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.