A senolytic must know which cell it is removing: cells with signs of senescence build protective barriers in the mouse brain
A senolytic must know which cell it is removing: cells with signs of senescence build protective barriers in the mouse brain
A study in Cell found that, during mouse brain development, some cells with signs of senescence help form blood vessels and the barriers that separate the brain from the blood. Some disappear after the vessels have formed, while others remain in the choroid plexus, the tissue that produces cerebrospinal fluid.
Senolytics are intended to be drugs that selectively remove senescent cells. The idea arose from the observation that these cells accumulate with age, stop dividing, and may release substances that sustain inflammation and tissue damage. However, the term “senescent cell” covers very different cells in very different locations.
In a Cell paper published on 9 July, the authors examined the developing mouse brain. The cells lining the inside of blood vessels and macrophages, which are immune cells that reside in brain tissue, temporarily developed signs of senescence while the vessels were growing. These cells exchanged signals that guided the branching of the vascular network. The signs later disappeared.
A subset of the choroid plexus epithelium behaved differently. This tissue produces cerebrospinal fluid and separates it from the blood. Its cells retained signs of senescence after birth and in adult mice, but they did not produce the inflammatory set of signals usually associated with age-related damage.
When the researchers removed all cells carrying the p21 marker during pregnancy, the embryos developed abnormalities in vascular patterning, choroid plexus function, and fluid movement through the brain ventricles. The researchers used a genetic system rather than a senolytic, and the intervention removed several cell populations at once because p21 is found in senescent cells as well as in other cells. Therefore, a single marker is not enough to determine whether a cell should be removed.
A similar warning has emerged outside the brain. In a 2020 study, the genetic removal of some p16High cells in old mice damaged liver barriers and caused fibrosis. Most of the removed cells in that study were endothelial cells, which form the inner lining of blood vessels.
Senolytics must distinguish between a pathological cellular state and a cell’s useful role in its tissue. Detecting p16 or p21 is not enough. The SenNet atlas of senescent cells has already shown that different tissues require different sets of markers. This requires a map of cell types, their locations within the organ, their signaling profiles, and evidence showing how tissue function changes after the cells are removed. Without this information, a drug intended to counter cellular senescence may remove part of a system that is still keeping the organ functional.