Portal de Periódicos da CAPES

Nuclear lamina defects cause ATM-dependent NF-κB activation and link accelerated aging to a systemic inflammatory response

2012; Cold Spring Harbor Laboratory Press; Volume: 26; Issue: 20 Linguagem: Inglês

10.1101/gad.197954.112

1549-5477

Fernando G. Osorio, Clea Bárcena, Clara Soria‐Valles, Andrew Ramsay, Félix de Carlos Villafranca, Juan Cobo, Antonio Fueyo, José M.P. Freije, Carlos López‐Otín,

RNA Research and Splicing

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.