Scientists reverse ageing in mice

Researchers have developed a molecule that selectively destroys senescent cells, which are frail and damaged cells that age people and promote disease (Science, 2017). The compound makes old mice act and appear more youthful.

“It’s definitely a landmark advance in the field,” said cell and molecular biologist Francis Rodier from the University of Montreal, who wasn’t connected to the study. He said “This is the first time that somebody has shown that you can get rid of senescent cells without having any obvious side effects.”

As people get older, senescent cells build up in their tissues, where researchers think they contribute to illnesses such as heart disease, arthritis, and diabetes. In the past, scientists have genetically modified mice to dispatch their senescent cells, allowing the rodents to live longer and reducing plaque buildup in their arteries. These kind of genetic alterations aren’t practical for humans, but researchers have reported at least seven compounds, known as senolytics, that kill senescent cells. A clinical trial is testing two of the drugs in patients with kidney disease, and other trials are in the works.

However, current senolytic compounds, many of which are cancer drugs, come with downsides. They can kill healthy cells or trigger side effects such as a drop in the number of platelets.

Cell biologist Peter de Keizer, from the Erasmus University Medical Centre in Rotterdam, and colleagues were investigating how senescent cells stay alive when they uncovered a different strategy for attacking them. Senescent cells carry the type of DNA damage that should spur a protective protein, called p53, to put them down. Instead, the researchers found that a different protein, FOXO4, latches onto p53 and prevents it from doing its duty. To counteract this effect, Peter de Keizer and colleagues designed a peptide that carries a shortened version of the segment of FOXO4 that attaches to p53. In a petri dish, this peptide prevented FOXO4 and p53 from hooking up, prompting senescent cells to commit suicide. But it spared healthy cells.

The researchers then injected the molecule into mutant mice that age rapidly. These rodents live about half as long as normal mice, and when they are only a few months old, their fur starts to fall out, their kidneys begin to falter, and they become sluggish. However, as the scientists have reported in Cell, the peptide boosted the density of their fur, reversed the kidney damage, and increased the amount of time they could scurry in a running wheel. When the researchers tested the molecule in normal, elderly mice, they saw a similar picture; in addition to helping their kidneys and fur, the molecule also increased their willingness to explore their surroundings.

“The paper adds a potentially new way to target senescent cells,” said diabetes researcher James Kirkland of the Mayo Clinic in Rochester, Minnesota. He cautioned, however, that peptides like the one Peter de Keizer and colleagues developed have their own limitations. The digestive system destroys them, so they can only be delivered through inhalation or an injection.

Although the molecule did not reduce the number of platelets in either mouse group, killing off large numbers of senescent cells could still trigger a potentially fatal complication sometimes suffered by cancer patients. Furthermore, senescent cells foster wound healing, and destroying the cells could impair this ability. That’s why Peter de Keizer said he and his colleagues plan to move cautiously with their molecule. He said “I don’t think you should start treating frail people in their 90s.” Instead, he said they want to determine whether the molecule kills cancer cells, which share some similarities with senescent cells, starting with the brain tumour glioblastoma. If the compound continues to prove safe, they can think about testing the peptide against age-related diseases or even ageing itself.

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