Genetic reduction of mTOR extends lifespan in a mouse model of Hutchinson-Gilford Progeria syndrome

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.

Automated summary

Hutchinson-Gilford progeria syndrome (HGPS) is a rare accelerated aging disorder characterized by cardiovascular disease and premature death, mostly caused by a single nucleotide mutation in the LMNA gene. A study using mice models carrying two copies of the BAC showed a more complete replication of HGPS phenotypic features in various tissues, and genetic reduction of mTOR extended the lifespan of these mice significantly, suggesting a potential treatment for HGPS through pharmacologic inhibition of the mTOR pathway.