I Will Never Ever Ever Grow So Old Again

Ageing: The girls who never grow older

From Mosaic

A handful of girls seem to defy one of the biggest certainties in life: ageing. Virginia Hughes reports on the families wrestling with a condition they can't explain, and the scientist who believes that these children could hold the key to immortality.

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Richard Walker has been trying to conquer ageing since he was a 26-year-erstwhile complimentary-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 crowing, of joie de vivre, and still was as well acutely enlightened of its passing. He was haunted by the noesis that ageing would somewhen steal abroad his vitality – that with each passing solar day his trunk was slightly less robust, slightly more than rust-covered. 1 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 upshot of a biological process, and therefore is controlled by a mechanism that nosotros tin understand."

Scientists accept published several hundred theories of ageing, and have tied it to a broad multifariousness of biological processes. Merely no one withal understands how to integrate all of this disparate data.

Walker, at present 74, believes that the fundamental to catastrophe ageing may prevarication in a rare affliction that doesn't even have a real name, "Syndrome X". He has identified four girls with this status, marked by what seems to exist a permanent state of infancy, a dramatic developmental arrest. He suspects that the illness 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 breed home from school. She drives an enormous SUV, but her half-dozen children and their coats and bags and snacks manage to fill every inch. The three big kids are bouncing in the very back. Sophia, 10, with a mouth of new braces, is complaining about a boy-crazy friend. She sits adjacent to Anthony, seven, and Aleena, five, who are glued to something on their mother's iPhone. The three niggling kids squirm in 3 car seats across the heart row. Myah, 2, is mining a blood-red slushy, and Luke, i, is pawing a bag of fresh crickets bought for the family gecko.

Finally there'due south Gabrielle, who'southward the smallest child, and the second oldest, at ix years quondam. 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'southward dusty-blue eyes gyre up towards the ceiling. By the calendar, she's about an adolescent. But she has the buttery skin, tightly clenched fingers and hazy awareness of a newborn.

Dorsum in 2004, when MaryMargret and her hubby, John, went to the infirmary to evangelize Gabby, they had no idea anything was wrong. They knew from an ultrasound that she would have clubbed feet, but and then had their other daughter, Sophia, who was otherwise healthy. And because MaryMargret was a calendar week early, they knew Gabby would be small, simply not abnormally so. "And so it was such a stupor to the states when she was born," MaryMargret says.

Gabby came out imperial 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 polish, 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 crack palate and an aberrant swallowing reflex, which meant she had to be fed through a tube in her olfactory organ. "They started trying to set us that she probably wouldn't come abode with us," John says. Their family priest came past to baptise her.

Unlike typical babies, Gabby Williams was built-in with a smooth frontal lobe in her brain, forth with a number of other developmental defects (SPL)

Day afterwards day, MaryMargret and John shuttled between Gabby in the hospital and xiii-calendar month-erstwhile Sophia at abode. The doctors tested for a few known genetic syndromes, but they all came dorsum negative. Nobody had a clue what was in shop for her. Her strong Cosmic family unit put their faith in God. "MaryMargret merely kept maxim, 'She's coming dwelling, she's coming habitation'," recalls her sis, Jennie Hansen. And afterwards forty days, she did.

Gabby cried a lot, loved to be held, and ate every iii hours, just similar any other newborn. Just of grade she wasn't. Her artillery would stiffen and fly up to her ears, in a pose that the family nicknamed her "Harley-Davidson". At four months erstwhile she started having seizures. Most puzzling and problematic, she however 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. "Y'all almost get your hopes upwards a little – 'This is heady! Nosotros're going to the gastro doctor, and maybe he'll have some answers'," MaryMargret says. Only the experts always said the same thing: cypher could be done.

The first few years with Gabby were stressful. When she was i and Sophia two, the Williamses drove from their home in Billings, Montana, to MaryMargret'southward blood brother'southward 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 float infection. Around the same menses, she caused a severe respiratory infection that left her struggling to breathe. John and MaryMargret tried to set up Sophia for the worst, and fifty-fifty planned which readings and songs to use at Gabby'southward 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 means, but at her own pace. MaryMargret vividly remembers a day at piece of work when she was pushing Gabby'due south stroller downwardly 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, yous'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 fourth dimension to make our peace."

Mortal questions

When Walker began his scientific career, he focused on the female reproductive organisation every bit a model of "pure ageing": a woman's ovaries, even in the absence of whatever affliction, slowly but inevitably slide into the throes of menopause. His studies investigated how food, light, hormones and encephalon chemicals influence fertility in rats. Only academic science is irksome. He hadn't cured ageing by his 40th birthday, nor past 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.

And then he went back to the drawing board. Equally he describes in his book, Why We Age, Walker began a serial of thought experiments to reflect on what was known and non known about ageing.

Ageing is unremarkably divers every bit the wearisome accumulation of damage in our cells, organs and tissues, ultimately causing the concrete transformations that we all recognise in elderly people. Jaws shrink and gums recede. Skin slacks. Bones breakable, 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 nosotros rarely question it. Merely biologists accept been questioning information technology for a long time.

Our Dna mechanics become less effective with age (SPL)

Information technology's a harsh world out at that place, and fifty-fifty young cells are vulnerable. Information technology'due south similar buying a new machine: the engine runs perfectly simply is nonetheless at adventure of getting smashed on the highway. Our young cells survive only because they have a slew of trusty mechanics on call. Accept DNA, which provides the all-important instructions for making proteins. Every fourth dimension a cell divides, it makes a almost-perfect re-create of its three-billion-letter of the alphabet code. Copying mistakes happen frequently along the way, just we have specialised repair enzymes to set them, like an automatic spellcheck. Proteins, as well, are e'er vulnerable. If it gets too hot, they twist into deviant shapes that go along them from working. Only here again, we accept a fixer: so-called 'heat daze proteins' that blitz to the aid of their misfolded brethren. Our bodies are as well regularly exposed to environmental poisons, such as the reactive and unstable 'free radical' molecules that come up from the oxidisation of the air we breathe. Happily, our tissues are stocked with antioxidants and vitamins that neutralise this chemical harm. 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, and then, does everything eventually go to hell?

Ane theory is that it all boils downwardly to the pressures of development. Humans reproduce early in life, well before ageing rears its ugly head. All of the repair mechanisms that are of import in youth – the DNA editors, the oestrus shock proteins, the antioxidants – aid the young survive until reproduction, and are therefore passed downwardly to future generations. Just problems that show up after nosotros're done reproducing cannot exist weeded out by development. Hence, ageing.

Most scientists say that ageing is non caused by whatsoever one culprit but by the breakdown of many systems at once. Our sturdy DNA mechanics get less effective with age, meaning that our genetic code sees a gradual increment in mutations. Telomeres, the sequences of Deoxyribonucleic acid that act as protective caps on the ends of our chromosomes, become shorter every year. Epigenetic messages, which assistance plow genes on and off, get corrupted with fourth dimension. Heat daze proteins run downwards, leading to tangled protein clumps that muck upward the smooth workings of a prison cell. Faced with all of this damage, our cells try to adjust by changing the mode they metabolise nutrients and store energy. To ward off cancer, they even know how to close themselves downward. But eventually cells stop dividing and stop communicating with each other, triggering the decline we run into from the outside.

The telomeres that protect our chromosomes get progressively shorter equally we historic period (SPL)

Scientists trying to slow the ageing procedure tend to focus on one of these interconnected pathways at a time. Some researchers take 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 of import cell-growth pathway, boosts their lifespan. Notwithstanding other groups are investigating substances that restore telomeres, Deoxyribonucleic acid repair enzymes and estrus shock proteins.

During his idea experiments, Walker wondered whether all of these scientists were fixating on the wrong affair. What if all of these various types of cellular damages were the consequences of ageing, simply 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 Oct 2005. He was working in his home office when his wife called out to him to join her in the family unit room. She knew he would want to see what was on TV: an episode of Dateline about 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 quondam, but but 13 pounds (6kg) and 27 inches (69cm) long. Her doctors had never seen anything like her condition, and suspected the crusade 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 every bit progeria and Werner syndrome, which cause premature ageing in children and adults respectively. But this girl seemed to be dissimilar. She had a genetic illness that stopped her evolution and with it, Walker suspected, the ageing procedure. Brooke Greenberg, in other words, could aid him test his theory.

Uneven growth

Brooke was born a few weeks premature, with many nascency defects. Her paediatrician labeled her with Syndrome 10, not knowing what else to call it.

After watching the show, Walker tracked down Howard Greenberg's address. Ii weeks went past before Walker heard back, and after much discussion he was allowed to test Brooke. He was sent Brooke'south medical records equally well equally blood samples for genetic testing. In 2009, his team published a brief written report describing her case.

Walker's analysis establish that Brooke's organs and tissues were developing at different rates. Her mental age, according to standardised tests, was between ane and 8 months. Her teeth appeared to exist viii years old; her bones, 10 years. She had lost all of her infant fat, and her pilus and nails grew unremarkably, 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 bear witness of what Walker dubbed "developmental disorganisation". Brooke's torso seemed to be developing not as a coordinated unit of measurement, he wrote, only rather as a collection of individual, out-of-sync parts. "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 respond had to be in her genes. Walker suspected that she carried a glitch in a factor (or a prepare of genes, or some kind of complex genetic program) that directed healthy development. At that place must be some mechanism, afterward all, that allows us to develop from a single cell to a system of trillions of cells. This genetic programme, Walker reasoned, would have two main functions: information technology would initiate and drive dramatic changes throughout the organism, and information technology would also coordinate these changes into a cohesive unit.

Ageing, he thought, comes about because this developmental programme, this constant alter, never turns off. From birth until puberty, change is crucial: we demand 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 lot would want to cease adding bricks at a certain indicate," Walker says. "When you've built a perfect body, you'd want to stop screwing around with information technology. Merely that's not how evolution works." Considering natural selection cannot influence traits that evidence upward after we take passed on our genes, we never evolved a "finish switch" for development, Walker says. So we keep adding bricks to the house. At commencement this doesn't cause much damage – a sagging roof hither, a cleaved window there. Simply somewhen the foundation can't sustain the additions, and the house topples. This, Walker says, is ageing.

Brooke was special considering she seemed to have been born with a finish switch. But finding the genetic culprit turned out to be difficult. Walker would need to sequence Brooke's entire genome, alphabetic character by alphabetic character.

That never happened. Much to Walker's chagrin, Howard Greenberg abruptly severed their relationship. The Greenbergs have not publicly explained why they ended their collaboration with Walker, and declined to comment for this article.

Second chance

In August 2009, MaryMargret Williams saw a photo of Brooke on the encompass of People magazine, just below the headline "Heartbreaking mystery: The 16-year-old baby". She thought Brooke sounded a lot like Gabby, and so contacted Walker.

After reviewing Gabby's details, Walker filled her in on his theory. Testing Gabby'south genes, he said, could help him in his mission to end age-related disease – and perchance even ageing itself.

This didn't sit well with the Williamses. John, who works for the Montana Section of Corrections, oftentimes interacts with people facing the reality of our finite time on Globe. "If you're spending the balance of your life in prison house, you lot know, it makes yous think about the bloodshed of life," he says. What's important is not how long you live, only rather what y'all do with the life yous're given. MaryMargret feels the same way. For years she has worked in a local dermatology office. She knows all likewise well the cultural pressures to stay young, and wishes more people would cover the inevitability of getting older. "You go wrinkles, you become onetime, that's role of the process," she says.

Botox, a solution for some who wish to stave off the signs of ageing (SPL)

Just Walker'southward research also had its upside. Beginning and foremost, it could reveal whether the other Williams children were at take chances of passing on Gabby'south condition.

For several months, John and MaryMargret hashed out the pros and cons. They were nether no illusion that the fruits of Walker'southward research would alter Gabby's condition, nor would they want it to. Merely they did want to know why. "What happened, genetically, to brand her who she is?" John says. And more than chiefly: "Is in that location a bigger significant for it?"

John and MaryMargret firmly believe that God gave them Gabby for a reason. Walker's enquiry offered them a comforting ane: to assistance treat Alzheimer'south and other historic period-related diseases. "Is there a small slice that Gabby could present to help people solve these awful diseases?" John asks. "Thinking nearly it, information technology's like, no, that'due south for other people, that's not for u.s.a.." But then he thinks back to the day Gabby was born. "I was in that delivery room, thinking the aforementioned affair – this happens to other people, not us."

Yet non entirely certain, the Williamses went alee with the research.

Amassing evidence

Walker published his theory in 2011, but he'southward 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 Joao Pedro de Magalhaes, 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 brute reaches a specific size. Ageing, Bidder thought, was the connected action of this regulator after growth was done.

Subsequent studies showed that Bidder wasn't quite right; in that location are lots of marine organisms, for example, that never cease growing but age anyway. Still, his key idea of a developmental programme leading to ageing has persisted.

For several years, Stuart Kim'southward group at Stanford University has been comparing which genes are expressed in young and onetime nematode 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 aggregating of cellular damage.

Mice on restricted diets alive longer (SPL)

Other groups have since institute similar patterns in mice and primates. One study, for case, found that many genes turned on in the brains of former monkeys and humans are the same equally those expressed in young brains, suggesting that ageing and evolution are controlled by some of the aforementioned gene networks.

Peradventure nigh provocative of all, some studies of worms have shown that shutting down essential development genes in adults significantly prolongs life. "We've plant quite a lot of genes in which this happened – several dozen," de Magalhaes says.

Nobody knows whether the aforementioned sort of developmental-plan genes exist in people. But say that they practice exist. If someone was built-in with a mutation that completely destroyed this programme, Walker reasoned, that person would undoubtedly dice. Just if a mutation only partially destroyed it, it might pb to a condition like what he saw in Brooke Greenberg or Gabby Williams. So if Walker could identify the genetic cause of Syndrome Ten, then he might also have a driver of the ageing process in the rest of us.

And if he constitute that, then could information technology atomic number 82 to treatments that slow – or fifty-fifty cease – ageing? "There'south no doubt about it," he says.

Public phase

After agreeing to participate in Walker's research, the Williamses, just like the Greenbergs earlier them, became famous. In Jan 2011, when Gabby was half-dozen, the television channel TLC featured her on a one-60 minutes documentary. The Williams family also appeared on Japanese television and in dozens of newspaper and magazine articles.

Other than becoming a local celebrity, though, Gabby'southward everyday life hasn't changed much since getting involved in Walker's research. She spends her days surrounded by her large family. She'll unremarkably lie on the floor, or in one of several cushions designed to proceed 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 nada of it. They play boisterously in the same room, somehow ever careful not to crash into her. In one case a week, a instructor comes to the firm to work with Gabby. She uses sounds and shapes on an iPad to try to teach cause and effect. When Gabby turned nine, final October, the family made her a birthday cake and had a party, just as they always do. Virtually of her gifts were blankets, stuffed animals and apparel, merely as they are every year. Her aunt Jennie gave her make-upwardly.

Walker teamed upward with geneticists at Duke University and screened the genomes of Gabby, John and MaryMargret. This exam looked at the exome, the 2% of the genome that codes for proteins. From this comparison, the researchers could tell that Gabby did non inherit any exome mutations from her parents – meaning that it wasn't likely that her siblings would be able to laissez passer 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'south illness. Gabby carries several mutations in her exome, merely none in a gene that would make sense of her condition. All of u.s.a. take mutations littering our genomes. And then 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 status.

All girls

Luckily for him, Walker's connected 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 former, with has long and skinny limbs, just like Gabby. "Nosotros have basically been stuck in a time warp," says her female parent, Kim Wittke. The fact that all of these possible Syndrome X cases are girls is intriguing – information technology could hateful that the crucial mutation is on their 10 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% of DNA code, which is thought to be responsible for regulating the expression of poly peptide-coding genes.

For his theory, Walker says, "this is do or die – we're going to practice every single bit of Dna in these girls. If nosotros observe a mutation that'due south mutual to them all, that would exist very exciting."

But that seems like a very large if.

Most researchers agree that finding out the genes behind Syndrome X is a worthwhile scientific endeavor, equally these genes volition no dubiousness 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 estimation to think that this is going to be relevant to ageing," says David Gems, a geneticist at University College London. It's not likely that these girls volition even make it to adulthood, he says, let lonely old age.

It's also not at all articulate that these girls have the aforementioned condition. Even if they practise, and even if Walker and his collaborators observe the genetic cause, there would still be a steep hill to climb. The researchers would need to silence the aforementioned gene or genes in laboratory mice, which typically have a lifespan of two or three years. "If that animal lives to exist ten, and so we'll know we're on the right track," Walker says. Then they'd have to find a manner to achieve the aforementioned genetic silencing in people, whether with a drug or some kind of cistron therapy. And and then they'd have to begin long and expensive clinical trials to make certain that the treatment was prophylactic and constructive. Science is often besides slow, and life too fast.

End of life

On 24 Oct 2013, Brooke passed away. She was 20 years sometime. MaryMargret heard most 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 only been such a part of our world," she says.

MaryMargret doesn't come across Brooke as a template for Gabby – it's not equally if she at present believes that she only has eleven years left with her girl. Merely she can empathise with the pain the Greenbergs must be feeling. "It just makes me feel so sad for them, knowing that there'south a lot that goes into a kid like that," she says. "You're prepared for them to dice, simply when information technology finally happens, yous can merely imagine the hurt."

Today Gabby is doing well. MaryMargret and John are no longer planning her funeral. Instead, they're showtime to call up virtually what would happen if Gabby outlives them. (Sophia has offered to take care of her sister.) John turned 50 this yr, and MaryMargret volition be 41. If there were a pill to end ageing, they say they'd have no interest in it. Quite the contrary: they wait forrard to getting older, because it means experiencing the new joys, new pains and new means to abound 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 past it, he says it stems from babyhood, when he watched his grandparents physically and psychologically deteriorate. "There was nothing mannerly to me about sedentary erstwhile people, rocking chairs, hot houses with Victorian trappings," he says. At his grandparents' funerals, he couldn't help only notice that they didn't look much different in death than they did at the terminate 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 also enlightened, though, that it would come too belatedly for him. Equally he writes in his book: "I experience a bit like Moses who, after wandering in the desert for most years of his life, was immune to gaze upon the Promised Land but not granted entrance into it."

This is an edited version of an commodity originally published by Mosaic, and is reproduced under a Creative Commons licence. For more than Mosaic articles click here .

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Source: https://www.bbc.com/future/article/20140520-the-girls-who-never-age

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