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.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Aging / immunology
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Aging / pathology
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Aging / physiology*
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Animals
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Anti-Inflammatory Agents, Non-Steroidal / pharmacology
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Ataxia Telangiectasia Mutated Proteins
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Cell Cycle Proteins / metabolism*
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Cell Line
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Cells, Cultured
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Cellular Senescence
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DNA-Binding Proteins / metabolism*
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Humans
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Inflammation / enzymology
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Inflammation / physiopathology
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Intracellular Signaling Peptides and Proteins / metabolism
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Lamin Type A
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Longevity / drug effects
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Longevity / genetics
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Membrane Proteins / deficiency
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Membrane Proteins / genetics
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Metalloendopeptidases / deficiency
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Metalloendopeptidases / genetics
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Mice
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NF-kappa B / genetics
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NF-kappa B / metabolism*
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Nuclear Lamina / enzymology
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Nuclear Lamina / genetics*
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Nuclear Lamina / metabolism*
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Nuclear Proteins / metabolism
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Protein Precursors / metabolism
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Protein Serine-Threonine Kinases / metabolism*
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Signal Transduction
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Sodium Salicylate / pharmacology
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Transcription Factor RelA / genetics
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Transcription Factor RelA / metabolism
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Transcriptional Activation / drug effects
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Tumor Suppressor Proteins / metabolism*
Substances
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Anti-Inflammatory Agents, Non-Steroidal
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Cell Cycle Proteins
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DNA-Binding Proteins
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Intracellular Signaling Peptides and Proteins
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Lamin Type A
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Membrane Proteins
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NEMO protein, mouse
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NF-kappa B
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Nuclear Proteins
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Protein Precursors
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Transcription Factor RelA
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Tumor Suppressor Proteins
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prelamin A
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ATM protein, human
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Ataxia Telangiectasia Mutated Proteins
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Atm protein, mouse
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Protein Serine-Threonine Kinases
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Metalloendopeptidases
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Zmpste24 protein, mouse
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Sodium Salicylate