The Atlanta Journal-Constitution
Decoding secrets to longevity
Nonprofit offers access to genomes of supercentenarians.
As one of the exceedingly rare members of her species to live beyond age 110, Goldie Michelson had divulged her secrets to longevity countless times before dying last year at 113.
“Morning walks and chocolate,” the Gloucester, Massachusetts, resident and onetime oldest living American told the steady stream of inquisitors that marked her final years.
Unlike the growing ranks of nonagenarians and centenarians, those who breach a 12th decade, known as supercentenarians, rarely face protracted illness or disability before they die, a boon that many of them have ascribed to personal habits.
“I try to live the truth,” said Shelby Harris, who threw out the first pitch of the local minor league baseball team’s 2012 season a few months before he died at 111 in Rock Island, Illinois. Emma Morano of Verbania, Italy, still cooking her own pasta until a few years before she died in April at 117, prescribed raw eggs, and no husband.
But even as they indulged the notion that exceptionally healthy longevity can be explained by lifestyle, each agreed to donate DNA to a private effort to find the secrets in supercentenarian genes.
The full genetic sequences of Michelson, Harris and Morano are among some three dozen genomes of North American, Caribbean and European supercentenarians being made available recently by a nonprofit called Betterhumans to any researcher who wants to dive in.
A few additional genomes come from people who died at 107, 108 or 109. If unusual patterns in their 3 billion pairs of A’s, C’s, G’s and T’s — the nucleobases that make up all genomes — can be shown to have prolonged their lives and protected their health, the logic goes, it is conceivable that a drug or gene therapy could be devised to replicate the effects in the rest of us.
“I hope you find something that does someone some good,” said Clarence Matthews, 110, who allowed his blood to be drawn as a final contribution to the database in 2016 at his Indian Wells, California, home while I watched at his side.
1 in 5 million
The rare cache of supercentenarian genomes, the largest yet to be sequenced and made public, comes as studies of garden-variety longevity have yielded few solid clues to healthy aging. Lifestyle and luck, it seems, still factor heavily into why people live into their 90s and 100s.
To the extent that they have a genetic advantage, it appears to come partly from having inherited fewer than usual DNA variations known to raise the risk of heart disease, Alzheimer’s disease and other afflictions.
That is not enough, some researchers say, to explain what they call “truly rare survival,” or why supercentenarians are more uniformly healthy than centenarians in their final months and years.
Rather than having won dozens of hereditary coin tosses with DNA variations that are less bad, scientists suggest, supercentenarians may possess genetic code that actively protects them from aging.
But the effort to find that code has been “challenged,” as a group of leading longevity researchers put it in a recent academic paper, in part by the difficulties in acquiring supercentenarian DNA.
The New England Centenarian Study, one of a handful of longevity research groups around the world focusing on supercentenarians, now turns down prospective DNA donors younger than 103: “We tell them they’re too young,” said Dr. Thomas Perls, the study’s director.
The DNA sequences being released this week were acquired almost single-handedly by James Clement, 61, the founder of a company advised by the prominent Harvard geneticist George Church.
A professed citizen-scientist, Clement collected blood, skin or saliva from supercentenarians in 14 states and seven countries over a sixyear period. Many were still gardening, arguing, driving and flirting. Michelson, for one, was fond of reading and reciting Shakespeare.
The usefulness of such a small group for a genetic study is unclear, which is one reason Clement’s company, now defunct, has turned into a crowdsourcing project.
Complex traits like height, body mass index and disease risk — phenotypes, as they are known in geneticsspeak — typically arise from a combination of hundreds of places in the genome where the DNA alphabet differs between individuals.
Zeroing in on which variations affect which phenotypes requires the statistical power of tens of thousands of DNA samples — almost certainly a deal-breaker when it comes to supercentenarians, whose verified number, worldwide, hovers at about 150.
On large swathes of the planet, where birth records are sketchy or nonexistent, identifying verified supercentenarians is virtually impossible. In the United States, researchers say supercentenarians account for about 1 in 5 million people.
A secretive Google spinoff called Calico, for California Life Co., is said to be scrutinizing the genome of the naked mole rat, celebrated for a life span 10 times longer than that of most of its rat cousins. Federally funded scientists are testing a drug on monkeys based on an experiment that doubled the lives of roundworms.
And in laboratories across the world, the markers of age in over-the-hill mice, rats and turquoise killifish are, sometimes, being reversed.
But what works in shorterlived organisms often does not translate to humans, whose average life span in developed countries is approaching 80 years. So despite the limitations of Clement’s database, several prominent researchers have already expressed interest in it.
“This could show the utility of starting a bigger collection,” said Paola Sebastiani, a longevity researcher at Boston University.
An account of what Clement calls the Supercentenarian Research Project offers a glimpse at what that might entail, including perseverance, compassion and a sense of humor that trends toward dark.
Life or death
It was an inauspicious start, Clement admitted in an email to a friend in January 2011. The first supercentenarian Clement had lined up to visit, Mississippi Winn, had died at 113 before he could get from his home in San Jose, California, to hers in Shreveport, Louisiana.
“RIP Miss Winn,” he posted on the Facebook page that family members had set up for Winn, believed to be the last living child of African-Americans born into slavery.
Such condolences would become a familiar refrain. Of the 70,000 or so Americans who live to be 100, only some two dozen are typically alive at 110.
Once that milestone is reached, as Clement quickly learned, the chance of dying within the next year is roughly 50 percent. After 113, the odds are closer to 66 percent. The oldest person on record, Jeanne Calment, was 122 when she died in 1997; only one other person is known to have lived beyond age 118.
“Even while you’re packing the car, the person may fall ill and say they’re not up to it,” Clement said, after the first of several plans for me to observe a DNA donation was abruptly canceled.
A birthday invitation
There was, nominally, the prospect of making money.
But with a business plan that, even to some of his investors, sounded more like a research project, Clement seems to have undertaken the task largely because it provided the chance to act on a long-standing interest in human longevity, including his own.
“My hat was off to someone who was willing to take the time out of his life to go get these precious specimens,” said Church, the Harvard geneticist, who has devoted a portion of his laboratory to research into the reversal of aging.
The kind of ultrarare mutations that supercentenarians might harbor, Church believed, were not likely to be detected with standard techniques, which scan only the places in the genome where DNA is already known to vary between individuals.
To look for as-yet-uncataloged variations would require sequencing all of the supercentenarians’ 6 billion genetic letters, a far more expensive procedure. When he and Clement first discussed the idea in 2010, the cost was about $50,000 per genome.
But the price was falling. And with the financial support of a handful of likeminded wealthy individuals who agreed to invest in the exploratory phase of the project, “it just seemed,” Clement said, “like something I could do.”
Even with the Harvard name as a calling card, several of the families he contacted over the next few years did not respond to his inquiries. A few, Clement knew, had already been approached by laboratories at Stanford and Boston University, which were collecting their own stashes of supercentenarian DNA.
“She already did her DNA donation,” Paul Cooper, the grandson of Besse Cooper, a 116-year-old former suffragist, told Clement, who had driven several hundred miles to her Monroe, Georgia, nursing home in 2012.
An invitation to the 111th birthday party of James Sisnett in Barbados finally served as Clement’s entree in February 2011. He died two years later.
Losing precious samples
Crisscrossing Europe in 2011, Clement hit his collecting stride. But there were some bumps.
He had ordered an inexpensive kit that allowed him to prick a supercentenarian’s finger and deposit a drop of blood on a card to preserve it, often used by geneticists in the field.
Within a few months he had blood drops from 15 donors, including Ralph Tarrant of Sheffield, England, who at 108 completed the London Times crossword puzzle every afternoon.
Not until he had switched to hiring a phlebotomist to perform blood draws with a needle did he learn that the cards with the original 15 samples were defective. “We could not detect any DNA,” read a 2011 email from the laboratory.
Clement confessed the news to Church in a meeting at his Harvard office. “You didn’t test the cards?” the geneticist asked him gently.
Still, Clement had 23 good samples in hand, and the cost of sequencing by this time had fallen to some $15,000 per genome. With his remaining funds, he sequenced 15, leaving the rest in cold storage.
Clement quickly discovered 2,500 differences between the supercentenarian DNA and those of controls. But even with help from graduate students in Church’s lab, it was hard with such a small group to know which, if any, were significant.
So over the next few years, Clement, working without a salary, collected samples whenever he could, adding another dozen from supercentenarians across the United States.
In the spring of 2016, a company Church had cofounded, Veritas Genetics, announced that it would sequence human genomes for $1,000 each. Church told Clement that Veritas would sequence the remaining samples, and so he set out to collect a few more.
Advice from America’s oldest man
In July 2016, I was invited to accompany Clement to Matthews’ home in California. As much as I looked forward to meeting my first supercentenarian, I was not prepared to envy his win in the genetic longevity lottery.
I had feared he would be lonely, a concern echoed by several of the Facebook viewers who watched me ply him with questions over a live video stream the morning we met. “I don’t want to outlive my friends and family,” one typed. “That’s no fun.”
Talking to him, it was hard not to fantasize about the possibility that, as another Facebook participant suggested, “by the time we get to that age, we may all be living to 110.”
At the time the oldest man in America, Matthews sometimes strained to hear, but his sense of humor and perspective were intact. If that was what we wanted, he advised, “Keep breathing.”