NF-kB in premature aging.

摘要: During decades, aging has been regarded as the consequence of a stochastic process caused by accumulative effect damaged molecules. However, recent experimental evidences have extended this view and suggested that also requires active signaling programs for maintenance aged state [1]. Beyond cell-autonomous alterations, age signals get systemic through changes in intercellular communication pathways [2]. The identification precise nature these mechanisms could provide valuable information, uncovering potential targets rejuvenation-aimed approaches [3]. Aging research greatly benefited from study progeroid syndromes, accelerated conditions an excessive accumulation cellular damage or inefficient response repair mechanisms. Progeroid laminopathies are syndromes defects nuclear lamina. Among them, Hutchinson-Gilford Progeria Syndrome (HGPS) is one most intensely studied. This syndrome point mutation LMNA gene, leading to truncated form lamin A called progerin which induces important alterations cell nucleus. Interestingly, reported during normal aging, adding new layer interest syndrome. NF-κB transcription factors respond large variety external internal stress signals, having essential roles development tissue homeostasis maintenance. Through two related mouse models (Zmpste24-deficient LmnaG609G knock-in mice), we recently found aberrant activation NF-κB involved pathogenesis providing insights into allow integration [4]. The vivo monitoring activity using reporter-based assay revealed pathway was constitutively hyperactivated mice. Further experiments allowed us unveil molecular activation. Thus, envelope some DNA sensors such p53 ATM were activated. In context, evidence kinase cooperates with NEMO, regulatory subunit, resulting NF-κB. We that, activation, several pro-inflammatory cytokines significantly up-regulated. secretion IL-6, CXCL-1 TNF-α causal role premature establishing chronic inflammatory situation feed-forward signaling, affecting distant cells tissues. Aimed at dissecting contribution hyperactivation phenotype, used anti-inflammatory genetic strategy based on crossing Zmpste24-deficient mice RelA haploinsufficient [5]. double mutant Zmpste24−/− RelA+/− displayed retardation process, showing longevity compared RelA+/+ Furthermore, showed remarkable recovery skin immunological consistent proposed relevance These results prompted test pharmacological approach target sodium salicylate treatment both LmnaG609G/G609G led significant prevention immune demonstrating feasibility targeting slowing down progression aging. Finally, our indicate findings can be suggesting common responsible, least part, abnormal tissues advanced donors. senescent together decline adult stem function primary cause compromise aging. context apoptosis cells, so subsequent preclude proper clearance cells. regard, report described involvement age-related [6]. Globally, data discussed herein clarify three aspects define confirm [7], its associated amelioration retards [4-5, 8]. characteristics support use strategies aimed controlling inflammation putative rejuvenation pathological Over last years, composed complex picture where autonomous cooperate organisms. Rational design interventions slow should act coordinate way, pro-aging well altered effective aging-related disorders. Figure 1 Exacerbated NF- κB leads loss homeostasis, takes place rate syndromes. phenomenon alleviated inhibition.