Cargando…

The mTOR pathway is necessary for survival of mice with short telomeres

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 inc...

Descripción completa

Detalles Bibliográficos
Autores principales: Ferrara-Romeo, Iole, Martinez, Paula, Saraswati, Sarita, Whittemore, Kurt, Graña-Castro, Osvaldo, Thelma Poluha, Lydia, Serrano, Rosa, Hernandez-Encinas, Elena, Blanco-Aparicio, Carmen, Maria Flores, Juana, Blasco, Maria A.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7054554/
https://www.ncbi.nlm.nih.gov/pubmed/32127537
http://dx.doi.org/10.1038/s41467-020-14962-1
_version_ 1783503218631770112
author Ferrara-Romeo, Iole
Martinez, Paula
Saraswati, Sarita
Whittemore, Kurt
Graña-Castro, Osvaldo
Thelma Poluha, Lydia
Serrano, Rosa
Hernandez-Encinas, Elena
Blanco-Aparicio, Carmen
Maria Flores, Juana
Blasco, Maria A.
author_facet Ferrara-Romeo, Iole
Martinez, Paula
Saraswati, Sarita
Whittemore, Kurt
Graña-Castro, Osvaldo
Thelma Poluha, Lydia
Serrano, Rosa
Hernandez-Encinas, Elena
Blanco-Aparicio, Carmen
Maria Flores, Juana
Blasco, Maria A.
author_sort Ferrara-Romeo, Iole
collection PubMed
description 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.
format Online
Article
Text
id pubmed-7054554
institution National Center for Biotechnology Information
language English
publishDate 2020
publisher Nature Publishing Group UK
record_format MEDLINE/PubMed
spelling pubmed-70545542020-03-05 The mTOR pathway is necessary for survival of mice with short telomeres Ferrara-Romeo, Iole Martinez, Paula Saraswati, Sarita Whittemore, Kurt Graña-Castro, Osvaldo Thelma Poluha, Lydia Serrano, Rosa Hernandez-Encinas, Elena Blanco-Aparicio, Carmen Maria Flores, Juana Blasco, Maria A. Nat Commun Article 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. Nature Publishing Group UK 2020-03-03 /pmc/articles/PMC7054554/ /pubmed/32127537 http://dx.doi.org/10.1038/s41467-020-14962-1 Text en © The Author(s) 2020 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
spellingShingle Article
Ferrara-Romeo, Iole
Martinez, Paula
Saraswati, Sarita
Whittemore, Kurt
Graña-Castro, Osvaldo
Thelma Poluha, Lydia
Serrano, Rosa
Hernandez-Encinas, Elena
Blanco-Aparicio, Carmen
Maria Flores, Juana
Blasco, Maria A.
The mTOR pathway is necessary for survival of mice with short telomeres
title The mTOR pathway is necessary for survival of mice with short telomeres
title_full The mTOR pathway is necessary for survival of mice with short telomeres
title_fullStr The mTOR pathway is necessary for survival of mice with short telomeres
title_full_unstemmed The mTOR pathway is necessary for survival of mice with short telomeres
title_short The mTOR pathway is necessary for survival of mice with short telomeres
title_sort mtor pathway is necessary for survival of mice with short telomeres
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7054554/
https://www.ncbi.nlm.nih.gov/pubmed/32127537
http://dx.doi.org/10.1038/s41467-020-14962-1
work_keys_str_mv AT ferrararomeoiole themtorpathwayisnecessaryforsurvivalofmicewithshorttelomeres
AT martinezpaula themtorpathwayisnecessaryforsurvivalofmicewithshorttelomeres
AT saraswatisarita themtorpathwayisnecessaryforsurvivalofmicewithshorttelomeres
AT whittemorekurt themtorpathwayisnecessaryforsurvivalofmicewithshorttelomeres
AT granacastroosvaldo themtorpathwayisnecessaryforsurvivalofmicewithshorttelomeres
AT thelmapoluhalydia themtorpathwayisnecessaryforsurvivalofmicewithshorttelomeres
AT serranorosa themtorpathwayisnecessaryforsurvivalofmicewithshorttelomeres
AT hernandezencinaselena themtorpathwayisnecessaryforsurvivalofmicewithshorttelomeres
AT blancoapariciocarmen themtorpathwayisnecessaryforsurvivalofmicewithshorttelomeres
AT mariafloresjuana themtorpathwayisnecessaryforsurvivalofmicewithshorttelomeres
AT blascomariaa themtorpathwayisnecessaryforsurvivalofmicewithshorttelomeres
AT ferrararomeoiole mtorpathwayisnecessaryforsurvivalofmicewithshorttelomeres
AT martinezpaula mtorpathwayisnecessaryforsurvivalofmicewithshorttelomeres
AT saraswatisarita mtorpathwayisnecessaryforsurvivalofmicewithshorttelomeres
AT whittemorekurt mtorpathwayisnecessaryforsurvivalofmicewithshorttelomeres
AT granacastroosvaldo mtorpathwayisnecessaryforsurvivalofmicewithshorttelomeres
AT thelmapoluhalydia mtorpathwayisnecessaryforsurvivalofmicewithshorttelomeres
AT serranorosa mtorpathwayisnecessaryforsurvivalofmicewithshorttelomeres
AT hernandezencinaselena mtorpathwayisnecessaryforsurvivalofmicewithshorttelomeres
AT blancoapariciocarmen mtorpathwayisnecessaryforsurvivalofmicewithshorttelomeres
AT mariafloresjuana mtorpathwayisnecessaryforsurvivalofmicewithshorttelomeres
AT blascomariaa mtorpathwayisnecessaryforsurvivalofmicewithshorttelomeres