,200 men and women, age 44-84, from white, African-American, Hispanic and Chinese backgrounds. All were followed for an average of 7.6 years. Those who adopted all four healthy behaviors had an 80 percent lower death rate over that time period compared to participants with none of the healthy behaviors," says Ahmed.

Study participants all took part in the ongoing Multi-Ethnic Study of Atherosclerosis (MESA), a prospective examination of the risk factors, prevalence and prevention of cardiovascular disease. MESA participants were recruited from six academic medical centers and did not have a diagnosis of cardiovascular disease when they were enrolled.

All participants had coronary calcium screening using computed tomography (a CT scan) when they were first enrolled in the study to see if there were early signs of calcium deposits in their heart arteries that are known to contribute to heart attack risk. As the study progressed, the researchers also assessed whether the participants had a heart attack, sudden cardiac arrest, chest pain, angioplasty or died due to coronary heart disease or other causes.

The researchers developed a lifestyle score for each of the participants, ranging from 0 (least healthy) to 4 (healthiest), based on their diet, body mass index (BMI), amount of regular moderate-intensity physical activity and smoking status. Only 2 percent, or 129 participants, satisfied all four healthy lifestyle criteria.

"Of all the lifestyle factors, we found that smoking avoidance played the largest role in reducing the risk of coronary heart disease and mortality," says Roger Blumenthal, M.D., a cardiologist and professor of medicine at the Johns Hopkins University School of Medicine, director of the Ciccarone Center and senior author of the study. "In fact, smokers who adopted two or more of the healthy behaviors still had lower survival rates after 7.6 years than did nonsmokers who were sedentary and obese."

Blumenthal, who is also the president of the American Heart Associations Maryland affiliate, says the findings "bolster recent recommendations by the American Heart Association, which call for maintaining a diet rich in vegetables, fruits, nuts, whole grains and fish, keeping a BMI of less than 25, being physically active and not smoking."

The researchers emphasize that their study shows the importance of healthy lifestyle habits not just for reducing the risk of heart disease, but also for preventing mortality from all causes.

"While there are risk factors that people cant control, such as their family history and age," says Ahmed, "these lifestyle measures are things that people can change and consequently make a big difference in their health. Thats why we think this is so important."