Baricitinib inhibits Janus kinases 1 and 2. These kinases are the first enzymes of the JAK-STAT signaling pathway. This pathway is important for many cell functions. Disorders of JAK-STAT can play a role in cancer and immune disease. For example, baricitinib, a JAK-STAT signaling disrupter, is approved in Europe to treat rheumatoid arthritis.
Progeria and JAK-STAT
Recently, researchers at the Technical University of Munich using a text mining approach had suspicions that a rare premature aging disorder, Hutchinson-Gilford progeria syndrome, is associated with the JAK-STAT pathway. It is known that this syndrome has four main symptoms that mimic normal aging: vascular disease, arthritis, lipodistrophy, and alopecia. In most cases of this disease, a single de novo mutation is responsible for causing the production of progerin, leading to a shortened life span. Unfortunately, sufferers rarely live past the age of thirteen.
The research team decided to run a literature meta-analysis on genes associated with each symptom of progeria. In all, seventeen genes implicated in all four symptoms were found, and of those seventeen, fourteen were part of the JAK-STAT pathway.
Baricitinib Inhibits Janus Kinases
Henceforth, to test the role of the JAK-STAT pathway in progeria experimentally, the team grew cells in culture from progeria patients and also from unaffected controls. The progeric cells expressed abnormal levels of the fourteen identified genes. When the researchers applied baricitinib to the cell culture, the gene expression levels normalized. After one month of baricitinib treatment, progeric cells were less likely to become senescent.
Furthermore, etoposide was also applied to the cell culture, which is known to worsen cell senescence. As anticipated, etoposide treatment disrupted expression of the fourteen genes.
In conclusion, this research shows that the JAK-STAT pathway is likely part of the Hutchinson-Gilford progeria disease mechanism, and baricitinib may have potential as a therapy.
Liu C, Arnold R, Henriques G, et al. Inhibition of JAK-STAT signaling with baricitinib reduces inflammation and improves cellular homeostasis in progeria cells. Cells. 2019 Oct 18;8(10):1276. doi: 10.3390/cells810276. PMID: 31635416.