Back to Search
Start Over
Genetic reduction of mTOR extends lifespan in a mouse model of Hutchinson‐Gilford Progeria syndrome
- Source :
- Aging Cell
- Publication Year :
- 2021
- Publisher :
- Wiley, 2021.
-
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.<br />Generation of animal models that express the mutant gene product in the context of the human sequence is critical for developing novel therapeutic approaches to treat HGPS. Here we show that transgenic mice harboring two copies of the human LMNA gene containing the G608G mutation recapitulate the human phenotype. Genetic reduction of mTOR in these mice extends lifespan and provides a rationale for clinical trials testing pharmacological inhibition of the mTOR signaling pathway in HGPS patients.
- Subjects :
- congenital, hereditary, and neonatal diseases and abnormalities
Aging
Transgene
Longevity
Mice, Transgenic
medicine.disease_cause
LMNA
Mice
medicine
Animals
Humans
Mechanistic target of rapamycin
Cells, Cultured
PI3K/AKT/mTOR pathway
lamin A/C
Mutation
Progeria
integumentary system
biology
laminopathies
TOR Serine-Threonine Kinases
progeria
nutritional and metabolic diseases
S6 Kinase
Cell Biology
Progerin
medicine.disease
Original Papers
Mice, Inbred C57BL
Disease Models, Animal
mTOR
biology.protein
Cancer research
Original Article
Lamin
Subjects
Details
- ISSN :
- 14749726 and 14749718
- Volume :
- 20
- Database :
- OpenAIRE
- Journal :
- Aging Cell
- Accession number :
- edsair.doi.dedup.....cf44e3f0c902cdadcccb9c056436b78d