First Longevity Gene Discovered

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.

The gene in question also governs a single amino acid in a protein that leads to the production of larger high-density lipoprotein (HDL) and low-density lipoprotein (LDL) particles. HDL is often referred to as “good” cholesterol, and LDL has the moniker of “bad” cholesterol. Apparently, these larger molecules protect against many diseases of aging, including heart disease, stroke and diabetes.

The larger the particles, the lower the odds of becoming sick. The researchers reached this conclusion following a previous study, in which they discovered a higher than average rate of the good HDL cholesterol in the blood of families of centenarians.

“An ordinary person, even if he eats right and exercises a lot, can only raise the rate of his good cholesterol by 10 percent. The normal HDL values are about 55 for women and 45 for men. In our research, we discovered that in half of the children of the centenarians had significantly higher HDL levels than the rest of the population.” Barzilai told Ha’aretz

“The good cholesterol plays a part in eliminating fats from the body,” says Barzilai. “But it also has independent purposes of its own. For example, HDL can act as an antioxidant in the cells, and oxidation is one of the processes involved in aging.”

From his research he found that 80 percent of the centenarians had very large cholesterol molecules, as did about half of their offspring. “It appeared that there were a few genes that regulate the size of the cholesterol particles, so we started to focus on them. We used different technical methods, and then we hit the bull’s-eye.”

“We think the larger cholesterol particles prevent fats from adhering to the sides of the arteries. Small particles adhere to the arteries much more easily. Our research showed that people with larger particles have a lower incidence of heart attacks, high blood pressure and metabolic syndrome (a precursor of diabetes). This genetic mutation also appears to be beneficial in warding off Alzheimer’s disease. When centenarians are given cognitive tests, those with the mutation always pass the test. Those with the smaller particles do less well on it. This tells us that the gene also protects brain function,” he told Ha’aretz.

Barzilai was the chief medic of the Israeli army before enrolling in the Israel Institute of Technology Medical School in 1985. As a medical student he provided medical assistance at third world locations, such as at a refugee camp in Cambodia (1979-80) and at a clinic of the Kwazulu homeland in Africa (1983), and conducted biomedical research at Baylor College, NIH, and The Royal Free Hospital in London. His residency was in Medicine and Geriatrics at Hadassah Hospital (Hebrew University) and at Yale University. His residency was in Medicine and Geriatrics at Hadassah Hospital (Hebrew University) and at Yale University.
Barzilai then trained in Endocrinology and Molecular Biology at Cornell University Medical College and at The Albert Einstein College of Medicine.

Barzilai’s 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 Barzilai. “Furthermore, finding this mutation in both the centenarians and their offspring suggests that the mutation may be inherited.”

“We know that centenarians in many cases seem to miss getting the major diseases that kill a lot of other people at much younger ages,” says Winifred K. Rossi, special assistant for planning at the National Institute on Aging, which helped fund the study. “The question is why are these people so good, and what are the protective factors that help them get away from those major diseases.”

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 Barzilai.

Interviewed in Ha’aretz two years ago, Barzilai “cautiously” predicted that a longevity gene would be discovered within five years, and that a longevity drug would be developed within 10. As it turned out, these developments are occurring much faster than predicted. Barzilai’s goal is to prevent chronic and debilitating age-related diseases: “Unfortunately” he told Ha’aretz this week, “my research may lead to longevity and not only to better health, but this was not my intention.”

Several drug companies, among them Pfizer, the company that developed Viagra, is currently developing a drug to reduce fats in the blood. One effect of using the drug – an increase in “good” cholesterol particles – is identical to what happens during genetic mutation. Pfizer developed its drug unaware of the potential contribution to longevity that an increase in these particles could have. Barzilai was the one who informed the company of the drug’s prospective benefit. The drug is now in the third stage of the U.S. Food and Drug Administration’s approval process, which means that, within a year or two, Pfizer could receive permission to market the drug.