The Emerging Role of Senescence in Ocular Disease

Abstract

Cellular senescence is a state of irreversible cell cycle arrest in response to an array of cellular stresses. An important role for senescence has been shown for a number of pathophysiological conditions that include cardiovascular disease, pulmonary fibrosis, and diseases of the skin. However, whether senescence contributes to the progression of age-related macular degeneration (AMD) has not been studied in detail so far and the present review describes the recent research on this topic. We present an overview of the types of senescence, pathways of senescence, senescence-associated secretory phenotype (SASP), the role of mitochondria, and their functional implications along with antisenescent therapies. As a central mechanism, senescent cells can impact the surrounding tissue microenvironment via the secretion of a pool of bioactive molecules, termed the SASP. An updated summary of a number of new members of the ever-growing SASP family is presented. Further, we introduce the significance of mechanisms by which mitochondria may participate in the development of cellular senescence. Emerging evidence shows that extracellular vesicles (EVs) are important mediators of the effects of senescent cells on their microenvironment. Based on recent studies, there is reasonable evidence that senescence could be a modifiable factor, and hence, it may be possible to delay age-related diseases by modulating basic aging mechanisms using SASP inhibitors/senolytic drugs. Thus, antisenescent therapies in aging and age-related diseases appear to have a promising potential.

Cellular senescence in the aging retina and developments of senotherapies for age-related macular degeneration

“…The existence of senescent cells in the human eyes during aging or with AMD is increasingly recognized [ 23 , 65 ]. The schematic presented in Fig.…”

“…In human neurodegenerative diseases and animal models, neurons of the CNS including cortical, Purkinje, and hippocampal cells, as well as peripheral neurons, display features of cellular senescence and release SASP cytokines [ 32 , 33 , 74 ]. To date, a severe impact of increased senescent neurons has been perceived to exacerbate neurodegeneration in the CNS [ 32 , 65 ]. In human aging retina, it has been shown that ganglion, amacrine, horizontal and rod cells, but not Müller or astrocyte neuroglia cells, acquire characteristics of cellular senescence [ 34 ].…”

“…It generates SASP-congruent inflammatory mediators detrimental to surrounding cells and tissue [ 119 ]. SASP is therefore considered a potential target for treating age-associated diseases, notwithstanding the fact that the composition of SASP differs in accordance with diseases, triggering factors and cell types [ 65 ]. To date, mainly in vitro studies of human RPE cells under RS or SIPS conditions (e.g., age-related DAMPs, Aβ, CSC, or oxidized photoreceptor outer segments) have revealed a panel of RPE-related SASP genes or proteins, including IL-6, IL-8, IL-10, IL-12, IL-17, MCP-1, TNF-α, VEGF, MMP-9, IFN-γ, CFB, and TGF-β [ 53 , 120 – 122 ] (Fig.…”

“…2 ). Senescent retinal microglia, systemic or infiltrating monocytes/macrophages associated with AMD, have been found to express escalated inflammatory factors IL-1α, IL-1β, IL-6, IL-8, IL-12, TNF-α, C3, CFB, CXCL1, TGF-β, nitric oxide (NO), superoxide anion (O2-), and glutamate [ 65 , 81 , 123 , 124 ]. Circumstantial evidence from murine models of diabetes-induced retinopathy and defects in lipoprotein receptor indicates inflammatory secretion of IL-1α, IL-1β, IL-6, IL-12, TNF-α, MCP-1, CCL25, CXCL1, CXCL12a, and I-309 by abnormal photoreceptors [ 125 , 126 ].…”

“…There is evidence indicating that both senescence and SASP directly contribute to cell loss and subsequent accumulation of ROS-producing deposits, together accelerate retinal dysfunction. Therefore, development of senolytic small molecules that selectively target senescent cells are directed to diseases of the aging eye [ 65 ]. For example, certain B cell lymphoma 2 (Bcl-2) family proteins are upregulated in senescent cells to evade apoptosis.…”