Einstein Researchers, in Jama Report, Identify Gene Connected to Human Aging and Exceptional Longevity

Dr. Nir Barzilai

Bronx, NY, Oct 15, 2003 — Researchers at the Albert Einstein College of Medicine and colleagues have discovered that a gene mutation helps people live exceptionally long lives and apparently can be passed from one generation to the next. The scientists, led by Dr. Nir Barzilai, director of the Institute for Aging Research at Einstein, report their findings in the October 15, 2003 issue of the Journal of the American Medical Association (JAMA).

The mutation alters the Cholestryl Ester Transfer Protein (CETP), an enzyme involved in regulating lipoproteins and their particle size. Compared with a control group representative of the general population, centenarians were three times as likely to have the mutation (24.8 percent of centenarians had it vs. 8.6 percent of controls) and the centenarians’ offspring were twice as likely to have it.

CETP affects the size of “good” HDL and “bad” LDL cholesterol, which are packaged into lipoprotein particles. The researchers found that the centenarians had significantly larger HDL and LDL lipoprotein particles than individuals in the control group. The same finding held true for offspring of the centenarians but not for control-group members of comparable ages.

Evidence increasingly indicates that people with small LDL lipoprotein particles are at increased risk for developing cardiovascular disease, the leading cause of death in the United States and the Western world. Dr. Barzilai and his colleagues believe that large LDL particles may be less apt than small LDL particles to penetrate artery walls and promote the development of atherosclerosis, a major contributor to heart disease and stroke. Their study found that HDL and LDL particles were significantly larger in those offspring and control-group members who were free of heart disease, hypertension and the metabolic syndrome (a pre-diabetic condition that increases risk for cardiovascular disease).

The research team studied people of Ashkenazic (Eastern European) Jewish descent because of the group’s genetic homogeneity — it had a small number of “founders” and was socially isolated for hundreds of years. Studying a group of genetically similar people speeds the identification of significant genetic differences and limits the amount of genetic “noise” that can result when examining more heterogeneous groups. (The research team also included scientists from the University of Maryland School of Medicine; Tufts University; Boston University School of Medicine; and Roche Molecular Systems Inc.)

To identify the biological and genetic underpinnings of exceptional longevity, the researchers studied 213 individuals between the ages of 95 and 107, along with 216 of their children. For comparison, they looked at 258 spouses of the offspring and their neighbors.

“These results are significant because they mean that the mutation of the CETP gene is clearly associated with longevity,” says Dr. Barzilai. “Furthermore, finding this mutation in both the centenarians and their offspring suggests that the mutation may be inherited.”

Dr. Barzilai notes that many studies have looked at the risk factors associated with developing age-related diseases. “But to date,” he notes, “little effort has been made to identify the reasons for longevity in exceptionally old people or, more specifically, their absence of disease. In studying these centenarians and their offspring, we hoped to learn what factors diminish their risk for diseases that affect the general population at a much younger age. We don’t have all the answers for why some people live healthily into their tenth and eleventh decades, but our findings bring us a step closer to understanding the role that genes play in longevity.”

The next step for the researchers is to try to develop drugs that mimic the effects of the CETP gene mutation and, ultimately, to test them on people who lack the mutation. “In this way, we can focus on preventing or delaying the onset of age-related diseases, which can help give people a better quality of life as they get older,” notes Dr. Barzilai.

Funding for the research was provided by the National Institute on Aging, Ellison Medical Foundation, Albert Einstein College of Medicine, and the Paul Beeson Physician Faculty Scholar in Aging Award.

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