麻豆传媒

A bizarre genetic disease that seems to accelerate ageing could hold the key to longer lives for everyone

LESLIE GORDON and her husband Scott Berns could not figure out what was ailing their infant son, despite the fact they were both paediatricians. He was failing to gain weight as he should, had cut no teeth and his hair was falling out.

The diagnosis, when it came in the summer of 1998, was devastating. Sam had progeria, a rare genetic condition that resembles the ageing process sped up. Gordon had never heard of it. She and her husband dropped everything and set about trying to learn more.

The news over the next week was bleak. Although progeria is a mysterious illness, some facts about it are undisputed. There was no cure and no treatments. Their son would get sicker and sicker and there was nothing they could do. The average age at which children with progeria died was 13.

There weren鈥檛 even any drugs in the pipeline. There was almost no research going on, says Gordon. 鈥淭here was no funding. No tissues. There was no central resource for families. It seemed like a huge void of nothing.鈥�

In one way that鈥檚 unsurprising 鈥� only 80 children in the world are known to have progeria. But the science void was something that Gordon could tackle. She quit her medical training to set up a charity, the Progeria Research Foundation, with the express goal of finding a cure, as well as providing support for affected families.

Gordon鈥檚 team and other researchers in this area have one mantra: understanding progeria won鈥檛 just help a few children and their families. It will also help unlock the secrets of the ageing process we all experience.

Now the latest evidence suggests they are at least partly right. Progeria does have parallels with normal ageing, at least in one key aspect: how our blood vessels deteriorate. And ageing blood vessels lead to two of the three biggest causes of death in the west: heart disease and stroke (the third being cancer). 鈥淲e have not had a brand new avenue for studying ageing and cardiovascular disease in some time,鈥� Gordon says. 鈥淧rogeria gives that.鈥�

鈥淲e have not had a brand new avenue for studying heart disease for quite some time 鈥� progeria gives that鈥�

Progeria was first described in 1886 by the English doctor Jonathan Hutchinson, and then in 1897 by his countryman Hastings Gilford. That鈥檚 why the full name of the best known form is Hutchinson-Gilford progeria syndrome. That鈥檚 what Sam Gordon has.

Children with progeria develop normally for the first year of life, but then their growth begins to slow. Soon they develop many medical problems usually the preserve of elderly people. Their bones weaken, their joints stiffen and they may get dislocated hips. Their skin becomes less elastic and creases into wrinkles. They often lose their hair.

Like a lot of old people, children with progeria tend to die from a heart attack or stroke. Their blood vessel walls thicken and stiffen, and can accumulate cholesterol-laden plaques and calcium, a direct cause of high blood pressure and heart disease.

Children with progeria do not get dementia or memory loss, nor are they more prone to cancer, the other main disease of ageing. That apart, progeria resembles ageing gone into hyperdrive. So the question has always been: is progeria relevant to what happens to us as we get older or is it just masquerading as ageing?

Not everyone is convinced the two are linked. 鈥淭he chances that [progeria syndromes] represent an authentic recapitulation of how ageing leads to symptoms, I think is a stab in the dark,鈥� says Richard A. Miller, who researches ageing at the University of Michigan in Ann Arbor. William Ershler, head of the Institute for Advanced Studies in Aging in Gaithersburg, Maryland, agrees, saying: 鈥淚 think it can be important in certain aspects of ageing, but I don鈥檛 think it explains 鈥榯he clock鈥�.鈥�

Rare mutation

One problem is that we know so little about normal ageing. While we have documented a vast list of changes that occur as we grow older at the level of our organs, hormones, cells and now genes, cause and effect are far from clear.

The first progeria breakthrough came in 2003, when two competing groups published their discovery of the gene for Hutchinson-Gilford progeria syndrome in the same week, one paper appearing in Nature (), the other in Science (vol 300, p 2055). One, funded by Gordon鈥檚 foundation, was led by Francis Collins, head of the Human Genome Project. The other was by a European group led by Nicolas L茅vy in Marseilles, France, which had been investigating rare genetic disorders.

Both teams had identified that the problem was a point mutation 鈥� in other words the swapping of just one 鈥渓etter鈥� of DNA 鈥� in a gene called LMNA. The mutation is rare, affecting 1 in 4 to 8 million births.

The gene encodes lamin A, a protein found in a cell鈥檚 nucleus. This is a major part of the lamina, a kind of scaffolding on the inner side of the nuclear envelope. It is also associated with DNA itself.

There is still a lot to discover about lamin A鈥檚 function, but one thing is for sure: the effects of the mutation are profound. Cells in people with progeria have strange, knobbly nuclei, with indentations and protrusions, quite unlike the smooth, spherical nuclei seen in normal human cells (see diagram). That such a dramatic difference was only described for the first time in 2003 suggests that no one had thought to look at a progeria patient鈥檚 cells under a microscope until then.

Things look just as strange inside the nucleus. In people without progeria most DNA is tightly coiled, with the only uncoiled genes those that are 鈥渟witched on鈥� 鈥� in other words, their protein is being produced. Not so in progeria, where all DNA is uncoiled, although not all genes are switched on. A further difference is that there are many changes to the genes鈥� normal chemical on/off switches.

One effect of the progeria mutation is fairly well understood. A sticky molecule called farnesyl is normally added to lamin A while it is being made, which helps the protein reach the lamina. Then the farnesyl group should be lopped off, allowing lamin A to properly join the scaffold structure. But the mutation keeps the farnesyl group in place, and the sticky mutated form of lamin A, dubbed progerin, piles up at the nuclear envelope.

Finding the LMNA gene has opened the door to drug treatments for progeria. The enzyme that adds farnesyl to lamin A is overactive in some types of tumours, and a group of drugs that block its action are being investigated as cancer therapies. After these 鈥渇arnesyl transferase inhibitors鈥� (FTIs) showed promise in a mouse version of progeria, the first human drug trial began in 2007, on 28 children at the Children鈥檚 Hospital Boston.

Double trouble

The results from this trial are still being analysed but in 2008 work on cells grown in the lab suggested there may be a hitch. Blocking the addition of farnesyl led to a different fatty group being added to lamin A later on, resulting in the same pile-up at the lamina (). 鈥淭he blockade of both modifications is necessary to treat progeria,鈥� says Carlos L贸pez-Ot铆n at the University of Oviedo, Spain, who led the work.

The Spanish group worked out that both additions could be blocked by either of two kinds of drugs in everyday use: statins, used to lower cholesterol, and bisphosphonates, bone-strengthening agents for treating osteoporosis. So two more trials have begun, one by L茅vy鈥檚 group, testing a statin and a bisphosphonate, and the other by the Boston group, combining a statin and bisphosphonate with an FTI. Both teams are due to report their first results soon.

In April, L茅vy told a conference that the results from his first six patients were 鈥渆ncouraging鈥�. But he acknowledged it is hard to know if the drugs are acting on progeria itself or just lessening its impact on heart and bone health. 鈥淚 think FTIs and the combination of statins and bisphosphonates are not a cure for progeria,鈥� he admitted to 麻豆传媒. 鈥淭his [approach] is dedicated to improving the symptoms and to have more time to find something more efficient.鈥�

As well as the possibility of new treatments, the discovery of the progeria gene and progerin has galvanised basic research in this area. In 2006 came a paper in showing that progerin turns up at low levels in skin cells from people without progeria (vol 312, p 1059). The older the individuals were, the more progeria-like changes appeared in the nucleus.

In progeria, the mutation in the LMNA gene causes a so-called 鈥渟plicing error鈥� in the multi-step process of copying DNA into a string of RNA, which is subsequently read off as a protein. This splicing error seems to occur spontaneously in people without progeria, perhaps more often as we get older.

Then last year two further papers firming up the connection between progeria and normal ageing were published. These look even more medically relevant, because they relate to cardiovascular disease. The first showed that levels of a protein called prelamin A, which is similar to progerin, increase with age in the muscle cells of blood vessel walls (). In this case the problem was not a splicing error, but lack of the enzyme that lops off the farnesyl group. 鈥淲e can see quite a lot of cells accumulating prelamin A in atherosclerosis and calcified arteries,鈥� says Catherine Shanahan, a biologist at King鈥檚 College London, who led the work.

Shanahan says her group has further evidence, not yet published, that prelamin A is actually driving the calcification of blood vessels. Their investigation of how this happens is being funded by the British Heart Foundation; progeria researchers are no longer the only ones interested in this area.

The second paper, from Gordon鈥檚 team, pinpoints progerin itself in the blood vessels of healthy people (). Looking at 29 people aged from 1 month to 97 years, levels of the aberrant protein rose by 3.3 per cent for every year of life.

These recent findings are 鈥渋ntriguing鈥�, says Brian Kennedy, head of the Buck Institute for Research on Aging in Novato, California, though he cautions: 鈥淚t鈥檚 too early to know if these proteins are causal.鈥�

It is certainly early days, but those two papers were the first strong evidence that the progeria researchers might be right 鈥� studying this disease could reap wider benefits. 鈥淚t turns out to be very biologically relevant,鈥� says Gordon. 鈥淚t affects all of us.鈥�

Then last month more findings were announced that made researchers sit up and take notice. They concerned telomeres, which some think are key to cellular ageing.

A cell鈥檚 DNA is organised into discrete strings or chromosomes, 46 per cell in the case of humans. On the chromosome ends are protective sequences of DNA bound with protein, the telomeres; they are often likened to the plastic caps on shoelaces. When a cell divides, its telomeres shorten, and this seems to help set a cell鈥檚 natural lifespan, which could explain many aspects of how our tissues age.

Telomere link

The new research, by Francis Collins鈥檚 group at the National Institutes of Health in Bethesda, Maryland, was on skin cells from people without progeria. As the cells divided and grew older in the lab, the normal shortening of telomeres caused splicing errors with several genes 鈥� including lamin A (, ). 鈥淭elomere shortening during cellular senescence plays a causative role in activating progerin production,鈥� says lead author Kan Cao, a cell biologist at the University of Maryland. Assuming the findings can be repeated, they will add a further strand of evidence linking progeria with normal ageing.

In further good news, Collins鈥檚 group showed last month in cells grown in the lab, and they plan to start trials of the drug in children with progeria. And the number of labs around the world taking an interest in the disease continues to grow. Tom Misteli, a cell biologist at the National Cancer Institute in Bethesda, is trying to develop a drug that would block the mutated splice site in the LMNA gene. Pharmaceutical companies are involved and Misteli is screening a library of small molecules to find one that does the job. Out of the 300,000 molecules tested so far, they are now following up several 鈥渋nteresting candidates鈥�, he says.

That suggests that at least some drug firms have bought into the progeria-ageing link. A medicine with a potential market of 80 people would probably come low down on most companies鈥� priority list.

But nothing could be a higher priority for those, like Gordon, with an affected child. Her son is now 14. Gordon will not say if Sam is in any of the drug trials, commenting only that he is doing well, is active in Boy Scouts and the school band. 鈥淭hese are incredible, courageous kids,鈥� she says. 鈥淚t鈥檚 essential to do everything we can for them.鈥�