Hunt for “Wellderly” Genes Comes Up Dry

Nonie Hickle’s hair is coal-dark. Her husband, Vincent, marvels at it. He points to it and says, “No gray!” Nonie’s a little amazed too; she thinks it’s kind of spooky. After all, she’s 91 years old.

Statistically speaking, Hickle, who lives in San Diego’s Hillcrest neighborhood, should be sick. She ought to have cardiovascular disease, cancer, or heart failure. Yet she doesn’t have any of those things. True, her hearing has been going bad over the past several years. And she has a touch, just a touch, of high blood pressure. But if you were to look at this 4’11” Korean-American nonagenarian, you wouldn’t peg her at a day over 70.

Just what makes Hickle so healthy? The answer to that question remains elusive despite one of the largest genetic studies to date of exceptionally healthy old people, carried out by Eric Topol of San Diego’s Scripps Translational Science Institute and reported today in the journal Cell.

Topol, a well-known cardiologist and digital-health proponent, launched the so-called “Wellderly” project in 2008, after becoming convinced that healthy old age, not just longevity, was its own distinct, identifiable, trackable trait, just like having schizophrenia or being very tall.

After analyzing the genomes of 600 exceptionally healthy old people, Topol believes that people like Hickle may have a constellation of genes that create resistance to Alzheimer’s and coronary artery disease. But so far there’s no smoking gun. He and coauthors from Cypher Genomics, a bioinformatics company, called their findings “preliminary” and said they would make the genomes available to other scientists.

Although Topol didn’t locate the fountain of youth, the project has been a pioneering attempt to identify genetic variants that contribute to good health rather than disease. Since then, Google’s life science subsidiary, Verily, has also launched an effort to study healthy people. Another, called the Resilience Project, is seeking individuals who appear to have shrugged off mutations that should cause serious disease.

Understanding why some people escape many of the debilitating afflictions of old age—even if they die at roughly the same ages as many of their peers—could be a boon to drug development, alleviate a great deal of human suffering, and help control soaring health-care costs for an aging population.

“Today you can keep people alive for a long time even though they have dementia, multiple cancers, very serious strokes, and chronic disease,” says Topol in his office overlooking a golf course and the Pacific Ocean. “But to have somebody who has reached their ninth or tenth decade free of serious diseases—that’s the group that’s most fascinating and the one we want to emulate.”

Some scientists say there are reasons to believe the gene hunt is misguided. Yaniv Erlich, a scientist affiliated with the New York Genome Center, says there may not be as much to know about DNA and aging as many people think. In 2013, he and coworkers created a family tree of 13 million people dating back to the 15th century, including their dates of birth and death. Erlich found that longevity “is one of the lowest heritable traits.”

Living a very long time, and staying healthy for the duration, probably has a lot to do with luck, he thinks: “The extent to which genes explain it is not very high.”

Hickle herself could be a case in point. Her two sisters died at 100 and 99. While that might suggest that longevity runs in the family, her four brothers died much younger, and her mother died when Hickle was a small child.

Other researchers believe that the genome you inherit at birth may be less important to aging well than epigenetics, or the way chemical groups glom onto DNA in response to environment and life experiences. In Hickle’s case these factors included growing up poor and deprived on Hilo, Hawaii, but enjoying a long, happy marriage.

The result of epigenetic changes that occur during life can turn genes up or down, off or on, and influence disease. A multinational 2005 study of identical twins showed that while the twins’ genomes looked largely identical at first, over time, as their life experiences diverged, the activity of their genes varied.

Large studies to correlate the genes with longevity or health “have not been very successful because, I think, the secret is in the gene-environment interaction,” says NIH scientist Luigi Ferrucci, director of the Baltimore Longitudinal Health Study, the world’s longest-running study of human aging.

Ferrucci has just launched an effort called GESTALT (it stands for “Genetic and Epigenetic Signatures of Translational Aging Laboratory Testing”) to test whether it’s possible to measure the interactions between our aging bodies, our genes, our environment, and the way we live. Instead of trying to mine many hundreds or thousands of genomes, Ferrucci is recruiting 100 people and will collect blood cells at regular intervals so epigenetic changes can be tracked over time. Everybody will also undergo a battery of tests and probes to measure how the body changes with age and life experience.

Topol says his group is starting to study epigenetic changes as well, and investigating whether the genomes of the “wellderly” possess healthy traits that can be transferred to other people’s cells. For instance, in a novel approach, the Scripps team has installed DNA sequences from these healthy patients into stem cells from people with coronary artery disease.

The lab used the technique to study 9p21—an enormous genetic locus implicated in clogged arteries, comprising several genes and regulatory regions that influence how the genes work. The Wellderly Study became the first group, Topol claims, to accurately splice a locus that big from a genome of one human cell into another.

When the stretch of DNA from a patient in the study was swapped into the sickly stem cells and then used to make arterial muscle cells, they “had a totally different look,” Topol says. “We can restore heart diseased people to healthy people—in a dish.”

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