JAK-STAT signaling

The JAK-STAT (Janus kinase – signal transducer and activator of transcription) pathway is a rapid, receptor-proximal signalling cascade through which cytokines and growth factors — including interferons, interleukins, and erythropoietin — transmit signals from the cell surface to the nucleus. Ligand binding induces receptor dimerisation and transphosphorylation of associated JAKs (JAK1, JAK2, JAK3, TYK2), which in turn phosphorylate STATs (STAT1–STAT6), enabling their dimerisation, nuclear translocation, and target gene activation. In ageing, persistent activation of JAK-STAT by the SASP and inflammaging-associated cytokines (notably IL-6/JAK1/STAT3 and IL-6/JAK2/STAT3 axes) is a driver of chronic tissue dysfunction; JAK1/2 inhibitors such as ruxolitinib have been shown to reduce SASP and improve healthspan parameters in aged mice, and clinical trials are underway.