Research ArticlesProgeria

Rapamycin Reverses Cellular Phenotypes and Enhances Mutant Protein Clearance in Hutchinson-Gilford Progeria Syndrome Cells

Science Translational Medicine  29 Jun 2011:
Vol. 3, Issue 89, pp. 89ra58
DOI: 10.1126/scitranslmed.3002346

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The Young and the Youthless

In the novel Brideshead Revisited, Evelyn Waugh reminisces about “the langor of youth” and laments “how quickly, how irrecoverably lost” is the bloom. Although every adult can relate to this cri de coeur, in no case is youth lost more swiftly or more dramatically than in children suffering from Hutchinson-Gilford progeria syndrome (HGPS), a genetic disease characterized by premature aging and death in adolescence or the teen years. In studies of the normal aging process, the versatile drug rapamycin has been shown to extend longevity in animal models. Now, Cao et al. reveal that the drug reverses disease-distinguishing defects in cells from HGPS patients. These findings raise the possibility that rapamycin might be repurposed for the treatment of this dire disease.

Children with HGPS display many of the phenotypes we associate with aging: hair loss, bone deficits, hardening of the skin by 1 or 2 years of age, and heart disease and stroke often by the age of 12. The disease is caused by a point mutation in the gene that encodes the nuclear structural protein lamin A. This genetic defect creates an improperly processed version of the lamin A protein—called progerin—that accumulates in HGPS cells and wreaks havoc on cellular form and function. Several studies indicate that normal human cells also express tiny amounts of progerin, which accumulates as a person ages. Skin cells (fibroblasts) from HGPS patients display a variety of blemishes, including slowed growth, an abbreviated life span, nuclear blebbing (bulging of the nuclear membrane), and the characteristic accumulation of insoluble progerin in the cytoplasm. Protein aggregation is also a hallmark of several neurodegenerative diseases, and there is some evidence that rapamycin might be useful in the treatment of these disorders by stimulating macroautophagy—a process by which cells clear junk protein and trashed organelles. Thus, Cao et al. tested whether rapamycin also helps to rid HGPS cells of progerin build-up and to remedy the resulting cellular quirks.

Indeed, HGPS cells treated with rapamycin showed enhanced progerin degradation, slowed senescence, and reduced nuclear blebbing relative to untreated cells. Mechanistic experiments in normal human fibroblasts revealed that rapamycin treatment increased clearance of soluble progerin by activating the autophagic-lysosomal pathway, which inhibited the formation of insoluble aggregates. Blocking the expression of an autophagy-related gene with small RNAs enhanced progerin accumulation. The new work has helped to form the basis for a clinical trial of the rapamycin analog everolimus in children with HGPS and may offer insights into normal aging as well. Thus, in science, as in youth—according to Waugh—new notions are continually “revealed to us in whose light all our previous knowledge must be rearranged.”


  • * These authors contributed equally to this work.

  • Citation: K. Cao, J. J. Graziotto, C. D. Blair, J. R. Mazzulli, M. R. Erdos, D. Krainc, F. S. Collins, Rapamycin Reverses Cellular Phenotypes and Enhances Mutant Protein Clearance in Hutchinson-Gilford Progeria Syndrome Cells. Sci. Transl. Med. 3, 89ra58 (2011).