Telomeres, oxidative stress and inflammatory factors: partners in cellular senescence?

Clara Correia-Melo,João F Passos,Graeme Hewitt

doi:10.1186/2046-2395-3-1

Abstract

Senescence, the state of irreversible cell-cycle arrest, plays paradoxical albeit important roles in vivo: it protects organisms against cancer but also contributes to age-related loss of tissue function. The DNA damage response (DDR) has a central role in cellular senescence. Not only does it contribute to the irreversible loss of replicative capacity but also to the production and secretion of reactive oxygen species (ROS), and bioactive peptides collectively known as the senescence-associated secretory phenotype (SASP). Both ROS and the SASP have been shown to impact on senescence in an autocrine as well as paracrine fashion; however, the underlying mechanisms are not well understood. In this review we describe our current understanding of cellular senescence, examine in detail the intricate pathways linking the DDR, ROS and SASP, and evaluate their impact on the stability of the senescent phenotype.

Highlights

Cellular senescence, the state of irreversible cell cycle arrest described by Hayflick and Moorhead [1] over 50 years ago, remains an intriguing biological process
Numerous lines of evidence indicate that senescence can, in the long run, have adverse effects, by impairing organ regeneration and releasing a host of bioactive molecules, including reactive oxygen species (ROS) and a wide variety of pro-inflammatory cytokines
The aim of this review is to describe the current understanding of cellular senescence, providing special focus on the intricate pathways that link the nucleus, mitochondria and secreted proteins, and contribute to the stability of the senescent phenotype

Summary

Introduction

The state of irreversible cell cycle arrest described by Hayflick and Moorhead [1] over 50 years ago, remains an intriguing biological process. In a murine model of XFE (xeroderma pigmentosum F–excision repair) progeroid syndrome, Ercc1–/Δ mice, inhibition of NF-κB signalling reduced the onset of several age-related pathologies, and both DNA and protein oxidation [87], suggesting a potential link between inflammation and ROS pathways Another link between ROS and the SASP during senescence involves the p38 mitogen-activated protein kinase (p38MAPK). Neutralising antibodies or chemical inhibitors against the TGFBR2 have been shown to decrease ROS production downstream of the DDR induced in a telomeredependent and -independent fashion [21] Another potential link between the SASP and ROS is the fact that several studies indicate that NF-κB, the main regulator of the SASP, is a major player in the regulation of mitochondrial function and oxidative stress (Figure 3c). Further work is needed in order to understand the kinetics of activation of these pathways during senescence

Conclusions

Findings

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