Glaucoma: A Disease of Early Cellular Senescence

Abstract

Coexistent with the age-related increase in the prevalence of glaucoma is the age-related decrease in anterior segment outflow facility. That is, the resistance to fluid flow across the trabecular meshwork (TM) increases with age in a linear fashion, and begins at a fairly young age. 11 This decreased outflow facility is largely responsible for the elevated IOP that is encountered in Western populations with increasing age. Markers of cellular senescence are found in the TM of patients with primary open-angle glaucoma (POAG) to a much greater degree than in age-matched controls. It is thought that aging of these cells leads to their decreased function and therefore a consequent decreased outflow facility. 12 It is hypothesized that aging failure of the normal, regulatory proteolytic systems in the TM may be responsible for the observed pathophysiological alterations of the outflow pathway that may contribute to glaucoma. 13 Along with the decreased function of the outflow apparatus with age is a decreased population of retinal ganglion cells (RGCs) in the retina. The RGC is the pivotal cell in the retina that electrically couples the retina with the brain; it is the cell that is primarily damaged by glaucoma. Pathological studies have shown a steady attrition of RGCs with normal aging, starting at a young age, in the amount of approximately 5000 cells per year. 14 Given that the average RGC population is approximately 1 million in the human eye, and that an individual can lose approximately half of that population before significant visual dysfunction occurs, every person would normally develop glaucoma by the age of 100! Glaucomatous loss of RGCs can be viewed as a premature aging effect, causing the typical and unique optic neuropathy that clinicians diagnose as glaucoma, and the consequent characteristic patterns of visual field loss. Clinical studies have also shown a decrease with age in the thickness of the nerve fiber layer in normal individuals. 15 The nerve fiber layer carries the axons of the RGCs to the optic nerve, where they exit the laminar cribrosa and connect to their targets in the central nervous system. Biomechanical factors within the optic nerve head have been hypothesized to play a central role in RGC physiology, and contribute to the optic neuropathy of aging and glaucoma. 16 The posterior sclera of old monkeys is significantly stiffer than that of younger individuals and leads to lower strains with the higher stresses associated with elevated levels of IOP. This agerelated stiffening of the sclera significantly influences the biomechanical properties of the optic nerve head and may contribute to age-related susceptibility to glaucomatous optic nerve damage. 17 Similar changes occur in humans, which may be an important underpinning of the age relationship with glaucoma. 18