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Gene Mutation Causes People to Live
Longer Lives
Researchers Find it in Centenarians and Their Children
 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.
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Dr. Nir Barzilai
His notes on research are below
the article |
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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.
Notes by Dr.Nir Barzilai
on the research.
Searching for
Longevity Genes in Humans
Why do some people live much longer than the others? What allows these
individuals to escape age-associated diseases that contribute to
mortality in the elderly? Is this a result of favorable genes or a
healthy life style? If there is a role for genes, what are the
mechanisms?
To address these questions, rather than investigating
age-related phenotype and disease, we chose a model of exceptional
longevity, i.e being ~100 years of age. We recruited nearly 800
Ashkenazi Jews. The Ashkenazi Jewish population is unique as it is
derived from a small number (several thousands) of founders. External
factors such as ecclesiastical edicts prohibiting all social contact
with Jews , the Crusades, the establishment of the Pale
of Settlement, numerous Pogroms, and ethnic bigotry resulted in social
isolation and inbreeding of the Ashkenazi Jews and led this population
through a genetic bottleneck resulting in founder effects. This
population has been utilized for identification of several genes, a
prominent example being the breast cancer (BRCA1) gene.
We divided our subjects into three groups; probands (average
age ~100 years old) with exceptional longevity (1; 10000 in
population); their offspring; and a control group consisting of
spouses of the offspring and a group of age-matched Ashkenazi Jewish
people recruited from the Einstein Aging Study.
We studied their genetic and metabolic profile. We found
certain physiological characteristics in our unique population such as
high levels of High-density lipoprotein (HDL) as well as extremely
large particle sizes of HDL and low-density lipoprotein (LDL) compared
to control group. This phenotype is associated with a lower prevalence
of hypertension, CVD, the metabolic syndrome, and homozygosity. This
phenotype suggested a search for mutations in candidate genes,
resulting in discovering a very high frequency of homozygosity in the
Cholestryl Ester Transfer Protein (CETP) gene.
Recently we used novel genetic screens such as analysis of
SNPs sites and genechip mapping techniques to identify mutations in
new, uncharacterized genes that may be linked to diseases of aging
such as cardiovascular disease and cancers. We hope this can explain
this novel trait and desirable state defined as longevity. In the near
future we plan to extend our usage of recently developed genetic
technologies.
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