The JAK1/2 inhibitor ruxolitinib delays premature aging phenotypes

• Published in: Aging cell Vol. 19; no. 4; pp. e13122 - n/a
• Main Authors: Griveau, Audrey, Wiel, Clotilde, Ziegler, Dorian V., Bergo, Martin O., Bernard, David
• Format: Journal Article
• Language: English
• Published: England John Wiley & Sons, Inc 01.04.2020; Wiley Open Access; John Wiley and Sons Inc
• Subjects: Aging; Aging, Premature - genetics; Aging, Premature - metabolism; Analysis; Animals; Bone mineral content; Cell cycle; Cell Cycle Checkpoints - drug effects; Cell Line; Cell Nucleus - drug effects; cellular senescence; Cellular Senescence - drug effects; Drug approval; Fibroblasts; Fibroblasts - drug effects; Fractures; Genetic aspects; Humans; JAK/STAT pathway; Janus kinase; Janus Kinase 1 - antagonists & inhibitors; Janus Kinase 1 - metabolism; Janus Kinase 2 - antagonists & inhibitors; Janus Kinase 2 - metabolism; Janus Kinase Inhibitors - pharmacology; Life Sciences; Life span; Mice; Phenotype; Phenotypes; Progeria; Pyrazoles - pharmacology; ruxolitinib; Senescence; Short Take; progeria; cellular senescence; ruxolitinib; JAK/STAT pathway
• ISSN: 1474-9718; 1474-9726; 1474-9726; 1474-9728
• DOI: 10.1111/acel.13122

Hutchinson–Gilford progeria syndrome (HGPS) is caused by an LMNA mutation that results in the production of the abnormal progerin protein. Children with HGPS display phenotypes of premature aging and have an average lifespan of 13 years. We found earlier that the targeting of the transmembrane protein PLA2R1 overcomes senescence and improves phenotypes in a mouse model of progeria. PLA2R1 is regulating the JAK/STAT signaling, but we do not yet know whether targeting this pathway directly would influence cellular and in vivo progeria phenotypes. Here, we show that JAK1/2 inhibition with ruxolitinib rescues progerin‐induced cell cycle arrest, cellular senescence, and misshapen nuclei in human normal fibroblasts expressing progerin. Moreover, ruxolitinib administration reduces several premature aging phenotypes: bone fractures, bone mineral content, grip strength, and a trend to increase survival in a mouse model of progeria. Thus, we propose that ruxolitinib, an FDA‐approved drug, should be further evaluated as a drug candidate in HGPS therapy. In this study, we have described that inhibition of JAK1/2 by ruxolitinib improves some progeria phenotypes in normal human fibroblasts and in a murine model of progeria. Our findings should encourage the design of new studies to explore the potential clinical benefits of treating by ruxolitinib, alone or in combination, HGPS patients.