In mice, eliminating cells with active <i>p16</i>, a marker of cellular senescence, four months after irradiation reduced the overall burden of age-related deficits
In mice, eliminating cells with active p16, a marker of cellular senescence, four months after irradiation reduced the overall burden of age-related deficits
In an article published on August 26 in Aging Cell, the authors eliminated these cells either one month or four months after irradiation. The early treatment did not affect survival or test performance. The late treatment improved movement and memory, and increased median lifespan in females.
The mice received three doses of whole-body irradiation. The researchers then monitored survival, movement, memory, liver function, and the overall burden of age-related deficits, measured as frailty, for several months. The authors wanted to determine when cells associated with cellular senescence begin to affect an animal after DNA damage.
To do this, they used INK-ATTAC mice. AP20187 activates a genetic switch that kills cells in which p16Ink4a is active. The researchers used p16 activity to identify one cell population associated with cellular senescence, which allowed them to eliminate that population at a chosen time after irradiation.
After one month, another gene, p21, was more often active in cells of the brain and the lining of its blood vessels. This represented an early cellular response to damage. At that time, the number of cells with active p16 had not increased in these tissues. By the fourth month, cells with active p16 had accumulated in the brain, liver, and muscles. The authors then began a course of AP20187 and repeated it two months later to test the role of this late cell population.
Treatment after one month did not affect survival or performance in functional tests. After treatment at four months, the frailty index was lower at 14 and 17 months of age. The mice remained on a rotating rod for longer and spent more time exploring the novel arm of a Y-maze. Median lifespan, the time by which half of the animals had died, also increased in females.
The role of p16 depends on the cell type and tissue. In another mouse model, immune cells with high p16 levels helped the animals tolerate irradiation. Eliminating these cells worsened the outcome.
In a 2022 study, early treatment with navitoclax or with a combination of dasatinib and quercetin after similar irradiation also reduced frailty in mice. The INK-ATTAC system targets cells with active p16 more selectively than these senolytic drugs, which eliminate senescent cells. Together, the two experiments define the next question more precisely: which cell population should be tested, and at what time after damage.