The Secrets to Living Past 100

July 10, 2007 — -- A new project to partially sequence the genomes of 100 people age 100 or older could shed light on the genetic variations that allow some people to stay healthy decades beyond the average life expectancy. Dubbed the Methuselah Project, the endeavor will serve as a test bed for a new approach to sequencing developed at the Rothberg Institute, a non-profit research center in Guilford, CT. About 1 in 7,000 people live to be 100, many of them spry well into their 90s, but the reasons for their good health remain largely unknown.

"One of the women we'd like to look at is over 100, and up to two years ago, she was still playing tennis," says Jonathan Rothberg, founder of both 454 Life Sciences, a sequencing technology company based in Branford, CT, and the Rothberg Institute. "My dream is that we will find [genetic variations] that are enriched in this population that are protective."

The project follows the highly publicized release of the genome of James Watson, codiscoverer of the structure of DNA. (See "The $2 Million Genome.") Carried out by 454 as a demonstration of its sequencing technology, the landmark project costs about an order of magnitude less than a human genome sequenced with traditional technologies. (See "Sequencing in a Flash.")

But the Methuselah effort will use a new, streamlined way of analyzing the genome by isolating and sequencing only the so-called coding regions of DNA. By focusing on this small portion of the genome--about 1 percent--scientists can sequence 100 genomes for the same price as sequencing Watson's entire genome.

"Even after you sequence the whole genome, what you look at and annotate is of course the 30,000 genes and, more specifically, changes in the coding region of these genes that would affect the proteins they encode," says Rothberg. "I know this 1 percent is not everything, but it is about 95 percent of the biology we understand at this time."

The Methuselah Project won't be the first to search for genetic variations linked to longevity. Other studies have used gene chips, which can quickly detect specific genetic variations. But Rothberg says that actually sequencing the genomes could detect some variations that whole-genome scans miss, including small insertions, duplications, and deletions in DNA, which have recently been determined to be more common than previously predicted. "We found 170,000 deletions in Watson's genome, which other analysis doesn't detect," Rothberg says.

Other experts agree."This might be a more direct and quick way of looking at the genome," says Thomas Perls, director of the New England Centenarian Study at Boston Medical Center. Perls is currently using gene chips to analyze the genomes of his large population of centenarians, and he says he is interested in collaborating with Rothberg.

According to Perls, centenarians could have different types of genetic characteristics underlying their extreme old age: they may lack the mutations that make some people more susceptible to the diseases of aging, such as Alzheimer's and heart disease. They may also possess variations that protect against these diseases, or even longevity-enhancing genes, which actually slow the aging process.

"I think it's unlikely there is going to be a single powerful gene for the fountain of youth," Perls says. "It's like the lottery in that you need six or seven numbers to win. Each is relatively common, but getting them all together is rare."

It's not yet clear if the Methuselah Project will be successful. If each of the genes responsible for healthy aging exerts only a modest effect, the 100 person project may be too small to pick them out. Genes that exert a modest effect on disease risk or other factors are much more difficult to identify than those that guarantee that the bearer will develop the disease, as is the case with Huntington's. Most gene-chip studies have required hundreds to thousands of people to identify genetic variants linked to complex diseases.

Rothberg isn't too concerned about his relatively small sample size at this point. He emphasizes that the first stage of the project is to test his new approach to sequencing. And as sequencing costs continue to fall, additional centenarians can be added to the pool. Fortunately, new members join this club of lucky lottery winners every day.