NF-κB activation impairs somatic cell reprogramming in ageing.

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.

• 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, Carlos López-Otín
• Journal: Nature cell biology (Nat Cell Biol) Vol. 17 Issue 8 Pg. 1004-13 (Aug 2015) ISSN: 1476-4679 [Electronic] England
• PMID: 26214134 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Retracted Publication)

Chemical References

• Membrane Proteins
• NF-kappa B
• DOT1L protein, human
• Dot1l protein, mouse
• Methyltransferases
• Histone-Lysine N-Methyltransferase
• Metalloendopeptidases
• Zmpste24 protein, mouse

Topics

• Age Factors
• Aged, 80 and over
• Aging (genetics, metabolism, pathology)
• Animals
• Case-Control Studies
• Cell Differentiation
• Cell Line
• Cell Proliferation
• Cellular Reprogramming (drug effects)
• Cellular Senescence
• Disease Models, Animal
• Female
• Fibroblasts (drug effects, metabolism, pathology)
• Gene Expression Regulation, Developmental
• Genetic Predisposition to Disease
• Histone-Lysine N-Methyltransferase
• Humans
• Induced Pluripotent Stem Cells (drug effects, metabolism, pathology)
• Male
• Membrane Proteins (deficiency, genetics)
• Metalloendopeptidases (deficiency, genetics)
• Methyltransferases (genetics, metabolism)
• Mice, Inbred C57BL
• Mice, Knockout
• NF-kappa B (antagonists & inhibitors, genetics, metabolism)
• Phenotype
• Progeria (genetics, metabolism, pathology)
• RNA Interference
• Signal Transduction
• Time Factors
• Transfection