An experimental vaccine tested in mice eliminated several targeted senescent cells. This helped prolong the life of the rodents and reverse some age-related signs of disease. Researchers are planning clinical trials in humans, but there is still a long way to go.
Our cells are programmed to divide a certain number of times during our lifetime, then stop doing so before dying (they are then senescent) and being eliminated by the immune system. With age, however, this elimination function becomes less effective. Senescent cells then accumulate and secrete factors that generate chronic inflammation often associated with age-related diseases.
Over the past few years, scientists have been working to develop "senolytic therapies" or drugs capable of eliminating senescent cells from our body. Some of these drugs have produced results and entered clinical trials. However, most of these senolytic agents inhibit anti-apoptotic pathways, increasing the possibility of off-target effects in normal tissues.
In new work, researchers have focused on developing a vaccine that can train the immune system to seek out senescent cells and kill them. destroy .
To develop their vaccine, the researchers targeted an antigen on a single type of cell:senescent vascular endothelial cells . These line the inside of the arteries, veins and capillaries. After analyzing the proteins appearing in large quantities on the surface of these cells, the researchers set their sights on the "non-metastatic glycoprotein of melanoma protein B" (or simply GPNMB).
For this work, the team then examined tissue samples from human patients with atherosclerosis (plaque deposits in the arteries). They then discovered that their vascular endothelial cells actually carried much more GPNMB than the cells of those who did not have the disease. Based on this observation, the researchers therefore wanted to see if the elimination of cells loaded with GPNMB would help reduce the density of these plaques.
To do this, they relied on mice with atherosclerosis. They eliminated cells loaded with GPNMB and discovered that the amount of plaques in the arteries of mice did indeed decrease rapidly . These results convinced the team to make GPNMB the preferred target of their vaccine.
Researchers have developed a so-called "peptide" vaccine, which targets short segments of a longer protein sequence. The team vaccinated mice that were middle-aged and just over a year old. Once injected, the serum would then induce the immune system to create antibodies against portions of the GPNMB protein . Positive cells, arterial plaques and inflammatory molecules would then have significantly decreased in mice that received the vaccine.
Senescence-specific molecular markers were also reduced in vaccinated mice. The mice injected with the placebo also moved less often and more slowly at the age of one and a half years, while the vaccinated ones remained much more lively. Finally, the team found that the mice given the vaccine lived slightly longer than the mice given the placebo. In addition, no side effects have been reported .
“The data was extremely strong…I think that's a pretty good proof of principle “, Paul Robbins, of the Institute on the Biology of Aging and Metabolism at the University of Minnesota.
These works are obviously encouraging. Eventually, the researchers plan to test the effectiveness of this product in clinical trials. Before that, however, they will have to test its safety on non-human primates. In addition, remember that not all results measured in mice necessarily translate to humans. The team also plans to develop additional vaccines that target different types of senescent cells.
