title: Nuclear lamina defects cause ATM-dependent NF-κB activation and link accelerated aging to a systemic inflammatory response.
abstract: Alterations in the architecture and dynamics of the nuclear lamina have a causal role in normal and accelerated aging through both cell-autonomous and systemic mechanisms. However, the precise nature of the molecular cues involved in this process remains incompletely defined. Here we report that the accumulation of prelamin A isoforms at the nuclear lamina triggers an ATM- and NEMO-dependent signaling pathway that leads to NF-κB activation and secretion of high levels of proinflammatory cytokines in two different mouse models of accelerated aging (Zmpste24(-/-) and Lmna(G609G/G609G) mice). Causal involvement of NF-κB in accelerated aging was demonstrated by the fact that both genetic and pharmacological inhibition of NF-κB signaling prevents age-associated features in these animal models, significantly extending their longevity. Our findings provide in vivo proof of principle for the feasibility of pharmacological modulation of the NF-κB pathway to slow down the progression of physiological and pathological aging.
authors.affiliation: Departamento de Bioquímica y Biología Molecular, Instituto Universitario de Oncología, Universidad de Oviedo, Oviedo, Spain.
authors.forename: Fernando G
authors.initials: FG
authors.lastname: Osorio
authors.forename: Clea
authors.initials: C
authors.lastname: Bárcena
authors.forename: Clara
authors.initials: C
authors.lastname: Soria-Valles
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Ramsay
authors.forename: Félix
authors.initials: F
authors.lastname: de Carlos
authors.forename: Juan
authors.initials: J
authors.lastname: Cobo
authors.forename: Antonio
authors.initials: A
authors.lastname: Fueyo
authors.forename: José M P
authors.initials: JM
authors.lastname: Freije
authors.forename: Carlos
authors.initials: C
authors.lastname: López-Otín
mesh_terms: D000375:Aging / Q000276:immunology / Q000473:pathology / Q000502:physiology*; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology; D064007:Ataxia Telangiectasia Mutated Proteins; D018797:Cell Cycle Proteins / Q000378:metabolism*; D002460:Cell Line; D002478:Cells, Cultured; D016922:Cellular Senescence; D004268:DNA-Binding Proteins / Q000378:metabolism*; D006801:Humans; D007249:Inflammation / Q000201:enzymology / Q000503:physiopathology; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism; D034904:Lamin Type A; D008136:Longevity / Q000187:drug effects / Q000235:genetics; D008565:Membrane Proteins / Q000172:deficiency / Q000235:genetics; D008666:Metalloendopeptidases / Q000172:deficiency / Q000235:genetics; D051379:Mice; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism*; D034881:Nuclear Lamina / Q000201:enzymology / Q000235:genetics* / Q000378:metabolism*; D009687:Nuclear Proteins / Q000378:metabolism; D011498:Protein Precursors / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D015398:Signal Transduction; D012980:Sodium Salicylate / Q000494:pharmacology; D051996:Transcription Factor RelA / Q000235:genetics / Q000378:metabolism; D015533:Transcriptional Activation / Q000187:drug effects; D025521:Tumor Suppressor Proteins / Q000378:metabolism*
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; D047908:Intracellular Signaling Peptides and Proteins; D034904:Lamin Type A; D008565:Membrane Proteins; C514981:NEMO protein, mouse; D016328:NF-kappa B; D009687:Nuclear Proteins; D011498:Protein Precursors; D051996:Transcription Factor RelA; D025521:Tumor Suppressor Proteins; C090764:prelamin A; C576324:ATM protein, human; D064007:Ataxia Telangiectasia Mutated Proteins; C576325:Atm protein, mouse; D017346:Protein Serine-Threonine Kinases; D008666:Metalloendopeptidases; C491250:Zmpste24 protein, mouse; D012980:Sodium Salicylate