| First Author | Soria-Valles C | Year | 2015 |
| Journal | Nat Cell Biol | Volume | 17 |
| Issue | 8 | Pages | 1004-13 |
| PubMed ID | 26214134 | Mgi Jnum | J:227286 |
| Mgi Id | MGI:5700115 | Doi | 10.1038/ncb3207 |
| Citation | Soria-Valles C, et al. (2015) NF-kappaB activation impairs somatic cell reprogramming in ageing. Nat Cell Biol 17(8):1004-13 |
| abstractText | 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-kappaB activation blocks the generation of iPSCs in ageing. We also show that NF-kappaB repression occurs during cell reprogramming towards a pluripotent state. Conversely, ageing-associated NF-kappaB hyperactivation impairs the generation of iPSCs by eliciting the reprogramming repressor DOT1L, which reinforces senescence signals and downregulates pluripotency genes. Genetic and pharmacological NF-kappaB inhibitory strategies significantly increase the reprogramming efficiency of fibroblasts from Nestor-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. |
