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.
Highlights
Telomerase deficiency leads to age-related diseases and shorter lifespans
We found that rapamycin treatment increased median longevity of wild-type mice (Terc+/+) by 39%, resulting in a median longevity of 26.5 months in rapamycin-fed Terc+/+ mice compared to only 19 months in the control-fed cohorts (Fig. 1b)
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 (Supplementary Fig. 1A, B)
Summary
Telomerase deficiency leads to age-related diseases and shorter lifespans. Inhibition of the mechanistic target of rapamycin (mTOR) delays aging and age-related pathologies. Deletion of mTORC1 downstream S6 kinase 1 in G3-Terc−/− mice 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. Mice genetically deficient for the RNA component of telomerase (Terc−/−) show accelerated telomere shortening and decreased lifespan owing to premature development of ageassociated pathologies, being intestinal atrophy the most prevalent[12,13,14]. These pathologies are anticipated with increasing generations of telomerase-deficient mice owing to inheritance of progressively shorter telomeres with each mouse generation[12,13,14]
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