Exceptional Longevity in Humans Accurately Predicted
from Genetic Signatures
Exceptional longevity may be the result of an
enrichment of longevity-associated variants that counter the effect of
disease-associated variants
July 8, 2010 - While environment and family history
are factors in healthy aging, genetic variants play a critical and
complex role in conferring exceptional longevity, according to a new
landmark study by a team of researchers from the Boston University
Schools of Public Health and Medicine and the Boston Medical Center.
The research team identified a group of genetic
variants that can predict exceptional longevity in humans with 77
percent accuracy a breakthrough, they say, in understanding the role
of genes in determining human lifespan.
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Based upon the hypothesis that exceptionally old
individuals are carriers of multiple genetic variants that influence
their remarkable survival, the team conducted a genome-wide association
study of centenarians. Centenarians are a model of healthy aging, as the
onset of disability in these individuals is generally delayed until they
are well into their mid-nineties.
Researchers led by Paola Sebastiani, PhD, a
professor of biostatistics at the BU School of Public Health and Thomas
Perls, MD, MPH, associate professor of medicine at the BU School of
Medicine and a geriatrician at Boston Medical Center, built a unique
genetic model that includes 150 genetic variants, known as single
nucleotide polymorphisms (SNPs).
They found that these 150 variants could be used to
predict if a person survived to very old ages (late 90s and older) with
a high rate of accuracy, according to the study released July 1 online
by the journal Science.
19 Genetic Signatures of Exceptional Longevity
In addition, the team's analysis identified 19
genetic clusters or "genetic signatures" of exceptional longevity that
characterized 90 percent of the centenarians studied. The different
signatures correlated with differences in the prevalence and
age-of-onset of diseases such as dementia and hypertension, and may help
identify key subgroups of healthy aging, the authors said.
Notably, the team found that 45 percent of the
oldest centenarians those 110 years and older had a genetic
signature with the highest proportion of longevity-associated genetic
variants.
"These genetic signatures are a new advance towards
personalized genomics and predictive medicine, where this analytic
method may prove to be generally useful in prevention and screening of
numerous diseases, as well as the tailored uses of medications," said
Dr. Perls, founder and director of the New England Centenarian Study
(www.bumc.bu.edu/centenarian).
The researchers developed a novel Bayesian
statistical approach to analyze genotype data from more than 1,000
centenarians and several control groups, and to identify those SNPs that
were most predictive of being centenarians or controls. The team began
by using the SNPs that were most likely associated with exceptional
longevity, and once the researchers identified 150 SNPs, they found that
adding more variants did not further improve the ability to predict
whether a person was a centenarian or a control subject.
"The methodology that we developed can be applied
to other complex genetic traits, including Alzheimer's disease,
Parkinson's, cardiovascular disease and diabetes. It reinvigorates the
potential high utility of collecting and analyzing such data," according
to Dr. Sebastiani.
Disease-Associated Variants
Besides looking at which genetic variants were
associated with longevity, the authors looked into whether the absence
of disease-associated variants also played an important role. They did
this by analyzing how many disease-associated variants each centenarian
had, compared to each of the controls. Their analysis found little
difference between the two groups, suggesting that the presence of
genetic variants associated with longevity is of more importance than
the absence of disease-associated variants.
If these findings are confirmed, they would suggest
that "predicting disease risk using disease-associated variants may be
inaccurate and potentially misleading, without more information about
other genetic variants that could attenuate such risk" the authors
commented.
Overall, the authors said, their preliminary data
"suggest that exceptional longevity may be the result of an enrichment
of longevity-associated variants that counter the effect of
disease-associated variants and contribute to the compression of
morbidity and/or disability towards the end of these very long lives."
They added that "further investigation is needed to
understand how and why these variants collectively predispose for
exceptional longevity."
The researchers noted that the 77-percent accuracy
rate of predictions "shows that genetic data can indeed predict
exceptional longevity without knowledge of any other risk factor."
But they added: "This prediction is not perfect,
however, and although it may improve with better knowledge of the
variations in the human genome, its limitations confirm that
environmental factors (e.g., lifestyle) also contribute in important
ways to the ability of humans to survive to very old ages."
Drs. Sebastiani and Perls also cautioned that they
developed this genetic risk model as a way to dissect the complex
genetic bases of exceptional longevity and to discover the different
genetic paths to age 100 and older. An understanding of the implications
of this model's use in the general population would be necessary before
this test is marketed, they said.
The study was funded by grants from the National
Institute of Aging (NIA) and the National Heart Lung and Blood Institute
(NHLBI) of the National Institutes of Health (NIH).
"This is a novel approach to studying genetic
contributions to exceptional longevity," said Winifred K. Rossi, deputy
director of the NIA's Division of Geriatrics and Clinical Gerontology.
"It adds to a growing set of analytical tools that
aim to identify and understand the complex genetic and environmental
factors that lead to healthy long life."
In addition to Perls and Sebastiani, other authors
include: Nadia Solovieff and Stephen W. Hartley of the BU School of
Public Health Biostatistics Department; Daniel A. Dworkis, Efthymia
Melista and Monty Montano of the BU School of Medicine Department of
Medicine; Jemma B. Wilk and Richard H. Myers of the BU School of
Medicine Department of Neurology; Martin H. Steinberg and Clinton T.
Baldwin of the BU School of Medicine Departments of Medicine and
Pediatrics and Boston Medical Center; Stacy Anderson of the BU School of
Medicine Department of Medicine, Section of Geriatrics, and Boston
Medical Center; and Annibale Puca of IRCCS Multimedica, Milano, Italy.
Keep up with the latest news for senior citizens, baby
boomers
July 8, 2010 - While environment and family history
are factors in healthy aging, genetic variants play a critical and
complex role in conferring exceptional longevity, according to a new
landmark study by a team of researchers from the Boston University
Schools of Public Health and Medicine and the Boston Medical Center.
