Posted from last weeks New Scientist:
Secret to old age health could lie in purging worn-out cells
A pill to wipe out the senescent cells that are linked to everything from Alzheimer’s to arthritis could let us all get old without the side effects
Here comes t
EVER wanted to be immortal? Be careful what you wish for. Living forever wouldn’t just mean outliving your friends, family and descendants, there’s also the inconvenient reality of ageing. Beyond the superficial stuff, such as wrinkles and saggy bits, you’d have a host of age-related diseases to contend with. The older we get, the greater our chances of developing cancer, heart disease, Alzheimer’s and almost every other common condition. Meanwhile our immune system wears out and puts up an increasingly weak defence against infections. Who wants to endure millennia of that? No thanks!
But imagine you could live a long life and remain healthy right to the end. That surely would be worth wishing for. Scientists have been seeking ways to achieve this. Now they might just have found one.
The discovery has raised the tantalising possibility that we could strike at every age-related disease with a single blow. “That’s the dream,” says Judith Campisi at the Buck Institute for Research on Aging in Novato, California. “It would revolutionise the way medicine is practised.” Instead of seeing separate specialists for heart disorders, cancer and dementia, a single doctor would take a more holistic, preventive approach to your health.
But there are philosophical and practical implications. Should we treat ageing as an illness that can be seen off with drugs? If we extend our years of good health, will we live longer too? What consequences will that have for individuals and society? And what will we ultimately die of?
The key to this improbable-sounding elixir of youth lies in targeting old, worn-out cells. Young organs are full of cells that divide to replace damaged neighbours. But each only divides a finite number of times. After that they might not die, but instead enter a state called senescence, in which they get bigger and flatter and undergo chemical changes (see diagram). The same fate awaits cells damaged or stressed by free radicals, reactive molecules created when cells metabolise. Senescent cells gradually accumulate as we get older, says Campisi, who studies them. “We’ve seen them in every organ we’ve looked at.” Until a few years ago, researchers weren’t sure what these cells were doing. Now, they believe the cells have a pivotal role in ageing.
rouble
Although they can’t divide, senescent cells do pump out a slew of proteins and other compounds that cause inflammation, an immune response that can damage healthy cells. As we grow older, and more and more of our cells senesce, the inflammation becomes chronic. Pretty much every age-related disease we know of involves inflammation: so far, researchers have found evidence of a link to muscle wasting, cataracts and glaucoma,Alzheimer’s and Parkinson’s, osteoporosis and arthritis, heart failure and high blood pressure, cancers, and lung, liver, kidney and skin disorders.
So senescent cells look like trouble. Can we get rid of them? In 2011, Darren Baker at the Mayo Clinic in Rochester, Minnesota, and his colleagues did just that. They genetically engineered mice so that senescing cells would carry a tag marking them out as targets for a drug capable of destroying them. Administering the drug every few days to mice from the age of three weeks significantly delayed the onset of age-related conditions such as hunchback and cataracts. These individuals were also stronger in old age than their untreated counterparts, and looked younger with plumper, less wrinkled skin. Baker’s team saw similar benefits when they gave the drug to mice already starting to show the signs of age.
“Treated mice were stronger in old age, and looked younger with plumper, less wrinkled skin”
It’s one thing to delay ageing in rodents, quite another to do it in people. We can’t genetically engineer humans to label their senescent cells. Nor can we turn these cells back into happily dividing ones – as far as anyone knows, senescence is irreversible.
In any case, we wouldn’t want to stop senescence completely because it appears to have some useful functions. Cells that have become cancerous are usually fast-tracked to senescence, stopping them from dividing further to form a tumour, and the compounds they subsequently release may trigger other cells to repair damaged tissue. Senescent cells may also play a part in wound healing and embryo development, says Thomas von Zglinicki at Newcastle University in the UK.
What to do? One alternative is to stop the cells pumping out their toxic chemical brew. This may be possible using existing drugs. Rapamycin, which helps prevent tissue rejection following an organ transplant, is known to expand the lifespan of mice by around 10 per cent. In July, Campisi’s team tested it on samples of senescent human cells and found that it lowered the production of inflammation-causing proteins. There’s a snag here too, though. Rapamycin is useful in organ transplants because it weakens the immune system, but that means it leaves people more susceptible to disease. The drug has also been linked with an increased risk of diabetes.
Some research groups are trying to find safer alternatives. Campisi and her colleagues have formed a company to screen drug databases for compounds that might have the same effect as rapamycin. “We have some hits, but it’s hard to predict what will make it into the clinic, although we’re optimistic,” she says. Meanwhile, a team led by Joan Mannick at Novartis Institutes for BioMedical Research in Cambridge, Massachusetts, has found that a drug similar to rapamycin appears to boost the immune system, rather than weakening it. She doesn’t know if the drug is safer than rapamycin, but is planning further tests to find out.
Pill of youth
This area of research is developing rapidly. But any treatment targeting the inflammatory chemicals pumped out by senescent cells would need to be taken regularly, and that is hard to justify in otherwise healthy people, no matter how safe the drug. A better option might be to periodically clear out senescent cells to limit the damage they cause. “We know from our mouse model that senescent cells accumulate slowly over time,” says Campisi. “You could take a drug to wipe them out every five years, for example.” Such a treatment would probably begin at around the age of 50, which is when rising numbers of senescent cells seem to start causing problems.
Can the Old Firm be made young again? (Image: Paul Lowe/Panos)
Earlier this year, another team identified two drugs that might do the job. James Kirkland at the Mayo Clinic and his colleagues started by thinking about how senescent cells work. Unlike normal cells, they don’t die, suggesting they possess some kind of survival mechanism. That makes them quite like cancer cells, says Kirkland, except they don’t divide. By exploring known tricks used by cancer cells to defy destruction, his team has identified two cancer drugs that essentially force senescent cells to commit suicide.
Combined, the drugs have impressive effects in rodents. Mice given a single dose of each when they were the equivalent of 80 human years old had better heart function than untreated mice. In mice that had one leg irradiated – which would normally prematurely age it – there was less muscle wasting and, seven months after treatment, they performed better on a treadmill than untreated mice. The fact that a single dose can have such long-lasting effects is particularly promising, says Kirkland. “The drug only stays in the circulation for about 12 hours. A continued presence is not required to have an effect.”
Kirkland’s team is now testing the drugs in monkeys. “The studies aren’t published yet, but we have an indication that we’re able to selectively kill senescent cells in monkeys as well,” he says. Human clinical trials are on the drawing board. The first candidates will be people with fatal or severe disorders linked to senescence, such as some lung and liver diseases. The drugs could also be injected into joints affected by osteoarthritis, where senescent cells are known to gather.
This approach might even be used to protect against age-related cancers, according to Campisi: although senescence stops cancers in some cases, in others senescent cells can actually promote the spread of tumours. Ultimately, Kirkland hopes his treatments might stave off frailty more generally, and keep older people living at home independently for longer. “A lot of 85-year-olds have five or six different conditions – diabetes, mild cognitive impairment, heart problems and osteoarthritis, say – and they’re on 20 different drugs,” he says. “The question is: can we use these agents to alleviate multiple conditions with one drug?”
The reality is likely to be more complicated. Even if we could rid ourselves of these damaging cells simply by taking a pill every few years, there may be unintended consequences that will only become apparent when such treatments are routine. And that’s not all. “I don’t think anyone believes that all of ageing is caused by senescent cells,” says Campisi. Even enthusiasts for this line of work acknowledge that tackling ageing – or at least the debilitating diseases that accompany it – will require a multi-pronged approach. What form this should take is still far from clear. “We don’t know much about the other factors,” Campisi admits.
Everyday painkillers that target inflammation may offer some benefits. Restricting food intake also looks promising: drastically cutting down on calories extends the lifespans of worms and mice, although it doesn’t seem to have the same effect in monkeys, and the jury is still out when it comes to humans.
Of course, simple lifestyle choices such as taking regular exercise and eating plenty of fruit and vegetables can help us age healthily. But despite knowing this, many of us fail to muster the will power required to change our ways. Still, Kirkland is optimistic. “I imagine there will be a combination of lifestyle interventions and drugs that will add substantially to the healthspan,” he says.
If so, that will have wider implications. As well as improving health, the two drugs his team used seem to increase lifespan, at least in mice and monkeys. While this may sound enticing, there is debate among researchers as to whether helping people live longer is a worthy goal. “To refuse to accept aging is a sign of weakness of character, of egotism,” David Gems, who researches ageing at University College London, wrote recently. “One should endure aging and bow out gracefully with stoicism and dignity in accordance with nature’s wishes.” Others argue from an ecological perspective, pointing out that the current human population of more than 7 billion is already unsustainable.
But Kirkland is not trying to extend life for its own sake. His goal, he says, is to stave off age-related diseases – if we live longer as a result, then that’s an added benefit. Gems, at least, is persuaded by the preventive approach. “I’m really excited about the idea of targeting senescent cells as a treatment for ageing,” he says. “There is nothing wrong with people living longer as a result of better health.” Even Paul Ehrlich, a demographer at Stanford University in California who famously warned of the perils overpopulation poses to the environment, approves. “Programmes that let all people live the healthiest lives possible to the end are very desirable,” he says, although they should be accompanied by incentives to lower birth rates and consumption.
That still leaves the intriguing questions of how much longer we might live, and what we will eventually die of. “It’s hard to know,” says Kirkland. Some clues come from exceptionally long-lived people. One such person was Hendrikje van Andel-Schipper, a Dutch woman who enjoyed good health and cognition almost to her death in 2005, aged 115.When researchers analysed samples of her blood last year, they found that the stem cell supply from which all blood cells originate was almost exhausted. A healthy young person might have 1500 such cells, which are used up over the years. She appeared to be down to her last two. All of our tissues rely on stem cells for regeneration, and those that undergo rapid renewal, such as blood, skin and guts, might be the first to wear out. “Without blood you’d become anaemic and die,” says Henne Holstege at VU University Medical Center in Amsterdam, who led the research.
This suggests that even if we could regularly clear senescent cells from our bodies, there is a natural limit to lifespan. Perhaps that’s no bad thing. On the other hand, it’s quite exciting to think that our attempts to defy ageing could now go more than skin deep. “We’re really starting to understand what’s going on,” says von Zglinicki. “We are getting to the stage where, for the first time, people will be able to realistically consider the prospect of anti-ageing solutions.”
