Genetic reduction of mTOR extends lifespan in a mouse model of Hutchinson‐Gilford Progeria syndrome |
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| Authors: | Wayne A. Cabral Urraca L. Tavarez Indeevar Beeram Diana Yeritsyan Yoseph D. Boku Michael A. Eckhaus Ara Nazarian Michael R. Erdos Francis S. Collins |
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| Affiliation: | 1. Molecular Genetics Section, Center for Precision Health Research, National Human Genome Research Institute, National Institutes of Health, Bethesda MD, USA ; 2. Translational Musculoskeletal Innovation Initiative, Carl J. Shapiro Department of Orthopedic Surgery, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston MA, USA ; 3. Diagnostic and Research Services Branch, Division of Veterinary Resources, Office of the Director, National Institutes of Health, Bethesda MD, USA |
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| Abstract: | Hutchinson‐Gilford progeria syndrome (HGPS) is a rare accelerated aging disorder most notably characterized by cardiovascular disease and premature death from myocardial infarction or stroke. The majority of cases are caused by a de novo single nucleotide mutation in the LMNA gene that activates a cryptic splice donor site, resulting in production of a toxic form of lamin A with a 50 amino acid internal deletion, termed progerin. We previously reported the generation of a transgenic murine model of progeria carrying a human BAC harboring the common mutation, G608G, which in the single‐copy state develops features of HGPS that are limited to the vascular system. Here, we report the phenotype of mice bred to carry two copies of the BAC, which more completely recapitulate the phenotypic features of HGPS in skin, adipose, skeletal, and vascular tissues. We further show that genetic reduction of the mechanistic target of rapamycin (mTOR) significantly extends lifespan in these mice, providing a rationale for pharmacologic inhibition of the mTOR pathway in the treatment of HGPS. |
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| Keywords: | lamin A/C, laminopathies, mTOR, progeria, S6 Kinase |
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