title: 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.affiliation: Departamento de Bioquímica y Biología Molecular, Facultad de Medicina, Instituto Universitario de Oncología, Universidad de Oviedo, 33006-Oviedo, Spain.
authors.forename: Clara
authors.initials: C
authors.lastname: Soria-Valles
authors.affiliation: Departamento de Bioquímica y Biología Molecular, Facultad de Medicina, Instituto Universitario de Oncología, Universidad de Oviedo, 33006-Oviedo, Spain.
authors.forename: Fernando G
authors.initials: FG
authors.lastname: Osorio
authors.affiliation: Departamento de Bioquímica y Biología Molecular, Facultad de Medicina, Instituto Universitario de Oncología, Universidad de Oviedo, 33006-Oviedo, Spain.
authors.forename: Ana
authors.initials: A
authors.lastname: Gutiérrez-Fernández
authors.affiliation: Department of Pediatric Oncology, Dana-Farber Cancer Institute and Division of Hematology/Oncology, Boston Children's Hospital, Harvard Stem Cell Institute, Harvard Medical School, Boston, Massachusetts 02115, USA.
authors.forename: Alejandro
authors.initials: A
authors.lastname: De Los Angeles
authors.affiliation: Josep Carreras Leukemia Research Institute, Cell Therapy Program of the University of Barcelona, Faculty of Medicine, 08036 Barcelona, Spain.
authors.forename: Clara
authors.initials: C
authors.lastname: Bueno
authors.affiliation: 1] Josep Carreras Leukemia Research Institute, Cell Therapy Program of the University of Barcelona, Faculty of Medicine, 08036 Barcelona, Spain [2] Institucio Catalana de Recerca i Estudis Avançats (ICREA), 08035 Barcelona, Spain.
authors.forename: Pablo
authors.initials: P
authors.lastname: Menéndez
authors.affiliation: Departamento de Anatomía Patológica, Farmacología y Microbiología, Universitat de Barcelona, IDIBAPS, 08036 Barcelona, Spain.
authors.forename: José I
authors.initials: JI
authors.lastname: Martín-Subero
authors.affiliation: 1] Department of Pediatric Oncology, Dana-Farber Cancer Institute and Division of Hematology/Oncology, Boston Children's Hospital, Harvard Stem Cell Institute, Harvard Medical School, Boston, Massachusetts 02115, USA [2] Howard Hughes Medical Institute, Boston, Massachusetts 02115, USA [3] Department of Stem Cell and Regenerative Biology, Harvard University and Harvard Medical School, Cambridge, Massachusetts 02138, USA.
authors.forename: George Q
authors.initials: GQ
authors.lastname: Daley
authors.affiliation: Departamento de Bioquímica y Biología Molecular, Facultad de Medicina, Instituto Universitario de Oncología, Universidad de Oviedo, 33006-Oviedo, Spain.
authors.forename: José M P
authors.initials: JM
authors.lastname: Freije
authors.affiliation: Departamento de Bioquímica y Biología Molecular, Facultad de Medicina, Instituto Universitario de Oncología, Universidad de Oviedo, 33006-Oviedo, Spain.
authors.forename: Carlos
authors.initials: C
authors.lastname: López-Otín
mesh_terms: D000367:Age Factors; D000369:Aged, 80 and over; D000375:Aging / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D000818:Animals; D016022:Case-Control Studies; D002454:Cell Differentiation; D002460:Cell Line; D049109:Cell Proliferation; D065150:Cellular Reprogramming / Q000187:drug effects; D016922:Cellular Senescence; D004195:Disease Models, Animal; D005260:Female; D005347:Fibroblasts / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D018507:Gene Expression Regulation, Developmental; D020022:Genetic Predisposition to Disease; D011495:Histone-Lysine N-Methyltransferase; D006801:Humans; D057026:Induced Pluripotent Stem Cells / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D008297:Male; D008565:Membrane Proteins / Q000172:deficiency / Q000235:genetics; D008666:Metalloendopeptidases / Q000172:deficiency / Q000235:genetics; D008780:Methyltransferases / Q000235:genetics / Q000378:metabolism; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D016328:NF-kappa B / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D010641:Phenotype; D011371:Progeria / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D034622:RNA Interference; D015398:Signal Transduction; D013997:Time Factors; D014162:Transfection
chemical_list: D008565:Membrane Proteins; D016328:NF-kappa B; C473477:DOT1L protein, human; C481527:Dot1l protein, mouse; D008780:Methyltransferases; D011495:Histone-Lysine N-Methyltransferase; D008666:Metalloendopeptidases; C491250:Zmpste24 protein, mouse