Progerin, the mutant protein driving Hutchinson-Gilford progeria syndrome, blocks autophagy at its final stages—preventing lysosomes from clearing the toxic protein itself. Selinexor restores this clearance mechanism by reactivating the autophagy-lysosome pathway, offering a therapeutic target for this severe premature aging condition.
Key Points
- Progerin blocks autophagosome-lysosome fusion, trapping defective cellular waste.
- Selinexor activates TFEB and restores lysosomal function and biogenesis.
- Restoring STX17 and LAMP1 expression improves autophagy flux in HGPS.
Longevity Analysis
This research identifies a self-perpetuating toxicity cycle central to progeria: the pathogenic protein actively interferes with the cellular machinery designed to remove it. By clarifying exactly where autophagy fails—not initiation, but completion—the work reveals why standard regenerative processes cannot self-correct HGPS. Selinexor's ability to reactivate lysosomal biogenesis and restore fusion capacity demonstrates that pharmacological intervention at this specific juncture can break the cycle. For broader longevity science, this exemplifies how impaired clearance systems accelerate aging, and how restoring these degradation pathways addresses the root interference rather than downstream compensation.
Original published by Wiley Aging Cell, by Ian García‐Aguirre, Jesús Alejandro Reyes‐Martínez, Juan Unzueta, Francisco Guevara‐Namorado, Solangy Lizcano‐Meneses, Susana Gonzalo, Angel Baldan, Claudia Rangel, Gerardo J. Alanis‐Funes, Francisco Garcia‐Sierra, Kevin Ruiz‐Fajardo, Simon Gormes‐Pinchanski, Susana Castro‐Obregón, Aranza Meza‐Dorantes, Rocio Alejandra Chavez‐Santoscoy, Isabel Arrieta‐Cruz, Paola Tristán‐Aburto, Jonathan J. Magaña, Bulmaro Cisneros .