Abemaciclib reduced the inflammatory secretions of senescent cells and improved physical function in aged mice
Abemaciclib reduced the inflammatory secretions of senescent cells and improved physical function in aged mice
On July 17, a study by Marco Demaria’s group in Groningen was published in Nature Aging. The authors linked CDK4/6 activity, the retinoic acid receptor RARα, and the inflammatory secretions of senescent cells. Two interventions targeting this pathway improved physical performance in aged mice.
A senescent cell stops dividing after it is damaged but remains in the tissue. Many such cells release signaling molecules that sustain inflammation in the surrounding tissue. This set of secretions is called the SASP. The component regulated by NF-κB is especially often associated with age-related inflammation. NF-κB is a regulatory protein that activates immune response genes.
In June, another Nature Aging study linked the SASP to the release of nuclear RNA and DNA hybrids into the cytoplasm and the activation of cGAS-STING. Demaria’s group approached the same inflammatory secretions from a different direction by examining CDK4 and CDK6, enzymes that normally help cells prepare for division.
The authors treated cells that were already senescent with a short course of abemaciclib. The inflammatory SASP genes became less active, and genetically disabling CDK4 and CDK6 produced a similar result. Abemaciclib altered the secretions of cells that were already senescent rather than removing the cells from the tissue. Agents with this effect are called senomorphics. They are intended to reduce the harmful behavior of senescent cells while leaving the cells in place.
The team then traced the underlying pathway. CDK4 and CDK6 interacted with NF-κB, while CDK4 also interacted with RARα, a receptor for retinoic acid, which is derived from vitamin A. Abemaciclib disrupted these interactions. A separate RARα antagonist, the compound agn194310, also reduced the inflammatory secretions. The study identifies the CDK4/6–RARα–NF-κB axis as a new target for the development of senomorphics.
In 22-month-old mice, both compounds reduced systemic markers of these inflammatory secretions and improved physical performance. The authors administered the compounds for two months, with four animals in each of the four groups. This small experiment requires independent replication, particularly because abemaciclib is used to treat certain cancers and has known toxicity.
A separate question shows the limits of this result. In a 2022 study from the same laboratory, CDK4/6 inhibitors induced a distinct senescent state in previously dividing normal cells. A recent preprint from another group found that some components of the NF-κB-dependent SASP were activated later in these cells. The current study examines inflammatory senescent cells that already existed before treatment. These two cellular states require different safety assessments.