1. Nuclear lamina defects cause ATM-dependent NF-κB activation and link accelerated aging to a systemic inflammatory response
- Author
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Andrew J. Ramsay, Clara Soria-Valles, Félix de Carlos, Carlos López-Otín, José M.P. Freije, Juan Cobo, Antonio Fueyo, Fernando G. Osorio, and Clea Bárcena
- Subjects
Transcriptional Activation ,endocrine system ,Aging ,Sodium Salicylate ,Longevity ,Cell Cycle Proteins ,Inflammation ,Ataxia Telangiectasia Mutated Proteins ,Protein Serine-Threonine Kinases ,Biology ,Cell Line ,Proinflammatory cytokine ,LMNA ,Mice ,03 medical and health sciences ,0302 clinical medicine ,Genetics ,medicine ,Animals ,Humans ,Protein Precursors ,Nuclear protein ,Cells, Cultured ,Cellular Senescence ,030304 developmental biology ,0303 health sciences ,Nuclear Lamina ,Tumor Suppressor Proteins ,Anti-Inflammatory Agents, Non-Steroidal ,Intracellular Signaling Peptides and Proteins ,NF-kappa B ,Transcription Factor RelA ,Membrane Proteins ,Metalloendopeptidases ,Nuclear Proteins ,Lamin Type A ,NFKB1 ,Cell biology ,DNA-Binding Proteins ,Immunology ,Nuclear lamina ,Signal transduction ,medicine.symptom ,Cell aging ,030217 neurology & neurosurgery ,Research Paper ,Signal Transduction ,Developmental Biology - 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 LmnaG609G/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.
- Published
- 2012