Rapamycin reverses cellular phenotypes and enhances mutant protein clearance in Hutchinson-Gilford progeria syndrome cells
Abstract
Hutchinson-Gilford progeria syndrome (HGPS) is a lethal genetic disorder characterized by premature aging. HGPS is most commonly caused by a de novo single-nucleotide substitution in the lamin A/C gene (LMNA) that partially activates a cryptic splice donor site in exon 11, producing an abnormal lamin A protein termed progerin. Accumulation of progerin in dividing cells adversely affects the integrity of the nuclear scaffold and leads to nuclear blebbing in cultured cells. Progerin is also produced in normal cells, increasing in abundance as senescence approaches. Here, we report the effect of rapamycin, a macrolide antibiotic that has been implicated in slowing cellular and organismal aging, on the cellular phenotypes of HGPS fibroblasts. Treatment with rapamycin abolished nuclear blebbing, delayed the onset of cellular senescence, and enhanced the degradation of progerin in HGPS cells. Rapamycin also decreased the formation of insoluble progerin aggregates and induced clearance through autophagic mechanisms in normal fibroblasts. Our findings suggest an additional mechanism for the beneficial effects of rapamycin on longevity and encourage the hypothesis that rapamycin treatment could provide clinical benefit for children with HGPS.
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Rapamycin inhibits cell senescence in vitro.
“Rapamycin, an inhibitor of mTOR, inhibits cell senescence in vitro and increases longevity in several species.”
From Rapamycin inhibits the secretory phenotype of senescent cells by a Nrf2-independent mechanism (2017) · cites this paper as Cao et al., 2011
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- Authors
- Cao, K., Graziotto, J. J., Blair, C. D., Mazzulli, J. R., Erdos, M. R., Krainc, D., & Collins, F. S.
- Affiliations
- National Institutes of Health (US)
- Harvard University (US)
- Corresponding author
- Cao, Kan
- Graziotto, John J.
- Krainc, Dimitri
- Collins, Francis S.
- ORCID
- Venue
- Science Translational Medicine
- Published
- 2011-06-29
- Volume
- 3
- Issue
- 89
- Pages
- 89ra58-89ra58
- ISSN
- 1946-6234 (ISSN-L)
- 1946-6242
- OpenAlex
- W2166403801
- Cited by
- 350
- References
- 38
- Citations by year
- 2026: 6 · 2025: 12 · 2024: 15 · 2023: 13 · 2022: 19 · 2021: 20 · 2020: 25 · 2019: 20 · 2018: 34 · 2017: 23 · 2016: 31 · 2015: 22 · 2014: 25 · 2013: 36 · 2012: 32
- FWCI
- 14.27
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Science Translational Medicine (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institutes of Health
- National Institute on Aging (R00AG029761)
- National Institute of Neurological Disorders and Stroke (R01NS051303)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Nuclear Structure and Function
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Aging › Genetics, Aging, and Longevity in Model Organisms
- Health Sciences › Medicine › Physiology › Telomeres, Telomerase, and Senescence
- Keywords
- Hutchinson-Gilford progeria syndrome, rapamycin, progerin, lamin A/C, cellular senescence, nuclear blebbing, autophagy, protein clearance, premature aging, fibroblasts, drug repurposing
- MeSH terms
- Animals, Antibiotics, Antineoplastic, Autophagy, Cell Nucleus, Cells, Cultured, Fibroblasts, HeLa Cells, Humans, Nuclear Proteins, Phenotype, Progeria, Protein Precursors, Recombinant Fusion Proteins, Sirolimus, Lamin Type A
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