2. Academic Validation
  3. Baricitinib and Lonafarnib Synergistically Target Progerin and Inflammation, Improving Lifespan and Health in Progeria Mice

Baricitinib and Lonafarnib Synergistically Target Progerin and Inflammation, Improving Lifespan and Health in Progeria Mice

  • Int J Mol Sci. 2025 May 19;26(10):4849. doi: 10.3390/ijms26104849.
Peter Krüger 1,  Moritz Schroll 1,  Felix Quirin Fenzl 1,  Ramona Hartinger 1,  Eva-Maria Lederer 1,  Agnes Görlach 2 3,  Leslie B Gordon 4 5,  Paola Cavalcante 6,  Nicola Iacomino 6,  Birgit Rathkolb 7 8 9,  Juan Antonio Aguilar Pimentel 7,  Manuela Östereicher 7,  Nadine Spielmann 7,  Cordula Maria Wolf 2 3,  Martin Hrabe de Angelis 7 9 10,  Karima Djabali 1
Affiliations

Affiliations

  • 1 Epigenetics of Aging, Department of Dermatology and Allergy, TUM School of Medicine and Health, Munich Institute of Biomedical Engineering (MIBE), Technical University of Munich (TUM), 85748 Garching, Germany.
  • 2 Experimental and Molecular Pediatric Cardiology, Department of Pediatric Cardiology and Congenital Heart Diseases, German Heart Center Munich, Technical University Hospital, TUM School of Medicine and Health, 80636 Munich, Germany.
  • 3 German Centre for Cardiovascular Research (DZHK), Partner Site Munich Heart Alliance, 80636 Munich, Germany.
  • 4 Department of Anesthesia, Boston Children's Hospital, Harvard Medical School, Boston, MA 02115, USA.
  • 5 Department of Pediatrics, Hasbro Children's Hospital, Warren Alpert Medical School of Brown University, Providence, RI 02912, USA.
  • 6 Neurology 4-Neuroimmunology and Neuromuscular Diseases, Fondazione IRCCS Istituto Neurologico Carlo Besta, 20133 Milan, Italy.
  • 7 Institute of Experimental Genetics, German Mouse Clinic, Helmholtz Center Munich (GmbH), German Research Center for Environmental Health, 85764 Neuherberg, Germany.
  • 8 Institute of Molecular Animal Breeding and Biotechnology, Gene Center, Ludwig Maximilian University of Munich, 81377 Munich, Germany.
  • 9 German Center for Diabetes Research (DZD), 85764 Neuherberg, Germany.
  • 10 Experimental Genetics, TUM School of Life Sciences, Technical University of Munich, 85354 Freising, Germany.
PMID: 40429989 DOI: 10.3390/ijms26104849
Abstract

Hutchinson-Gilford progeria syndrome (HGPS) is a rare, fatal, and premature aging disorder caused by progerin, a truncated form of lamin A that disrupts nuclear architecture, induces systemic inflammation, and accelerates senescence. While the farnesyltransferase inhibitor lonafarnib extends the lifespan by limiting progerin farnesylation, it does not address the chronic inflammation or the senescence-associated secretory phenotype (SASP), which worsens disease progression. In this study, we investigated the combined effects of baricitinib (BAR), a JAK1/2 inhibitor, and lonafarnib (FTI) in a LmnaG609G/G609G mouse model of HGPS. BAR + FTI therapy synergistically extended the lifespan by 25%, surpassing the effects of either monotherapy. Treated mice showed improved health, as evidenced by reduced kyphosis, better fur quality, decreased incidence of cataracts, and less severe dysgnathia. Histological analyses indicated reduced fibrosis in the dermal, hepatic, and muscular tissues, restored cellularity and thickness in the aortic media, and improved muscle fiber integrity. Mechanistically, BAR decreased the SASP and inflammatory markers (e.g., IL-6 and PAI-1), complementing the progerin-targeting effects of FTI. This preclinical study demonstrates the synergistic potential of BAR + FTI therapy in addressing HGPS systemic and tissue-specific pathologies, offering a promising strategy for enhancing both lifespan and health.

Keywords

Hutchinson–Gilford progeria syndrome; JAK-STAT; baricitinib; inflammation; lamin A; lifespan; progerin.

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