Drug reverses ageing in mice

23 March 2017
Posted by Chris Smith.

A drug that reverses the ageing process and makes balding mice hairy again, restores kidney function and enables the animals to run with renewed vigour has been developed by researchers in the Netherlands.

The new agent targets a process called senescence. This refers to a state adopted by some worn out or injured cells that retire from active duty and steadily build up in tissues as an animal ages. But far from being benign pensioners, these cells instead continue to secrete a cocktail of inflammatory and other factors that actually accelerate the ageing process. Removing them is known to lead to improvements in the function of a range of organs. How to do so safely, however, wasn't known.

Now Erasmus Medical Centre scientist Peter de Keizer and his colleagues have stumbled upon a solution in the form of an artificially-designed protein that biochemically crowbars the senescence process inside a cell.

Presenting their data in Cell, The team began by trying to understand why senescent cells form in the first place. Normally, when cells are injured or aged they activate a suicide programme to remove themselves from the tissue. This is known as a death programme or apoptosis and it's controlled by a cell signal called p53.

"This would normally trigger a damaged cell to destroy itself," explains de Keizer. "But it's not always advantageous to do this, such as when we are very small or when you need cells to heal an injury. So there is a molecular switch inside the cell called FOXO4."

FOXO4 grabs p53 and blocks it from tripping the cell suicide switch. "So what we did was to design our own small protein that forces FOXO4 to release p53," says de Keizer. "Then the cell dies."

The team first tested their protein drug on senescent cells in the culture dish before also injecting it into mice with an accelerated ageing syndrome as well as naturally aged animals.

In the dish, the new agent selectively triggered the death of the senescent cells. In the animals, the effects were equally profound. Age-related hair loss was reversed, the mice had better activity profiles, and markers of kidney function were significantly improved compared with control animals. Moreover, long term administration of the drug to a group of animals was not associated with any obvious harmful side effects.

"There were no excess numbers of cancers, or problems with the blood system," says de Keizer. 

Trials to stave off the ageing process in humans are some way off, but much more likely to come to fruition soon is another benefit of the new agent, an ability to reduce the toxicity of chemotherapy.

When drugs like doxorubicin are administered to destroy cancer cells, healthy tissues are also hit and many of them enter a senescent state. This ultimately limits the potential of the therapy and has consequences for the long term health of the patient. But by administering the new drug alongside doxorubicin in an experimental setting, the Dutch team found that senescence could be prevented, which could have dramatic impacts on the future of cancer management.

Unsurprisingly, de Keizer concluded, "I've had a very good week!"

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