Figure 1. Schematic model showing phenotypic rescue of HGPS cells through pharmacological modulation of CRM1-mediated nuclear export signaling. (Normal) CRM1 in complex with Ran-GTP drives the export of proteins from the nucleus (Nu) to the cytoplasm (Cyt) across the nuclear pore complex (NPC), via recognition of a nuclear export signal on the cargo molecules, maintaining thereby a balanced partition of proteins between these cellular compartments. INM, inner nuclear membrane; ONM, outer nuclear membrane; ER endoplasmic reticulum. (HGPS) HGPS cells exhibit exacerbated nuclear protein export activity due to progerin-driven CRM1 overexpression, which in turn provokes the appearance of cellular marks of aging, including mitochondrial dysfunction, the loss of heterochromatin, decreased lamin B1 levels, nucleolar expansion and aberrant nuclear morphology. (HGPS+LMB) Mitigation of CRM1 activity by treatment of HGPS cells with specific CRM1 inhibitor (LMB) alleviates all aforementioned aging marks, by restoring proper nuclear-cytoplasmic distribution of proteins.