Krüger Peter, Schroll Moritz, Fenzl Felix Quirin, Hartinger Ramona, Lederer Eva-Maria, Görlach Agnes, Gordon Leslie B, Cavalcante Paola, Iacomino Nicola, Rathkolb Birgit, Pimentel Juan Antonio Aguilar, Östereicher Manuela, Spielmann Nadine, Wolf Cordula Maria, de Angelis Martin Hrabe, Djabali Karima
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.
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.
Int J Mol Sci. 2025 May 19;26(10):4849. doi: 10.3390/ijms26104849.
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 Lmna 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.
哈钦森-吉尔福德早衰综合征（HGPS）是一种罕见的、致命的早衰疾病，由早老素引起，早老素是核纤层蛋白A的一种截短形式，会破坏核结构，引发全身炎症，并加速衰老。虽然法尼基转移酶抑制剂洛那法尼通过限制早老素的法尼基化来延长寿命，但它并不能解决慢性炎症或衰老相关分泌表型（SASP）问题，而这会使疾病进展恶化。在本研究中，我们在HGPS的Lmna小鼠模型中研究了JAK1/2抑制剂巴瑞替尼（BAR）和洛那法尼（FTI）的联合作用。BAR + FTI疗法协同作用使寿命延长了25%，超过了单一疗法的效果。治疗后的小鼠健康状况有所改善，表现为脊柱后凸减轻、毛发质量更好、白内障发病率降低以及颌骨发育异常不那么严重。组织学分析表明，皮肤、肝脏和肌肉组织中的纤维化减少，主动脉中膜的细胞数量和厚度恢复，肌肉纤维完整性得到改善。从机制上讲，BAR降低了SASP和炎症标志物（如IL-6和PAI-1），补充了FTI靶向早老素的作用。这项临床前研究证明了BAR + FTI疗法在解决HGPS全身和组织特异性病理方面的协同潜力，为延长寿命和改善健康提供了一种有前景的策略。
