NF-κB in premature aging

consequence of a stochastic process caused by the accumulative effect of damaged molecules. However, recent experimental evidences have extended this view and suggested that aging also requires active signaling programs for the maintenance of the aged state [1]. Beyond cell-autonomous alterations, age signals get systemic through changes in intercellular communication pathways [2]. The identification of the precise nature of these mechanisms and signals could provide valuable information, uncovering potential targets for rejuvenation-aimed approaches [3]. Aging research has greatly benefited from the study of progeroid syndromes, accelerated aging conditions caused by an excessive accumulation of cellular damage or by an inefficient response of the repair mechanisms. Progeroid laminopathies are accelerated aging syndromes caused by defects of the nuclear lamina. Among them, Hutchinson-Gilford Progeria Syndrome (HGPS) is one the most intensely studied. This syndrome is caused by a point mutation in the LMNA gene, leading to the accumulation of a truncated form of lamin A called progerin which induces important alterations in the cell nucleus. Interestingly, progerin accumulation has also been reported during normal aging, adding a new layer of interest to the study of this syndrome. NF-κB transcription factors respond to a large variety of external and internal stress signals, having essential roles in development and tissue homeostasis maintenance. Through the study of two related mouse models of progeroid laminopathies (Zmpste24-deficient and Lmna G609G knock-in mice), we have recently found that aberrant activation of NF-κB is involved in the pathogenesis of accelerated aging syndromes, providing new insights into the mechanisms that allow the integration of cellular and systemic alterations in the aging process [4]. The in vivo monitoring of NF-κB activity by using a reporter-based assay revealed that this pathway was constitutively hyperactivated in progeroid mice. Further experiments allowed us to unveil the molecular pathway Editorial involved in this aberrant activation. Thus, in response to nuclear envelope alterations some important DNA damage sensors such as p53 or ATM were activated. In this context, we provide evidence that active ATM kinase cooperates with nuclear NEMO, an NF-κB regulatory subunit, resulting in the activation of NF-κB. We also found that, in response to NF-κB activation, several pro-inflammatory cytokines were significantly up-regulated. Among them, secretion of IL-6, CXCL-1 and TNF-α could have a causal role in the premature aging syndrome by establishing a chronic inflammatory situation through feed-forward regulatory signaling, affecting distant cells and tissues. Aimed at dissecting the precise contribution of NF-κB hyperactivation …