Reference

PortadaNCBNature Cell Biol 2015; 17(8): 1004-13; PMID:26214134; http://dx.doi.org/10.1038/ ncb3207

Authors

Clara Soria-Valles, Fernando G. Osorio, Ana Gutiérrez-Fernández, Alejandro De Los Angeles, Clara Bueno, Pablo Menéndez, José I. Martín-Subero, George Q. Daley, José M. P. Freije and Carlos López-Otín.

Abstract

Ageing constitutes a critical impediment to somatic cell reprogramming. We have explored the regulatory mechanisms that constitute age-associated barriers, through derivation of induced pluripotent stem cells (iPSCs) from individuals with premature or physiological ageing. We demonstrate that NF-κB activation blocks the generation of iPSCs in ageing. We also show that NF-κB repression occurs during cell reprogramming towards a pluripotent state. Conversely, ageing-associated NF-κB hyperactivation impairs the generation of iPSCs by eliciting the reprogramming repressor DOT1L, which reinforces senescence signals and downregulates pluripotency genes. Genetic and pharmacological NF-κB inhibitory strategies significantly increase the reprogramming efficiency of fibroblasts from Néstor–Guillermo progeria syndrome and Hutchinson–Gilford progeria syndrome patients, as well as from normal aged donors. Finally, we demonstrate that DOT1L inhibition in vivo extends lifespan and ameliorates the accelerated ageing phenotype of progeroid mice, supporting the interest of studying age-associated molecular impairments to identify targets of rejuvenation strategies.

Description

En este trabajo hemos estudiado los mecanismos moleculares implicados en la reducida eficiencia de reprogramación celular durante el envejecimiento. Así, hemos demostrado que la hiperactivación de NF-κB constituye una barrera a la reprogramación celular a través de la regulación directa de la expresión del modulador epigenético DOT1L. Además, hemos comprobado que el uso de inhibidores de DOT1L es una estrategia de rejuvenecimiento eficaz, permitiendo extender la vida media de ratones progeroides en más de un 60%.

 

Equipo Otín mod6

 

REFERENCIA DEL GRUPO INVESTIGADOR

El laboratorio dirigido por Carlos López-Otín pertenece al Departamento de Bioquímica y Biología Molecular y al Instituto de Oncología de la Universidad de Oviedo. Uno de los principales objetivos del grupo es el estudio de los sistemas proteolíticos implicados en el cáncer y en otras patologías humanas. Por otra parte, el laboratorio estudia los mecanismos responsables del proceso del envejecimiento y el desarrollo de terapias frente a los síndromes de envejecimiento acelerado, mediante el empleo de ratones modificados genéticamente y el uso de modelos celulares. Finalmente, el laboratorio de López-Otín contribuye activamente a la secuenciación, anotación y análisis funcional de los genomas tumorales y los de distintas especies de interés evolutivo y biomédico.

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