Extending healthy life by getting rid of retired cells

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As we get older, many of the cells in our bodies go into retirement. Throughout our lives, they divided time and again, all in the face of radiation bombardments and chemical attacks. Slowly but surely, their DNA builds up damage to that threatens to turn them into tumours. Some repair the damage; others give up the ghost. But some cells opt for a third strategy – they shut down. No longer growing or dividing, they enter a state called senescence.

But they aren’t idle. Senescent cells still secrete chemicals into the body, and some scientists have suggested that they’re responsible for many of the health problems that accompany old age. And the strongest evidence for this claim comes from a new study by Darren Baker from the Mayo Clinic College of Medicine.

Baker has developed a way of killing all of a mouse’s senescent cells by feeding them with a specific drug. When he did that in middle age, he gave the mice many more healthy years. He delayed the arrival of cataracts in their eyes, put off the weakening of their muscles, and held back the loss of their body fat. He even managed to reverse some of these problems by removing senescent cells from mice that had already grown old. There is a lot of work to do before these results could be applied to humans, but for now, Baker has shown that senescent cells are important players in the ageing process.

Note that the mice in this study didn’t live any longer; they just spent more of their life being healthy. That is an incredibly important distinction and one that scientists who work on ageing are starting to bear in mind. James Kirkland, one of the study’s leaders, says, “Until two or three years ago, the basic biology was focused on lifespan. Increasingly, it’s become more focused on increasing healthspan too. People may want to live longer but they don’t want to live longer at all costs. They want to live more healthily. Older people value independence and the ability to carry out the activities of daily life.”

Baker exploited the fact that many senescent cells rely on a protein called p16-Ink4a. He created a genetic circuit that reacts to the presence of p16-Ink4a by manufacturing an executioner: a protein called caspase-8 that kills its host cell. Caspase-8 is like a pair of scissors – it comes in two halves that only work when they unite. Baker could link the two halves together using a specific drug. By sneaking the drug into a mouse’s food, he activated the executioners, which only killed off the cells that have lots of p16-Ink4a. Only the senescent ones get the chop.

Baker tested out this system in a special strain of genetically engineered mice that age very quickly. It worked. The senescent cells disappeared, and that substantially delayed the onset of muscle loss, cataracts, and fat loss.  Typically, around half of these mice show signs of muscle loss by five months of age. Without their senescent cells, only a quarter of them showed the same signs at ten months. Their muscle fibres were larger, and they ran further on treadmills. Even old mice, whose bodies had started to decline, showed improvements.

“There’s been a question of whether senescent cells are important, since they’re only a small proportion of cells,” says Kirkland. “Our work indicates that a small number of these cells can have a big impact.”

While several scientists agree that senescent cells are somehow harmful, they’ve disagreed as to how. Some say that they’ve lost important functions, while others think that they gain harmful ones. Baker’s study supports the latter camp. “The reason why that model is very attractive is that it’s a lot easier to drug,” says Norman Sharpless, who also works on senescence and ageing. “It’s good news if you want to treat or reverse ageing.”

To get to that point, the team has many challenges in store. Now that they’ve shown that senescent cells are important in a strain of mice that age quickly, they need to show that the same applies to rodents that age normally. Those studies are underway, but they will take years. Even then, there’s no guarantee that the results will apply to humans, since there are important differences in the ways the two species age.

After that, the team will have to work out a practical way of destroy senescent cells. Baker’s approach didn’t work in the heart or liver, where senescent cells don’t rely on the p16-Ink4a protein. As such, his mice suffered from the usual slew of heart problems and thickened arteries.

Alternatively, the team could interfere with the chemicals that senescent cells produce, but there are hundreds of these and finding the right target is another challenge. Then, there are many tangential questions. “Are there drawbacks to removing senescent cells?” asks Kirkland. “Do you want to use continuous approaches of intermittent ones? Can this approach improve function in models of arteriosclerosis or diabetes or Alzheimer’s? Our study raises more questions than answers. There’s a long way to go.”

It might seem that there’s an obvious drawback to Baker’s approach. Senescence keeps cancer at bay, by cordoning off the most damaged cells from the growing population. If you get rid of these cells, will animals develop raging tumours?

Kirkland thinks not. He points out that senescent cells also produce inflammatory chemicals that might enhance the spread of some cancers. And many cancers develop from senescent cells, by shaking off their restraints and growing out of control. Get rid of these cells, and you could potentially nip cancers in the bud before they even form. “We anticipate that removing senescent cells may actually decrease the risk of cancer,” says Kirkland. Other scientists, like Judith Campisi, have suggested something similar.

There may be other unwanted side effects. “There are so many trade-offs with ageing. You make cancer less common but you might worsen things in other ways,” says Sharpless. Senescent cells may be involved in repairing skin wounds, and the inflammatory chemicals they secrete can help to keep infections under control.

So far, there are no signs of these potential problems. Baker saw no side effects after treating his mice once every three days, for 15 months – in human terms, that’s equivalent to the period between weaning and the end of middle age. But Kirkland says, “We don’t know if there would be problems if we stressed the animals, say with chemotherapy or putting them out in the wild.” The team still needs to see if the loss of senescent cells leads to problems under more realistic conditions.

Reference: Baker, Wijshake, Tchkonia, LeBrasseur, Childs, van de Sluis, Kirkland & van Deursen. 2011.  Clearance of p16-Ink4a-positive senescent cells delays ageing-associated disorders. Nature http://dx.doi.org/10.1038/nature10600

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