Baricitinib and Lonafarnib Synergistically Target Progerin and Inflammation, Improving Lifespan and Health in Progeria Mice
Abstract
1. Introduction
2. Results
2.1. Baricitinib and Lonafarnib Combination Therapy Extends Survival and Improves Systemic Health
2.2. The Baricitinib and Lonafarnib Combination Reduces STAT1/STAT3 Activation and Progerin Accumulation in LmnaG609G/G609G Mice
2.3. Baricitinib and Lonafarnib Therapy Reduces Tissue Degeneration and Fibrosis in LmnaG609G/G609G Mice
2.4. BAR + FTI Therapy Mitigates Proinflammatory Profiles, SASP, and ECM Remodeling Across Organ Systems
2.5. Baricitinib and Lonafarnib Therapy Mitigates Senescence and Structural Damage in Aortic and Renal Tissue
3. Discussion
4. Materials and Methods
4.1. Mouse Model and Breeding
4.2. Intraperitoneal Glucose Tolerance Test (ipGTT)
4.3. Western Blot Analysis
4.4. Histology
4.5. Immunofluorescence Staining
4.6. RT-qPCR Analysis
4.7. Blood Biochemistry and Blood Cytokine Analysis
4.8. Electrocardiography and Transthoracic Echocardiography in Awake Mice
4.9. Statistical Analysis
Supplementary Materials
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Conflicts of Interest
References
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Antibody ID | Company | Ref # | Incubation Time | Dilution |
---|---|---|---|---|
Lamin A/C | Proteintech (Munich, Germany) | 81042-1-RR | ON | 1:250 |
αSMA | MERCK (Darmstadt, Germany) | C6198-100UL | ON | 1:1000 |
Il-6 | Invitrogen (Waltham, MA, USA) | P620 | ON | 1:1000 |
P16/NK4a | Invitrogen (Waltham, MA, USA) | MA5-17142 | ON | 1:500 |
PAI-1/serpine-1 | Invitrogen (Waltham, MA, USA) | MA5-17171 | ON | 1:500 |
Vimentin | Cell Signaling (Danvers, MA, USA) | D21H3 | ON | 1:500 |
Alexa Fluor 555(mouse) | Life Technologies (Carlsbad, CA, USA) | A31570 | 1 h | 1:1000 |
Alexa Fluor 488(mouse) | Life Technologies (Carlsbad, CA, USA) | A21202 | 1 h | 1:1000 |
Alexa Fluor 555(rabbit) | Life Technologies (Carlsbad, CA, USA) | A31572 | 1 h | 1:1000 |
Alexa Fluor 488(rabbit) | Life Technologies (Carlsbad, CA, USA) | A21206 | 1 h | 1:1000 |
Biomarker | GenID | Forward Primer (5′-3′) | Reverse Primer (5′-3′) |
---|---|---|---|
GAPDH | 14433 | AGGTCGGTGTGAACGGATTTG | TGTAGACCATGTAGTTGAGGTCA |
IL-6 | 16193 | TAGTCCTTCCTACCCCAATTTCC | TTGGTCCTTAGCCACTCCTTC |
IL-8 | 20309 | CTGGGATTCACCTCAAGAACATC | CAGGGTCAAGGCAAGCCTC |
IL-1a | 16175 | GCACCTTACACCTACCAGAGT | AAACTTCTGCCTGACGAGCTT |
IL-1b | 16176 | GAAATGCCACCTTTTGACAGTG | TGGATGCTCTCATCAGGACAG |
IL-10 | 16153 | CTTACTGACTGGCATGAGGATCA | GCAGCTCTAGGAGCATGTGG |
TNFα | 21926 | CCTGTAGCCCACGTCGTAG | GGGAGTAGACAAGGTACAACCC |
PAI-1/serpine-1 | 18787 | TTCAGCCCTTGCTTGCCTC | ACACTTTTACTCCGAAGTCGGT |
TGF-1b | 21803 | CTCCCGTGGCTTCTAGTGC | GCCTTAGTTTGGACAGGATCTG |
VCAM-1 | 22329 | AGTTGGGGATTCGGTTGTTCT | CCCCTCATTCCTTACCACCC |
HIF-1 | 15251 | ACCTTCATCGGAAACTCCAAAG | CTGTTAGGCTGGGAAAAGTTAGG |
VEGF | 22339 | GCACATAGAGAGAATGAGCTTCC | CTCCGCTCTGAACAAGGCT |
CXCL1 | 14825 | CTGGGATTCACCTCAAGAACATC | CAGGGTCAAGGCAAGCCTC |
CCL2 | 20296 | TTAAAAACCTGGATCGGAACCAA | GCATTAGCTTCAGATTTACGGGT |
CTGF | 14219 | GGGCCTCTTCTGCGATTTC | ATCCAGGCAAGTGCATTGGTA |
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Krüger, P.; Schroll, M.; Fenzl, F.Q.; Hartinger, R.; Lederer, E.-M.; Görlach, A.; Gordon, L.B.; Cavalcante, P.; Iacomino, N.; Rathkolb, B.; et al. Baricitinib and Lonafarnib Synergistically Target Progerin and Inflammation, Improving Lifespan and Health in Progeria Mice. Int. J. Mol. Sci. 2025, 26, 4849. https://doi.org/10.3390/ijms26104849
Krüger P, Schroll M, Fenzl FQ, Hartinger R, Lederer E-M, Görlach A, Gordon LB, Cavalcante P, Iacomino N, Rathkolb B, et al. Baricitinib and Lonafarnib Synergistically Target Progerin and Inflammation, Improving Lifespan and Health in Progeria Mice. International Journal of Molecular Sciences. 2025; 26(10):4849. https://doi.org/10.3390/ijms26104849
Chicago/Turabian StyleKrüger, Peter, Moritz Schroll, Felix Quirin Fenzl, Ramona Hartinger, Eva-Maria Lederer, Agnes Görlach, Leslie B. Gordon, Paola Cavalcante, Nicola Iacomino, Birgit Rathkolb, and et al. 2025. "Baricitinib and Lonafarnib Synergistically Target Progerin and Inflammation, Improving Lifespan and Health in Progeria Mice" International Journal of Molecular Sciences 26, no. 10: 4849. https://doi.org/10.3390/ijms26104849
APA StyleKrüger, P., Schroll, M., Fenzl, F. Q., Hartinger, R., Lederer, E.-M., Görlach, A., Gordon, L. B., Cavalcante, P., Iacomino, N., Rathkolb, B., Pimentel, J. A. A., Östereicher, M., Spielmann, N., Wolf, C. M., de Angelis, M. H., & Djabali, K. (2025). Baricitinib and Lonafarnib Synergistically Target Progerin and Inflammation, Improving Lifespan and Health in Progeria Mice. International Journal of Molecular Sciences, 26(10), 4849. https://doi.org/10.3390/ijms26104849