The senescent bystander effect is caused by ROS-activated NF-κB signalling

Glyn Nelson,Olena Kucheryavenko,James Wordsworth,Thomas Von Zglinicki

doi:10.1016/j.mad.2017.08.005

Abstract

Cell senescence is an important driver of the ageing process. The accumulation of senescent cells in tissues is accelerated by stress signals from senescent cells that induce DNA damage and ultimately senescence in bystander cells. We examine here the interplay of senescence-associated mitochondrial dysfunction (SAMD)—driven production of reactive oxygen species (ROS) and senescence-associated secretory phenotype (SASP) in causing the bystander effect. We show that in various modes of fibroblast senescence ROS are necessary and sufficient to activate the transcription factor nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB), which facilitates a large part of the SASP. This ROS-NF-κB axis causes the DNA damage response in bystander cells. Cytokines IL-6 and IL-8 are major components of the pro-inflammatory SASP in senescent fibroblasts. However, their activation in senescence is only partially controlled by NF-κB, and they are thus not strong candidates as intercellular mediators of the bystander effect as mediated by the ROS-NF-κB axis.

Highlights

It is becoming increasingly clear that cell senescence is an important cause of the loss of tissue functionality and homeostatic capacity that characterizes ageing
We tested the interaction between senescence-associated secretory phenotype (SASP) and senescence-associated mitochondrial dysfunction (SAMD) in multiple human fibroblast systems, using two independent cell strains (MRC5 and IMR90) and three different modes of senescence
While we are aware that DHE fluorescence intensity is a marker but not a quantitative measure of cytoplasmic superoxide, and that cytoplasmic reactive oxygen species (ROS) originate from multiple sources including nonmitochondrial ones, we have previously shown that the increase in ROS markers associated with senescence can solely be attributed to mitochondria (Correia-Melo et al, 2016)

Summary

Introduction

It is becoming increasingly clear that cell senescence is an important cause of the loss of tissue functionality and homeostatic capacity that characterizes ageing. Senescent cells accumulate in many, if not all, tissues with age (Dimri et al, 1995; Herbig et al, 2006; Jurk et al, 2012; Wang et al, 2009). The rate of this accumulation predicts mean and maximum lifespan of animals over an almost threefold difference in life expectancy between slow- and fast-ageing cohorts (Jurk et al, 2014). Selective ablation of senescent cells postponed the development of age-associated tissue dysfunction/disease and extended mean lifespan in mice (Baker et al, 2016, 2011). First experimental drugs that selectively kill senescent cells have been developed and show encouraging results in a number of mouse models of age-related diseases (Roos et al, 2016; Schafer et al, 2017; Zhu et al, 2015)

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