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.
Dr.
Nir Barzilai
His
notes on research are below the article
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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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 