Aging, Cellular Senescence, and Glaucoma

Abstract

Aging is one of the most serious risk factors for glaucoma, and according to age-standardized prevalence, glaucoma is the second leading cause of legal blindness worldwide. Cellular senescence is a hallmark of aging that is defined by a stable exit from the cell cycle in response to cellular damage and stress. The potential mechanisms underlying glaucomatous cellular senescence include oxidative stress, DNA damage, mitochondrial dysfunction, defective autophagy/mitophagy, and epigenetic modifications. These phenotypes interact and generate a sufficiently stable network to maintain the cell senescent state. Senescent trabecular meshwork (TM) cells, retinal ganglion cells (RGCs) and vascular endothelial cells reportedly accumulate with age and stress and may contribute to glaucoma pathologies. Therapies targeting the suppression or elimination of senescent cells have been found to ameliorate RGC death and improve vision in glaucoma models, suggesting the pivotal role of cellular senescence in the pathophysiology of glaucoma. In this review, we explore the biological links between aging and glaucoma, specifically delving into cellular senescence. Moreover, we summarize the current data on cellular senescence in key target cells associated with the development and clinical phenotypes of glaucoma. Finally, we discuss the therapeutic potential of targeting cellular senescence for the management of glaucoma.

Aging in Ocular Blood Vessels: Molecular Insights and the Role of Oxidative Stress

“…The condition is characterized by the accelerated loss of retinal neurons and their axons, often coexisting with other age-related eye diseases that share molecular mechanisms resulting from repeated light damage and subsequent oxidative stress [132]. Aging contributes to abnormal peripheral blood flow, vascular stenosis, and endothelial dysfunction, all closely linked to the development of glaucoma [133]. Studies have found that in addition to increased intraocular pressure, an important risk factor, increased glutamate levels, changes in nitric oxide (NO) metabolism, vascular changes, and oxidative damage caused by ROS are also important factors in glaucoma [134].…”

“…Studies have found that in addition to increased intraocular pressure, an important risk factor, increased glutamate levels, changes in nitric oxide (NO) metabolism, vascular changes, and oxidative damage caused by ROS are also important factors in glaucoma [134]. Cellular senescence has been shown to lead to impaired angiogenesis, with multiple studies finding reduced retinal blood flow and capillary density in patients with glaucoma [133]. In patients with glaucoma with impaired retinal vascular function and reduced retinal vascular reactivity, RGCs and their axons are exposed to increased oxidative stress, which leads to further progression of glaucomatous damage [135].…”

“…Table 1 outlines the key pathophysiological drivers and their associated molecular pathways that play pivotal roles in vascular aging processes. Oxidative stress pivotal factor in vascular endothelial cell dysfunction and subsequent damage, exacerbating aging process, cell death and DNA damage in several ocular disorders [51,101] Mitochondrial dysfunction reduced mitochondrial biogenesis and SIRT activity [102,103,129] Telomere alteration telomere shortening and damage to DNA [17,103] Ca 2+ signaling anomalies remodeling processes induce impairment in Ca 2+ signals, impacting vascular function [112] Angiogenetic dysregulation, endothelial dysfunction accumulation of genetic damage and epigenetic changes affecting gene expression, leads to vascular impairment [103][104][105]133,137,138] Vascular obstruction aging may exacerbate the pro-inflammatory activity of IL-6, IL-8, and MMP-9, all agents related to retinal vascular occlusion [139][140][141][142][143] Androgen decline enhanced synthesis of the serum sex hormone-binding globulin may lead to a reduced level of androgens, which physiologically exert an anti-inflammatory effect [114,115] Traffic noise and air pollution exposure -Traffic noise exposure: alteration in stress hormone levels and heart rate as well as establishment of neuroinflammation. -Air pollution: ultrafine particles induce immune reactions and ROS formation.collectively, these factors trigger mitochondrial dysfunction, oxidative stress, telomere shortening, and chronic inflammation [116,117] UV exposure raised ROS formation, and subsequently elevated VEGF, MMP-2, and MMP-9, causing neoangiogenesis and degradation of ECM [122] High myopia age-related decreased tissue perfusion and loss of endothelial cells, aggravating the reduced ocular blood flow in high myopia [68,82,126,127]…”