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Secret to long life may lie in the DNA

Amy Harmon/NYT Nov 21 2017, 1:05 IST
Those who breach a 12th decade rarely face illness or disability before they die.

Those who breach a 12th decade rarely face illness or disability before they die.

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," she 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.

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 some three dozen genomes of North American, Caribbean and European supercentenarians are made available by a non-profit called Betterhumans to any researcher who wants to dive in. If unusual patterns in their three 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.

Fewer variations

The rare cache of supercentenarian genomes comes as studies of garden-variety longevity have yielded few solid clues to healthy ageing. Lifestyle and luck, it seems, still factor heavily into why people live into their 90s and 100s. This appears to have 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 healthy than centenarians in their final 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 protects them from ageing. 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 DNA sequences that were released, were acquired almost single-handedly by James Clement, the founder of a company advised by the prominent Harvard geneticist George Church, who has devoted a part of his laboratory for research into the reversal of ageing. James collected blood, skin or saliva from supercentenarians in eight countries over a six-year period.

Complex traits like height, body mass index and disease risk - called phenotypes - 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, identifying verified supercentenarians is virtually impossible.

Still, some researchers hope that despite the limited number of available genomes, it will be possible to identify the secret sauce of supercentenarians with methods used to uncover the genetic basis for other rare conditions. No one quite knows how many genomes might be necessary. "This is what we call an 'extreme phenotype'," said George. "The farther out you go on the bell curve, the more likely you are to find something, even with a small sample size."

As the goal of slowing ageing to extend human 'health span' has gained traction in the scientific mainstream, research has largely been limited to animal studies. A secretive Google spinoff called Calico, for California Life Co, is said to be scrutinising the genome of the naked mole rat, celebrated for a life span 10 times longer than that of most of its rat cousins.

But what works in shorter-lived organisms often does not translate to humans, whose average life span in developed countries is approaching 80 years. So despite the limitations of James' 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, USA.

Sequencing the genome

It was an inauspicious start, James admitted in an email to a friend in 2011. The first supercentenarian James had lined up to visit had died at 113 before he could reach her home. Once elderly people reached the age of 110, James learned, the chance of dying within the next year is roughly 50%. To improve the odds of getting samples he lowered his target age from 110 to 106. "It's better to get there when they are alive," he said.

The kind of ultrarare mutations that supercentenarians might harbour, George 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-uncatalouged variations would require sequencing all of the supercentenarians' six billion genetic letters, an expensive procedure.

When he and James 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 like-minded individuals, "it just seemed," James said, "like something I could do."

Losing precious samples

Crisscrossing Europe in 2011, James 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. Within a few months, he had blood samples of 15 people.

It was not until he had switched to hiring a phlebotomist to perform blood draws with a needle did he learn that the cards were defective. "We could not detect any DNA," read an email from the laboratory. Still, James had 23 good samples in hand. James quickly discovered 2,500 differences between the supercentenarian DNA and those of controls. But even with help from graduate students in George's lab, it was hard with such a small group to know which were significant.

In 2016, I was invited to accompany James to Clarence's home. As much as I looked forward to meeting him, I was not prepared to envy his win in the genetic longevity lottery. The prospect of shifting today's average life span to that of the known limit of all humanity is disorienting. An average life expectancy of 80 in some ways seems generous - it was 48 when Clarence was born in 1906.

Clarence died this summer. His DNA was sequenced a few weeks later, and last month James uploaded it to the database. Whether, in combination with the genomes of his fellow supercentenarians, the rest contains the secret to a long, healthy and happy life remains to be seen.

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