Cellular Senescence in Age-Related Macular Degeneration: Can Autophagy and DNA Damage Response Play a Role?

Janusz Blasiak,Malgorzata Piechota,Kai Kaarniranta,Elzbieta Pawlowska,Ewa Sikora,Magdalena Szatkowska

doi:10.1155/2017/5293258

Abstract

Age-related macular degeneration (AMD) is the main reason of blindness in developed countries. Aging is the main AMD risk factor. Oxidative stress, inflammation and some genetic factors play a role in AMD pathogenesis. AMD is associated with the degradation of retinal pigment epithelium (RPE) cells, photoreceptors, and choriocapillaris. Lost RPE cells in the central retina can be replaced by their peripheral counterparts. However, if they are senescent, degenerated regions in the macula cannot be regenerated. Oxidative stress, a main factor of AMD pathogenesis, can induce DNA damage response (DDR), autophagy, and cell senescence. Moreover, cell senescence is involved in the pathogenesis of many age-related diseases. Cell senescence is the state of permanent cellular division arrest and concerns only mitotic cells. RPE cells, although quiescent in the retina, can proliferate in vitro. They can also undergo oxidative stress-induced senescence. Therefore, cellular senescence can be considered as an important molecular pathway of AMD pathology, resulting in an inability of the macula to regenerate after degeneration of RPE cells caused by a factor inducing DDR and autophagy. It is too early to speculate about the role of the mutual interplay between cell senescence, autophagy, and DDR, but this subject is worth further studies.

Highlights

Age-related macular degeneration affects the macula, a specific structure in the central retina, leading to worsening of visual acuity
Arend et al observed a significant increase in cell viability and reduced SA-β-gal activity, reactive oxygen species (ROS) amount, and DNA damage foci in ARPE-19 cells induced to senescence with H2O2 and pretreated with idebenone, which is a derivative of coenzyme Q10, but with a tenfold higher antioxidant capacity than its parental compound [64]
We showed an impaired autophagy in retinal pigment epithelium (RPE) upon chronic oxidative stress, but senescence was not induced in that study [125]

Summary

Introduction

Age-related macular degeneration affects the macula, a specific structure in the central retina, leading to worsening of visual acuity. It is the major cause of blindness in the elderly in developed countries. Its global pooled prevalence is estimated to be more than 8% It is an emerging problem, as it is estimated that the number of people affected by AMD in 2020 will be about 200 million, increasing to almost 300 million in 2040 [1, 2]. The exact mechanism of AMD pathogenesis is not known, oxidative stress, protein aggregation, and inflammation as well as some genetic factors play a central role in AMD development (Figure 1) [5]. Autophagy may be involved in the regulation of the cell death mode in AMD [8] (Figure 2)

Cell Senescence and Aging in AMD

Autophagy and DDR-Dependent or DDRIndependent Players in AMD Pathogenesis

Findings

Conclusions and Perspectives