Geneticists are studying supercentenarians in the hope we can all hang on to our grey matter. By Wendy Zukerman.
Supercentenarians show the power of good genes
Holstege first met the modern Methuselah when she was 111 and he was working at the University of Groningen in the Netherlands. “She knew everything from the beginning of her life up to today,” he says. She could recount stories of her childhood in the small Dutch village of Smilde, and how her mother forbid her from partying with soldiers during World War I. “She still was angry!” Holstege says with a laugh.
Scientists are now poring over van Andel-Schipper’s body – and others like hers – in a bid to unlock the secrets of a long and healthy life. The key is learning how to keep our wits during ageing.
Dr Stephen Coles, director of the Supercentenarian Research Foundation, in Los Angeles, has been tracking the extreme end of life for more than two decades. He says that many of those who live beyond 110 – so called “supercentenarians” – somehow avoid dementia. “For the most part,” he says, “our subjects were mentally sharp.” According to Coles, untapping how these supercentenarians have been largely shielded from cognitive decline promises to be “one of the most successful and quickest roads” to protective drugs.
Currently, there is nothing we can do to definitively stave off dementia, although a healthy diet, exercise and bit of sudoku might help. While news articles fawn over the advice of supercentenarians, in reality, their lifestyles reveal few clues as to their mental health. “There is very little that supercentenarians share in common,” says Coles. “They don’t really exercise or have the same nutrition.” But no supercentenarian to date has been recorded as obese.
Charlotte Hughes – notorious for her warning to Margaret Thatcher: “Don’t cuddle me, I’m Labour” – lived until she was 115, still enjoying a stiff brandy and bacon and eggs. The oldest person in history, madame Jeanne Louise Calment of France, smoked a cigarette every day until she died, aged 122.
So, how are these supercentenarians so resilient? “They chose their parents wisely,” quips Coles, referring to the power of “good genes”. Van Andel-Schipper’s mother survived until she was 100, while Calment – whose memory improved in her twilight years – had 62 ancestors who lived longer than the average of their day.
Part of the quest to unravel which part of our incredibly complicated genome keeps us in good shape requires the scrutiny of extraordinarily old and healthy bodies. Van Andel-Schipper was 82 when she consented to donating her body to science. Almost four decades later, she contacted the local university to see if science still wanted her. Gert Holstege picked up the phone. “When I found out how old she was, I told her we were very interested in her,” he says. “And she was excited about being important for science.”
A few years later, on August 30, 2005, Holstege received another call, this time in the middle of the night. He was told that the 115-year-old woman had slipped away.
About 1am the neuroscientist drove to the outskirts of Groningen to pick up her body for an autopsy. Back at the university, he worked through the night, collecting blood samples and snap-freezing organs. His autopsy revealed that van Andel-Schipper died of undiagnosed stomach cancer, which spread to her liver and kidney.
Over the next few weeks, Holstege began slicing her brain in search for typical signs of ageing, but there were few. Lurking in the brain of 95 per cent of mentally healthy geriatrics hide the early markers of Alzheimer’s, but in this remarkable woman there were almost no signs of decline. “It was the brain of a 60-year-old, not someone who is 115,” says Holstege. There were also no signs of atherosclerosis, meaning her brain received an untainted blood supply. To the neuroscientist, “her brain was perfect”.
Holstege had thought that dementia was an inevitable part of ageing, but van Andel-Schipper showed him it wasn’t. “She changed everything for me,” he says. He recruited his daughter, Henne Holstege, who studies the genetic mutations of cancer, to help discover how van Andel-Schipper was protected from dementia. She started looking at the supercentenarian’s blood, which is the life support of cells in the brain.
Each time blood cells divide and reproduce there is an opportunity for mistakes, called mutations, to arise in the DNA. Traditionally, it was thought to be a matter of luck whether these mutations ended up being harmless or dangerous, but there is a lot that is unknown about how these mistakes accumulate over our lives.
So Henne Holstege, now at the VU University Medical Centre in Amsterdam, created a map of the lifetime of genetic mistakes that built up in van Andel-Schipper’s blood. Publishing the results in May, Holstege found that all of the hundreds of mutations she detected were hidden away in places of the genome that were unlikely to ever cause damage. The question now is whether this really is simply luck, or perhaps evidence of a hitherto unknown system in the blood that can prevent the accumulation of dangerous cells.
Evidence for the protective powers of blood is coming from a series of rather gruesome animal studies. A few years ago, Saul Villeda, now at the University of California in San Francisco, led a team connecting the circulatory system of old and young mice, by cutting the rodents and physically stapling them together. As the young blood coursed through the old mice, the researchers were stunned to find that it triggered the birth of new brain cells and even improved the ageing rodents’ brain function.
In May, Villeda’s team showed that vampirish surgery isn’t necessary to spark rejuvenation – simply injecting young blood into middle-aged mice can do the job. Buoyed by the results, they are already planning a small clinical trial to give Alzheimer’s patients a series of injections of plasma from young donors.
It’s unclear what gives the young blood this remarkable quality, although the researchers are keenly trying to pin this down. It’s also a mystery whether van Andel-Schipper somehow managed to retain these protective factors into her extraordinary old age.
Meanwhile, Henne Holstege has started the “100-plus study”, for which she will compare the genomes of 100 cognitively healthy Dutch centenarians against those suffering from dementia. Using this strategy she hopes to untangle other genetic elements that may have protected van Andel-Schipper, and others like her, from cognitive decline.
In the US, Dr Coles recently joined forces with a team at Stanford University to conduct a similar study. He says their group has already discovered a smoking gun. While Coles cannot provide details of the findings until the work is published in a few months, he says, “The genes that we have found are brand new – even geneticists are not familiar with them.” He later added, “This is Nobel prize-winning work.”
These advances are generating much hype in the scientific community. But even if Coles has uncovered a life-giving genetic network, the genome is notoriously complex. It could take years, if not decades, before such a discovery is converted into drugs to help the elderly.
In the meantime, we are likely to continue to be captivated by the advice of those who escaped decline. How do you live longer? What’s the secret? In one interview, Hendrikje van Andel-Schipper recommended herring and orange juice to keep healthy. On another occasion, she simply offered: “Continue to breathe, nothing more.”
This article was first published in the print edition of The Saturday Paper on July 5, 2014 as "Gene genies".
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