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Hutchinson‐Gilford progeria syndrome (HGPS) is a premature aging disease caused by progerin, a mutant variant of lamin A. Progerin anchors aberrantly to the nuclear envelope disrupting a plethora of cellular processes, which in turn elicits senescence. We previously showed that the chromosomal region maintenance 1 (CRM1)‐driven nuclear export pathway is abnormally enhanced in patient‐derived fibroblasts, due to overexpression of CRM1. Interestingly, pharmacological inhibition of CRM1 using leptomycin B rescues the senescent phenotype of HGPS fibroblasts, delineating CRM1 as a potential therapeutic target against HGPS. As a proof of concept, we analyzed the beneficial effects of pharmacologically modulating CRM1 in dermal fibroblasts from HGPS patients and the LMNAG609G/G609G mouse, using the first‐in‐class selective inhibitor of CRM1 termed selinexor. Remarkably, treatment of HGPS fibroblasts with selinexor mitigated senescence and promoted progerin clearance via autophagy, while at the transcriptional level restored the expression of numerous differentially‐expressed genes and rescued cellular processes linked to aging. In vivo, oral administration of selinexor to the progeric mouse resulted in decreased progerin immunostaining in the liver and aorta, decreased progerin levels in most liver, lung and kidney samples analyzed by immunoblotting, and improved aortic histopathology. Collectively our data indicate that selinexor exerts its geroprotective action by at least two mechanisms: normalizing the nucleocytoplasmic partition of proteins with a downstream effect on the aging‐associated transcriptome and decreasing progerin levels. Further investigation of the overall effect of selinexor on LmnaG609G/G609G mouse physiology, with emphasis in cardiovascular function is warranted, to determine its therapeutic utility for HGPS and aging‐associated disorders characterized by CRM1 overactivity. Pharmacological inhibition of CRM1 mediated by selinexor, the first‐in‐class selective inhibitor of CRM1, mitigates the senescent phenotype of Hutchinson‐Gilford progeria syndrome (HGPS) patients‐derived primary fibroblasts. Treatment of HGPS fibroblasts with selinexor promotes the clearances of progerin via autophagy activation, restores the expression of numerous differentially expressed genes, and rescues various aging‐linked cellular processes. Oral administration of selinexor to the LmnaG609G/G609G progeric mouse decreased progerin immunostaining in the liver and aorta and improved aortic histopathology.

Nuclear β-dystroglycan (β-DG) is involved in the maintenance of nuclear architecture and function. Nonetheless, its relevance in defined nuclear processes remains to be determined. In this study we generated a C2C12 cell-based DG-null model using CRISPR-Cas9 technology to provide insights into the role of β-DG on nuclear processes. Since DG-null cells exhibited decreased levels of lamin B1, we aimed to elucidate the contribution of DG to senescence, owing to the central role of lamin B1 in this pathway. Remarkably, the lack of DG enables C2C12 cells to acquire senescent features, including cell-cycle arrest, increased senescence-associated-β-galactosidase activity, heterochromatin loss, aberrant nuclear morphology and nucleolar disruption. We demonstrated that genomic instability is one driving cause of the senescent phenotype in DG-null cells via the activation of a DNA-damage response associated with mitotic failure, as shown by the presence of multipolar mitotic spindles, which in turn induced the formation of micronuclei and γH2AX foci (DNA-damage marker), telomere shortening and p53/p21 upregulation. Altogether, these events might ultimately lead to premature senescence, impeding the replication of the damaged genome. In summary, we present evidence supporting a role for DG in protecting against senescence, through the maintenance of proper lamin B1 expression/localization and proper mitotic spindle organization.

Hutchinson-Gilford progeria syndrome (HGPS) is a rare premature aging disorder caused by the expression of progerin, a mutant variant of Lamin A. Recently, HGPS studies have gained relevance because unraveling its underlying mechanism would help to understand physiological aging. We previously reported that the CRM1-mediated nuclear protein export pathway is exacerbated in HGPS cells, provoking the mislocalization of numerous protein targets of CRM1. We showed that normalization of this mechanism by pharmacologically inhibiting CRM1 with LMB (specific CRM1 inhibitor), mitigates the senescent phenotype of HGPS cells. Since mitochondrial dysfunction is a hallmark of HGPS, in this study we analyze the effect of LMB on mitochondrial function. Remarkably, LMB treatment induced the recovery of mitochondrial function in HGPS cells, as shown by the improvement in mitochondrial morphology, mitochondrial membrane potential, and ATP levels, which consequently impeded the accumulation of ROS but not mitochondrial superoxide. We provide evidence that the beneficial effect of LMB is mechanistically based on a combinatory effect on mitochondrial biogenesis via upregulation of PGC-1α expression (master transcription cofactor of mitochondrial genes), and mitophagy through the recovery of lysosomal content. The use of exportin CRM1 inhibitors constitutes a promising strategy to treat HGPS and other diseases characterized by mitochondrial impairment.