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

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.

Only IL‐1β release is inflammasome‐dependent upon ultraviolet B irradiation although IL‐18 is also secreted

“…Aging is associated with the presence of elevated amounts of reactive oxygen species (ROS), the accumulation of nonfunctional cellular organelles, as well as persistent DNA damage, such as double‐strand breaks and other DNA aberrations 1,2 . Over time, the DNA repair mechanisms tend to become either inadequate or incapable of repairing the increasing amount of DNA damage, resulting in impaired cellular functionality and the appearance of cellular senescence 1,2 .…”

“…Aging is associated with the presence of elevated amounts of reactive oxygen species (ROS), the accumulation of nonfunctional cellular organelles, as well as persistent DNA damage, such as double‐strand breaks and other DNA aberrations 1,2 . Over time, the DNA repair mechanisms tend to become either inadequate or incapable of repairing the increasing amount of DNA damage, resulting in impaired cellular functionality and the appearance of cellular senescence 1,2 . It is believed that the increased DNA damage along with other detrimental cellular events are causative factors in many age‐related diseases, such as Alzheimer disease, Parkinson's disease, and age‐related macular degeneration (AMD) 1,2 …”

“…Over time, the DNA repair mechanisms tend to become either inadequate or incapable of repairing the increasing amount of DNA damage, resulting in impaired cellular functionality and the appearance of cellular senescence 1,2 . It is believed that the increased DNA damage along with other detrimental cellular events are causative factors in many age‐related diseases, such as Alzheimer disease, Parkinson's disease, and age‐related macular degeneration (AMD) 1,2 …”

Resveratrol as Inducer of Autophagy, Pro-Survival, and Anti-Inflammatory Stimuli in Cultured Human RPE Cells

“…The leading cause of blindness in the elderly in developed countries is age-related macular degeneration (AMD). Many risk factors have been associated with the development and progression of the disease, most importantly aging, although other factors, such as inflammation, oxidative stress, and genetic predisposition have been strongly linked [1].…”

“…Proper clearance of such cellular debris is important for maintaining cell survival and vitality of cells and tissues in general. Possibly, autophagy contributes to the turnover and regulation of proteins responsible for countering oxidative stress, such as NFE2L2, that is known to interact with p62, the latter being an important autophagic protein [1][2][3].…”