Palbociclib reduced inflammation from senescent cells and improved physical performance in old mice
Palbociclib reduced inflammation from senescent cells and improved physical performance in old mice
Cyclin D1 usually helps cells initiate division, but the authors found that it also accumulated in cells that had already stopped dividing. In their model, cyclin D1 and CDK6 sustained DNA damage and activated inflammatory genes. In old male mice, two months of palbociclib treatment stabilized the frailty index and improved rotarod performance.
On August 20, Nature Aging published a study describing an unexpected role for cyclin D1 in senescent cells. Senescence is a stable state that develops after stress, such as DNA damage. A senescent cell stops dividing but remains in the tissue and may release signaling molecules that sustain inflammation.
In July, abemaciclib also reduced the inflammatory secretory activity of senescent cells in old mice. The authors of that study attributed the effect to the CDK4/6–RARα–NF-κB axis. The new paper examines a different mechanism involving cyclin D1 and CDK6 in cells that have already exited the cell cycle.
Cyclin D1 usually works with CDK4 and CDK6 to initiate cell division. Its accumulation in cells that had stopped dividing led the authors to investigate what function the protein retained in those cells. In irradiated human fibroblasts, which are connective tissue cells, the researchers separately reduced the levels of cyclin D1, CDK4, and CDK6. Reducing cyclin D1 or CDK6 suppressed the activity of inflammatory and interferon genes, whereas targeting CDK4 produced only minor changes.
The researchers then examined the mechanism. In their model, the CCND1–CDK6 complex sustains DNA damage. Some chromatin, which consists of DNA and associated proteins and is normally contained within the nucleus, enters the cytoplasm. There, the enzyme cGAS detects the DNA and activates interferon and inflammatory genes through the STING protein. In the open access full text of the study, reducing cyclin D1 or CDK6 decreased both DNA damage markers and the number of these chromatin fragments. Palbociclib, which inhibits CDK4 and CDK6, reduced the same measures and weakened cGAS–STING signaling.
The researchers also tested this pathway in the livers of old mice. After Ccnd1 was inactivated in hepatocytes, the main cell type in the liver, markers of DNA damage and interferon gene expression decreased. In a separate experiment, 18-month-old male mice received palbociclib three times a week for two months. In the treatment group, the frailty index remained stable, while performance on a rotating rod, a test of motor coordination, improved.