Even if you aren’t elderly, your body is home to agents of senility—frail and damaged cells that age us and promote disease. Now, researchers have developed a molecule that selectively destroys these so-called senescent cells. The compound makes old mice act and appear more youthful, providing hope that it may do the same for us.
“It’s definitely a landmark advance in the field,” says cell and molecular biologist Francis Rodier of the University of Montreal in Canada who wasn’t connected to the study.
“This is the first time that somebody has shown that you can get rid of senescent cells without having any obvious side effects.”
As we get older, senescent cells build up in our 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. Such genetic alterations aren’t practical for people, 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.
Previous work has revealed that a combination of the natural product Quercetin with the cancer drug Dasatnib is able to remove some senescent cells, but with poor specificity. Another class of drugs called Bcl inhibitors has proven able to target and destroy senescent cells – including the drug ABT-263. These have known side effects and drawbacks however, and researchers have been searching for better, more accurate ways of killing these cells without harming the rest of the body. While gene directed therapies such as liposomal delivery or RNA based therapeutics could conceivably be an effective therapeutic route, finding a more easily applied pharmacological approach may be more cost effective in the short term.
Cell biologist Peter de Keizer of Erasmus University Medical Center in Rotterdam, the Netherlands, 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, De Keizer and colleagues designed a molecule, known as 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, 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, the scientists report online today in Cell. 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,” says diabetes researcher James Kirkland of the Mayo Clinic in Rochester, Minnesota. He cautions, however, that peptides like the one 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–you can’t just swallow a pill, he notes.
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. Moreover, senescent cells foster wound healing, and destroying the cells could impair this ability.
That’s why De Keizer says he and his colleagues plan to move cautiously with their molecule. “I don’t think you should start treating frail people in their 90s.” Instead, he says, they want to determine whether the molecule kills cancer cells, which share some similarities with senescent cells, starting with the brain tumor glioblastoma. If the compound continues to prove safe, they can think about testing the peptide against age-related diseases or even aging itself.