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^G609G/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.

Skin aging is driven by cellular senescence, oxidative stress, and diminished regenerative capacity. In this study, we investigated the effects of PhytoCellTec™ Argan, an argan callus extract (PC), on primary human fibroblasts and adult stem cells. PC treatment (0.1% and 0.5%) significantly enhanced fibroblast proliferation, reduced senescence-associated β-galactosidase activity, and decreased the expression of p16, p21, and phosphorylated NFκB. PC treatment lowered intracellular ROS levels, increased ATP production, and promoted autophagy via LC3B-II accumulation and p62 reduction. In skin-derived precursor cells (SKPs), as well as mesenchymal stem cells (MSCs), PC treatment improved spheroid formation and growth while preserving the expression of key stemness markers, including Sox2, Oct4, and Nestin. Furthermore, PC exhibited antioxidant capacity (TEAC assay) and inhibited elastase, supporting its anti-aging potential. These findings suggest that PC is safe at concentrations below 1% and may serve as an effective natural compound to restore cellular homeostasis, reduce senescence and inflammation, and support stem cell health during aging.

Background/Objectives: Hutchinson–Gilford progeria syndrome (HGPS) is a rare and fatal genetic disease caused by a silent mutation in the LMNA gene, leading to the production of progerin, a defective prelamin A variant. Progerin accumulation disrupts nuclear integrity, alters chromatin organization, and drives systemic cellular dysfunction. While autophagy and inflammation are key dysregulated pathways in HGPS, the role of microRNAs (miRNAs) in these processes remains poorly understood. Methods: We performed an extensive literature review to identify miRNAs involved in autophagy and inflammation. Through stem-loop RT-qPCR in aging HGPS and control fibroblast strains, we identified significant miRNAs and focused on the most prominent one, miR-181a-5p, for in-depth analysis. We validated our in vitro findings with miRNA expression studies in skin biopsies from an HGPS mouse model and conducted functional assays in human fibroblasts, including immunofluorescence staining, β-Galactosidase assay, qPCR, and Western blot analysis. Transfection studies were performed using an miR-181a-5p mimic and its inhibitor. Results: We identified miR-181a-5p as a critical regulator of premature senescence in HGPS. miR-181a-5p was significantly upregulated in HGPS fibroblasts and an HGPS mouse model, correlating with Sirtuin 1 (SIRT1) suppression and induction of senescence. Additionally, we demonstrated that TGFβ1 induced miR-181a-5p expression, linking inflammation to miRNA-mediated senescence. Inhibiting miR-181a-5p restored SIRT1 levels, increased proliferation, and alleviated senescence in HGPS fibroblasts, supporting its functional relevance in disease progression. Conclusions: These findings highlight the important role of miR-181a-5p in premature aging and suggest its potential as a therapeutic target for modulating senescence in progeroid syndromes.