October 16, 2003
Genetic Variation For Big Cholesterol Molecules Increases Longevity

A genetic variation of a cholesterol metabolism protein increases cholesterol particle size and seems to slow the aging process.

October 15, 2003 -- (BRONX, NY) -- Researchers at the Albert Einstein College of Medicine of Yeshiva University 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."

Keep in mind that slightly over half of the long-lived did not have this cholesterol size boosting genetic variation. Likely there are a number of genetic variations in a variety of genes that affect longevity.

Want another 20 years of life?

"Large particle size seems to give people an extra 20 years of life, with very little disability to go along with it," said Dr. Nir Barzilai, who directed the study at the Albert Einstein College of Medicine in the Bronx.

Another 20 years would be great. During those 20 additional years more medical advances will happen that will increase your odds of living even longer. How could this be done? CETP is made in the liver and released into the blood. Possibly a drug could be developed to either mirror the effects of CETP in the blood or interact with it to change its shape or to increase its synthesis and release from the liver. But another strong possibility would be the development of a gene therapy to do to liver cells to provide one's body with the variation of Cholestryl Ester Transfer Protein that increases cholesterol particle size. One thing you can do now: exercise.

One caveat: A person who has large cholesterol particles from birth is going to age more slowly from the very start. A person first getting a treatment to increase cholesterol particle size at age 50 will already have 50 years of aging at a faster rate due to smaller cholesterol particles. So the benefit will not be as great for anyone who gets some future cholesterol particle boosting treatment later in life.

When people who have been sedentary start performing regular exercise, their L.D.L. particles grow bigger, as shown by Dr. William E. Kraus, a cardiologist at the Duke University Medical Center, and his colleagues a year ago in a study of people 40 to 65.

Some of the long-lived with the CETP genetic variation for large cholesterol particles are cigarette smokers.

Though Barzilai doesn't endorse smoking, he noted that the cholesterol mutation exerted such a powerful protective effect that many of his volunteers never developed lung disease despite decades of puffing cigarettes and cigars.

Among his volunteers was a 95-year-old woman who had smoked since she was 8 and who - not coincidentally- has a 100-year-old sister and a brother who's 97.

Expect more reports of this sort where life-extending genetic variations are identified. Each one will become a target of either drug development, gene therapy development, or both.

Share |      Randall Parker, 2003 October 16 12:14 PM  Aging Reversal

Bob Badour said at October 18, 2003 7:06 AM:

Those who start late can still reverse some of the plaques they have already grown. Tocotrienols combined with tocopherols can reverse recent plaque formation. I expect we will develop methods to reverse even archaic plaque, and of course there is always bypass surgery.

Yaser R. alshaikh said at December 25, 2003 12:56 PM:

I think it is anice article.
thanking your good self for such a puplication.

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