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NATURE CELL BIOLOGY | ARTICLE

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NF-κB activation impairs somatic cell reprogramming in ageing

• 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
• & Carlos López-Otín

• Affiliations
• Contributions
• Corresponding authors

Nature Cell Biology
17,
1004–1013
(2015)
doi:10.1038/ncb3207

Received
18 April 2015
Accepted
18 June 2015
Published online
27 July 2015

• Abstract•
• References•
• Author information•
• Supplementary information

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.