The mTOR pathway is necessary for survival of mice with short telomeres
Abstract
Telomerase deficiency leads to age-related diseases and shorter lifespans. Inhibition of the mechanistic target of rapamycin (mTOR) delays aging and age-related pathologies. Here, we show that telomerase deficient mice with short telomeres (G2-Terc-/-) have an hyper-activated mTOR pathway with increased levels of phosphorylated ribosomal S6 protein in liver, skeletal muscle and heart, a target of mTORC1. Transcriptional profiling confirms mTOR activation in G2-Terc-/- livers. Treatment of G2-Terc-/- mice with rapamycin, an inhibitor of mTORC1, decreases survival, in contrast to lifespan extension in wild-type controls. Deletion of mTORC1 downstream S6 kinase 1 in G3-Terc-/- mice also decreases longevity, in contrast to lifespan extension in single S6K1-/- female mice. These findings demonstrate that mTOR is important for survival in the context of short telomeres, and that its inhibition is deleterious in this setting. These results are of clinical interest in the case of human syndromes characterized by critically short telomeres.
From the paper
- Events by group
When survival curves were separated by sex, rapamycin-fed Terc+/+ females showed an increase in median lifespan of 23% compared to control diet-fed females, while the increase was of 43% in the case of the rapamycin-fed males compared to control-diet Terc+/+ males.
Results, Chronic rapamycin diet decreases lifespan of Terc−/− mice
Quoted word for word from the full text on PubMed Central.
The paper
Spanish National Cancer Research Centre
Nature Communications, 3 Mar 2020, Open access
