March 9, 2010
L’Chaim! Want to live to 100? Check your genes.
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Barzilai and his colleagues tested blood samples from the centenarians, their children and the control group. In a study published in the October 2003 edition of the Journal of the American Medical Association (JAMA), they demonstrated that centenarians and their offspring were more likely to have a specific variation of the gene that regulates cholesteryl ester transfer protein (CETP), a protein that moves fat and cholesterol through the body, including high-density lipoproteins (HDL, or good cholesterol) and low-density lipoproteins (LDL, or bad cholesterol).
Because of this variation, the centenarians and their children had more HDL in their blood and larger lipoprotein particle sizes than the control group, indicating that this genetic mutation has a positive impact on longevity. About 8 percent of the general population has this variation, but it was present among 24 percent of the centenarians and their children.
The finding was exciting, but it didn’t address one of Barzilai’s primary concerns: quality of life.
“If I ask you if you want to be 100,” he said, “and [whether] you want to get there with just your body or also with your brain, you might choose to do it with cognitive function intact.”
And many of the centenarians were doing just that – in addition to good physical health, most, like Biderman, also retained their memory and wit.
The CETP gene, in which researchers had just identified a variation affecting longevity, happens to share some characteristics with a gene linked to Alzheimer’s— the apolipoprotein (APOE) allele. Based on this knowledge, the researchers initiated a new study that would ultimately follow 523 subjects of mixed ethnicities and religious backgrounds over the course of 4.3 years, to find out whether CETP also played a role in the development of age-related diseases that lead to cognitive decline.
Throughout the course of the study, the researchers tracked which participants developed dementia and Alzheimer’s. In a study published in January of this year in JAMA, they demonstrated that, indeed, the same genetic variation that causes higher levels of good cholesterol may also protect carriers from developing Alzheimer’s – a protection, said Barzilai, of up to 70 percent.
At UCLA, Cohen has been grappling with similar issues. His research, which touches on aging in a slightly more peripheral manner, has ranged from prostate cancer to cerebral palsy. It was primarily his work with diabetes, though, that led his path to continually cross with Barzilai’s over the years.
“We’ve been collaborating for 25 to 30 years,” said Cohen, adding that their association began when they attended the Israel Institute of Technology together in the 1980s. “[But] the work that led to the most current and exciting discovery is something we started doing about five or six years ago.”
At that time, Barzilai had already assembled his cohort of centenarians, and Cohen had been studying a naturally occurring protein in the body called humanin.
Humanin had previously been shown to slow the death of brain cells associated with Alzheimer’s disease. Like Type 2 diabetes, Alzheimer’s is associated with poor insulin function. Taking into consideration the link between the two age-related diseases, Cohen and Barzilai set out to discover whether humanin also plays a role in the development of Type 2 diabetes.
In a study published in the journal PLoS One in July 2009, researchers tested the effects of humanin on lab rats. They were able to demonstrate that the protein works in part to help the liver metabolize glucose, a process linked to insulin action that is impaired with the onset of Type 2 diabetes. Humanin, they concluded, likely has a role in preventing both diseases as people age.
And sure enough, while humanin in the general population decreases with age, the centenarians and their offspring had notably higher levels and significantly fewer instances of Type 2 diabetes.
A genetic predisposition for either the CETP variation or higher levels of humanin are part of what researchers call “longevity genes” — a series of variations that likely will lead its lucky carrier to live an unprecedented long and healthy life. But the findings, while exciting, don’t necessarily mean that the key to long life has been definitively identified.
And, in fact, said Cohen, researchers may never know exactly why some people live for so long and others don’t.
“It’s impossible to say what the contribution of each genetic observation is, in terms of the years it adds. I don’t think we have the tools to put it that way,” he said. “From, say, 75 to 100, you probably need cumulative effects of 10 to 20 genes that each add a few years.”
But that won’t stop them from trying. One gene that currently shows promise is a growth hormone, called insulin-like growth factor 1 (IGF-1).