A handful of girls diagnosed as having 'Syndrome X' seem to defy one of the biggest certainties in life: aging. Scientists who are working to understand this rare condition say it could inform our efforts to radically extend the human lifespan.
Richard Walker has been trying to conquer ageing since he was a 26-year-old free-loving hippie. It was the 1960s, an era marked by youth: Vietnam War protests, psychedelic drugs, sexual revolutions. The young Walker relished the culture of exultation, of joie de vivre, and yet was also acutely aware of its passing. He was haunted by the knowledge that ageing would eventually steal away his vitality – that with each passing day his body was slightly less robust, slightly more decayed. One evening he went for a drive in his convertible and vowed that by his 40th birthday, he would find a cure for ageing.
Walker became a scientist to understand why he was mortal. "Certainly it wasn't due to original sin and punishment by God, as I was taught by nuns in catechism," he says. "No, it was the result of a biological process, and therefore is controlled by a mechanism that we can understand."
Medical science has already stretched the average human lifespan. Because of public health programmes and treatments for infectious diseases, the number of people over age 60 has doubled since 1980. By 2050, the over-60 set is expected to number 2 billion, or 22 per cent of the world's population. But this leads to a new problem: more people are living long enough to get chronic and degenerative conditions. Age is one of the strongest risk factors for heart disease, stroke, macular degeneration, dementia and cancer. For adults in high-income nations, that means age is the biggest risk factor for death.
A drug that slows ageing, even modestly, would be a blockbuster. Scientists have published several hundred theories of ageing (and counting), and have tied it to a wide variety of biological processes. But no one yet understands how to integrate all of this disparate information. Some researchers have slowed ageing and extended life in mice, flies and worms by tweaking certain genetic pathways. But it's unclear whether these manipulations would work in humans. And only a few age-related genes have been discovered in people, none of which is a prime suspect.
Walker, now 74, believes that the key to ending ageing may lie in a rare disease that doesn't even have a real name, "syndrome X". He has identified four girls with this condition, marked by what seems to be a permanent state of infancy, a dramatic developmental arrest. He suspects that the disease is caused by a glitch somewhere in the girls' DNA. His quest for immortality depends on finding it.
It's the end of another busy week and MaryMargret Williams is shuttling her brood home from school. She drives an enormous SUV, but her six children and their coats and bags and snacks manage to fill every inch. The three big kids are bouncing in the very back. Sophia, ten, with a mouth of new braces, is complaining about a boy-crazy friend. She sits next to Anthony, seven, and Aleena, five, who are glued to something on their mother's iPhone. The three little kids squirm in three car seats across the middle row. Myah, two, is mining a cherry slushy, and Luke, one, is pawing a bag of fresh crickets bought for the family gecko.
Finally there's Gabrielle, who's the smallest child, at just 12 pounds, and the second oldest, at nine years old. She has long, skinny legs and a long, skinny ponytail, both of which spill out over the edges of her car seat. While her siblings giggle and squeal, Gabby's dusty-blue eyes roll up towards the ceiling. By the calendar, she's almost an adolescent. But she has the buttery skin, tightly clenched fingers and hazy awareness of a newborn.
Back in 2004, when MaryMargret and her husband, John, went to the hospital to deliver Gabby, they had no idea anything was wrong. They knew from an ultrasound that she would have club feet, but so had their other daughter, Sophia, who was otherwise healthy. And because MaryMargret was a week early, they knew Gabby would be small, but not abnormally so. "So it was such a shock to us when she was born," MaryMargret says.
Gabby came out purple and limp. Doctors stabilised her in the neonatal intensive care unit and then began a battery of tests. Within days the Williamses knew their new baby had lost the genetic lottery. Her brain's frontal lobe was smooth, lacking the folds and grooves that allow neurons to pack in tightly. Her optic nerve, which runs between the eyes and the brain, was atrophied, which would probably leave her blind. She had two heart defects. Her tiny fists couldn't be pried open. She had a cleft palate and an abnormal swallowing reflex, which meant she had to be fed through a tube in her nose. "They started trying to prepare us that she probably wouldn't come home with us," John says. Their family priest came by to baptise her.
Day after day MaryMargret and John shuttled between Gabby in the hospital and 13-month-old Sophia at home. Gabby gradually learned to feed from a bottle and gained a bit of weight, though she was still less than five pounds. The doctors tested for a few known genetic syndromes, but they all came back negative. Nobody had a clue what was in store for her. Her strong Catholic family put their faith in God. "MaryMargret just kept saying, 'She's coming home, she's coming home'," recalls her sister, Jennie Hansen. And after 40 days, she did.
Gabby cried a lot, loved to be held, and ate every three hours, just like any other newborn. But of course she wasn't. Her arms would stiffen and fly up to her ears, in a pose that the family nicknamed her "Harley-Davidson". At four months old she started having seizures. Most puzzling and problematic, she still wasn't growing. John and MaryMargret took her to specialist after specialist: a cardiologist, a gastroenterologist, a geneticist, a neurologist, an ophthalmologist and an orthopaedist. "You almost get your hopes up a little – 'This is exciting! We're going to the gastro doctor, and maybe he'll have some answers'," MaryMargret says. But the experts always said the same thing: nothing could be done.
The first few years with Gabby were stressful. When she was one and Sophia two, the Williamses drove from their home in Billings, Montana, to MaryMargret's brother's home outside of St Paul, Minnesota. For nearly all of those 850 miles, Gabby cried and screamed. This continued for months until doctors realised she had a run-of-the-mill bladder infection. Around the same period, she acquired a severe respiratory infection that left her struggling to breathe. John and MaryMargret tried to prepare Sophia for the worst, and even planned which readings andsongs to use at Gabby's funeral. But the tiny toddler toughed it out.
While Gabby's hair and nails grew, her body wasn't getting bigger. She was developing in subtle ways, but at her own pace. MaryMargret vividly remembers a day at work when she was pushing Gabby's stroller down a hallway with skylights in the ceiling. She looked down at Gabby and was shocked to see her eyes reacting to the sunlight. "I thought, 'Well, you're seeing that light!'" MaryMargret says. Gabby wasn't blind, after all.
Despite the hardships, the couple decided they wanted more children. In 2007 MaryMargret had Anthony, and the following year she had Aleena. By this time, the Williamses had stopped trudging to specialists, accepting that Gabby was never going to be fixed. "At some point we just decided," John recalls, "it's time to make our peace."
Why We Age
When Walker began his scientific career, he focused on the female reproductive system as a model of "pure ageing": a woman's ovaries, even in the absence of any disease, slowly but inevitably slide into the throes of menopause. His studies investigated how food, light, hormones and brain chemicals influence fertility in rats. But academic science is slow. He hadn't cured ageing by his 40th birthday, nor by his 50th or 60th. His life's work was tangential, at best, to answering the question of why we're mortal, and he wasn't happy about it. He was running out of time.
So he went back to the drawing board. As he describes in his book, Why We Age, Walker began a series of thought experiments to reflect on what was known and not known about ageing.
Ageing is usually defined as the slow accumulation of damage in our cells, organs and tissues, ultimately causing the physical transformations that we all recognise in elderly people. Jaws shrink and gums recede. Skin slacks. Bones brittle, cartilage thins and joints swell. Arteries stiffen and clog. Hair greys. Vision dims. Memory fades. The notion that ageing is a natural, inevitable part of life is so fixed in our culture that we rarely question it. But biologists have been questioning it for a long time.
It's a harsh world out there, and even young cells are vulnerable. It's like buying a new car: the engine runs perfectly but is still at risk of getting smashed on the highway. Our young cells survive only because they have a slew of trusty mechanics on call. Take DNA, which provides the all-important instructions for making proteins. Every time a cell divides, it makes a near-perfect copy of its three-billion-letter code. Copying mistakes happen frequently along the way, but we have specialised repair enzymes to fix them, like an automatic spellcheck. Proteins, too, are ever vulnerable. If it gets too hot, they twist into deviant shapes that keep them from working. But here again, we have a fixer: so-called 'heat shock proteins' that rush to the aid of their misfolded brethren. Our bodies are also regularly exposed to environmental poisons, such as the reactive and unstable 'free radical' molecules that come from the oxidisation of the air we breathe. Happily, our tissues are stocked with antioxidants and vitamins that neutralise this chemical damage. Time and time again, our cellular mechanics come to the rescue.
Which leads to the biologists' longstanding conundrum: if our bodies are so well tuned, why, then, does everything eventually go to hell?
One theory is that it all boils down to the pressures of evolution. Humans reproduce early in life, well before ageing rears its ugly head. All of the repair mechanisms that are important in youth – the DNA editors, the heat shock proteins, the antioxidants – help the young survive until reproduction, and are therefore passed down to future generations. But problems that show up after we're done reproducing cannot be weeded out by evolution. Hence, ageing.
Most scientists say that ageing is not caused by any one culprit but by the breakdown of many systems at once. Our sturdy DNA mechanics become less effective with age, meaning that our genetic code sees a gradual increase in mutations. Telomeres, the sequences of DNA that act as protective caps on the ends of our chromosomes, get shorter every year. Epigenetic messages, which help turn genes on and off, get corrupted with time. Heat shock proteins run down, leading to tangled protein clumps that muck up the smooth workings of a cell. Faced with all of this damage, our cells try to adjust by changing the way they metabolise nutrients and store energy. To ward off cancer, they even know how to shut themselves down. But eventually cells stop dividing and stop communicating with each other, triggering the decline we see from the outside.
Scientists trying to slow the ageing process tend to focus on one of these interconnected pathways at a time. Some researchers have shown, for example, that mice on restricted-calorie diets live longer than normal. Other labs have reported that giving mice rapamycin, a drug that targets an important cell-growth pathway, boosts their lifespan. Still other groups are investigating substances that restore telomeres, DNA repair enzymes and heat shock proteins.
During his thought experiments, Walker wondered whether all of these scientists were fixating on the wrong thing. What if all of these various types of cellular damage were the consequences of ageing, but not the root cause of it? He came up with an alternative theory: that ageing is the unavoidable fallout of our development.
The idea sat on the back burner of Walker's mind until the evening of 23 October 2005. He was working in his home office when his wife called out to him to join her in the family room. She knew he would want to see what was on TV: an episode of Datelineabout a young girl who seemed to be "frozen in time". Walker watched the show and couldn't believe what he was seeing. Brooke Greenberg was 12 years old, but just 13 pounds, and 27 inches long. Her doctors had never seen anything like her condition, and suspected the cause was a random genetic mutation. "She literally is the Fountain of Youth," her father, Howard Greenberg, said.
Walker was immediately intrigued. He had heard of other genetic diseases, such as progeria and Werner syndrome, which cause premature ageing in children and adults respectively. But this girl seemed to be different. She had a genetic disease that stopped her development and with it, Walker suspected, the ageing process. Brooke Greenberg, in other words, could help him test his theory.
Brooke was born a few weeks premature at just over 4 pounds. She had many birth defects, including moderate hearing loss, dislocated hips and dysmorphic facial features. Her brain had abnormally large chambers of fluid and lacked a corpus callosum, the bundle of nerve fibres that connects the right and left hemispheres. She had trouble swallowing, and by six months was eating through a feeding tube in her stomach. She always coughed and wheezed. Her paediatrician labelled her with "syndrome X", not knowing what else to call it.
By age three, Brooke had reached 12 pounds, and she hovered around that weight until age 12, when she appeared on Dateline. After watching the show, Walker tracked down Howard Greenberg's address and sent him a letter about his scientific background and his interest in Brooke's case. Two weeks went by before Walker heard back, and after much discussion he was allowed to test Brooke. He was sent Brooke's medical records as well as blood samples for genetic testing. In 2009, his team published a brief report describing her case.
Walker's analysis found that Brooke's organs and tissues were developing at different rates. Her mental age, according to standardised tests, was between one and eight months. Her teeth appeared to be eight years old; her bones, ten years. She had lost all of her baby fat, and her hair and nails grew normally, but she had not reached puberty. Her telomeres were considerably shorter than those of healthy teenagers, suggesting that her cells were ageing at an accelerated rate.
All of this was evidence of what Walker dubbed "developmental disorganisation". Brooke's body seemed to be developing not as a coordinated unit, he wrote, but rather as a collection of individual, out-of-sync parts. He used her feeding problems as a primary example. To feed normally, an infant must use mouth muscles to create suction, jaw muscles to open and close the mouth, and the tongue to move the food to the back of the throat. If these systems weren't coordinated properly in Brooke, it could explain why she had such trouble feeding. Her motor development had gone similarly awry: she didn't learn to sit up until she was six years old and never learned to walk. "She is not simply 'frozen in time'," Walker wrote. "Her development is continuing, albeit in a disorganised fashion."
The big question remained: why was Brooke developmentally disorganised? It wasn't nutritional and it wasn't hormonal. The answer had to be in her genes. Walker suspected that she carried a glitch in a gene (or a set of genes, or some kind of complex genetic program) that directed healthy development. There must be some mechanism, after all, that allows us to develop from a single cell to a system of trillions of cells. This genetic program, Walker reasoned, would have two main functions: it would initiate and drive dramatic changes throughout the organism, and it would also coordinate these changes into a cohesive unit.
Ageing, he thought, comes about because this developmental program, this constant change, never turns off. From birth until puberty, change is crucial: we need it to grow and mature. After we've matured, however, our adult bodies don't need change, but rather maintenance. "If you've built the perfect house, you would want to stop adding bricks at a certain point," Walker says. "When you've built a perfect body, you'd want to stop screwing around with it. But that's not how evolution works." Because natural selection cannot influence traits that show up after we have passed on our genes, we never evolved a "stop switch" for development, Walker says. So we keep adding bricks to the house. At first this doesn't cause much damage – a sagging roof here, a broken window there. But eventually the foundation can't sustain the additions, and the house topples. This, Walker says, is ageing.
Brooke was special because she seemed to have been born with a stop switch. The media were fascinated by her case. Walker appeared with the Greenberg family on television several times and explained why he was so interested in Brooke's genes. "This is an opportunity for us to answer the question 'Why are we mortal?'" he said onGood Morning America. "If we're right, we've got the golden ring."
But finding the genetic culprit turned out to be difficult. Walker partnered with geneticist Maxine Sutcliffe of All Children's Hospital in St Petersburg, Florida, to screen Brooke's DNA for large deletions or duplications in her chromosomes. They didn't find anything out of the ordinary. But these tests were somewhat rudimentary, only scratching the surface of her full genetic code. In order to find the answer, Walker would need to sequence Brooke's entire genome, letter by letter.
That never happened. Much to Walker's chagrin, Howard Greenberg abruptly severed their relationship.
In August 2009, MaryMargret Williams saw a photo of Brooke on the cover of Peoplemagazine, just below the headline "HEARTBREAKING MYSTERY: THE 16-YEAR-OLD BABY". After reading the piece, she thought Brooke sounded a lot like Gabby. She was even more convinced after Googling Brooke's name and watching a few videos of her media appearances. The article had mentioned Walker's research, and his idea that Brooke was "not developing as a unit". She wondered: could that be Gabby's problem, too? MaryMargret called an editor at People, who gave her Walker's email address.
At this time, Walker was devastated about losing the opportunity to study Brooke. But he was still hopeful about continuing his research on other children. After all of the publicity with Brooke, Walker says he received calls and emails from about 20 people claiming that their child had the same condition. Most of these leads didn't go anywhere; the kids were abnormally small or developmentally delayed, but otherwise didn't have anything like Brooke's syndrome.
Then Walker got an email from MaryMargret with a brief description of Gabby's condition. Intrigued, he wrote back asking for more details. So MaryMargret collected all of Gabby's various tests and scans, organised them in a thick binder, and shipped it off to Florida. After reviewing them, Walker thought he had finally found another Brooke. He called MaryMargret and filled her in on his theory. Testing Gabby's genes, he said, could help him in his mission to end age-related disease – and maybe even ageing itself.
This didn't sit well with the Williamses. John, who works for the Montana Department of Corrections, often interacts with people facing the reality of our finite time on Earth. "If you're spending the rest of your life in prison, you know, it makes you think about the mortality of life," he says. What's important is not how long you live, but rather what you do with the life you're given. MaryMargret feels the same way. For years she has worked in a local dermatology office. She knows all too well the cultural pressures to stay young, and wishes more people would embrace the inevitability of getting older. "You get wrinkles, you get old, that's part of the process," she says. So the idea of Walker someday tweaking a gene to get rid of this crucial life stage, just so that vain 30-year-olds don't have to get old? They didn't want anything to do with that.
But Walker's research also had its upside. First and foremost, it could reveal whether the other Williams children were at risk of passing on Gabby's condition.
For several months, John and MaryMargret hashed out the pros and cons. They talked about it every night before bed, and solicited opinions from close friends and family. They were under no illusion that the fruits of Walker's research would change Gabby's condition, nor would they want them to. But they did want to know why. "What happened, genetically, to make her who she is?" John says. And more importantly: "Is there a bigger meaning for it?"
John and MaryMargret firmly believe that God gave them Gabby for a reason. Walker's research offered them a comforting one: to help treat Alzheimer's and other age-related diseases. "Is there a small piece that Gabby could present to help people solve these awful diseases?" John asks. "Thinking about it, it's like, no, that's for other people, that's not for us." But then he thinks back to the day Gabby was born. "I was in that delivery room, thinking the same thing – this happens to other people, not us."
Still not entirely certain, the Williamses went ahead with the research.
Walker published his theory in 2011, but he's only the latest of many researchers to think along the same lines. "Theories relating developmental processes to ageing have been around for a very long time, but have been somewhat under the radar for most researchers," says João Pedro de Magalhães, a biologist at the University of Liverpool. In 1932, for example, English zoologist George Parker Bidder suggested that mammals have some kind of biological "regulator" that stops growth after the animal reaches a specific size. Ageing, Bidder thought, was the continued action of this regulator after growth was done.
Subsequent studies showed that Bidder wasn't quite right; there are lots of marine organisms, for example, that never stop growing but age anyway. Still, his fundamental idea of a developmental program leading to ageing has persisted. In the mid-2000s, Mikhail V Blagosklonny of the Roswell Park Cancer Institute in Buffalo, New York, published a string of articles on "hyper-function theory", which is in some ways similar to Walker's. "Senescence is a quasi-program, just a continuation of the developmental program," Blagosklonny wrote. "The force that drives development is constantly turned on, becoming hyper-functional and damaging."
All of these developmental theories are "right on", says David Gems, a geneticist at University College London. The current fashion in ageing research is "to throw up your hands and say, 'Well, there's just lots of things going on'," he says. Developmental theories, in contrast, could provide "a main, central picture of ageing".
Gems points out that these developmental theories are bolstered by studies ofCaenorhabditis elegans, a roundworm (or nematode). Many labs, including his, use this animal to study ageing because it has a brief lifespan (less than a month) and is easy to manipulate genetically. For several years, Stuart Kim's group at Stanford University has been comparing which genes are expressed in young and old worms. It turns out that some genes involved in ageing also help drive development in youth.
Kim suggested that the root cause of ageing is the "drift", or mistiming, of developmental pathways during the ageing process, rather than an accumulation of cellular damage.
Other groups have since found similar patterns in mice and primates. One study, for example, reported that genes expressed in ageing mice are involved in slowing down growth at the end of youth. Another showed that many genes turned on in the brains of old monkeys and humans are the same as those expressed in young brains, suggesting that ageing and development are controlled by some of the same gene networks.
Perhaps most provocative of all, some studies of worms have shown that shutting down essential development genes in adults significantly prolongs life. "We've found quite a lot of genes in which this happened – several dozen," de Magalhães says.
Nobody knows whether the same sort of developmental-program genes exist in people. But say that they do exist. If someone was born with a mutation that completely destroyed this program, Walker reasoned, that person would undoubtedly die. But if a mutation only partially destroyed it, it might lead to a condition like what he saw in Brooke Greenberg or Gabby Williams. So if Walker could identify the genetic cause of syndrome X, then he might also have a driver of the ageing process in the rest of us.
And if he found that, then could it lead to treatments that slow – or even end – ageing? "There's no doubt about it," he says, pointing out that scientists have already developed methods for silencing genes in people. "Technology is moving so fast."
Looking For Genetic Clues
After agreeing to participate in Walker's research, the Williamses, just like the Greenbergs before them, became famous. In January 2011, when Gabby was six, the television channel TLC featured her on a one-hour documentary, and the producers came back two years later for a follow-up show. The Williams family also appeared on Japanese television and in dozens of newspaper and magazine articles. Just about every time they go out to dinner, strangers approach them to meet the 'doll baby' with the long hair.
Other than becoming a local celebrity, though, Gabby's everyday life hasn't changed much since getting involved in Walker's research. She spends her days surrounded by her large family. She'll usually lie on the floor, or in one of several cushions designed to keep her spine from twisting into a C shape. She makes noises that would make an outsider worry: grunting, gasping for air, grinding her teeth. Her siblings think nothing of it. They play boisterously in the same room, somehow always careful not to crash into her. Once a week, a teacher comes to the house to work with Gabby. She uses sounds and shapes on an iPad to try to teach cause and effect. When Gabby turned nine, last October, the family made her a birthday cake and had a party, just as they always do. Most of her gifts were blankets, stuffed animals and clothes, just as they are every year. Her aunt Jennie gave her make-up.
Walker teamed up with geneticists at Duke University and screened the genomes of Gabby, John and MaryMargret. This test looked at the exome, the 2 per cent of the genome that codes for proteins. From this comparison, the researchers could tell that Gabby did not inherit any exome mutations from her parents – meaning that it wasn't likely that her siblings would be able to pass on the condition to their kids. "It was a huge relief – huge," MaryMargret says.
Still, the exome screening didn't give any clues as to what was behind Gabby's disease. Gabby carries several mutations in her exome, but none in a gene that would make sense of her condition. All of us have mutations littering our genomes. So it's impossible to know, in any single individual, whether a particular mutation is harmful or benign – unless you can compare two people with the same condition.
Luckily for him, Walker's continued presence in the media has led him to two other young girls who he believes have the same syndrome. One of them, Mackenzee Wittke, of Alberta, Canada, is now five years old, 15 pounds, and has long and skinny limbs, just like Gabby. "We have basically been stuck in a time warp," says her mother, Kim Wittke. The fact that all of these possible syndrome X cases are girls is intriguing – it could mean that the crucial mutation is on their X chromosome. Or it could just be a coincidence.
Walker is working with a commercial outfit in California to compare all three girls' entire genome sequences – the exome plus the other 98 per cent of DNA code, which is thought to be responsible for regulating the expression of protein-coding genes. He says he is also collaborating with Steve Horvath, a researcher at the University of California, Los Angeles, who specialises in the epigenome – the chemical markings on DNA that affect how it is packaged and expressed.
For his theory, Walker says, "this is do or die – we're going to do every single bit of DNA in these girls. If we find a mutation that's common to them all, that would be very exciting."
But that seems like a very big if. It's not at all clear that these girls have the same condition. Even if they do, and even if Walker and his collaborators discover the genetic cause, there would still be a steep hill to climb. The researchers would need to silence the same gene or genes in laboratory mice, which typically have a lifespan of two or three years. "If that animal lives to be ten, then we'll know we're on the right track," Walker says. Then they'd have to find a way to achieve the same genetic silencing in people, whether with a drug or some kind of gene therapy. And then they'd have to begin long and expensive clinical trials to make sure that the treatment was safe and effective. Science is often too slow, and life too fast.
A few researchers share Walker's enthusiasm for ending ageing as we know it – someday. "A lot of people have the notion that ageing is natural and you just accept it, like taxes," says de Magalhães. "I don't." He points out that a lot of technological innovations were born out of problems that most people thought were unsolvable. "I think there are a lot of natural causes of death and natural phenomena that human ingenuity and human technology can overcome."
De Magalhães gleans hope from what has evolved naturally in the animal kingdom. All mammals age, but there are large differences in lifespan: mice live for just a year or so, whereas bowhead whales are thought to live up to 200 years. So if scientists can understand the differences in biochemistry between a mouse and a whale, there's some reason to believe they could apply that knowledge to our own genomes to extend human life. (De Magalhães and his colleagues are in the process of sequencing the genome of the bowhead whale.)
"In theory, there is no reason to think that in the future we cannot completely abolish ageing," he says. "Having said that, it's extremely complicated and difficult." He says the best-case scenario over the next 20 or 30 years is that we'll be able to take what's been tested in mice and apply it to humans. In mice that's resulted, in some cases, in an increase of half their lifespan, but achieving the same extension in humans is an unrealistic goal – efforts in other primates have shown much less impressive results.
And there are unfortunate consequences to hyping treatments that claim to end ageing. In August 2003, researchers published a study showing that resveratrol, a chemical in red wine, extended the lifespan of yeast by 70 per cent. A flurry of subsequent studies showed that it also increased lifespan in fruit flies, fish and worms. Suddenly resveratrol was all over the popular press, trumpeted as an anti-ageing elixir.
But things often happen in laboratory animals that don't pan out in humans. And because we live so long already, it will take decades before science can prove that any particular drug extends our life. In 2008 GlaxoSmithKline spent $720 million to acquire a company developing resveratrol, but it has since scaled back on that research with nothing actually brought to market. Several human trials are underway to test the effectiveness of the drug, with lacklustre results so far. However, food-supplement companies have been less deterred – unlike the pharmaceutical industry, they didn't need to know whether it works to capitalise on the public's yearning for youth. In 2012 the global market for resveratrol supplements was valued at $50m. They're sold on Amazon for $5 to $150 per bottle, depending on the dosage and quantity. Consumers seem not to know or care that resveratrol research in humans is scant, nor that in pill form it isn't well absorbed by the body.
There are probably a couple of dozen compounds that, like resveratrol, extend life in the lab and could be developed for human applications, says Matt Kaeberlein, a molecular biologist at the University of Washington in Seattle. The ideal outcome of these drugs, though, will not be an infinitely long life, but rather an increase in "health span", or the number of years we have before age-related disease begins. "My guess is that they would work at the level of 15 per cent increase in lifespan and a few decades' increase in health span," he says. The best-case scenario, he speculates, is that "we live to 120 but don't start to get sick until 110".
This is more profound than it may seem: if science suddenly eliminated all forms of cancer, for instance, life expectancy at birth would only increase by about three years. Implicit in Kaeberlein's argument is that ageing cannot be separated from age-related disease; it's just a matter of time before its symptoms emerge. "It's a logical fallacy to talk about curing cancer or curing Alzheimer's," he says, despite the billions of dollars that have been spent on these efforts. "The system is breaking down. Until you actually deal with the underlying problem – which is the molecular changes that are occurring during ageing – you have zero chance of curing these diseases."
Staving off these diseases – in other words, preventative medicine – is what scientists should be focused on, rather than a silly quest for immortality, says Tom Kirkwood, an ageing expert at Newcastle University. "The agenda of focusing on a life without ageing diverts much-needed attention from the real agenda," Kirkwood said in a talk at the British Science Festival last year. As the world gets older and older, research funding should be funneled into studies that help elderly people mitigate their inevitable decline. "And if, at some time in the future, that leads to a life without ageing, I would be one of the first to celebrate," Kirkwood said. "But I ain't gonna be around to see it."
Walker doesn't accept the expert consensus that immortality is scientifically impossible. But he reluctantly agrees that it's unrealistic – if not because of the science, then because of all of the social, ethical and political problems that would come with it.
The Greenbergs have not publicly explained why they ended their collaboration with Walker, and Howard Greenberg declined to comment for this article. Sometime after they ended their collaboration with Walker, they began working with Eric Schadt of the Icahn School of Medicine at Mount Sinai Hospital, New York. Schadt has become quite famous over the past few years for his work sequencing the genomes of people with extremely rare diseases.
After sequencing Brooke Greenberg's whole genome, as well as the exomes of her parents and three siblings, Schadt's team found that Brooke carries three mutations that have never been reported in the general population, two of which may be relevant to ageing. The researchers have not yet published their findings, however, and are waiting until they can confirm them with more data from similar patients.
Schadt's team has begun to reprogram some of Brooke's skin cells into stem cells so they can be differentiated into other types of cells, such as neurons. By analysing these cultured cells in the lab, the researchers hope to find out whether these three mutations of Brooke's are damaging or benign.
Most researchers agree that finding out the genes behind syndrome X is a worthwhile scientific endeavour, as these genes will no doubt be relevant to our understanding of development. They're far less convinced, though, that the girls' condition has anything to do with ageing. "It's a tenuous interpretation to think that this is going to be relevant to ageing," Gems says. It's not likely that these girls will even make it to adulthood, he says, let alone old age.
On 24 October 2013, Brooke passed away. She was 20 years old. MaryMargret heard about it when a friend called after reading it in a magazine. The news hit her hard. "Even though we've never met the family, they've just been such a part of our world," she says.
MaryMargret doesn't see Brooke as a template for Gabby – it's not as if she now believes that she only has 11 years left with her daughter. But she can empathise with the pain the Greenbergs must be feeling. "It just makes me feel so sad for them, knowing that there's a lot that goes into a child like that," she says. "You're prepared for them to die, but when it finally happens, you can just imagine the hurt."
Today Gabby is doing well. MaryMargret and John are no longer planning her funeral. Instead, they're beginning to think about what would happen if Gabby outlives them. (Sophia has offered to take care of her sister.) John turned 50 this year, and MaryMargret will be 41. If there were a pill to end ageing, they say they'd have no interest in it. Quite the contrary: they look forward to getting older, because it means experiencing the new joys, new pains and new ways to grow that come along with that stage of life.
Richard Walker, of course, has a fundamentally different view of growing old. When asked why he's so tormented by it, he says it stems from childhood, when he watched his grandparents physically and psychologically deteriorate. "There was nothing charming to me about sedentary old people, rocking chairs, hot houses with Victorian trappings," he says. At his grandparents' funerals, he couldn't help but notice that they didn't look much different in death than they did at the end of life. And that was heartbreaking. "To say I love life is an understatement," he says. "Life is the most beautiful and magic of all things."
If his hypothesis is correct – who knows? – it might one day help prevent disease and modestly extend life for millions of people. Walker is all too aware, though, that it would come too late for him. As he writes in his book: "I feel a bit like Moses who, after wandering in the desert for most years of his life, was allowed to gaze upon the Promised Land but not granted entrance into it."
David Gems receives funding from the Wellcome Trust, which publishes Mosaic.