Nuclear lamina defects cause ATM-dependent NF-κB activation and link accelerated aging to a systemic inflammatory response
- Fernando G. Osorio1,
- Clea Bárcena1,
- Clara Soria-Valles1,
- Andrew J. Ramsay1,
- Félix de Carlos2,
- Juan Cobo2,
- Antonio Fueyo3,
- José M.P. Freije1,4 and
- Carlos López-Otín1,4
- 1Departamento de Bioquímica y Biología Molecular, Facultad de Medicina, Instituto Universitario de Oncología, Universidad de Oviedo, 33006-Oviedo, Spain;
- 2Departamento de Cirugía y Especialidades Médico-Quirúrgicas, Instituto Asturiano de Odontología, Universidad de Oviedo, 33006-Oviedo, Spain;
- 3Área de Fisiología, Departamento de Biología Funcional, Facultad de Medicina, Instituto Universitario de Oncología, Universidad de Oviedo, 33006-Oviedo, Spain
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.
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Footnotes
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↵4 Corresponding authors
E-mail clo{at}uniovi.es
E-mail jmpf{at}uniovi.es
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Supplemental material is available for this article.
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Article published online ahead of print. Article and publication date are online at http://www.genesdev.org/cgi/doi/10.1101/gad.197954.112.
- Received June 5, 2012.
- Accepted September 4, 2012.
- Copyright © 2012 by Cold Spring Harbor Laboratory Press